Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Thiele H, Akin I, Sandri M, et al. PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N Engl J Med. DOI: /NEJMoa

2 SUPPLEMENTARY APPENDIX STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN CULPRIT-SHOCK TRIAL TABLE OF CONTENTS This supplement contains the following items: 1) Study protocol Version 1.1 2) Final study protocol Version 1.2 3) Summary of changes: Major changes made: a) Address changes b) Transfer primary investigator from Leipzig to Lübeck, Germany with address changes and sponsor change c) Belgium as substitute for Sweden 4) Statistical analysis plan Version 1.0 5) Statistical analysis plan Version 1.1 6) Major changes made: See page 3 in Statistical analysis plan Version 1.1 1

3 Prospective randomized multicenter study comparing immediate multivessel revascularization by PCI versus culprit lesion PCI with staged non-culprit lesion revascularization in patients with acute myocardial infarction complicated by cardiogenic shock CULPRIT-SHOCK Study protocol Version 1.1.;

4 CULPRIT-SHOCK Study Protocol Version 1.1, STUDY SYNOPSIS COORDINATING INVESTIGATORS CO-INVESTIGATORS NATIONAL COORDINATING INVESTIGATORS STEERING COMMITTEE SPONSOR STUDY TITLE TYPE OF STUDY CONDITION DATA SAFETY MONITORING Prof. Dr. med. Ferenc Follath Prof. Dr. med. Holger Thiele University of Leipzig Heart Center Department of Internal Medicine/Cardiology Strümpellstr Leipzig, Germany Tel: /1428; Fax: Prof. Dr. med. Uwe Zeymer Stiftung Institut für Herzinfarktforschung at the University of Heidelberg Bremserstraße 79 - Haus R Ludwigshafen am Rhein, Germany Tel: ; Fax: zeymeru@klilu.de or uwe.zeymer@t-online.de PD Dr. med. S. Desch Department of Internal Medicine/Cardiology, University of Leipzig Heart Center stdesch@web.de Prof. Dr. med. G. Schuler Director Department of Internal Medicine/Cardiology, University of Leipzig Heart Center gerhard.schuler@med.uni-leipzig.de Prof. Dr. med. K. Werdan Director Department of Internal Medicine III - University Hospital, Martin-Luther- University Halle-Wittenberg karl.werdan@medizin.uni-halle.de Prof. Dr. med. Gert Richardt Director Department of Internal Medicine/Cardiology, Heart Center Bad Segeberg gert.richardt@segebergerkliniken.de Prof. Dr. med. Kurt Huber Director Department of Internal Medicine/Cardiology, Wilhelminenspital of the city Vienna, Vienna, Austria kurt.huber@wienkav.at Prof. Dr. med. Stephan Windecker Deputy Director Department of Internal Medicine/Cardiology, University of Bern, Switzerland Stephan.Windecker@insel.ch Prof. Dr. med. Stefan James Director Department of Medical Sciences and Uppsala Clinical Research Center Uppsala University, Uppsala, Sweden stefan.james@akademiska.se Prof. Dr. med. Pranas Serpytis Vilnius University Hospital, Santariskiu klinikos, Vilnius, Lithuania pranas.serpytis@santa.lt Prof. Dr. med. Gilles Montalescot Centre Hospitalier Universitaire Pitié-Salpetrière, Institut de Cardiologie, Paris, France Gilles.montalescot@psl.aphp.fr Prof. Dr. med. Marco Noc University Medical Center Ljubljana, Division of Internal Medicine, Ljubljana, Slovenia marko.noc@mf.uni-lj.si Prof. Dr. med. Jan J. Piek Academic Medical Center, Amsterdam, The Netherlands j.j.piek@amc.uva.nl Prof. Dr. Med. Janina Stępińska Institute of Cardiology, Warsaw, Poland janina@stepinska.pl.pl Consists of the two coordinating investigators, co-investigators, and all national coordinating investigators University of Leipzig Heart Center Department of Internal Medicine/Cardiology Strümpellstr Leipzig, Germany CULPRIT-SHOCK Prospective, controlled, international, multicenter, randomized, open-label Acute myocardial infarction Cardiogenic shock Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center 2

5 CULPRIT-SHOCK Study Protocol Version 1.1, BOARD STATISTICAL ANALYSIS DATA MANAGEMENT OBJECTIVE INTERVENTIONS KEY INCLUSION AND EXCLUSION CRITERIA ENDPOINTS University Hospital Zürich, Switzerland Prof. Dr. med. Peter Clemmensen Rigshospitalet, The Heart Center, Copenhagen, Denmark Prof. Dr. Johannes Haerting University of Halle, Germany Dr. Steffen Schneider Stiftung Institut für Herzinfarktforschung at the University of Heidelberg Bremserstraße Ludwigshafen am Rhein, Germany Tel: ; Fax: Belgin Özdemir-Cetinkaya Stiftung Institut für Herzinfarktforschung at the University of Heidelberg Bremserstraße Ludwigshafen am Rhein, Germany Tel: ; Fax: To examine whether culprit lesion only percutaneous coronary intervention (PCI) with subsequent staged revascularization is beneficial over immediate multivessel revascularization by PCI for patients with cardiogenic shock complicating acute myocardial infarction with respect to 30-day mortality and/or severe renal failure requiring renal replacement therapy. Experimental intervention: Culprit lesion only PCI with staged non-culprit revascularization Control intervention: Immediate multivessel PCI Follow-up per patient: 30-days primary endpoint plus 6 months and 12 months long-term follow-up Duration of intervention per patient: <1 day Experimental and / or control off label or on label: no off-label use Key inclusion criteria: cardiogenic shock complicating myocardial infarction presenting with multivessel disease (>70% stenoses in 2- or 3 major vessels of 2 mm diameter and identifiable culprit lesion) with indication for PCI Key exclusion criteria: Need for primary urgent bypass surgery (to be determined after diagnostic angiography) Mechanical complication complicating myocardial infarction Severe neurological deficit Shock onset >12 h Age >90 years Comorbidity with life expectancy <6 months Primary efficacy endpoint: 30-day mortality and/or severe renal failure requiring renal replacement therapy Secondary endpoints: 30-day mortality Requirement of renal replacement therapy Procedural success Time to hemodynamic stabilization Duration of catecholamine therapy Serial creatinine-level creatinine-clearance (Cockcroft-Gault-Formula) until stabilization Length of ICU-stay Serial SAPS-II score until stabilization Requirement and length of mechanical ventilation All-cause death within 6 and 12 months follow-up Recurrent infarction within 30-days, 6 and 12 months follow-up Death or recurrent infarction at 6 and 12 months follow-up Rehospitalization for congestive heart failure within 30-days, 6 and 12 months follow-up Death/recurrent infarction/rehospitalization for congestive heart failure within 30- days, 6 and 12 months Need for repeat revascularization (PCI and/or CABG) within 30-days, 6 and 12 months follow-up Peak creatine kinase, creatine kinase-mb and troponin level during hospital stay Quality of life at 6 and 12 months assessed using Euroqol 5D (EQ-5D) questionnaire ( Safety: Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center 3

6 CULPRIT-SHOCK Study Protocol Version 1.1, Severe and moderate bleeding complications (BARC definition type 2-3 and 5) Stroke STATISTICAL ANALYSIS Efficacy / test accuracy: Assessed by mortality and/or severe renal failure within 30 days after randomization. Evaluation of secondary endpoints serves to obtain explanatory and predictive information. Description of the primary efficacy / test accuracy analysis and population: Chi- Square test to compare the rates of patients experiencing primary endpoint within 30 days after randomization in both groups. All randomized subjects to be analyzed on the intent-to-treat basis. Safety: Fisher s test to compare groups with respect to frequencies of occurrence of complications. Mann-Whitney U test to compare groups with respect to severities of complications. Secondary endpoints: Group comparison by Mann-Whitney U test. Logistic regression to assess predictors of primary endpoint. SAMPLE SIZE To be assessed for eligibility (n=900) To be allocated to trial (n=706) To be analyzed (n=684) TRIAL DURATION First patient in to last patient out (months): 30 Duration of the entire trial (months): 32 (primary study endpoint), 44 (long-term follow-up) Recruitment period (months): 30 PARTICIPATING CENTERS (n): >40 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center 4

7 CULPRIT-SHOCK Study Protocol Version 1.1, Table of Contents 1 Trial description 7 2 Study chairs Coordinating investigators Co-investigators National coordinating investigators 7 3 Participating centers 8 4 Local investigators 8 5 Clinical and scientific expertise of the study chairs 8 6 Aim of the trial 8 7 Trial type 8 8 Informed consent and ethical considerations 8 9 Data documentation 9 10 Insurance 9 11 Timeline 10 Study protocol 1 Trial description Topic The medical problem Evidence Reperfusion Reperfusion in multivessel coronary artery disease and cardiogenic shock Reperfusion by PCI or CABG Reperfusion in multivessel coronary artery disease without cardiogenic shock IABP Additional supportive therapy The need for a trial 15 2 Study aims Study endpoints Primary study endpoint Secondary study endpoints Safety aspects Data Safety Monitoring Board Steering committee Methods against bias Study procedures Randomization in the catheterization laboratory Revascularization Antithrombotic therapy Mechanical hemodynamic support Documentation of hemodynamic parameters in the catheterization laboratory Post-PCI ICU therapy Hemodynamic monitoring at ICU Laboratory monitoring at ICU day follow-up month follow-up month follow-up Study flow-chart Assessment of study endpoints Inclusion criteria Exclusion criteria Prospective CULPRIT-SHOCK registry 22 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center 5

8 CULPRIT-SHOCK Study Protocol Version 1.1, Sample size calculation Statistical analysis Treatment compliance/drop-out Regulations for premature study termination Risk-benefit evaluation Feasibility of the study International cooperations Personnel and technical requirements 25 4 Ethical and regulatory specifications GCP guidelines Application Qualification of investigators and participating centers Investigators Participating centers Ethics committee application Subsequent changes of the study protocol 27 5 Documentation Electronic case report forms (ecrf) Data management Archiving Study survey Source data access Monitoring Audits Inspections Independent surveillance of the study Data protection and confidentiality 29 6 Administrative regulations Study execution in accordance with the protocol Publishing agreement and registration 30 7 Definitions 31 8 References 36 9 Signature page 41 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center 6

9 CULPRIT-SHOCK Study Protocol Version 1.1, Trial description Prospective, randomized, international, multicenter, open-label study to compare immediate multivessel revascularization by percutaneous coronary intervention (PCI) to culprit lesion only PCI with staged non-culprit lesion revascularization in patients with cardiogenic shock complicating acute myocardial infarction presenting with multivessel disease. Acronym: CULPRIT-SHOCK trial 2 Study chairs 2.1 Coordinating investigators Prof. Dr. med. Holger Thiele Department of Internal Medicine/Cardiology, University of Leipzig - Heart Center, Germany Prof. Dr. med. Uwe Zeymer Institut für Herzinfarktforschung, Ludwigshafen, Germany 2.2 Co-investigators PD Dr. med. S. Desch Director Department of Internal Medicine/Cardiology, University of Leipzig Heart Center stdesch@web.de Prof. Dr. med. G. Schuler Director Department of Internal Medicine/Cardiology, University of Leipzig Heart Center gerhard.schuler@med.uni-leipzig.de Prof. Dr. med. K. Werdan Director Department of Internal Medicine III - University Hospital, Martin-Luther-University Halle- Wittenberg karl.werdan@medizin.uni-halle.de 2.3 National coordinating investigators Prof. Dr. med. Gert Richardt Director Department of Internal Medicine/Cardiology, Heart Center Bad Segeberg, Germany gert.richardt@segebergerkliniken.de Prof. Dr. med. Kurt Huber Director Department of Internal Medicine/Cardiology, Wilhelminenspital of the city Vienna, Vienna, Austria kurt.huber@wienkav.at Prof. Dr. med. Stephan Windecker Deputy Director Department of Internal Medicine/Cardiology, University of Bern, Switzerland Stephan.Windecker@insel.ch Prof. Dr. med. Stefan James Director Department of Medical Sciences and Uppsala Clinical Research Center Uppsala University, Uppsala, Sweden stefan.james@akademiska.se Prof. Dr. med. Pranas Serpytis Vilnius University Hospital, Santariskiu klinikos, Vilnius, Lithuania pranas.serpytis@santa.lt Prof. Dr. med. Gilles Montalescot Centre Hospitalier Universitaire Pitié-Salpetrière, Institut de Cardiologie, Paris, France Gilles.montalescot@psl.aphp.fr Prof. Dr. med. Marco Noc University Medical Center Ljubljana, Division of Internal Medicine, Ljubljana, Slovenia marko.noc@mf.uni-lj.si Prof. Dr. med. Jan J. Piek Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center 7

10 CULPRIT-SHOCK Study Protocol Version 1.1, Academic Medical Center, Amsterdam, The Netherlands Prof. Dr. Med. Janina Stępińska Institute of Cardiology, Warsaw, Poland 3 Participating centers See attachment 1 4 Local investigators All interventional cardiologists of participating centers All physicians of intensive care unit (ICU) of participating centers 5 Clinical and scientific expertise of the study chairs The coordinating investigators form a team and have comprehensive expertise in the preparation, organization and conduct of clinical studies in particular in acute myocardial infarction and cardiogenic shock. The CVs of the two coordinating investigators are attached to this application. 6 Aim of the trial This trial examines if culprit vessel only PCI with potentially subsequent staged revascularization in comparison to immediate multivessel revascularization by PCI in patients with cardiogenic shock complicating acute myocardial infarction reduces the incidence of 30- day mortality and/or severe renal failure requiring renal replacement therapy. 7 Trial type Prospective, randomized, international, multicenter, controlled, open-label trial. 8 Informed consent and ethical considerations For ethical considerations and patient risk assessment in both treatment groups a careful interim analysis as well as regular meetings of the Data Safety Monitoring Board (DSMB) will be established to minimize the risk for the patients. In addition, insurance will be obtained for all patients. One important aspect in cardiogenic shock patients is informed consent. The majority of patients will not be able to give informed consent due to intubation, mechanical ventilation, and sedation. Another proportion of patients will have impaired peripheral and central perfusion induced by the cardiogenic shock itself and will be only partially able to give informed consent. Only a minority of patients will be able to give full informed consent in the acute setting. In the SHOCK-trial 88% were not able to give informed consent, 1 in the TRIUMPH trial 86%, 2 and in previous trials involving cardiogenic shock patients at the University of Leipzig Heart Center 90-95%. 3, 4 The percentage of patients not being able to consent in the IABP-SHOCK II trial, the largest trial in cardiogenic shock to date, is currently evaluated. Summarizing the current evidence, we assume that 90% of patients will not be able to give informed consent at the time of randomization. As the majority of patients will not be able to consent a 4 step informed consent process has been validated and approved: 1) Patient not able to consent 2 independent physicians assess supposed patient s will (if possible by contact of relatives). 2) Patient with impaired ability to consent Short version of informed consent 3) Patient with full consent Long version of informed consent 4) Patient recovers to full consent retrospective long version of informed consent 8 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

11 CULPRIT-SHOCK Study Protocol Version 1.1, Patient information and informed consent will be handled according to the rules of Good Clinical Practice and the Declaration of Helsinki. All eligible patients will undergo the consent process prior to randomization as described above using 4 different forms (see appendix 2 a-d). All possible risks will be specifically pointed out in the patient information. It will be explicitly highlighted that non-participation in the trial or withdrawal of a prior given consent can be carried out at all times with no subsequent disadvantages and that management of all data will be performed according to data privacy policy. The process of study information and informed consent has been established in several previous clinical trials in cardiogenic shock (i.e. TRIUMPH-trial EudraCT Number: , ethics committee approval number in Germany at Landesärztekammer Brandenburg S 9/2006; 2 IABP SHOCK Pilot-trial; ethics committee approval number in Germany at Martin- Luther-Universität Halle dated Ethical approval has also been granted from the University of Leipzig with Reg.Nr for the IABP-SHOCK II-trial in 600 patients using the same informed consent process as described here. 5 9 Data documentation All data will be collected prospectively by standardized electronical case report forms (ecrf) provided by the Institut für Herzinfarktforschung in Ludwigshafen. The link is For data entry, each study coordinator at each participating center receives individual login information for the ecrf. The database will be kept on the server of the Institut für Herzinfarktforschung Ludwigshafen. Data are entered by each participating center directly into the internet-based ecrf. Data entered are immediately tested for plausibility in order to prevent unnecessary queries. Data will be entered via a SSL-secured internet line. The ecrf will be self-explaining. To facilitate data entry, the definitions of the various parameters will be accessible by a simple mouse click behind the related question in the ecrf. Further data analysis will be conducted electronically encrypted. Through anonymization of all personal information all regulations of data privacy policy will be respected. In addition, adherence to data privacy protection will be guaranteed by the SOP of the Institut für Herzinfarktforschung. 10 Insurance For the general risk of the procedure patients are insured through the typical patient insurance of the individual hospitals. PCI including multivessel and culprit lesion only is a standard treatment of cardiogenic shock. Any potential additional risks for the patients caused by studyspecific procedures will be covered by an additional insurance (see risk-benefit evaluation 2.13). A copy of the insurance certificate will be handed out to the patient: Insurance-Police-Number: xx-xxxxx HDI-Gerling Industrie Versicherung AG Eisenbahnstr Leipzig Deutschland Telefon: Telefax: The maximum cover per patient is ,00. A copy of the insurance certificate is filed in the trial folder. Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center 9

12 CULPRIT-SHOCK Study Protocol Version 1.1, Timeline Figure 1: Timeline and milestones of the CULPRIT-SHOCK trial This clinical trial will start with the first obtained written informed consent and will end by the time all patients completed clinical long-term follow-up at 12 months after randomization. For the individual patient, the clinical trial will start after informed consent and randomization after diagnostic coronary angiography. The patient will reach the end of the study by the time the follow-up examinations at 30-days, 6 months, and at 12 months are completed. Patient recruitment will last approximately 30 months, leading to total study duration of 42 months including the long-term follow-up at 12 months post randomization. Primary analysis will require up to 2 months. Thus, the time from first randomization to primary analysis (completion of 30-days follow-up of the last patient) will be 32 months for the primary study endpoint and 44 months until the end of the study with termination of the long-term followup of the last patient. 10 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

13 CULPRIT-SHOCK Study Protocol Version 1.1, Study protocol 1 Trial description 1.1 Topic Prospective, randomized, international, multicenter, open-label study to compare immediate multivessel revascularization by PCI to culprit lesion only PCI with staged non-culprit lesion revascularization in patients with cardiogenic shock complicating acute myocardial infarction presenting with multivessel disease. Acronym: CULPRIT-SHOCK trial 1.2 The medical problem Despite aggressive treatment modalities such as PCI as well as mechanical and inotropic support, mortality of cardiogenic shock complicating acute myocardial infarction remains at a 3, 4, 6-10 very high level with mortality rates between 45-70%. The majority of patients in cardiogenic shock presents with multivessel coronary artery disease and the mortality of these patients is higher than mortality in patients with single vessel disease From a pathophysiological standpoint it might be beneficial to reperfuse all relevant coronary arteries with significant coronary artery stenoses in addition to the culprit lesion to improve myocardial perfusion. On the other hand immediate multivessel PCI might pose additional risk for the patients. However, there are no randomized clinical trials assessing the optimal reperfusion strategy. 1.3 Evidence Reperfusion The most important therapeutic measure in cardiogenic shock complicating acute myocardial infarction is early reperfusion of the infarct related artery. Historically, the introduction of fibrinolysis failed to substantially lower the mortality of patients in cardiogenic shock which remained high at a rate of 70-85% Subsequently, non-randomized and partly retrospective studies in cardiogenic shock suggested that PCI can reduce the high mortality The landmark SHOCK trial is one of the rare adequately powered randomized trials in cardiogenic shock complicating acute myocardial infarction. 1 Although it failed to meet the primary endpoint - reduction of 30-day mortality by an early revascularization-based management either by PCI or coronary artery bypass grafting (CABG) - (46.7% versus 56.0%, p=0.11), there was a significant mortality reduction at 6 months (50.3% versus 63.1%, p=0.027), 12 months (53.3% versus 66.4%, p=0.03), 30 and long-term follow-up at 6 years (67.2% versus 80.4%, p=0.03). 31 To save 1 life, <8 patients need to be treated by early revascularization in comparison to initial medical stabilization. The Swiss Multicenter trial of Angioplasty for Shock (SMASH) trial, although stopped prematurely due to slow enrolment, showed similar effects by early revascularization. 32 Based on the current evidence PCI plus stent implantation (or CABG) is recommended for all patients in particular those aged <75 years to allow recovery of stunned myocardium and prevention of life-threatening arrhythmias For patients aged >75 years an early interventional treatment is recommended depending on the patient condition and comorbidities The more widespread establishment of an early interventional treatment in cardiogenic shock irrespective of age was likely the most important factor for a reduction of mortality to 40-50% observed in recent years Reperfusion in multivessel coronary artery disease and cardiogenic shock Approximately 70-80% of patients with cardiogenic shock complicating acute myocardial infarction have multivessel disease , 41 These patients have a higher mortality compared to patients with single vessel disease Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

14 CULPRIT-SHOCK Study Protocol Version 1.1, Current ESC and AHA/ACC guidelines recommend PCI of all high-grade lesions in patients with acute myocardial infarction complicated by cardiogenic shock (class IIa, level of evidence B recommendation), while in hemodynamically stable patients without shock culprit-lesion only PCI should be preferred (class III, level of evidence B recommendation). 34, 35, 37, 42 In contrast to these recommendations, the German/Austrian S3-guideline recommends multivessel PCI only 43, 44 in selected individual cases. Nevertheless, these guideline recommendations in cardiogenic shock are not based on strong clinical evidence because it is not clear whether multivessel PCI might be beneficial in cardiogenic shock. There are no randomized data evaluating the benefit of a multivessel PCI approach in cardiogenic shock and these recommendations are mainly based on pathophysiological considerations. Despite these guideline recommendations and possibly owing to the limited evidence supporting these recommendations multivessel PCI is currently 45, 46 performed in only 1/3 to 1/4 of cardiogenic shock patients with multivessel disease. So far reports from registries comparing culprit-lesion only versus multivessel PCI in patients with acute myocardial infarction complicated by cardiogenic shock do not support immediate multivessel PCI. In the SHOCK trial more complete revascularization by immediate multivessel PCI was associated with an unfavorable outcome compared to culprit lesion only PCI. 47 In a single center observational study 1-year mortality did not significantly differ between culpritlesion PCI (n=124) and immediate multivessel PCI (n=37). 48 Data from the multicenter National Cardiovascular Data Registry reported an increased mortality for multivessel PCI. Among patients with cardiogenic shock (n=3,087), those receiving multivessel PCI had greater inhospital mortality (36.5% vs 27.8%; adjusted odds ratio 1.54, 95% confidence interval 1.22 to 1.95). 49 In the recently published Euro Heart Survey PCI registry there was a trend towards higher mortality after multivariable adjustment for the multivessel PCI strategy (n=82) versus culprit lesion only PCI (n=254) in multivessel disease. 45 In addition, data from the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK) also showed an unfavorable outcome with immediate multivessel PCI. 50 A summary of current data from registries is shown in Table 1: Trial N Mortality Multivessel PCI Mortality Culprit Lesion only PCI Adjusted OR (95% CI) Webb %* 20%* 2.75 ( ) Van der Schaaf %* 53%* Not reported (p=0.05) Cavender % 27.8% 1.5 ( ) Bauer % 37.4% 1.28 ( ) Zeymer % 35.6% 1.5 ( ) *1-year mortality Table 1: Current evidence of multivessel PCI versus culprit lesion only PCI on death Currently, there is no trial assessing multivessel revascularization by PCI (or CABG) versus culprit lesion only PCI with a potential staged revascularization strategy in case of ischemia. Given the conflicting data the current guideline recommendations are questionable and it remains to be determined which strategy is preferable Reperfusion by PCI or CABG Theoretically, there might be some influence by the revascularization type - PCI versus CABG - on outcome similar to stable coronary artery disease. 51 Nevertheless, there is much uncertainty regarding the optimal revascularization type for patients in cardiogenic shock, 9 because all previous trials assessing the effect of revascularization or adjunctive treatment on outcome did not specify the type of reperfusion in the study protocol. 1, 2, 32 Given the current evidence there are no randomized data that the type of revascularization influences the outcome of patients in cardiogenic shock. 52 Therefore, in addition to the uncertainty regarding culprit lesion versus multivessel PCI, the optimal revascularization strategy - PCI versus CABG - for patients in shock with multivessel 12 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

15 CULPRIT-SHOCK Study Protocol Version 1.1, disease is not clear. 46 Randomized clinical trials addressing this question are missing for the cardiogenic shock subset. Currently, there are only 4 observational reports evaluating PCI versus CABG and the limited data suggest similar mortality rates with CABG and PCI in patients 46, 52 with infarction and multivessel coronary artery disease complicated by cardiogenic shock. In the current ESC revascularization guidelines emergent surgery after failure of PCI or fibrinolysis is only indicated in patients with persistent instability or life-threatening ventricular arrhythmia due to extensive ischemia such as left main or severe triple vessel disease (class 1, level of evidence C recommendation) Reperfusion in multivessel coronary artery disease without cardiogenic shock In ST-elevation myocardial infarction (STEMI) patients without cardiogenic shock multivessel disease has a lower incidence in comparison to shock patients and is present in 40-70% of patients depending upon the baseline characteristics of the population studied In these patients an immediate non-culprit lesion intervention is not recommended by ESC and 34, 35, 37 AHA/ACC guidelines despite limited evidence (class III B recommendation). Several prior registry studies have shown that treatment of non-culprit lesions during primary PCI for STEMI in hemodynamically stable patients was associated with increased postprocedural morbidity in the absence of a mortality benefit. 49, 53, 56, 57 Other registries found similar results for an immediate versus a culprit lesion only PCI strategy or a culprit lesion with subsequent staged PCI strategy. 58, 59 There are only 2 small randomized trials. 60, 61 In one randomized clinical trial involving only 214 patients with multivessel disease undergoing randomization to 3 arms, culprit lesion only was associated with the highest major adverse cardiac event rate, whereas there was no difference in the immediate multivessel PCI strategy and the planned culprit lesion with staged PCI strategy. In the other randomized trial immediate multivessel PCI was also safe without complications in 60 randomized patients. 60 These conflicting results have recently been confirmed in 3 different meta-analyses. One metaanalysis included 4 prospective and 14 retrospective trials comparing 3 different strategies for multivessel PCI; 1) culprit lesion only PCI versus 2) multivessel PCI and 3) immediate culprit lesion PCI and subsequent staged PCI of other relevant stenoses. 62 This meta-analysis reported the lowest mortality rates for an immediate culprit lesion only with subsequent staged PCI, worse mortality with a culprit lesion only strategy and the worst outcome for an immediate multivessel PCI strategy. 62 In contrast, another meta-analysis including 19 registry studies that compared culprit lesion only versus multivessel PCI (either performed immediately or staged) found similar mortality and reinfarction rates. 63 The 3 rd meta-analysis including 2 randomized and 8 registry studies comparing an immediate multivessel PCI strategy (excluding staged PCI procedures) versus a culprit lesion only strategy found no difference in mortality rates. 64 Currently, there are 3 ongoing randomized trials (COMPARE-ACUTE; PRAGUE-13; CROSS- AMI) recruiting non-shock STEMI patients with multivessel disease with randomization to immediate multivessel PCI or culprit lesion only PCI with or without staged PCI ( IABP The hemodynamic effects of IABP in cardiogenic shock are well established. 65 However, the evidence regarding the benefits of IABP on mortality is limited. A recent meta-analysis revealed the conflicting results in different reperfusion strategies. 66 The main results of this meta-analysis are shown in Figure 2: 13 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

16 CULPRIT-SHOCK Study Protocol Version 1.1, Figure 2: Trials of IABP versus no IABP in cardiogenic shock. Adapted according to Sjauw et al. 66 The IABP-SHOCK II trial randomized 600 patients with acute myocardial infarction and cardiogenic shock undergoing early revascularization to either IABP or optimal medical therapy only. With 600 randomized patients the IABP-SHOCK II trial is the largest trial in cardiogenic shock performed so far. The results have been recently published and did not show a benefit for the IABP on 30-day mortality or on secondary endpoints. 67, 68 Therefore, IABP use cannot be not recommended anymore on a regular basis Additional supportive therapy The current evidence in the treatment of cardiogenic shock has recently been summarized. 9 Except for early revascularization and - in case of vasopressor requirement - treatment with norepinephrine instead of dopamine, no treatment option including glycoprotein IIb/IIIainhibitors, NO-production modulation, or early use of active left ventricular assist devices showed a benefit with respect to mortality reduction. The current evidence in cardiogenic shock with the results of the IABP-SHOCK II-trial is 9, 68 summarized in Figure 3. Figure 3: Randomized clinical trials in cardiogenic shock. Adapted according to Thiele et 9, 68 al. 14 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

17 CULPRIT-SHOCK Study Protocol Version 1.1, The need for a trial Of estimated 140,000 cases of acute myocardial infarctions admitted to hospitals in Germany per year, 69 approximately 10,000 are resulting in cardiogenic shock (7-8%). 7 Of these 70-80% of patients have multivessel disease translating into 7500 patients in Germany , 41 For the European population this translates in approximately 60,000 to 70,000 cardiogenic shock cases 70, 71 per year and 45,000 to 52,000 multivessel disease patients. These patients with multivessel disease have a higher mortality compared to patients with single vessel disease. Current European Society of Cardiology (ESC) as well as American Heart Association (AHA)/American College of Cardiology (ACC) guidelines recommend PCI of all high-grade lesions in patients with acute myocardial infarction complicated by cardiogenic 33-37, 42 shock, while in hemodynamic stable patients culprit-lesion only PCI should be preferred. However, these recommendations are not based on randomized trials. Therefore, currently there is no consensus on the optimal management of significant non-culprit coronary artery lesions identified at angiography for primary PCI and a randomized clinical trial therefore necessary. Theoretically, treatment of non-culprit lesions could help limiting the infarct size and preserve left ventricular function, which are major prognostic factors in patients with acute myocardial infarction. It may also be hypothesized that multivessel PCI may reduce the subsequent adverse events after primary PCI by preventing the incidence of both early and late recurrent ischemia in the non-infarct related lesions, which in turn could obviate the need for recurrent procedures, reducing overall ischemic burden and attenuating the incidence of unpredictable subsequent cardiac events. Complete revascularization at the time of infarction may also reduce overall hospital stay and total cost of care. On the other hand, major concern exists regarding the risks of prolonged interventional procedures with higher amounts of contrast dye and the hypothetical risk of stent thrombosis in non-culprit lesions when stent implantation has taken place in the thrombogenic milieu of acute myocardial infarction. 72 A successful primary PCI of the infarct related artery and a complicated or unsuccessful PCI to the non-infarct related artery would be potentially hazardous, especially in the setting of cardiogenic shock. Contrast load also has to be taken into account which might lead to a volume load of the left ventricle with subsequent ischemia. In addition, multivessel PCI is likely to be associated with an increased risk of contrast-induced nephropathy, which is associated with adverse clinical outcome Furthermore, unnecessary PCI might increase the need for subsequent revascularization procedures due to restenosis, acute stent thrombosis, or might induce periprocedural myocardial infarction by distal embolization, side branch occlusion, acute vessel occlusion, or other inherited technical problems. 45 Therefore, it is not surprising that treatment modalities for multivessel disease diagnosed during PCI for cardiogenic shock differ widely among different institutions and are largely operator dependant. Therefore a prospective randomized clinical trial is warranted to determine the optimal revascularization therapy in patients with multivessel disease treated with early revascularization preferably PCI for cardiogenic shock. 15 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

18 CULPRIT-SHOCK Study Protocol Version 1.1, Study aims 2.1 Study endpoints Primary study endpoint All-cause death and/or severe renal failure requiring renal replacement therapy within 30-days after randomization according to the intention-to-treat principle. (For definitions see 7) Mortality is surely the strongest endpoint for acute heart failure syndrome trials. 76 Renal failure requiring renal replacement therapy is also associated with increased morbidity and mortality In the recently published IABP-SHOCK II trial the mortality of patients with renal replacement therapy was 56% versus 37% for those without renal replacement therapy (p<0.001) underlining the prognostic relevance of this endpoint. 68 In addition, the combination of these two individual endpoints has recently been used in a randomized clinical trial in patients with severe sepsis Secondary study endpoints 30-day all-cause mortality Renal failure with requirement of renal replacement therapy Procedural success Time to hemodynamic stabilization Duration of catecholamine therapy Serial creatinine-level creatinine-clearance (Cockcroft-Gault-Formula) 78 until stabilization Length of ICU-stay Serial SAPS-II score until stabilization Requirement and length of mechanical ventilation All-cause death within 6 and 12 months follow-up Recurrent infarction within 30-days, 6 and 12 months follow-up Death or recurrent infarction at 6 and 12 months follow-up Rehospitalization for congestive heart failure within 30-days, 6 and 12 months follow-up Death/recurrent infarction/rehospitalization for congestive heart failure within 30-days, 6 and 12 months Need for repeat revascularization (PCI and/or CABG) within 30-days, 6 and 12 months follow-up Peak creatine kinase, creatine kinase-mb and troponin level during hospital stay Quality of life at 6 and 12 months assessed using Euroqol 5D (EQ-5D) questionnaire ( Except for the direct clinical events, the secondary endpoints are surrogate measures for 1, 3, outcome and complications and have been used in several previous cardiogenic shock trials. 4 In addition, although 30-day death and/or severe renal failure is the primary endpoint, it is important to confirm a potential advantage at long-term follow-up. Therefore, a 6- and 12-month follow-up will be analyzed which will also encompass rehospitalisation for congestive heart failure and recurrent infarction among other clinical endpoints Safety aspects Immediate multivessel revascularization by preferably PCI will be performed in patients randomized in group 1 and culprit lesion only PCI with potential staged additional revascularization if indicated in group 2. There are no additional study related examinations or procedures. Apart from the two revascularization strategies all patients will be treated according to current guidelines of the ESC and the AHA/ACC as well as the German-Austrian S3-33, 34, 36, guideline for the treatment of cardiogenic shock. Safety will be assessed by bleeding and occurrence of stroke. 16 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

19 CULPRIT-SHOCK Study Protocol Version 1.1, Bleeding according to the BARC-definition grade 2-3 and Stroke: any new neurological symptoms in association with signs of ischemia or hemorrhage in a cranial CT or MRI Data Safety Monitoring Board The external independent DSMB consists of international experts in the treatment of cardiogenic shock and acute heart failure. Confirmed members of the DSMB are: Name Affiliation Prof. Dr. Ferenc Follath Universitätsspital Zürich, Switzerland ferenc.follath@usz.ch Prof. Dr. Peter Clemmensen Rigshospitalet, The Heart Center, Copenhagen, Denmark Prof. Dr. Johannes Haerting (independent statistician) Steering committee peter.clemmensen@rh.regionh.dk Universität Halle-Wittenberg, Germany johannes.haerting@medizin.uni-halle.de The steering committee of the CULPRIT-SHOCK trial consists of the two coordinating investigators, co-investigators, and the national coordinating investigators. 2.2 Methods against bias Blinding is not possible as a result of the intervention used. Methods against bias used are a central computerized randomization; independent clinical endpoint committee to assess adverse events other than death; blinded laboratory for secondary laboratory parameters; high standard requirements concerning the clinical level and experience of centers and investigators in terms of numbers of PCI performed, cases of cardiogenic shock treated, intensive care unit treatment, and participation in clinical trials. In order to prevent informative censoring, informed consent will include access to all relevant sources to determine the patient s life status at 6- month and 12-month follow-up. 2.3 Study procedures Patients with cardiogenic shock complicating acute myocardial infarction (inclusion criteria see 2.6) will be transferred to the catheterization laboratory as soon as possible after primary admission to the tertiary care center or after transfer from a primary or secondary care center. Left heart catheterization is performed and coronary anatomy with the extent of coronary artery disease including identification of the culprit lesion is assessed Randomization in the catheterization laboratory After check of all in- and exclusion criteria (see 2.6 and 2.7) randomization after the initial diagnostic angiography is performed into the groups 1 and 2. Group 1: 353 patients with immediate multivessel revascularization preferably by PCI Group 2: 353 patients with culprit lesion only PCI with potential staged revascularization Randomization is performed internet-based using a secure system using the homepage of the Institut für Herzinfarktforschung: Revascularization Group 1: Revascularization plan in the immediate multivessel PCI group After diagnostic angiography the culprit lesion should be identified and PCI should be performed using the standard technique of the participating center. The use of drug-eluting stents is 17 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

20 CULPRIT-SHOCK Study Protocol Version 1.1, recommended but not mandatory. Thrombectomy and additional interventional techniques are left to the discretion of the operator. All additional lesions in other major coronary arteries defined by a diameter >2 mm with high grade stenoses (>70% by visual assessment) should be intervened using standard techniques of the participating center. Other major coronary arteries are defined by stenoses of other vessels and are not confined to a diagonal branch if the left anterior descending coronary artery was identified as the culprit lesion. The use of drug-eluting stents is also recommended for these lesions but not mandatory. In patients with prior CABG and culprit lesion in a bypass graft the same strategy applies with PCI of the culprit lesion and additional revascularization of additional significant stenoses in native coronary arteries or bypass grafts. In patients with triple vessel disease and chronic total occlusions (CTO) the culprit lesion should be targeted and additional revascularization of the CTO attempted. However, no excessive revascularization attempts should be applied. The overall amount of contrast dye should not exceed 300 ml. In case of unsuitable anatomy for PCI such as severe multivessel disease with multiple chronic total occlusions and/or high SYNTAX-score revascularisation by primary immediate CABG might be considered according to operator discretion to ensure complete revascularization. Patients undergoing primary urgent CABG will not be randomized. However, it is recommended that treatment of left main stem stenoses or triple vessel disease should be performed by PCI whenever possible. No fractional flow reserve measurement is recommended in the acute setting for assessment of the functional relevance of non-culprit lesions. 35 Group 2: Revascularization plan in the culprit lesion PCI only group After the diagnostic angiography the culprit lesion should be identified and PCI of the culprit lesion should be performed using the standard technique of the participating center. Patients considered candidates for primary urgent CABG according to operator discretion will not be randomized. The use of drug-eluting stents is recommended but not mandatory. Thrombectomy and additional interventional techniques are left to the discretion of the operator. All other lesions should be left untreated in the acute setting. In group 2, complete revascularization of the non-culprit lesions may be performed at a later time point as staged procedure depending on remaining ischemia (as per guideline recommendations either by PCI or CABG). 35 It is strongly recommended that all patients depending on the clinical situation and hemodynamic stability - undergo non-invasive evaluation for residual myocardial ischemia at 1-4 weeks post index PCI of the culprit lesion by means of a stress ECG or an imaging stress test such as nuclear perfusion scintigraphy, stress echocardiography, or stress magnetic resonance imaging. Alternatively, the functional relevance of initially untreated stenoses can be assessed by invasive fractional flow reserve. 35 All patients manifesting significant symptoms of angina pectoris or significant reversible ischemic burden should be revascularized Antithrombotic therapy Antithrombotic therapy should be given according to local standards of the participating centers. According to the current guidelines aspirin and an ADP-receptor antagonist should be given for 12 months. In patients without contra-indications prasugrel or ticagrelor is recommended over clopidogrel , 42 Glycoprotein IIb/IIIa-inhibitors might be considered in reduced flow after PCI or high thrombus burden Mechanical hemodynamic support Mechanical hemodynamic support such as active left ventricular assist devices, or extracorporeal membrane oxygenation can be considered based on current guideline recommendations , Based on the results of the IABP-SHOCK II trial an IABP is not recommended anymore, 68 however, its use is left to the discretion of the operators. Mechanical hemodynamic support can be performed before or after PCI. 18 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

21 CULPRIT-SHOCK Study Protocol Version 1.1, Documentation of hemodynamic parameters in the catheterization laboratory Hemodynamic parameters such as systolic, diastolic, mean arterial pressure, and heart rate will be assessed in the catheterization laboratory before and after revascularization. In addition, an arterial blood gas analysis with assessment of serum lactate will be performed. By study design detailed hemodynamic parameters (such as cardiac output, cardiac index, cardiac power index, central venous pressure, pulmonary artery pressure, PCWP) will not be assessed in the catheterization laboratory, as this might delay revascularization and would lead to the necessity of pulmonary artery catheterization Post-PCI After cardiac catheterization patients will be transferred to the ICU by continuous ECGmonitoring and arterial invasive blood pressure monitoring ICU therapy ICU therapy is adapted and performed to general accepted intensive care guidelines. 43, 44 There is no difference in the treatment between patients in group 1 and 2. In both groups treatment with catecholamines (i.e. preferably dobutamine for inotropic support and norepinephrine as vasoconstrictor) according to local practice is performed. If considered necessary, the use of Ca-sensitizers (levosimendan) is allowed according to the individual intensive care evaluation The duration of catecholamines and other hemodynamically relevant drugs will be documented. 43, 44 The mean blood pressure goal during requirement of hemodynamic support is 65 mmhg. If renal replacement therapy is necessary the reason for initiating renal replacement therapy [Otherwise untreatable volume overload; hyperpotassemia (>6.0 mmol/l); severe uremia (>50 mg/dl or >8.4 mmol/l); persistent severe metabolic acidosis (ph <7.2)], the mode, and the duration will be documented. Any need for mechanical or assisted ventilation and its duration will be assessed in the ecrf Hemodynamic monitoring at ICU Hemodynamic parameters such as systolic, diastolic, mean arterial pressure, and heart rate will be assessed according to local practice. In addition, arterial blood gas analyses with assessment of ph and serum lactate will be performed according to local practice. If deemed necessary, expanded hemodynamic monitoring by PICCO-system or pulmonary artery catheter can be applied. Data will not be assessed in the ecrf Laboratory monitoring at ICU Blood is drawn for the assessment of inflammatory markers (CRP and white blood cell count) once daily and also markers of myocardial damage such as creatine kinase (CK), CK-MB, and troponin for the indirect assessment of infarct size. In addition, renal function will be assessed by serum creatinine. All other laboratory parameters will be collected according to the ecrf (see 2.5) day follow-up At 30-days after randomization the vital status will be assessed by structured telephone interview. Any potential event (death, severe renal failure requiring renal replacement, reinfarction, repeat revascularization, new congestive heart failure leading to hospital admission) will be verified by original records month follow-up At 6 months after randomization the vital status will be assessed by structured telephone interview. Any potential event (death, severe renal failure requiring renal replacement, reinfarction, repeat revascularization, new congestive heart failure leading to hospital admission) will be verified by original records. The quality of life will be assessed by the Euroqol 5D questionnaire month follow-up At 12 months after randomization the vital status will be assessed once again by structured 19 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

22 CULPRIT-SHOCK Study Protocol Version 1.1, telephone interview. Any potential event (death, severe renal failure requiring renal replacement, reinfarction, repeat revascularization, new congestive heart failure leading to hospital admission) will be verified by original records. The quality of life will be assessed by the Euroqol 5D questionnaire. 20 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

23 CULPRIT-SHOCK Study Protocol Version 1.1, Study flow-chart Figure 4: Study flow-chart 21 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

24 CULPRIT-SHOCK Study Protocol Version 1.1, Assessment of study endpoints An overview of the timepoints for assessment of study endpoints is provided in Table 2: 22 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

25 CULPRIT-SHOCK Study Protocol Version 1.1, Inclusion criteria Cardiogenic shock complicating acute myocardial infarction (STEMI or NSTEMI) with obligatory: I) Planned early revascularization by PCI II) Multivessel coronary artery disease defined as >70% stenosis in at least 2 major vessels ( 2 mm diameter) with identifiable culprit lesion III) a) Systolic blood pressure <90 mmhg for >30 min or b) catecholamines required to maintain pressure >90 mmhg during systole and IV) Signs of pulmonary congestion V) Signs of impaired organ perfusion with at least one of the following criteria a) Altered mental status b) Cold, clammy skin and extremities c) Oliguria with urine output <30 ml/h d) Serum-lactate >2.0 mmol/l VI) Informed consent 2.7 Exclusion criteria Resuscitation >30 minutes No intrinsic heart action Cerebral deficit with fixed dilated pupils (not drug-induced) Need for primary urgent bypass surgery (to be determined after diagnostic angiography) Single vessel disease Mechanical cause of cardiogenic shock Onset of shock >12 h Massive lung emboli Age >90 years Shock of other cause (bradycardia, sepsis, hypovolemia, etc.) Other severe concomitant disease with limited life expectancy <6 months 2.8 Prospective CULPRIT-SHOCK registry Patients not fulfilling the above mentioned inclusion criteria or those with exclusion criteria will be entered into the prospective CULPRIT-SHOCK registry (see Figure 4). Parameters evaluated will be essentially the same as for the randomized clinical trial. This registry will give an estimate of the patients screened and finally included into the randomized trial. Furthermore and more importantly, this trial will allow describing the current treatment strategies for patients in cardiogenic shock. 2.9 Sample size calculation The 30-day mortality of patients with multivessel disease and cardiogenic shock undergoing immediate multivessel PCI is approximately 50% as indicated in multiple registries (see Table 1). 45, 47, 48, 50 The 30-day death rate in the culprit lesion only group is supposed to be 39% based on reported mortality rates from registries. 45, These assumptions are at the lower end of the estimated difference in mortality reduction by culprit lesion only PCI with current registry data suggesting an absolute mortality reduction of 7-35% and the most recent data suggesting 11%. 45, It should, however, be taken into account that registry data might overestimate treatment effects and therefore a conservative estimate is justified. The incidence of severe renal failure requiring renal replacement therapy is estimated to be absolutely 2% lower in the culprit lesion only group. 49 Based on these data and with regard to the combined primary endpoint of death and renal replacement therapy, event rates of 50% in the multivessel PCI group vs. 38% in the culprit lesion only group were used for sample size calculation. A total of 684 patients are needed to test the null hypothesis of no difference between groups (two-sided test Chi 2 test; power: 80%, 23 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

26 CULPRIT-SHOCK Study Protocol Version 1.1, alpha=0.048 for final analysis). Allowing for a 3% drop-out rate, 706 patients will be recruited. Based on previous clinical trials a higher drop-out rate is not expected. 1-4, 80 The software used for sample size calculation was nquery Advisor 7.0, Statistical Solutions, Cork, Ireland Statistical analysis All data will be analyzed according to the intention-to-treat principle. A sensitivity analysis according to the per protocol population evaluating the robustness of the data will also be performed. The per protocol population is defined by patients undergoing successful or unsuccessful revascularisation. Patients who die before the start of revascularisation or who do not undergo revascularisation for other reasons will not be included in the per protocol analysis. For the primary endpoint Chi 2 test will be used to compare the event rates in both arms. Additionally, Kaplan-Meier curves will be calculated for visualizing the cumulative events in both groups during 30-day follow-up. Secondary endpoints will be assessed by Fisher s or Chi 2 test for binary and Mann-Whitney U test for quantitative secondary endpoints to compare both treatment arms. Since the presumed event rates in both groups are derived from registry data, these might be prone to error. Therefore, a group sequential statistical design with one interim analysis will be chosen. The interim analysis will be performed using the O'Brien-Fleming method without any specified alpha spending function. 81 Thus, the analysis will be equally spaced in terms of the numbers of patients involved at the interim analysis and will be performed after 50% (342) of all analysable patients have completed 30-day follow-up. The global type I error level is set at The trial will be discontinued if the null hypothesis of equal event rates can be rejected with a significance level of at the interim analysis. The final analysis will be performed with α= In case of trial discontinuation at the interim analysis secondary endpoints will be analyzed before finalization of the trial. For missing values sensitivity analyses with multiple imputations will be performed. Long-term survival over 6- and 12 months will also be assessed by Kaplan-Meier analysis. Predefined subgroup analyses will be performed for gender, age groups <50 years, years, >75 years, diabetes, arterial hypertension, STEMI versus NSTEMI, anterior myocardial infarction versus infarct at another location, previous infarction, and 2- versus 3-vessel disease Treatment compliance/drop-out Treatment compliance is not affected by the patient but exclusively by the interventional cardiologist. However, in group 1 anatomical reasons such as CTO or severe calcification leading to unsuccessful PCI or also unstable clinical situation together with comorbidities not qualifying the patient for immediate CABG may lead to incomplete revascularization. In group 2, compliance to the study protocol with culprit lesion only PCI is expected to approach 100%. However, some patients may not qualify subsequently for a staged revascularization procedure because of hemodynamic instability or premature death. In total a treatment compliance of 85% is anticipated. This has been taken into account in the sample size calculation. Based on previous trials in cardiogenic shock the rate of loss to followup is estimated to be 1-4, 80 <2% Regulations for premature study termination a. For the individual patient: Withdrawal of consent throughout the study or following hospital discharge or after 6- and 12-month follow-up. In general discontinuation of the study should be avoided. Discontinuation is only possible by withdrawal of the patient s consent. Violation of the protocol does not lead to termination of the study for the individual patient. Likewise incomplete revascularization due to unsuccessful PCI of a CTO in the immediate multivessel PCI group is not a criterion for study discontinuation. In case of study discontinuation the reasons and circumstances, as well as the clinical state of the patient should be documented. If the study is continued, follow-up should be conducted as planned 24 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

27 CULPRIT-SHOCK Study Protocol Version 1.1, (exception: withdrawal of consent). Randomized patients should therefore generally complete follow-up and documentation. In case patients are ineligible for further analysis in the follow-up period (=no contact can be established neither personally to the patient nor through family members) the exact time of the loss of contact should be documented (if possible with an explanatory statement, e.g. relocation). According to the intention-to-treat-analysis all events and parameters will be evaluated until the last date of contact. b. For the entire study: The study might be halted and stopped in case of reaching the boundaries set for the interim analysis. c. The study can be prematurely discontinued by the principal investigator in case of Serious adverse events Insufficient recruitment rate The final decision on a premature discontinuation of the study lies within the discretion of the coordinating investigators. By means of the meeting of the independent DSMB serious adverse events as well as the primary study endpoint will be analyzed. Including two clinical cardiologists and a statistician, the DSMB is able to provide a professional evaluation, if premature discontinuation is indicated. The evaluation of events will be carried out in regular intervals and the information will be passed on to the DSMB after verification. d. The study can be discontinued at an investigating center in case of Failure to comply with the study protocol Insufficient data quality Inadequate recruitment The coordinating investigators, if needed in accordance with the responsible biometrician, will decide on exclusion. The reasons for discontinuation should be clarified. Further treatment for the previously included patients should be discussed with the coordinating investigators Risk-benefit evaluation The study will be performed in accordance with: the requirements of Good Clinical Practice (GCP) the principles stated in the Declaration of Helsinki As outlined above there is equivocal evidence for an immediate multivessel PCI strategy in comparison to a culprit lesion only strategy with subsequent staged PCI. Potential advantages and disadvantages of ad hoc multivessel PCI are outlined in the Table 3: Advantages Immediate complete revascularization Improved hemodynamics Treatment of remote ischemia Treatment of secondary unstable lesions Patient preference/comfort Limit infarct size and preserve left ventricular ejection fraction Disadvantages Increased contrast load risk of contrastinduced nephropathy Radiation exposure Complications of treating additional lesions may induce a second hit Hemodynamic instability might be worsened by treating additional lesions Increased risk of stent thrombosis in the prothrombotic and inflammatory milieu in the acute phase Coronary spasm might overestimate stenosis severity of non-culprit stenoses 25 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

28 CULPRIT-SHOCK Study Protocol Version 1.1, Feasibility of the study All participating centers are tertiary cardiology centers with high expertise in performing clinical trials in acute myocardial infarction in particular cardiogenic shock. Many of the German centers are university hospitals or are organized in the network of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK), which has high expertise to perform cardiovascular and particular cardiogenic shock clinical trials in Germany. 10 The estimated inclusion rates per year by centers are estimated by individual estimations, the current number of patients with cardiogenic shock according to ICD-10 classification, previous recruitment rates, registries plus current screening rates, the number of PCI performed in each center, and also recruitment in the IABP-SHOCK II trial. Based on these data (excluding patients due to in- and exclusion criteria) the annual inclusion rate is estimated for the individual hospitals. In addition, the IABP-SHOCK II trial had included 600 patients at 35 centers in Germany within 2 ½ years with similar inclusion criteria except for the requirement of multivessel disease in the CULPRIT-SHOCK trial. 5 Of these randomized patients in IABP-SHOCK II approximately 75% had multivessel disease. Therefore, this trial extends the number of study sites to recruit patients within the projected 2 ½ years showing feasibility of the estimated inclusion rate. Assuming a certain overestimation of the potentially recruitable patients in the dimension of 1.5-2, inclusion of 706 patients should realistically be possible within 2 ½ years. 3.1 International cooperations At the current stage international cooperations are planned for Austrian, Swiss, French, Dutch, Swedish, Lithuanian, and Slovenian study sites. In addition, international cooperations are agreed on with the DSMB as mentioned above. 3.2 Personnel and technical requirements To provide the ability for early revascularization, a 24 h stand-by of the catheterization laboratory including all personal and technical requirements is mandatory for the participating centers. In general, PCI is performed by specially trained and experienced interventional cardiologists. After PCI, the patient is deferred to the ICU. Thus, such units are obligatory for participation in the study. The required staff is present at all participating centers. Although it is not mandatory, a study nurse may be helpful for the assessment of study endpoints and data handling. The co-investigators should hold appropriate qualification, skills and experience in realizing a clinical trial. 82 Prior to participation these qualification and skills of all collaborating personnel will be revised. In the particular hospitals, as well as during investigator meetings, informative functions and special trainings will be organized to guarantee correct execution of the study. In addition to the presence of a catheterization laboratory and an ICU, the participating centers have to have access to a laboratory for the processing of blood products. As randomization generally ought to be performed internet-based, a computer with internetaccess must be available. 26 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

29 CULPRIT-SHOCK Study Protocol Version 1.1, Ethical and regulatory specifications 4.1 GCP guidelines Staff involved in any aspect is committed to perform this clinical study according to national laws, to the requirements of the ICH Guideline for Good Clinical Practice (GCP) E6 published June 1996 and the CPMP/ICH/135/95 published September 1997 and in adherence to the Declaration of Helsinki (version 2008). 4.2 Application Qualification of investigators and participating centers The coordinating investigators and national coordinating investigators have specifically classified all participating centers to be appropriate investigating centers and have distinctly discussed the possibility to participate in this study with the eligible centers. On demand of local ethics committees based on 7 (2) and 8 (5) of the GCP-regulation it is possible that further information on the eligibility of the participating centers, as well as on the corresponding funds and facilities or on the disposable staff and their experience in performing clinical trials is required. For this purpose and subsequent evaluation all required documents will be provided if requested by the involved ethics committees Investigators 1. Résumé including name, office address, current employment and occupation, professional development, specialties, additional qualifications, previous performed studies (number, phase of the trials, field of indication), date and signature. 2. Selected information on prior publications or certificates of further training related to clinical studies, if possible. 3. Confirmation on the knowledge of ICH-GCP-guidelines and the GCP-requirements (including awareness of the study protocol, definitions of AE and SAE, notifiable events, record retention, requirements for monitoring, audits and inspections); if possible results of previous performed monitoring, audits and inspections. 4. Financial disclosure form and statement on possible conflicts of interest related to the current study (including date and signature) Participating centers Designation on the available staff: number, function and qualification (education, experience in performing clinical trials), delineation on the delegated duties relevant for the current study 1. Eligibility and proof of qualification of the participating center Evaluation of the feasibility through the sponsor ( pre-study -visits) Key aspects of treatment and special focuses 2. Infrastructure: depiction of the institution including the funds and equipment relevant for the study; resource, experience and qualification in emergency care. 4.3 Ethics committee application Legal restrictions concerning ethical approval may vary in the different participating countries. It is therefore the responsibility of each national coordinating investigator of each specific country that participates in the CULPRIT-SHOCK trial to warrant, that the protocol is reviewed and approved by a local ethical committee if local rules require such review and approval. For Germany the current study is not performed under the Arzneimittelgesetz or Medizinproduktegesetz of the Federal Republic of Germany. Thus there is no official 27 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

30 CULPRIT-SHOCK Study Protocol Version 1.1, competent authority, but instead the participating centers will apply at the particular regional ethics committees. The study protocol will be submitted initially to the ethical committee of the University of Leipzig. In addition, the study protocol will also be sent to the other ethical committees of the sites involved in the trial after ethical approval of the lead ethical committee in Leipzig, Germany. The coordinating investigator of each country will support all applications. Participation in the study can only begin after positive approval of the responsible local ethics committees. The written approval will be filed in the trial master file. Additionally, every participating center will file a copy of the approval/evaluation in the trial investigator file. 4.4 Subsequent changes of the study protocol After ethics committee approval, further changes of the study protocol can only be conducted if these modifications are again evaluated and accepted by the responsible ethics committee. Potential changes may affect: The safety of the patients, e.g. essential modifications of therapeutic regimens. Additional data assessment or analysis requiring modifications of the informed consent form. Interpretation of scientific documents on which the current study is based or which might influence the interpretation of the obtained results. The form of administration and conduction of the study. Only the coordinating investigators may carry out changes of the study protocol. However, all co-investigators can address remarks if modifications seem to be necessary. If changes in the study protocol occur, all investigators will be informed after a positive ethics committee approval and the notice has to be confirmed. 28 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

31 CULPRIT-SHOCK Study Protocol Version 1.1, Documentation 5.1 Electronic case report forms (ecrf) To record all anonymized findings of each visit, the Institut für Herzinfarktforschung will generate an ecrf. For data entry, each study coordinator at each participating center will receive individual login information for the ecrf. The data base will be kept on the server of the Institut für Herzinfarktforschung Ludwigshafen. Data are entered by each participating center directly into the internet based ecrf. Data entered are immediately tested for plausibility in order to prevent unnecessary queries. Data will be entered via an SSL-secured internet line. The ecrf will be self-explaining. To facilitate data entry, the definitions of the various parameters will be accessible by a simple mouse click behind the related question in the ecrf. The corresponding source documents will be archived in the patients record (in- or out-patient). At the time of screening, baseline and at all other visits, relevant information on anamnesis, current medication, vital signs and clinical state will be documented on a separate and specifically prepared sheet. In case of error detection and subsequent correction, the original entry will remain readable and the correction will be signed and dated by the person authorized to amend. All relevant pages of the ecrf will be controlled for integrity and validity and electronically signed by either the local principal investigator or a co-investigator. The electronic signature serves as a verification of the ecrf. According to the ICH-guideline E6, source documents are defined as all data of the patient file, as well as all routinely assessed information including laboratory findings. 5.2 Data management Data management and statistics will be performed at the Institut für Herzinfarktforschung in Ludwigshafen, Germany. All relevant data will be assessed and documented at the local investigating sites and then send directly to the Institut für Herzinfarktforschung for further analysis. For this purpose an established study management tool of the Institut für Herzinfarktforschung will be used. For the preparation of the study database the responsible project manager in cooperation with a biometrician will design a requirement specification. This provides the basis for the database programmer, who creates the database applications. Database applications will be tested for errors and validated before release for general use. The process of validation will be documented. The data documented on the ecrf will be recorded in the electronical research database through an input mask. The data will be automatically checked for integrity, consistency and plausibility using pre-assigned checks. In case of pending unclarities (e-queries) the affected center will be immediately informed through an electronic form. Random samples of the data entered into the database may be subject to an audit. Data will be completely secured on a daily base. Due to a hierarchical, roll-based access concept an unauthorized access on patient data is impossible. Anonymity of the data is preserved. Any change on data, for e.g. due to adjustment of pending queries, will be documented through an automatic audit trail of the database. 5.3 Archiving All relevant study documents included in the trial master file and all electronically assessed data will be stored at the Institut für Herzinfarktforschung for at least 10 years after the end of the study. In the participating centers the trial investigator files, the patient identification list, as well as all consent forms and the patient files will be retained for at least 10 years after the end of the study. Other in-house regulations or legislations demanding longer retention periods (e.g. radiation control regulation, radiation protection law) should be respected. 29 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

32 CULPRIT-SHOCK Study Protocol Version 1.1, Study survey Source data access Due to statutory provisions to ensure protection of data quality and verification of study execution, investigators are obligated to provide insight on source data to authorized third parties. This includes monitors, auditors and staff members of the responsible surveillance authorities, all bound to professional secrecy Monitoring For surveillance of the investigating centers on-site monitoring is planned for 10% of the active sites. These will be randomly selected for validation of the data entered in the ecrf against patients source data. Because of the expected high number of patients at each site, monitoring will be possible in a sample of all of the site s patients only. Sites and patients to be monitored will be randomly selected by the Institut für Herzinfarktforschung. Monitors will have to ensure that in every individual case informed consent is available before they request access to the patient s files. Additional monitoring can be carried out if indicated after evaluation of the steering committee in case of insufficient data quality or delayed ecrf input. In context of these specific monitoring visits all data relevant for the study will be controlled and eventually updated. To ensure the capability for inspections the investigators will provide access to the study-related facilities and to all files of every study participant to guarantee a complete source data verification. The exact planning and execution of the monitoring is based on the eligible SOPs of the Institut für Herzinfarktforschung and will be delineated in a monitoring manual Audits As part of this study no regular audits are planned. However, to ensure correct execution of the study, audits may be conducted if necessary Inspections As the current study is not linked to the German pharmaceutical or medicinal product act (AMG 82, 83 or MPG), no inspections of higher federal authorities are scheduled Independent surveillance of the study To ensure the safety interests of the participants, an independent DMSB will regularly evaluate the safety and efficacy of the study treatment, as well as the integrity and validity of the collected data. Additionally, the DMSB should make recommendations concerning further execution of the study (e.g. termination or modification) based on the recorded data and the planned interim analysis Data protection and confidentiality The recorded information include personal data (e.g. date of birth and gender) as well as data on medical treatment and the course of treatment (medical findings, treatment strategies, administered medication, etc.) of the study participants. These data will be electronically stored and analyzed in pseudonymized form (i.e. unrelated to the name of the patient) using an electronic identification number. Data processing will be carried out at the Institut für Herzinfarktforschung. Based on a security model, protection against unauthorized access and protection against data loss in accordance with data protection acts will be guaranteed. Data will be stored electronically and evaluated in anonymized form and any inferences in respect of the actual persons will not be possible. All data are protected from external unauthorized access as only members of the research team are permitted and enabled to access these data. In case of withdrawal of a prior given consent it will be assessed to what extent the data are still required. If data are no longer necessitated they will be erased immediately. The recorded personal data will be erased/anomyzed after completion of all study related projects, at the latest after 10 years in case no legal, statutory or contractual regulations oppose. 30 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

33 CULPRIT-SHOCK Study Protocol Version 1.1, Administrative regulations 6.1 Study execution in accordance with the protocol The trial is planned, executed and analyzed according to ICH-GCP requirements. Protocol violations are all deviations from the directives and procedures described in this protocol. Only violation of in- and exclusion criteria are defined as major protocol violations. After inclusion of a patient, the investigator has the responsibility to avoid protocol violations, to ensure patients further participation in the study. Major protocol violations must be reported immediately to the principal investigator and the sponsor. All protocol violations will be documented and discussed with the responsible biometrician prior to analysis. The investigator has to ensure that all recorded data are documented according to the study protocol. Minor deviations can certainly not be eliminated completely; nevertheless this has to be documented including an explanatory statement. 6.2 Publishing agreement and registration After the database has been closed, the Institut für Herzinfarktforschung Ludwigshafen will hand a final report of the study to the steering committee. The steering committee owns the data that has been collected with the CULPRIT-SHOCK trial and decides on the further use of the data. It is aimed to publish the results of this clinical trial in a renowned international medical journal. In this context the study will be registered at ClinicalTrials.gov ( Authorship will be selected according to the requirements of the New England Journal of Medicine ( These indicate that every author provided such contribution to the clinical trial and the subsequent publication that he can take public responsibility for the integrity of the entire work. Therefore the credit for authorship requires substantial contributions to: 1. The conception and design or analysis and interpretation of the data. 2. The drafting of the article or critical revision for important intellectual content. 3. Final approval of the version to be published. Authors must have fundamentally taken part in all of the 3 aspects. In the Acknowledgement- Section of the publication, the names of all responsible investigators of the regional participating centers will be listed. The local centers are entitled to use the recorded data for additional scientific exploitation. Following the consultation of the steering committee the local centers may work on other scientific questions and may publish the results under their own name. For the main publication each of the 10 main centers will obtain at least 1 authorship, if the above mentioned requirements 1-3 are met. Prior to sub-publication consultation and agreement of the coordinating investigator and the steering committee are mandatory. For publications of any kind the study acronym CULPRIT-SHOCK will be used. 31 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

34 CULPRIT-SHOCK Study Protocol Version 1.1, Definitions Death Death of all cause. Death cardiovascular Death due to cardiovascular causes, such as heart failure, cardiac arrhythmias, myocardial infarction, sudden cardiac death or all deaths of unknown cause. Severe renal failure requiring renal replacement therapy Any indication for renal replacement therapy such as dialysis, hemofiltration or hemodiafiltration such as renal failure with one of the following criteria: - Otherwise untreatable volume overload - hyperpotassemia (>6.0 mmol/l) - severe uremia (>50 mg/dl or >8.4 mmol/l) - persistent severe metabolic acidosis (ph <7.2) Myocardial reinfarction The definition of myocardial reinfarction in the CULPRIT-SHOCK trial is based on the universal definition of myocardial infarction. 84 Thus, myocardial reinfarction is defined according to the specific situation (see Table 4). Re-MI <24 h Symptoms, such as angina pectoris for 20 minutes, most likely due to myocardial ischemia and or new ST-elevation 1 mm in 2 contiguous leads or new left bundle branch block or angiographic evidence of reocclusion of a previously open coronary artery or graft Re-MI 24 h 7 days Symptoms, such as angina pectoris for 20 minutes, most likely due to myocardial ischemia and or if cardiac markers are still elevated, new increase >20% from the last non-normalized measurement or if cardiac markers are normalized, application of the universal definition for myocardial infarction (see next column) Re-MI >7 days Universal definition for myocardial infarction 1. Rise and/or fall of cardiac biomarkers above the 99 th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following: Symptoms of ischemia ECG changes indicative of new ischemia Development of pathological Q waves in ECG Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 2. Sudden, unexpected cardiac death with ST-elevation and presumably new LBBB or evidence of fresh thrombus by coronary angiography, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood. 3. Peri-PCI myocardial infarction: increases of biomarkers > 3 of the upper reference level 4. Peri-CABG myocardial infarction: increases of biomarkers > 5 of the upper reference level plus new pathological Q waves or new LBBB or angiographically documented new graft or native coronary artery occlusion 5. Pathological findings of acute myocardial infarction 32 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

35 CULPRIT-SHOCK Study Protocol Version 1.1, Repeat revascularization Any revascularization procedure (PCI or CABG) after the initial intervention. Chronic total occlusion (CTO) Complete obstruction of a coronary artery, described as 99% stenosis of >3 months duration with poor or no antegrade blood flow (TIMI 0-1). Stent thrombosis Stent thrombosis is classified in definite, probable and possible stent thrombosis according to the Academic Research Consortium (ARC) definition: 85 Definite Probable Possible Acute coronary syndrome and angiographic OR pathological confirmation of stent thrombosis Unexplained death within the first 30 days OR acute ischemia in the territory of an implanted stent without angiographic confirmation of stent thrombosis in the absence of another culprit lesion Unexplained death >30 days Bleeding complications Bleeding complications will be classified according to 3 different definitions (for further evaluation which one best predicts outcome in cardiogenic shock patients). BARC bleeding definition: 79 Type Bleeding definition Type 0 Type 1 Type 2 Type 3 Type 3a Type 3b Type 3c Type 4 no bleeding bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional (2) leading to hospitalization or increased level of care, or (3) prompting evaluation Overt bleeding plus hemoglobin drop of 3 to <5 g/dl* (provided hemoglobin drop is related to bleed) Any transfusion with overt bleeding Overt bleeding plus hemoglobin drop 5 g/dl* (provided hemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) Bleeding requiring intravenous vasoactive agents Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal) Subcategories confirmed by autopsy or imaging or lumbar puncture Intraocular bleed compromising vision CABG-related bleeding Perioperative intracranial bleeding within 48 h Reoperation after closure of sternotomy for the purpose of controlling bleeding 33 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

36 CULPRIT-SHOCK Study Protocol Version 1.1, Type 5 Type 5a Type 5b Transfusion of 5 U whole blood or packed red blood cells within a 48-h period Chest tube output 2L within a 24-h period Fatal bleeding Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation GUSTO-definition: 86 Severe/life-threatening bleeding complications Intracranial hemorrhage or bleeding that causes hemodynamic compromise requiring intervention Moderate bleeding Bleeding that requires blood transfusion but does not result in hemodynamic compromise Mild bleeding Bleeding that does not meet criteria for either severe or moderate bleeding. TIMI definition: 87 Classification Description TIMI major Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of 5 g/dl Fatal bleeding (bleeding that directly results in death within 7 d) TIMI minor Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dl Stroke Stroke will be classified in hemorrhagic (cranial CT, MRI, or autopsy) or non-hemorrhagic Stroke is defined as an acute new neurological deficit ending in death or lasting longer than 24 hours, and classified by a physician as a stroke. 1. Primary hemorrhagic - defined as an intracerebral hemorrhage or subdural hematoma a. Intracerebral hemorrhage - Stroke with focal collections of intracerebral blood seen on brain imaging (CT or MRI) or a post-mortem examination, not felt to represent hemorrhagic conversion. Subarachnoid hemorrhage should be included in this category. b. Subdural hematoma - High density fluid collection in subdural space on brain images or blood in the subdural space on autopsy. 2. Non-hemorrhagic cerebral infarction - Stroke without focal collections of intracerebral blood on brain imaging. 3. Non-hemorrhagic infarction with hemorrhagic conversion - Cerebral infarction with blood felt to represent hemorrhagic conversion and not a primary hemorrhage. 4. Uncertain - Any stroke without brain imaging (CT or MRI) or autopsy documentation of type, or if tests are inconclusive. New congestive heart failure Occurrence of congestive heart failure after hospital discharge: Defined as; Re-hospitalization due to new or worsening heart failure >24 h after hospital discharge. 34 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

37 CULPRIT-SHOCK Study Protocol Version 1.1, Infarct artery/culprit vessel Artery responsible for acute myocardial infarction. In general its identification is based on 1) ECG 2) Wall motion abnormalities 3) Angiographic morphology of the lesion (e.g. ulceration and/or thrombus consistent with plaque rupture). Patency of culprit vessel and additional major vessels before and after PCI (TIMI-Flow) The TIMI-flow is visually assessed according to the following grading system: 88 Grade Perfusion Characterization 0 No Perfusion No antegrade flow beyond the point of occlusion 1 Penetration without perfusion Contrast material passes beyond the area of obstruction but fails to opacify the entire coronary distal bed 2 Partial reperfusion Contrast material passes across the obstruction with delayed entry and clearance from the distal bed 3 Complete reperfusion Normal flow Hemodynamic stability criterion Sustained (> 60 min) systolic blood pressure >90 mmhg WITHOUT requirement for catecholamines AND WITHOUT signs of peripheral endorgan hypoperfusion Sepsis Sepsis is defined according to the ACCP/SCCM Consensus-conference plus additional 89, 90 elevated pro-calcitonin ( 2 pg/ml). I) Signs of infection Diagnosis of infection via microbiological evaluation or by clinical criteria II) Systemic Inflammatory Response Syndrome (SIRS) ( 2 criteria required) Body temperature >38 C or <36 C Tachycardia: Heart rate >90/min Tachypnoe: ventilation rate >20/min or hyperventilation (PaCO 2 <4,3 kpa or 33 mmhg) White blood cell count (>12.000/mm 3 ) or (<4.000/mm 3 ) or >10 % premature neutrophil granulocytes SAPS II-Score The severity of cardiogenic shock and concomitant organ dysfunction will be assessed by the SAPS II-Score. 91 This score is evaluated on a routine basis in all hospitals in Germany. The calculation of the SAPS II-Score can be done using the following link: The individual parameters of the SAPS-II-score can be found in Figure Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

38 CULPRIT-SHOCK Study Protocol Version 1.1, Figure 5: Parameters of the SAPS-II Score 91 Quality of life Quality of life will be assessed using the Euroqol 5D-questionnaire ( Euroqol 5D: Quality of life Mobility Self-Care Usual Activities (e.g. work, study, housework, family or leisure activities) Pain/Discomfort Anxiety/Depression In comparison to the general health state (GHS) in the past 12 months, today s GHS of the patient is How does the patient scales his GHS today? Best imaginable GHS: 100% Worst imaginable GHS: 0% Pat. has no problems in walking about Pat. has some problems in walking about Pat. is confined to bed Pat. has no problems with self-care Pat. has some problems washing or dressing himself Pat. is unable to wash or dress himself Pat. has no problems with performing his usual activities Pat. has some problems with performing his usual activities Pat. is unable to perform his usual activities Pat. has no pain or discomfort Pat. has moderate pain or discomfort Pat. has extreme pain or discomfort Pat. is not anxious or depressed Pat. is moderately anxious or depressed Pat. is extremely anxious or depressed better overall similar worse % 36 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

39 CULPRIT-SHOCK Study Protocol Version 1.1, References 1. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med 1999;341: The TRIUMPH Investigators. Effect of Tilarginine Acetate in patients with acute myocardial infarction and cardiogenic shock. The TRIUMPH Randomized Controlled Trial. JAMA 2007;297: Thiele H, Lauer B, Hambrecht R, Boudriot E, Cohen HA, Schuler G. Reversal of cardiogenic shock by percutaneous left-atrial-to-femoral arterial bypass assistance. Circulation 2001;104: Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intraaortic balloon support versus a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005;26: Thiele H, Schuler G, Neumann FJ, et al. Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: Design and rationale of the intraaortic balloon pump in cardiogenic shock II trial (IABP-SHOCK II). Am Heart J 2012;in press. 6. Barron HV, Every NR, Parsons LS, et al. The use of intra-aortic balloon counterpulsation in patients with cardiogenic shock complicating acute myocardial infarction: data from the National Registry of Myocardial Infarction 2. Am Heart J 2001;141: Goldberg RJ, Samad NA, Yarzebski J, Gurwitz J, Bigelow C, Gore JM. Temporal trends in cardiogenic shock complicating acute myocardial infarction. N Engl J Med 1999;340: Hochman JS, Buller CE, Sleeper LA, et al. Cardiogenic shock complicating acute myocardial infarction--etiologies, management and outcome: a report from the SHOCK Trial Registry. J Am Coll Cardiol 2000;36: Thiele H, Allam B, Chatellier G, Schuler G, Lafont A. Shock in acute myocardial infarction: the Cape Horn for trials? Eur Heart J 2010;31: Zeymer U, Vogt A, Zahn R, et al. Predictors of in-hospital mortality in 1333 patients with acute myocardial infarction complicated by cardiogenic shock treated with primary percutaneous coronary intervention (PCI). Eur Heart J 2004;25: Sanborn TA, Sleeper LA, Webb JG, et al. Correlates of one-year survival in patients with cardiogenic shock complicating acute myocardial infarction: angiographic findings from the SHOCK trial. J Am Coll Cardiol 2003;42: Webb JG, Sanborn TA, Sleeper LA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK Trial Registry. Am Heart J 2001;141: Wong SC, Sanborn T, Sleeper LA, et al. Angiographic findings and clinical correlates in patients with cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. J Am Coll Cardiol 2000;36: Goldberg RJ, Gore JM, Alpert JS, et al. Cardiogenic shock after acute myocardial infarction. Incidence and mortality from a community-wide perspective, 1975 to 1988 [see comments]. N Engl J Med 1991;325: Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Gruppo Italiano per lo Studio della Streptochi-nasi nell'infarto Miocardico (GISSI). Lancet 1987;2: In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. The International Study Group [see comments]. Lancet 1990;336: Bengtson JR, Kaplan AJ, Pieper KS, et al. Prognosis in cardiogenic shock after acute myocardial infarction in the interventional era. J Am Coll Cardiol 1992;20: Disler L, Haitas B, Benjamin J, Steingo L, McKibbin J. Cardiogenic shock in evolving myocardial infarction: treatment by angioplasty and streptokinase. Heart Lung 1987;16: Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

40 CULPRIT-SHOCK Study Protocol Version 1.1, Eltchaninoff H, Simpfendorfer C, Franco I, Raymond RE, Casale PN, Whitlow PL. Early and 1-year survival rates in acute myocardial infarction complicated by cardiogenic shock: a retrospective study comparing coronary angioplasty with medical treatment. Am Heart J 1995;130: Ellis SG, O'Neill WW, Bates ER, et al. Implications for patient triage from survival and left ventricular functional recovery analyses in 500 patients treated with coronary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1989;13: Gacioch GM, Ellis SG, Lee L, et al. Cardiogenic shock complicating acute myocardial infarction: the use of coronary angioplasty and the integration of the new support devices into patient management [see comments]. J Am Coll Cardiol 1992;19: Hibbard MD, Holmes DR, Jr., Bailey KR, Reeder GS, Bresnahan JF, Gersh BJ. Percutaneous transluminal coronary angioplasty in patients with cardiogenic shock [see comments]. J Am Coll Cardiol 1992;19: Lee L, Bates ER, Pitt B, Walton JA, Laufer N, O'Neill WW. Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by cardiogenic shock. Circulation 1988;78: Lee L, Erbel R, Brown TM, Laufer N, Meyer J, O'Neill WW. Multicenter registry of angioplasty therapy of cardiogenic shock: initial and long-term survival. J Am Coll Cardiol 1991;17: Meyer P, Blanc P, Baudouy M, Morand P. [Treatment of primary cardiogenic shock by coronary transluminal angioplasty during the acute phase of myocardial infarction]. Arch Mal Coeur Vaiss 1990;83: Moosvi AR, Khaja F, Villanueva L, Gheorghiade M, Douthat L, Goldstein S. Early revascularization improves survival in cardiogenic shock complicating acute myocardial infarction [see comments]. J Am Coll Cardiol 1992;19: O'Keefe JH, Jr., Bailey WL, Rutherford BD, Hartzler GO. Primary angioplasty for acute myocardial infarction in 1,000 consecutive patients. Results in an unselected population and high-risk subgroups. Am J Cardiol 1993;72:107G-15G. 28. Seydoux C, Goy JJ, Beuret P, et al. Effectiveness of percutaneous transluminal coronary angioplasty in cardiogenic shock during acute myocardial infarction. Am J Cardiol 1992;69: Verna E, Repetto S, Boscarini M, Ghezzi I, Binaghi G. Emergency coronary angioplasty in patients with severe left ventricular dysfunction or cardiogenic shock after acute myocardial infarction. Eur Heart J 1989;10: Hochman JS, Sleeper LA, White HD, et al. One-year survival following early revascularization for cardiogenic shock. JAMA 2001;285: Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction. JAMA 2006;295: Urban P, Stauffer JC, Bleed D, et al. A randomized evaluation of early revascularization to treat shock complicating acute myocardial infarction. The (Swiss) Multicenter Trial of Angioplasty for Shock-(S)MASH. Eur Heart J 1999;20: Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction - executive summary. Circulation 2004;110: Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008;29: Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010;31: Hamm CW, Bassand J-P, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2011;32: Kushner FG, Hand M, Smith SC, Jr., et al Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 38 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

41 CULPRIT-SHOCK Study Protocol Version 1.1, Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009;120: Babaev A, Frederick PD, Pasta DJ, Every N, Sichrovsky T, Hochman JS. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005;294: Goldberg RJ, Spencer FA, Gore JM, Lessard D, Yarzebski J. Thirty-year trends (1975 to 2005) in the magnitude of, management of, and hospital death rates associated with cardiogenic shock in patients with acute myocardial infarction: a population-based perspective. Circulation 2009;119: Jeger RV, Radovanovic D, Hunziker PR, et al. Ten-year incidence and treatment of cardiogenic shock. Ann Intern Med 2008;149: Hochman JS, Sleeper LA, Godfrey E, et al. SHould we emergently revascularize Occluded Coronaries for cardiogenic shock: an international randomized trial of emergency PTCA/CABG-trial design. The SHOCK Trial Study Group. Am Heart J 1999;137: Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;epub ahead of print:doi: /eurheartj/ehs Werdan K, Ruß M, Buerke M, et al. [German-Austrian S3-guideline: Diagnosis, monitoring, and therapy of cardiogenic shock due to myocardial infarction]. Intensivmed 2011;48: Werdan K, Ruß M, Buerke M, Delle-Karth G, Geppert A, Schöndube FA. Cardiogenic shock due to myocardial infarction: diagnosis, monitoring and treatment - A German- Austrian S3 Guideline. Dtsch Arztebl Int 2012;109: Bauer T, Zeymer U, Hochadel M, et al. Use and outcomes of multivessel percutaneous coronary intervention in patients with acute myocardial infarction complicated by cardiogenic shock (from the EHS-PCI Registry). Am J Cardiol 2012;109: White HD, Assmann SF, Sanborn TA, et al. Comparison of percutaneous coronary intervention and coronary artery bypass grafting after acute myocardial infarction complicated by cardiogenic shock: Results from the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) Trial. Circulation 2005;112: Webb JG, Lowe AM, Sanborn TA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol 2003;42: van der Schaaf RJ, Claessen BE, Vis MM, et al. Effect of multivessel coronary disease with or without concurrent chronic total occlusion on one-year mortality in patients treated with primary percutaneous coronary intervention for cardiogenic shock. Am J Cardiol 2010;105: Cavender MA, Milford-Beland S, Roe MT, Peterson ED, Weintraub WS, Rao SV. Prevalence, predictors, and in-hospital outcomes of non-infarct artery intervention during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (from the National Cardiovascular Data Registry). Am J Cardiol 2009;104: Zeymer U, Hochadel M, Mudra H, Brachmann J, Hoffmann S, Zahn R. Impact of immediate multivessel intervention on outcome of patients with multivessel disease undergoing primary PCI for cardiogenic shock. Clin Res Cardiol 2012;101 (Suppl): Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360: Mehta RH, Lopes RD, Ballotta A, et al. Percutaneous coronary intervention or coronary artery bypass surgery for cardiogenic shock and multivessel coronary artery disease? Am Heart J 2010;159: Toma M, Buller CE, Westerhout CM, et al. Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial. Eur Heart J 2010;31: Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

42 CULPRIT-SHOCK Study Protocol Version 1.1, Cardarelli F, Bellasi A, Ou FS, et al. Combined impact of age and estimated glomerular filtration rate on in-hospital mortality after percutaneous coronary intervention for acute myocardial infarction (from the American College of Cardiology National Cardiovascular Data Registry). Am J Cardiol 2009;103: Lee JH, Park HS, Chae SC, et al. Predictors of six-month major adverse cardiac events in 30-day survivors after acute myocardial infarction (from the Korea Acute Myocardial Infarction Registry). Am J Cardiol 2009;104: Kornowski R, Mehran R, Dangas G, et al. Prognostic impact of staged versus "one-time" multivessel percutaneous intervention in acute myocardial infarction: Analysis from the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial. J Am Coll Cardiol 2011;58: Hannan EL, Samadashvili Z, Walford G, et al. Culprit vessel percutaneous coronary intervention versus multivessel and staged percutaneous coronary intervention for STsegment elevation myocardial infarction patients with multivessel disease. JACC Cardiovasc Interv 2010;3: Bauer T, Zeymer U, Hochadel M, et al. Prima-vista multi-vessel percutaneous coronary intervention in haemodynamically stable patients with acute coronary syndromes: Analysis of over patients in the EHS-PCI registry. Int J Cardiol Khattab AA, Abdel-Wahab M, Rother C, et al. Multi-vessel stenting during primary percutaneous coronary intervention for acute myocardial infarction. A single-center experience. Clin Res Cardiol 2008;97: Di Mario C, Sansa M, Airoldi F, et al. Single vs multivessel treatment during primary angioplasty: results of the multicentre randomised HEpacoat for culprit or multivessel stenting for Acute Myocardial Infarction HELP AMI Study. Int J Cardiovasc Intervent 2004;6: Politi L, Sgura F, Rossi R, et al. A randomised trial of target-vessel versus multi-vessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up. Heart 2010;96: Vlaar PJ, Mahmoud KD, Holmes Jr DR, et al. Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: A pairwise and network meta-analysis. J Am Coll Cardiol 2011;58: Bangalore S, Kumar S, Poddar KL, Ramasamy S, Rha S-W, Faxon DP. Meta-analysis of multivessel coronary artery revascularization versus culprit-only revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease. Am J Cardiol 2011;107: Navarese E, De Servi S, Buffon A, Suryapranata H, De Luca G. Clinical impact of simultaneous complete revascularization vs. culprit only primary angioplasty in patients with ST-elevation myocardial infarction and multivessel disease: a meta-analysis. J Thromb Thrombolysis 2011;31: Santa-Cruz RA, Cohen MG, Ohman EM. Aortic counterpulsation: a review of the hemodynamic effects and indications for use. Cath Cardiovasc Inter 2006;67: Sjauw KD, Engstrom AE, Vis MM, et al. A systematic review and meta-analysis of intra aortic balloon pump therapy in ST-elevation myocardial infarction: should we change the guidelines? Eur Heart J 2009;30: Thiele H, Schuler G, Neumann F-J, et al. Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: Design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. Am Heart J 2012;163: Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;epub ahead of print. 69. Lowel H, Meisinger C, Heier M, Hörmann A, von Scheidt W. [Myocardial infarction and coronary mortality in Southern Germany]. Deutsches Ärzteblatt 2006;103: Thom T, Haase N, Rosamund W, et al. Heart disease and stroke statistics-2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcomittee. Circulation 2006;113:e85-e Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

43 CULPRIT-SHOCK Study Protocol Version 1.1, Thiele H, Schuler G. Cardiogenic shock: To pump or not to pump? Eur Heart J 2009;30: Ambrose JA, Weinrauch M. Thrombosis in ischemic heart disease. Arch Intern Med 1996;156: Thiele H, Hildebrand L, Schirdewahn C, et al. Impact of high-dose N-acetylcysteine versus placebo on contrast-induced nephropathy and myocardial reperfusion injury in unselected patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol 2009;in press. 74. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354: Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44: Allen LA, Hernandez AF, O'Connor CM, Felker GM. End points for clinical trials in acute heart failure syndromes. J Am Coll Cardiol 2009;53: Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012;367: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation 2011;123: Prondzinsky R, Lemm H, Swyter M, et al. Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock - the prospective, randomized IABP SHOCK Trial for attenuation of multi-organ dysfunction syndrome. Crit Care Med 2010;38: O Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35: Gesetz über Verkehr mit Arzneimitteln (Arzneimittelgesetz AMG) in der Fassung der Bekanntmachung vom 05. August BGBI I 2004: Verordnung über die Anwendung der Guten Klinischen Praxis bei der Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen (GCP-Verordnung - GCP-V) in der Fassung der Bekanntmachung vom 12.August BGBI I 2004: Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Circulation 2007;116: Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. Circulation 2007;115: The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991;115: The TIMI Research Group. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI II A results. JAMA 1988;260: ACCP/SCCM Consensus Conference Committee. Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20: S-2 Leitlinien der Deutschen Sepsis-Gesellschaft e.v. (DSG) und der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI). Diagnose und Therapie der Sepsis. Clin Res Cardiol 2006;95: Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993;270: Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

44 CULPRIT-SHOCK Study Protocol Version 1.1, Signature Page Prof. Dr. med. Holger Thiele Klinik für Innere Medizin/Kardiologie, Universität Leipzig, Herzzentrum, Germany Leipzig, Place, Date Prof. Dr. med. Uwe Zeymer Institut für Herzinfarktforschung, Ludwigshafen, Germany Ludwigshafen, Place, Date 42 Stiftung Institut für Herzinfarktforschung and University of Leipzig Heart Center

45 Prospective randomized multicenter study comparing immediate multivessel revascularization by PCI versus culprit lesion PCI with staged non-culprit lesion revascularization in patients with acute myocardial infarction complicated by cardiogenic shock CULPRIT-SHOCK Study protocol Version 1.2.;

46 CULPRIT-SHOCK Study Protocol Version 1.2, STUDY SYNOPSIS COORDINATING INVESTIGATOR CO-INVESTIGATORS NATIONAL COORDINATING INVESTIGATORS STEERING COMMITTEE SPONSOR STUDY TITLE TYPE OF STUDY Prof. Dr. med. Holger Thiele Medizinische Klinik II (Kardiologie, Angiologie, Intensivmedizin) Universitätsklinikum Schleswig-Holstein (UKSH) - Campus Lübeck Universität Lübeck Ratzeburger Allee 160 D Lübeck, Germany Tel: ; Fax: holger.thiele@uksh.de Prof. Dr. med. Uwe Zeymer Stiftung Institut für Herzinfarktforschung at the University of Heidelberg Bremserstraße 79 - Haus R Ludwigshafen am Rhein, Germany Tel: ; Fax: zeymeru@klilu.de or uwe.zeymer@t-online.de PD Dr. med. S. Desch Department of Internal Medicine/Cardiology, University of Leipzig Heart Center stdesch@web.de Prof. Dr. med. K. Werdan Director Department of Internal Medicine III - University Hospital, Martin-Luther- University Halle-Wittenberg karl.werdan@medizin.uni-halle.de Prof. Dr. med. Holger Thiele Director Medical Clinic II, University of Lübeck, Lübeck, Germany holger.thiele@uksh.de Prof. Dr. med. Kurt Huber Director Department of Internal Medicine/Cardiology, Wilhelminenspital of the city Vienna, Vienna, Austria kurt.huber@wienkav.at Prof. Dr. med. Stephan Windecker Deputy Director Department of Internal Medicine/Cardiology, University of Bern, Switzerland Stephan.Windecker@insel.ch Prof. Dr. med. Stefan James Director Department of Medical Sciences and Uppsala Clinical Research Center Uppsala University, Uppsala, Sweden stefan.james@akademiska.se Prof. Dr. med. Pranas Serpytis Vilnius University Hospital, Santariskiu klinikos, Vilnius, Lithuania pranas.serpytis@santa.lt Prof. Dr. med. Gilles Montalescot Centre Hospitalier Universitaire Pitié-Salpetrière, Institut de Cardiologie, Paris, France Gilles.montalescot@psl.aphp.fr Prof. Dr. med. Marco Noc University Medical Center Ljubljana, Division of Internal Medicine, Ljubljana, Slovenia marko.noc@mf.uni-lj.si Prof. Dr. med. Jan J. Piek Academic Medical Center, Amsterdam, The Netherlands j.j.piek@amc.uva.nl Prof. Dr. med. Janina Stępińska Institute of Cardiology, Warsaw, Poland janina@stepinska.pl.pl Dr. med. Stefano Savonitto Department of Cardiology, Servizio Sanitario Regionale, Emilia Romagna, Italy stefano.savonitto@asmn.re.it Prof. Dr. med. Keith G. Oldroyd Department of Cardiology, Western Infirmary, Glasgow, United Kingdom keith.oldroyd@nhs.net Consists of the coordinating investigator, co-investigators, and all national coordinating investigators University of Lübeck Ratzeburger Allee 160 D Lübeck, Germany CULPRIT-SHOCK Prospective, controlled, international, multicenter, randomized, open-label Stiftung Institut für Herzinfarktforschung and University of Lübeck 2

47 CULPRIT-SHOCK Study Protocol Version 1.2, CONDITION Acute myocardial infarction Cardiogenic shock DATA SAFETY MONITORING Prof. Dr. med. Ferenc Follath BOARD University Hospital Zürich, Switzerland Prof. Dr. med. Peter Clemmensen Rigshospitalet, The Heart Center, Copenhagen, Denmark Prof. Dr. Karl Wegscheider University Hospital Hamburg-Eppendorf, Hamburg, Germany STATISTICAL ANALYSIS Dr. Steffen Schneider Stiftung Institut für Herzinfarktforschung at the University of Heidelberg Bremserstraße Ludwigshafen am Rhein, Germany Tel: ; Fax: DATA MANAGEMENT AND Monitoring: MONITORING Karin Vonderschmitt Stiftung Institut für Herzinfarktforschung Bremserstraße Ludwigshafen am Rhein, Germany Tel: ; Fax: Sonja Frey Stiftung Institut für Herzinfarktforschung Bremserstraße Ludwigshafen am Rhein, Germany Tel: ; Fax: electronic CRF: Alexander Neumer Stiftung Institut für Herzinfarktforschung Bremserstraße 79 - Haus R Ludwigshafen a. Rhein, Germany Tel: ; Fax: neumer@herzinfarktforschung.de OBJECTIVE To examine whether culprit lesion only percutaneous coronary intervention (PCI) with subsequent staged revascularization is beneficial over immediate multivessel revascularization by PCI for patients with cardiogenic shock complicating acute myocardial infarction with respect to 30-day mortality and/or severe renal failure requiring renal replacement therapy. INTERVENTIONS Experimental intervention: Culprit lesion only PCI with staged non-culprit revascularization Control intervention: Immediate multivessel PCI Follow-up per patient: 30-days primary endpoint plus 6 months and 12 months long-term follow-up Duration of intervention per patient: <1 day Experimental and / or control off label or on label: no off-label use KEY INCLUSION AND Key inclusion criteria: cardiogenic shock complicating myocardial infarction EXCLUSION CRITERIA presenting with multivessel disease (>70% stenoses in 2- or 3 major vessels of 2 mm diameter and identifiable culprit lesion) with indication for PCI Key exclusion criteria: Need for primary urgent bypass surgery (to be determined after diagnostic angiography) Mechanical complication complicating myocardial infarction Severe neurological deficit Shock onset >12 h Age >90 years Comorbidity with life expectancy <6 months Pregnancy Known severe renal insufficiency (creatinine clearance <30 ml/min) ENDPOINTS Primary efficacy endpoint: 30-day mortality and/or severe renal failure requiring renal replacement therapy Secondary endpoints: 30-day mortality Requirement of renal replacement therapy Procedural success Time to hemodynamic stabilization Duration of catecholamine therapy 3 Stiftung Institut für Herzinfarktforschung and University of Lübeck

48 CULPRIT-SHOCK Study Protocol Version 1.2, Serial creatinine-level creatinine-clearance (Cockcroft-Gault-Formula) until stabilization Length of ICU-stay Serial SAPS-II score until stabilization Requirement and length of mechanical ventilation All-cause death within 6 and 12 months follow-up Recurrent infarction within 30-days, 6 and 12 months follow-up Death or recurrent infarction at 6 and 12 months follow-up Rehospitalization for congestive heart failure within 30-days, 6 and 12 months follow-up Death/recurrent infarction/rehospitalization for congestive heart failure within 30- days, 6 and 12 months Need for repeat revascularization (PCI and/or CABG) within 30-days, 6 and 12 months follow-up Peak creatine kinase, creatine kinase-mb and troponin level during hospital stay Quality of life at 6 and 12 months assessed using Euroqol 5D (EQ-5D) questionnaire ( Safety: Severe and moderate bleeding complications (BARC definition type 2-3 and 5) Stroke STATISTICAL ANALYSIS Efficacy / test accuracy: Assessed by mortality and/or severe renal failure within 30 days after randomization. Evaluation of secondary endpoints serves to obtain explanatory and predictive information. Description of the primary efficacy / test accuracy analysis and population: Chi- Square test to compare the rates of patients experiencing primary endpoint within 30 days after randomization in both groups. All randomized subjects to be analyzed on the intent-to-treat basis. Safety: Fisher s test to compare groups with respect to frequencies of occurrence of complications. Mann-Whitney U test to compare groups with respect to severities of complications. Secondary endpoints: Group comparison by Mann-Whitney U test. Logistic regression to assess predictors of primary endpoint. SAMPLE SIZE To be assessed for eligibility (n=1200) To be allocated to trial (n=706) To be analyzed (n=684) TRIAL DURATION First patient in to last patient out (months): 30 Duration of the entire trial (months): 32 (primary study endpoint), 44 (long-term follow-up) Recruitment period (months): 30 PARTICIPATING CENTERS (n): >100 Stiftung Institut für Herzinfarktforschung and University of Lübeck 4

49 CULPRIT-SHOCK Study Protocol Version 1.2, Table of Contents 1 Trial description 7 2 Study chairs Coordinating investigators Co-investigators National coordinating investigators 7 3 Participating centers 8 4 Local investigators 8 5 Clinical and scientific expertise of the study chairs 8 6 Aim of the trial 8 7 Trial type 8 8 Informed consent and ethical considerations 8 9 Data documentation 9 10 Insurance 9 11 Timeline 10 Study protocol 1 Trial description Topic The medical problem Evidence Reperfusion Reperfusion in multivessel coronary artery disease and cardiogenic shock Reperfusion by PCI or CABG Reperfusion in multivessel coronary artery disease without cardiogenic shock IABP Additional supportive therapy The need for a trial 15 2 Study aims Study endpoints Primary study endpoint Secondary study endpoints Safety aspects Data Safety Monitoring Board Steering committee Methods against bias Study procedures Randomization in the catheterization laboratory Revascularization Antithrombotic therapy Mechanical hemodynamic support Documentation of hemodynamic parameters in the catheterization laboratory Post-PCI ICU therapy Hemodynamic monitoring at ICU Laboratory monitoring at ICU day follow-up month follow-up month follow-up Study flow-chart Assessment of study endpoints Inclusion criteria Exclusion criteria Prospective CULPRIT-SHOCK registry 22 Stiftung Institut für Herzinfarktforschung and University of Lübeck 5

50 CULPRIT-SHOCK Study Protocol Version 1.2, Sample size calculation Statistical analysis Treatment compliance/drop-out Regulations for premature study termination Risk-benefit evaluation Feasibility of the study International cooperations Personnel and technical requirements 25 4 Ethical and regulatory specifications GCP guidelines Application Qualification of investigators and participating centers Investigators Participating centers Ethics committee application Subsequent changes of the study protocol 27 5 Documentation Electronic case report forms (ecrf) Data management Archiving Study survey Source data access Monitoring Audits Inspections Independent surveillance of the study Data protection and confidentiality 29 6 Administrative regulations Study execution in accordance with the protocol Publishing agreement and registration 30 7 Definitions 31 8 References 36 9 Signature page 41 Stiftung Institut für Herzinfarktforschung and University of Lübeck 6

51 CULPRIT-SHOCK Study Protocol Version 1.2, Trial description Prospective, randomized, international, multicenter, open-label study to compare immediate multivessel revascularization by percutaneous coronary intervention (PCI) to culprit lesion only PCI with staged non-culprit lesion revascularization in patients with cardiogenic shock complicating acute myocardial infarction presenting with multivessel disease. Acronym: CULPRIT-SHOCK trial 2 Study chairs 2.1 Coordinating investigator Prof. Dr. med. Holger Thiele Medical Clinic II, University of Lübeck, Lübeck, Germany 2.2 Co-investigators Primary: Prof. Dr. med. Uwe Zeymer Institut für Herzinfarktforschung, Ludwigshafen, Germany zeymeru@klilu.de or uwe.zeymer@t-online.de Secondary: PD Dr. med. S. Desch Department of Internal Medicine/Cardiology, University of Leipzig Heart Center stdesch@web.de Prof. Dr. med. K. Werdan Director Department of Internal Medicine III - University Hospital, Martin-Luther-University Halle- Wittenberg karl.werdan@medizin.uni-halle.de 2.3 National coordinating investigators Prof. Dr. med. Holger Thiele Director, Medical Clinic II, University of Lübeck, Lübeck, Germany holger.thiele@uksh.de Prof. Dr. med. Kurt Huber Director Department of Internal Medicine/Cardiology, Wilhelminenspital of the city Vienna, Vienna, Austria kurt.huber@wienkav.at Prof. Dr. med. Stephan Windecker Deputy Director Department of Internal Medicine/Cardiology, University of Bern, Switzerland Stephan.Windecker@insel.ch Prof. Dr. med. Stefan James Director Department of Medical Sciences and Uppsala Clinical Research Center Uppsala University, Uppsala, Sweden stefan.james@akademiska.se Prof. Dr. med. Pranas Serpytis Vilnius University Hospital, Santariskiu klinikos, Vilnius, Lithuania pranas.serpytis@santa.lt Prof. Dr. med. Gilles Montalescot Centre Hospitalier Universitaire Pitié-Salpetrière, Institut de Cardiologie, Paris, France Gilles.montalescot@psl.aphp.fr Prof. Dr. med. Marco Noc University Medical Center Ljubljana, Division of Internal Medicine, Ljubljana, Slovenia marko.noc@mf.uni-lj.si Prof. Dr. med. Jan J. Piek Stiftung Institut für Herzinfarktforschung and University of Lübeck 7

52 CULPRIT-SHOCK Study Protocol Version 1.2, Academic Medical Center, Amsterdam, The Netherlands Prof. Dr. med. Janina Stępińska Institute of Cardiology, Warsaw, Poland Dr. med. Stefano Savonitto Department of Cardiology, Servizio Sanitario Regionale, Emilia Romagna, Italy Prof. Dr. med. Keith G. Oldroyd Department of Cardiology, Western Infirmary, Glasgow, United Kingdom 3 Participating centers See attachment 1 4 Local investigators All interventional cardiologists of participating centers All physicians of intensive care unit (ICU) of participating centers 5 Clinical and scientific expertise of the study chairs The coordinating investigators form a team and have comprehensive expertise in the preparation, organization and conduct of clinical studies in particular in acute myocardial infarction and cardiogenic shock. The CVs of the two coordinating investigators are attached to this application. 6 Aim of the trial This trial examines if culprit vessel only PCI with potentially subsequent staged revascularization in comparison to immediate multivessel revascularization by PCI in patients with cardiogenic shock complicating acute myocardial infarction reduces the incidence of 30- day mortality and/or severe renal failure requiring renal replacement therapy. 7 Trial type Prospective, randomized, international, multicenter, controlled, open-label trial. 8 Informed consent and ethical considerations For ethical considerations and patient risk assessment in both treatment groups a careful interim analysis as well as regular meetings of the Data Safety Monitoring Board (DSMB) will be established to minimize the risk for the patients. In addition, insurance will be obtained for all patients. One important aspect in cardiogenic shock patients is informed consent. The majority of patients will not be able to give informed consent due to intubation, mechanical ventilation, and sedation. Another proportion of patients will have impaired peripheral and central perfusion induced by the cardiogenic shock itself and will be only partially able to give informed consent. Only a minority of patients will be able to give full informed consent in the acute setting. In the SHOCK-trial 88% were not able to give informed consent, 1 in the TRIUMPH trial 86%, 2 and in previous trials involving cardiogenic shock patients at the University of Leipzig Heart Center 90-95%. 3, 4 The percentage of patients not being able to consent in the IABP-SHOCK II trial, the largest trial in cardiogenic shock to date, is currently evaluated. Summarizing the current evidence, we assume that 90% of patients will not be able to give informed consent at the time of randomization. Stiftung Institut für Herzinfarktforschung and University of Lübeck 8

53 CULPRIT-SHOCK Study Protocol Version 1.2, As the majority of patients will not be able to consent a 4 step informed consent process has been validated and approved: 1) Patient not able to consent 2 independent physicians assess supposed patient s will (if possible by contact of relatives). 2) Patient with impaired ability to consent Short version of informed consent 3) Patient with full consent Long version of informed consent 4) Patient recovers to full consent retrospective long version of informed consent Patient information and informed consent will be handled according to the rules of Good Clinical Practice and the Declaration of Helsinki. All eligible patients will undergo the consent process prior to randomization as described above using 4 different forms (see appendix 2 a-d). All possible risks will be specifically pointed out in the patient information. It will be explicitly highlighted that non-participation in the trial or withdrawal of a prior given consent can be carried out at all times with no subsequent disadvantages and that management of all data will be performed according to data privacy policy. For non-consent patients a legal representative, e.g. relative or person in charge by the guardianship court, needs to be contacted after inclusion to provide informed consent. The process of study information and informed consent has been established in several previous clinical trials in cardiogenic shock (i.e. TRIUMPH-trial EudraCT Number: , ethics committee approval number in Germany at Landesärztekammer Brandenburg S 9/2006; 2 IABP SHOCK Pilot-trial; ethics committee approval number in Germany at Martin- Luther-Universität Halle dated Ethical approval has also been granted from the University of Leipzig with Reg.Nr for the IABP-SHOCK II-trial in 600 patients using the same informed consent process as described here. 5 9 Data documentation All data will be collected prospectively by standardized electronical case report forms (ecrf) provided by the Institut für Herzinfarktforschung in Ludwigshafen. The link is For data entry, each study coordinator at each participating center receives individual login information for the ecrf. The database will be kept on the server of the Institut für Herzinfarktforschung Ludwigshafen. Data are entered by each participating center directly into the internet-based ecrf. Data entered are immediately tested for plausibility in order to prevent unnecessary queries. Data will be entered via a SSL-secured internet line. The ecrf will be self-explaining. To facilitate data entry, the definitions of the various parameters will be accessible by a simple mouse click behind the related question in the ecrf. Further data analysis will be conducted electronically encrypted. Through anonymization of all personal information all regulations of data privacy policy will be respected. In addition, adherence to data privacy protection will be guaranteed by the SOP of the Institut für Herzinfarktforschung. 10 Insurance For the general risk of the procedure patients are insured through the typical patient insurance of the individual hospitals. PCI including multivessel and culprit lesion only is a standard treatment of cardiogenic shock. Any potential additional risks for the patients caused by studyspecific procedures will be covered by an additional insurance (see risk-benefit evaluation 2.13). A copy of the insurance certificate will be handed out to the patient: Insurance-Police-Number: HDI-Gerling Industrie Versicherung AG Eisenbahnstr Leipzig Deutschland Telefon: Stiftung Institut für Herzinfarktforschung and University of Lübeck 9

54 CULPRIT-SHOCK Study Protocol Version 1.2, Telefax: The maximum cover per patient is ,00. A copy of the insurance certificate is filed in the trial folder. Stiftung Institut für Herzinfarktforschung and University of Lübeck 10

55 CULPRIT-SHOCK Study Protocol Version 1.2, Timeline Figure 1: Timeline and milestones of the CULPRIT-SHOCK trial This clinical trial will start with the first obtained written informed consent and will end by the time all patients completed clinical long-term follow-up at 12 months after randomization. For the individual patient, the clinical trial will start after informed consent and randomization after diagnostic coronary angiography. The patient will reach the end of the study by the time the follow-up examinations at 30-days, 6 months, and at 12 months are completed. Patient recruitment will last approximately 30 months, leading to total study duration of 42 months including the long-term follow-up at 12 months post randomization. Primary analysis will require up to 2 months. Thus, the time from first randomization to primary analysis (completion of 30-days follow-up of the last patient) will be 32 months for the primary study endpoint and 44 months until the end of the study with termination of the long-term followup of the last patient. Stiftung Institut für Herzinfarktforschung and University of Lübeck 11

56 CULPRIT-SHOCK Study Protocol Version 1.2, Study protocol 1 Trial description 1.1 Topic Prospective, randomized, international, multicenter, open-label study to compare immediate multivessel revascularization by PCI to culprit lesion only PCI with staged non-culprit lesion revascularization in patients with cardiogenic shock complicating acute myocardial infarction presenting with multivessel disease. Acronym: CULPRIT-SHOCK trial 1.2 The medical problem Despite aggressive treatment modalities such as PCI as well as mechanical and inotropic support, mortality of cardiogenic shock complicating acute myocardial infarction remains at a 3, 4, 6-10 very high level with mortality rates between 45-70%. The majority of patients in cardiogenic shock presents with multivessel coronary artery disease and the mortality of these patients is higher than mortality in patients with single vessel disease From a pathophysiological standpoint it might be beneficial to reperfuse all relevant coronary arteries with significant coronary artery stenoses in addition to the culprit lesion to improve myocardial perfusion. On the other hand immediate multivessel PCI might pose additional risk for the patients. However, there are no randomized clinical trials assessing the optimal reperfusion strategy. 1.3 Evidence Reperfusion The most important therapeutic measure in cardiogenic shock complicating acute myocardial infarction is early reperfusion of the infarct related artery. Historically, the introduction of fibrinolysis failed to substantially lower the mortality of patients in cardiogenic shock which remained high at a rate of 70-85% Subsequently, non-randomized and partly retrospective studies in cardiogenic shock suggested that PCI can reduce the high mortality The landmark SHOCK trial is one of the rare adequately powered randomized trials in cardiogenic shock complicating acute myocardial infarction. 1 Although it failed to meet the primary endpoint - reduction of 30-day mortality by an early revascularization-based management either by PCI or coronary artery bypass grafting (CABG) - (46.7% versus 56.0%, p=0.11), there was a significant mortality reduction at 6 months (50.3% versus 63.1%, p=0.027), 12 months (53.3% versus 66.4%, p=0.03), 30 and long-term follow-up at 6 years (67.2% versus 80.4%, p=0.03). 31 To save 1 life, <8 patients need to be treated by early revascularization in comparison to initial medical stabilization. The Swiss Multicenter trial of Angioplasty for Shock (SMASH) trial, although stopped prematurely due to slow enrolment, showed similar effects by early revascularization. 32 Based on the current evidence PCI plus stent implantation (or CABG) is recommended for all patients in particular those aged <75 years to allow recovery of stunned myocardium and prevention of life-threatening arrhythmias For patients aged >75 years an early interventional treatment is recommended depending on the patient condition and comorbidities The more widespread establishment of an early interventional treatment in cardiogenic shock irrespective of age was likely the most important factor for a reduction of mortality to 40-50% observed in recent years Reperfusion in multivessel coronary artery disease and cardiogenic shock Approximately 70-80% of patients with cardiogenic shock complicating acute myocardial infarction have multivessel disease , 41 These patients have a higher mortality compared to patients with single vessel disease Stiftung Institut für Herzinfarktforschung and University of Lübeck 12

57 CULPRIT-SHOCK Study Protocol Version 1.2, Current ESC and AHA/ACC guidelines recommend PCI of all high-grade lesions in patients with acute myocardial infarction complicated by cardiogenic shock (class IIa, level of evidence B recommendation), while in hemodynamically stable patients without shock culprit-lesion only PCI should be preferred (class III, level of evidence B recommendation). 34, 35, 37, 42 In contrast to these recommendations, the German/Austrian S3-guideline recommends multivessel PCI only 43, 44 in selected individual cases. Nevertheless, these guideline recommendations in cardiogenic shock are not based on strong clinical evidence because it is not clear whether multivessel PCI might be beneficial in cardiogenic shock. There are no randomized data evaluating the benefit of a multivessel PCI approach in cardiogenic shock and these recommendations are mainly based on pathophysiological considerations. Despite these guideline recommendations and possibly owing to the limited evidence supporting these recommendations multivessel PCI is currently 45, 46 performed in only 1/3 to 1/4 of cardiogenic shock patients with multivessel disease. So far reports from registries comparing culprit-lesion only versus multivessel PCI in patients with acute myocardial infarction complicated by cardiogenic shock do not support immediate multivessel PCI. In the SHOCK trial more complete revascularization by immediate multivessel PCI was associated with an unfavorable outcome compared to culprit lesion only PCI. 47 In a single center observational study 1-year mortality did not significantly differ between culpritlesion PCI (n=124) and immediate multivessel PCI (n=37). 48 Data from the multicenter National Cardiovascular Data Registry reported an increased mortality for multivessel PCI. Among patients with cardiogenic shock (n=3,087), those receiving multivessel PCI had greater inhospital mortality (36.5% vs 27.8%; adjusted odds ratio 1.54, 95% confidence interval 1.22 to 1.95). 49 In the recently published Euro Heart Survey PCI registry there was a trend towards higher mortality after multivariable adjustment for the multivessel PCI strategy (n=82) versus culprit lesion only PCI (n=254) in multivessel disease. 45 In addition, data from the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK) also showed an unfavorable outcome with immediate multivessel PCI. 50 A summary of current data from registries is shown in Table 1: Trial N Mortality Multivessel PCI Mortality Culprit Lesion only PCI Adjusted OR (95% CI) Webb %* 20%* 2.75 ( ) Van der Schaaf %* 53%* Not reported (p=0.05) Cavender % 27.8% 1.5 ( ) Bauer % 37.4% 1.28 ( ) Zeymer % 35.6% 1.5 ( ) *1-year mortality Table 1: Current evidence of multivessel PCI versus culprit lesion only PCI on death Currently, there is no trial assessing multivessel revascularization by PCI (or CABG) versus culprit lesion only PCI with a potential staged revascularization strategy in case of ischemia. Given the conflicting data the current guideline recommendations are questionable and it remains to be determined which strategy is preferable Reperfusion by PCI or CABG Theoretically, there might be some influence by the revascularization type - PCI versus CABG - on outcome similar to stable coronary artery disease. 51 Nevertheless, there is much uncertainty regarding the optimal revascularization type for patients in cardiogenic shock, 9 because all previous trials assessing the effect of revascularization or adjunctive treatment on outcome did not specify the type of reperfusion in the study protocol. 1, 2, 32 Given the current evidence there are no randomized data that the type of revascularization influences the outcome of patients in cardiogenic shock. 52 Therefore, in addition to the uncertainty regarding culprit lesion versus multivessel PCI, the optimal revascularization strategy - PCI versus CABG - for patients in shock with multivessel Stiftung Institut für Herzinfarktforschung and University of Lübeck 13

58 CULPRIT-SHOCK Study Protocol Version 1.2, disease is not clear. 46 Randomized clinical trials addressing this question are missing for the cardiogenic shock subset. Currently, there are only 4 observational reports evaluating PCI versus CABG and the limited data suggest similar mortality rates with CABG and PCI in patients 46, 52 with infarction and multivessel coronary artery disease complicated by cardiogenic shock. In the current ESC revascularization guidelines emergent surgery after failure of PCI or fibrinolysis is only indicated in patients with persistent instability or life-threatening ventricular arrhythmia due to extensive ischemia such as left main or severe triple vessel disease (class 1, level of evidence C recommendation) Reperfusion in multivessel coronary artery disease without cardiogenic shock In ST-elevation myocardial infarction (STEMI) patients without cardiogenic shock multivessel disease has a lower incidence in comparison to shock patients and is present in 40-70% of patients depending upon the baseline characteristics of the population studied In these patients an immediate non-culprit lesion intervention is not recommended by ESC and 34, 35, 37 AHA/ACC guidelines despite limited evidence (class III B recommendation). Several prior registry studies have shown that treatment of non-culprit lesions during primary PCI for STEMI in hemodynamically stable patients was associated with increased postprocedural morbidity in the absence of a mortality benefit. 49, 53, 56, 57 Other registries found similar results for an immediate versus a culprit lesion only PCI strategy or a culprit lesion with subsequent staged PCI strategy. 58, 59 There are only 2 small randomized trials. 60, 61 In one randomized clinical trial involving only 214 patients with multivessel disease undergoing randomization to 3 arms, culprit lesion only was associated with the highest major adverse cardiac event rate, whereas there was no difference in the immediate multivessel PCI strategy and the planned culprit lesion with staged PCI strategy. In the other randomized trial immediate multivessel PCI was also safe without complications in 60 randomized patients. 60 These conflicting results have recently been confirmed in 3 different meta-analyses. One metaanalysis included 4 prospective and 14 retrospective trials comparing 3 different strategies for multivessel PCI; 1) culprit lesion only PCI versus 2) multivessel PCI and 3) immediate culprit lesion PCI and subsequent staged PCI of other relevant stenoses. 62 This meta-analysis reported the lowest mortality rates for an immediate culprit lesion only with subsequent staged PCI, worse mortality with a culprit lesion only strategy and the worst outcome for an immediate multivessel PCI strategy. 62 In contrast, another meta-analysis including 19 registry studies that compared culprit lesion only versus multivessel PCI (either performed immediately or staged) found similar mortality and reinfarction rates. 63 The 3 rd meta-analysis including 2 randomized and 8 registry studies comparing an immediate multivessel PCI strategy (excluding staged PCI procedures) versus a culprit lesion only strategy found no difference in mortality rates. 64 Currently, there are 3 ongoing randomized trials (COMPARE-ACUTE; PRAGUE-13; CROSS- AMI) recruiting non-shock STEMI patients with multivessel disease with randomization to immediate multivessel PCI or culprit lesion only PCI with or without staged PCI ( IABP The hemodynamic effects of IABP in cardiogenic shock are well established. 65 However, the evidence regarding the benefits of IABP on mortality is limited. A recent meta-analysis revealed the conflicting results in different reperfusion strategies. 66 The main results of this meta-analysis are shown in Figure 2: Stiftung Institut für Herzinfarktforschung and University of Lübeck 14

59 CULPRIT-SHOCK Study Protocol Version 1.2, Figure 2: Trials of IABP versus no IABP in cardiogenic shock. Adapted according to Sjauw et al. 66 The IABP-SHOCK II trial randomized 600 patients with acute myocardial infarction and cardiogenic shock undergoing early revascularization to either IABP or optimal medical therapy only. With 600 randomized patients the IABP-SHOCK II trial is the largest trial in cardiogenic shock performed so far. The results have been recently published and did not show a benefit for the IABP on 30-day mortality or on secondary endpoints. 67, 68 Therefore, IABP use cannot be not recommended anymore on a regular basis Additional supportive therapy The current evidence in the treatment of cardiogenic shock has recently been summarized. 9 Except for early revascularization and - in case of vasopressor requirement - treatment with norepinephrine instead of dopamine, no treatment option including glycoprotein IIb/IIIainhibitors, NO-production modulation, or early use of active left ventricular assist devices showed a benefit with respect to mortality reduction. The current evidence in cardiogenic shock with the results of the IABP-SHOCK II-trial is 9, 68 summarized in Figure 3. Figure 3: Randomized clinical trials in cardiogenic shock. Adapted according to Thiele et 9, 68 al. Stiftung Institut für Herzinfarktforschung and University of Lübeck 15

60 CULPRIT-SHOCK Study Protocol Version 1.2, The need for a trial Of estimated 140,000 cases of acute myocardial infarctions admitted to hospitals in Germany per year, 69 approximately 10,000 are resulting in cardiogenic shock (7-8%). 7 Of these 70-80% of patients have multivessel disease translating into 7500 patients in Germany , 41 For the European population this translates in approximately 60,000 to 70,000 cardiogenic shock cases 70, 71 per year and 45,000 to 52,000 multivessel disease patients. These patients with multivessel disease have a higher mortality compared to patients with single vessel disease. Current European Society of Cardiology (ESC) as well as American Heart Association (AHA)/American College of Cardiology (ACC) guidelines recommend PCI of all high-grade lesions in patients with acute myocardial infarction complicated by cardiogenic 33-37, 42 shock, while in hemodynamic stable patients culprit-lesion only PCI should be preferred. However, these recommendations are not based on randomized trials. Therefore, currently there is no consensus on the optimal management of significant non-culprit coronary artery lesions identified at angiography for primary PCI and a randomized clinical trial therefore necessary. Theoretically, treatment of non-culprit lesions could help limiting the infarct size and preserve left ventricular function, which are major prognostic factors in patients with acute myocardial infarction. It may also be hypothesized that multivessel PCI may reduce the subsequent adverse events after primary PCI by preventing the incidence of both early and late recurrent ischemia in the non-infarct related lesions, which in turn could obviate the need for recurrent procedures, reducing overall ischemic burden and attenuating the incidence of unpredictable subsequent cardiac events. Complete revascularization at the time of infarction may also reduce overall hospital stay and total cost of care. On the other hand, major concern exists regarding the risks of prolonged interventional procedures with higher amounts of contrast dye and the hypothetical risk of stent thrombosis in non-culprit lesions when stent implantation has taken place in the thrombogenic milieu of acute myocardial infarction. 72 A successful primary PCI of the infarct related artery and a complicated or unsuccessful PCI to the non-infarct related artery would be potentially hazardous, especially in the setting of cardiogenic shock. Contrast load also has to be taken into account which might lead to a volume load of the left ventricle with subsequent ischemia. In addition, multivessel PCI is likely to be associated with an increased risk of contrast-induced nephropathy, which is associated with adverse clinical outcome Furthermore, unnecessary PCI might increase the need for subsequent revascularization procedures due to restenosis, acute stent thrombosis, or might induce periprocedural myocardial infarction by distal embolization, side branch occlusion, acute vessel occlusion, or other inherited technical problems. 45 Therefore, it is not surprising that treatment modalities for multivessel disease diagnosed during PCI for cardiogenic shock differ widely among different institutions and are largely operator dependant. Therefore a prospective randomized clinical trial is warranted to determine the optimal revascularization therapy in patients with multivessel disease treated with early revascularization preferably PCI for cardiogenic shock. Stiftung Institut für Herzinfarktforschung and University of Lübeck 16

61 CULPRIT-SHOCK Study Protocol Version 1.2, Study aims 2.1 Study endpoints Primary study endpoint All-cause death and/or severe renal failure requiring renal replacement therapy within 30-days after randomization according to the intention-to-treat principle. (For definitions see 7) Mortality is surely the strongest endpoint for acute heart failure syndrome trials. 76 Renal failure requiring renal replacement therapy is also associated with increased morbidity and mortality In the recently published IABP-SHOCK II trial the mortality of patients with renal replacement therapy was 56% versus 37% for those without renal replacement therapy (p<0.001) underlining the prognostic relevance of this endpoint. 68 In addition, the combination of these two individual endpoints has recently been used in a randomized clinical trial in patients with severe sepsis Secondary study endpoints 30-day all-cause mortality Renal failure with requirement of renal replacement therapy Procedural success Time to hemodynamic stabilization Duration of catecholamine therapy Serial creatinine-level creatinine-clearance (Cockcroft-Gault-Formula) 78 until stabilization Length of ICU-stay Serial SAPS-II score until stabilization Requirement and length of mechanical ventilation All-cause death within 6 and 12 months follow-up Recurrent infarction within 30-days, 6 and 12 months follow-up Death or recurrent infarction at 6 and 12 months follow-up Rehospitalization for congestive heart failure within 30-days, 6 and 12 months follow-up Death/recurrent infarction/rehospitalization for congestive heart failure within 30-days, 6 and 12 months Need for repeat revascularization (PCI and/or CABG) within 30-days, 6 and 12 months follow-up Peak creatine kinase, creatine kinase-mb and troponin level during hospital stay Quality of life at 6 and 12 months assessed using Euroqol 5D (EQ-5D) questionnaire ( Except for the direct clinical events, the secondary endpoints are surrogate measures for 1, 3, outcome and complications and have been used in several previous cardiogenic shock trials. 4 In addition, although 30-day death and/or severe renal failure is the primary endpoint, it is important to confirm a potential advantage at long-term follow-up. Therefore, a 6- and 12-month follow-up will be analyzed which will also encompass rehospitalisation for congestive heart failure and recurrent infarction among other clinical endpoints Safety aspects Immediate multivessel revascularization by preferably PCI will be performed in patients randomized in group 1 and culprit lesion only PCI with potential staged additional revascularization if indicated in group 2. There are no additional study related examinations or procedures. Apart from the two revascularization strategies all patients will be treated according to current guidelines of the ESC and the AHA/ACC as well as the German-Austrian S3-33, 34, 36, guideline for the treatment of cardiogenic shock. Safety will be assessed by bleeding and occurrence of stroke. Stiftung Institut für Herzinfarktforschung and University of Lübeck 17

62 CULPRIT-SHOCK Study Protocol Version 1.2, Bleeding according to the BARC-definition grade 2-3 and Stroke: any new neurological symptoms in association with signs of ischemia or hemorrhage in a cranial CT or MRI Data Safety Monitoring Board The external independent DSMB consists of international experts in the treatment of cardiogenic shock and acute heart failure. Confirmed members of the DSMB are: Name Affiliation Prof. Dr. Ferenc Follath Universitätsspital Zürich, Switzerland ferenc.follath@usz.ch Prof. Dr. Peter Clemmensen Rigshospitalet, The Heart Center, Copenhagen, Denmark Prof. Dr. Johannes Haerting (independent statistician) Steering committee peter.clemmensen@rh.regionh.dk Universität Halle-Wittenberg, Germany johannes.haerting@medizin.uni-halle.de The steering committee of the CULPRIT-SHOCK trial consists of the two coordinating investigators, co-investigators, and the national coordinating investigators. 2.2 Methods against bias Blinding is not possible as a result of the intervention used. Methods against bias used are a central computerized randomization; independent clinical endpoint committee to assess adverse events other than death; blinded laboratory for secondary laboratory parameters; high standard requirements concerning the clinical level and experience of centers and investigators in terms of numbers of PCI performed, cases of cardiogenic shock treated, intensive care unit treatment, and participation in clinical trials. In order to prevent informative censoring, informed consent will include access to all relevant sources to determine the patient s life status at 6- month and 12-month follow-up. 2.3 Study procedures Patients with cardiogenic shock complicating acute myocardial infarction (inclusion criteria see 2.6) will be transferred to the catheterization laboratory as soon as possible after primary admission to the tertiary care center or after transfer from a primary or secondary care center. Left heart catheterization is performed and coronary anatomy with the extent of coronary artery disease including identification of the culprit lesion is assessed Randomization in the catheterization laboratory After check of all in- and exclusion criteria (see 2.6 and 2.7) randomization after the initial diagnostic angiography is performed into the groups 1 and 2. Group 1: 353 patients with immediate multivessel revascularization preferably by PCI Group 2: 353 patients with culprit lesion only PCI with potential staged revascularization Randomization is performed internet-based using a secure system using the homepage of the Institut für Herzinfarktforschung: Revascularization Group 1: Revascularization plan in the immediate multivessel PCI group After diagnostic angiography the culprit lesion should be identified and PCI should be performed using the standard technique of the participating center. The use of drug-eluting stents is Stiftung Institut für Herzinfarktforschung and University of Lübeck 18

63 CULPRIT-SHOCK Study Protocol Version 1.2, recommended but not mandatory. Thrombectomy and additional interventional techniques are left to the discretion of the operator. All additional lesions in other major coronary arteries defined by a diameter >2 mm with high grade stenoses (>70% by visual assessment) should be intervened using standard techniques of the participating center. Other major coronary arteries are defined by stenoses of other vessels and are not confined to a diagonal branch if the left anterior descending coronary artery was identified as the culprit lesion. The use of drug-eluting stents is also recommended for these lesions but not mandatory. In patients with prior CABG and culprit lesion in a bypass graft the same strategy applies with PCI of the culprit lesion and additional revascularization of additional significant stenoses in native coronary arteries or bypass grafts. In patients with triple vessel disease and chronic total occlusions (CTO) the culprit lesion should be targeted and additional revascularization of the CTO attempted. However, no excessive revascularization attempts should be applied. The overall amount of contrast dye should not exceed 300 ml. In case of unsuitable anatomy for PCI such as severe multivessel disease with multiple chronic total occlusions and/or high SYNTAX-score revascularisation by primary immediate CABG might be considered according to operator discretion to ensure complete revascularization. Patients undergoing primary urgent CABG will not be randomized. However, it is recommended that treatment of left main stem stenoses or triple vessel disease should be performed by PCI whenever possible. No fractional flow reserve measurement is recommended in the acute setting for assessment of the functional relevance of non-culprit lesions. 35 Group 2: Revascularization plan in the culprit lesion PCI only group After the diagnostic angiography the culprit lesion should be identified and PCI of the culprit lesion should be performed using the standard technique of the participating center. Patients considered candidates for primary urgent CABG according to operator discretion will not be randomized. The use of drug-eluting stents is recommended but not mandatory. Thrombectomy and additional interventional techniques are left to the discretion of the operator. All other lesions should be left untreated in the acute setting. In group 2, complete revascularization of the non-culprit lesions may be performed at a later time point as staged procedure depending on remaining ischemia (as per guideline recommendations either by PCI or CABG). 35 It is strongly recommended that all patients depending on the clinical situation and hemodynamic stability - undergo non-invasive evaluation for residual myocardial ischemia at 1-4 weeks post index PCI of the culprit lesion by means of a stress ECG or an imaging stress test such as nuclear perfusion scintigraphy, stress echocardiography, or stress magnetic resonance imaging. Alternatively, the functional relevance of initially untreated stenoses can be assessed by invasive fractional flow reserve. 35 All patients manifesting significant symptoms of angina pectoris or significant reversible ischemic burden should be revascularized Antithrombotic therapy Antithrombotic therapy should be given according to local standards of the participating centers. According to the current guidelines aspirin and an ADP-receptor antagonist should be given for 12 months. In patients without contra-indications prasugrel or ticagrelor is recommended over clopidogrel , 42 Glycoprotein IIb/IIIa-inhibitors might be considered in reduced flow after PCI or high thrombus burden Mechanical hemodynamic support Mechanical hemodynamic support such as active left ventricular assist devices, or extracorporeal membrane oxygenation can be considered based on current guideline recommendations , Based on the results of the IABP-SHOCK II trial an IABP is not recommended anymore, 68 however, its use is left to the discretion of the operators. Mechanical hemodynamic support can be performed before or after PCI. Stiftung Institut für Herzinfarktforschung and University of Lübeck 19

64 CULPRIT-SHOCK Study Protocol Version 1.2, Documentation of hemodynamic parameters in the catheterization laboratory Hemodynamic parameters such as systolic, diastolic, mean arterial pressure, and heart rate will be assessed in the catheterization laboratory before and after revascularization. In addition, an arterial blood gas analysis with assessment of serum lactate will be performed. By study design detailed hemodynamic parameters (such as cardiac output, cardiac index, cardiac power index, central venous pressure, pulmonary artery pressure, PCWP) will not be assessed in the catheterization laboratory, as this might delay revascularization and would lead to the necessity of pulmonary artery catheterization Post-PCI After cardiac catheterization patients will be transferred to the ICU by continuous ECGmonitoring and arterial invasive blood pressure monitoring ICU therapy ICU therapy is adapted and performed to general accepted intensive care guidelines. 43, 44 There is no difference in the treatment between patients in group 1 and 2. In both groups treatment with catecholamines (i.e. preferably dobutamine for inotropic support and norepinephrine as vasoconstrictor) according to local practice is performed. If considered necessary, the use of Ca-sensitizers (levosimendan) is allowed according to the individual intensive care evaluation The duration of catecholamines and other hemodynamically relevant drugs will be documented. 43, 44 The mean blood pressure goal during requirement of hemodynamic support is 65 mmhg. If renal replacement therapy is necessary the reason for initiating renal replacement therapy [Otherwise untreatable volume overload; hyperpotassemia (>6.0 mmol/l); severe uremia (>50 mg/dl or >8.4 mmol/l); persistent severe metabolic acidosis (ph <7.2)], the mode, and the duration will be documented. Any need for mechanical or assisted ventilation and its duration will be assessed in the ecrf Hemodynamic monitoring at ICU Hemodynamic parameters such as systolic, diastolic, mean arterial pressure, and heart rate will be assessed according to local practice. In addition, arterial blood gas analyses with assessment of ph and serum lactate will be performed according to local practice. If deemed necessary, expanded hemodynamic monitoring by PICCO-system or pulmonary artery catheter can be applied. Data will not be assessed in the ecrf Laboratory monitoring at ICU Blood is drawn for the assessment of inflammatory markers (CRP and white blood cell count) once daily and also markers of myocardial damage such as creatine kinase (CK), CK-MB, and troponin for the indirect assessment of infarct size. In addition, renal function will be assessed by serum creatinine. All other laboratory parameters will be collected according to the ecrf (see 2.5) day follow-up At 30-days after randomization the vital status will be assessed by structured telephone interview. Any potential event (death, severe renal failure requiring renal replacement, reinfarction, repeat revascularization, new congestive heart failure leading to hospital admission) will be verified by original records month follow-up At 6 months after randomization the vital status will be assessed by structured telephone interview. Any potential event (death, severe renal failure requiring renal replacement, reinfarction, repeat revascularization, new congestive heart failure leading to hospital admission) will be verified by original records. The quality of life will be assessed by the Euroqol 5D questionnaire month follow-up At 12 months after randomization the vital status will be assessed once again by structured 20 Stiftung Institut für Herzinfarktforschung and University of Lübeck

65 CULPRIT-SHOCK Study Protocol Version 1.2, telephone interview. Any potential event (death, severe renal failure requiring renal replacement, reinfarction, repeat revascularization, new congestive heart failure leading to hospital admission) will be verified by original records. The quality of life will be assessed by the Euroqol 5D questionnaire. Stiftung Institut für Herzinfarktforschung and University of Lübeck 21

66 CULPRIT-SHOCK Study Protocol Version 1.2, Study flow-chart Figure 4: Study flow-chart Stiftung Institut für Herzinfarktforschung and University of Lübeck 22

67 CULPRIT-SHOCK Study Protocol Version 1.2, Assessment of study endpoints An overview of the timepoints for assessment of study endpoints is provided in Table 2: Stiftung Institut für Herzinfarktforschung and University of Lübeck 23

68 CULPRIT-SHOCK Study Protocol Version 1.2, Inclusion criteria Cardiogenic shock complicating acute myocardial infarction (STEMI or NSTEMI) with obligatory: I) Planned early revascularization by PCI II) Multivessel coronary artery disease defined as >70% stenosis in at least 2 major vessels ( 2 mm diameter) with identifiable culprit lesion III) a) Systolic blood pressure <90 mmhg for >30 min or b) catecholamines required to maintain pressure >90 mmhg during systole and IV) Signs of pulmonary congestion V) Signs of impaired organ perfusion with at least one of the following criteria a) Altered mental status b) Cold, clammy skin and extremities c) Oliguria with urine output <30 ml/h d) Serum-lactate >2.0 mmol/l VI) Informed consent 2.7 Exclusion criteria Resuscitation >30 minutes No intrinsic heart action Cerebral deficit with fixed dilated pupils (not drug-induced) Need for primary urgent bypass surgery (to be determined after diagnostic angiography) Single vessel disease Mechanical cause of cardiogenic shock Onset of shock >12 h Massive lung emboli Age >90 years Shock of other cause (bradycardia, sepsis, hypovolemia, etc.) Other severe concomitant disease with limited life expectancy <6 months Pregnancy Known severe renal insufficiency (creatinine clearance <30 ml/min) 2.8 Prospective CULPRIT-SHOCK registry Patients not fulfilling the above mentioned inclusion criteria or those with exclusion criteria will be entered into the prospective CULPRIT-SHOCK registry (see Figure 4). Parameters evaluated will be essentially the same as for the randomized clinical trial. This registry will give an estimate of the patients screened and finally included into the randomized trial. Furthermore and more importantly, this trial will allow describing the current treatment strategies for patients in cardiogenic shock. 2.9 Sample size calculation The 30-day mortality of patients with multivessel disease and cardiogenic shock undergoing immediate multivessel PCI is approximately 50% as indicated in multiple registries (see Table 1). 45, 47, 48, 50 The 30-day death rate in the culprit lesion only group is supposed to be 39% based on reported mortality rates from registries. 45, These assumptions are at the lower end of the estimated difference in mortality reduction by culprit lesion only PCI with current registry data suggesting an absolute mortality reduction of 7-35% and the most recent data suggesting 11%. 45, It should, however, be taken into account that registry data might overestimate treatment effects and therefore a conservative estimate is justified. The incidence of severe renal failure requiring renal replacement therapy is estimated to be absolutely 2% lower in the culprit lesion only group. 49 Based on these data and with regard to the combined primary endpoint of death and renal replacement therapy, event rates of 50% in the multivessel PCI group vs. 38% in the culprit 24 Stiftung Institut für Herzinfarktforschung and University of Lübeck

69 CULPRIT-SHOCK Study Protocol Version 1.2, lesion only group were used for sample size calculation. A total of 684 patients are needed to test the null hypothesis of no difference between groups (two-sided test Chi 2 test; power: 80%, alpha=0.048 for final analysis). Allowing for a 3% drop-out rate, 706 patients will be recruited. Based on previous clinical trials a higher drop-out rate is not expected. 1-4, 80 The software used for sample size calculation was nquery Advisor 7.0, Statistical Solutions, Cork, Ireland Statistical analysis All data will be analyzed according to the intention-to-treat principle. A sensitivity analysis according to the per protocol population evaluating the robustness of the data will also be performed. The per protocol population is defined by patients undergoing successful or unsuccessful revascularisation. Patients who die before the start of revascularisation or who do not undergo revascularisation for other reasons will not be included in the per protocol analysis. For the primary endpoint Chi 2 test will be used to compare the event rates in both arms. Additionally, Kaplan-Meier curves will be calculated for visualizing the cumulative events in both groups during 30-day follow-up. Secondary endpoints will be assessed by Fisher s or Chi 2 test for binary and Mann-Whitney U test for quantitative secondary endpoints to compare both treatment arms. Since the presumed event rates in both groups are derived from registry data, these might be prone to error. Therefore, a group sequential statistical design with one interim analysis will be chosen. The interim analysis will be performed using the O'Brien-Fleming method without any specified alpha spending function. 81 Thus, the analysis will be equally spaced in terms of the numbers of patients involved at the interim analysis and will be performed after 50% (342) of all analysable patients have completed 30-day follow-up. The global type I error level is set at The trial will be discontinued if the null hypothesis of equal event rates can be rejected with a significance level of at the interim analysis. The final analysis will be performed with α= In case of trial discontinuation at the interim analysis secondary endpoints will be analyzed before finalization of the trial. For missing values sensitivity analyses with multiple imputations will be performed. Long-term survival over 6- and 12 months will also be assessed by Kaplan-Meier analysis. Predefined subgroup analyses will be performed for gender, age groups <50 years, years, >75 years, diabetes, arterial hypertension, STEMI versus NSTEMI, anterior myocardial infarction versus infarct at another location, previous infarction, and 2- versus 3-vessel disease. The maximum inclusion rate per center is restricted to 35% of the overall patient number, i.e. 247 patients, to avoid a dominance of the results by one single center. In the unlikely event of inclusion of 247 patients in one single center further recruitment will not be possible in this center Treatment compliance/drop-out Treatment compliance is not affected by the patient but exclusively by the interventional cardiologist. However, in group 1 anatomical reasons such as CTO or severe calcification leading to unsuccessful PCI or also unstable clinical situation together with comorbidities not qualifying the patient for immediate CABG may lead to incomplete revascularization. In group 2, compliance to the study protocol with culprit lesion only PCI is expected to approach 100%. However, some patients may not qualify subsequently for a staged revascularization procedure because of hemodynamic instability or premature death. In total a treatment compliance of 85% is anticipated. This has been taken into account in the sample size calculation. Based on previous trials in cardiogenic shock the rate of loss to followup is estimated to be 1-4, 80 <2% Regulations for premature study termination a. For the individual patient: Withdrawal of consent throughout the study or following hospital discharge or after 6- and 12-month follow-up. In general discontinuation of the study should be avoided. Discontinuation is only possible by withdrawal of the patient s consent. Violation of the protocol does not lead 25 Stiftung Institut für Herzinfarktforschung and University of Lübeck

70 CULPRIT-SHOCK Study Protocol Version 1.2, to termination of the study for the individual patient. Likewise incomplete revascularization due to unsuccessful PCI of a CTO in the immediate multivessel PCI group is not a criterion for study discontinuation. In case of study discontinuation the reasons and circumstances, as well as the clinical state of the patient should be documented. If the study is continued, follow-up should be conducted as planned (exception: withdrawal of consent). Randomized patients should therefore generally complete follow-up and documentation. In case patients are ineligible for further analysis in the follow-up period (=no contact can be established neither personally to the patient nor through family members) the exact time of the loss of contact should be documented (if possible with an explanatory statement, e.g. relocation). According to the intention-to-treat-analysis all events and parameters will be evaluated until the last date of contact. b. For the entire study: The study might be halted and stopped in case of reaching the boundaries set for the interim analysis. c. The study can be prematurely discontinued by the principal investigator in case of Serious adverse events Insufficient recruitment rate The final decision on a premature discontinuation of the study lies within the discretion of the coordinating investigators. By means of the meeting of the independent DSMB serious adverse events as well as the primary study endpoint will be analyzed. Including two clinical cardiologists and a statistician, the DSMB is able to provide a professional evaluation, if premature discontinuation is indicated. The evaluation of events will be carried out in regular intervals and the information will be passed on to the DSMB after verification. d. The study can be discontinued at an investigating center in case of Failure to comply with the study protocol Insufficient data quality Inadequate recruitment The coordinating investigators, if needed in accordance with the responsible biometrician, will decide on exclusion. The reasons for discontinuation should be clarified. Further treatment for the previously included patients should be discussed with the coordinating investigators Risk-benefit evaluation The study will be performed in accordance with: the requirements of Good Clinical Practice (GCP) the principles stated in the Declaration of Helsinki As outlined above there is equivocal evidence for an immediate multivessel PCI strategy in comparison to a culprit lesion only strategy with subsequent staged PCI. Potential advantages and disadvantages of ad hoc multivessel PCI are outlined in the Table 3: Advantages Immediate complete revascularization Improved hemodynamics Treatment of remote ischemia Treatment of secondary unstable lesions Disadvantages Increased contrast load risk of contrastinduced nephropathy Radiation exposure Complications of treating additional lesions may induce a second hit Hemodynamic instability might be worsened by treating additional lesions Stiftung Institut für Herzinfarktforschung and University of Lübeck 26

71 CULPRIT-SHOCK Study Protocol Version 1.2, Patient preference/comfort Limit infarct size and preserve left ventricular ejection fraction Increased risk of stent thrombosis in the prothrombotic and inflammatory milieu in the acute phase Coronary spasm might overestimate stenosis severity of non-culprit stenoses 3 Feasibility of the study All participating centers are tertiary cardiology centers with high expertise in performing clinical trials in acute myocardial infarction in particular cardiogenic shock. Many of the German centers are university hospitals or are organized in the network of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK), which has high expertise to perform cardiovascular and particular cardiogenic shock clinical trials in Germany. 10 The estimated inclusion rates per year by centers are estimated by individual estimations, the current number of patients with cardiogenic shock according to ICD-10 classification, previous recruitment rates, registries plus current screening rates, the number of PCI performed in each center, and also recruitment in the IABP-SHOCK II trial. Based on these data (excluding patients due to in- and exclusion criteria) the annual inclusion rate is estimated for the individual hospitals. In addition, the IABP-SHOCK II trial had included 600 patients at 35 centers in Germany within 2 ½ years with similar inclusion criteria except for the requirement of multivessel disease in the CULPRIT-SHOCK trial. 5 Of these randomized patients in IABP-SHOCK II approximately 75% had multivessel disease. Therefore, this trial extends the number of study sites to recruit patients within the projected 2 ½ years showing feasibility of the estimated inclusion rate. Assuming a certain overestimation of the potentially recruitable patients in the dimension of 1.5-2, inclusion of 706 patients should realistically be possible within 2 ½ years. 3.1 International cooperations At the current stage international cooperations are planned for Austrian, Swiss, French, Dutch, Swedish, Lithuanian, and Slovenian study sites. In addition, international cooperations are agreed on with the DSMB as mentioned above. 3.2 Personnel and technical requirements To provide the ability for early revascularization, a 24 h stand-by of the catheterization laboratory including all personal and technical requirements is mandatory for the participating centers. In general, PCI is performed by specially trained and experienced interventional cardiologists. After PCI, the patient is deferred to the ICU. Thus, such units are obligatory for participation in the study. The required staff is present at all participating centers. Although it is not mandatory, a study nurse may be helpful for the assessment of study endpoints and data handling. The co-investigators should hold appropriate qualification, skills and experience in realizing a clinical trial. 82 Prior to participation these qualification and skills of all collaborating personnel will be revised. In the particular hospitals, as well as during investigator meetings, informative functions and special trainings will be organized to guarantee correct execution of the study. In addition to the presence of a catheterization laboratory and an ICU, the participating centers have to have access to a laboratory for the processing of blood products. As randomization generally ought to be performed internet-based, a computer with internetaccess must be available. Stiftung Institut für Herzinfarktforschung and University of Lübeck 27

72 CULPRIT-SHOCK Study Protocol Version 1.2, Ethical and regulatory specifications 4.1 GCP guidelines Staff involved in any aspect is committed to perform this clinical study according to national laws, to the requirements of the ICH Guideline for Good Clinical Practice (GCP) E6 published June 1996 and the CPMP/ICH/135/95 published September 1997 and in adherence to the Declaration of Helsinki (version 2008). 4.2 Application Qualification of investigators and participating centers The coordinating investigators and national coordinating investigators have specifically classified all participating centers to be appropriate investigating centers and have distinctly discussed the possibility to participate in this study with the eligible centers. On demand of local ethics committees based on 7 (2) and 8 (5) of the GCP-regulation it is possible that further information on the eligibility of the participating centers, as well as on the corresponding funds and facilities or on the disposable staff and their experience in performing clinical trials is required. For this purpose and subsequent evaluation all required documents will be provided if requested by the involved ethics committees Investigators 1. Résumé including name, office address, current employment and occupation, professional development, specialties, additional qualifications, previous performed studies (number, phase of the trials, field of indication), date and signature. 2. Selected information on prior publications or certificates of further training related to clinical studies, if possible. 3. Confirmation on the knowledge of ICH-GCP-guidelines and the GCP-requirements (including awareness of the study protocol, definitions of AE and SAE, notifiable events, record retention, requirements for monitoring, audits and inspections); if possible results of previous performed monitoring, audits and inspections. 4. Financial disclosure form and statement on possible conflicts of interest related to the current study (including date and signature) Participating centers Designation on the available staff: number, function and qualification (education, experience in performing clinical trials), delineation on the delegated duties relevant for the current study 1. Eligibility and proof of qualification of the participating center Evaluation of the feasibility through the sponsor ( pre-study -visits) Key aspects of treatment and special focuses 2. Infrastructure: depiction of the institution including the funds and equipment relevant for the study; resource, experience and qualification in emergency care. 4.3 Ethics committee application Legal restrictions concerning ethical approval may vary in the different participating countries. It is therefore the responsibility of each national coordinating investigator of each specific country that participates in the CULPRIT-SHOCK trial to warrant, that the protocol is reviewed and approved by a local ethical committee if local rules require such review and approval. For Germany the current study is not performed under the Arzneimittelgesetz or Medizinproduktegesetz of the Federal Republic of Germany. Thus there is no official Stiftung Institut für Herzinfarktforschung and University of Lübeck 28

73 CULPRIT-SHOCK Study Protocol Version 1.2, competent authority, but instead the participating centers will apply at the particular regional ethics committees. The study protocol will be submitted initially to the ethical committee of the University of Leipzig. In addition, the study protocol will also be sent to the other ethical committees of the sites involved in the trial after ethical approval of the lead ethical committee in Leipzig, Germany. The coordinating investigator of each country will support all applications. Participation in the study can only begin after positive approval of the responsible local ethics committees. The written approval will be filed in the trial master file. Additionally, every participating center will file a copy of the approval/evaluation in the trial investigator file. 4.4 Subsequent changes of the study protocol After ethics committee approval, further changes of the study protocol can only be conducted if these modifications are again evaluated and accepted by the responsible ethics committee. Potential changes may affect: The safety of the patients, e.g. essential modifications of therapeutic regimens. Additional data assessment or analysis requiring modifications of the informed consent form. Interpretation of scientific documents on which the current study is based or which might influence the interpretation of the obtained results. The form of administration and conduction of the study. Only the coordinating investigators may carry out changes of the study protocol. However, all co-investigators can address remarks if modifications seem to be necessary. If changes in the study protocol occur, all investigators will be informed after a positive ethics committee approval and the notice has to be confirmed. Stiftung Institut für Herzinfarktforschung and University of Lübeck 29

74 CULPRIT-SHOCK Study Protocol Version 1.2, Documentation 5.1 Electronic case report forms (ecrf) To record all anonymized findings of each visit, the Institut für Herzinfarktforschung will generate an ecrf. For data entry, each study coordinator at each participating center will receive individual login information for the ecrf. The data base will be kept on the server of the Institut für Herzinfarktforschung Ludwigshafen. Data are entered by each participating center directly into the internet based ecrf. Data entered are immediately tested for plausibility in order to prevent unnecessary queries. Data will be entered via an SSL-secured internet line. The ecrf will be self-explaining. To facilitate data entry, the definitions of the various parameters will be accessible by a simple mouse click behind the related question in the ecrf. The corresponding source documents will be archived in the patients record (in- or out-patient). At the time of screening, baseline and at all other visits, relevant information on anamnesis, current medication, vital signs and clinical state will be documented on a separate and specifically prepared sheet. In case of error detection and subsequent correction, the original entry will remain readable and the correction will be signed and dated by the person authorized to amend. All relevant pages of the ecrf will be controlled for integrity and validity and electronically signed by either the local principal investigator or a co-investigator. The electronic signature serves as a verification of the ecrf. According to the ICH-guideline E6, source documents are defined as all data of the patient file, as well as all routinely assessed information including laboratory findings. 5.2 Data management Data management and statistics will be performed at the Institut für Herzinfarktforschung in Ludwigshafen, Germany. All relevant data will be assessed and documented at the local investigating sites and then send directly to the Institut für Herzinfarktforschung for further analysis. For this purpose an established study management tool of the Institut für Herzinfarktforschung will be used. For the preparation of the study database the responsible project manager in cooperation with a biometrician will design a requirement specification. This provides the basis for the database programmer, who creates the database applications. Database applications will be tested for errors and validated before release for general use. The process of validation will be documented. The data documented on the ecrf will be recorded in the electronical research database through an input mask. The data will be automatically checked for integrity, consistency and plausibility using pre-assigned checks. In case of pending unclarities (e-queries) the affected center will be immediately informed through an electronic form. Random samples of the data entered into the database may be subject to an audit. Data will be completely secured on a daily base. Due to a hierarchical, roll-based access concept an unauthorized access on patient data is impossible. Anonymity of the data is preserved. Any change on data, for e.g. due to adjustment of pending queries, will be documented through an automatic audit trail of the database. 5.3 Archiving All relevant study documents included in the trial master file and all electronically assessed data will be stored at the Institut für Herzinfarktforschung for at least 10 years after the end of the study. In the participating centers the trial investigator files, the patient identification list, as well as all consent forms and the patient files will be retained for at least 10 years after the end of the study. Other in-house regulations or legislations demanding longer retention periods (e.g. radiation control regulation, radiation protection law) should be respected. Stiftung Institut für Herzinfarktforschung and University of Lübeck 30

75 CULPRIT-SHOCK Study Protocol Version 1.2, Study survey Source data access Due to statutory provisions to ensure protection of data quality and verification of study execution, investigators are obligated to provide insight on source data to authorized third parties. This includes monitors, auditors and staff members of the responsible surveillance authorities, all bound to professional secrecy Monitoring For surveillance of the investigating centers on-site monitoring is planned for 10% of the active sites. These will be randomly selected for validation of the data entered in the ecrf against patients source data. Because of the expected high number of patients at each site, monitoring will be possible in a sample of all of the site s patients only. Sites and patients to be monitored will be randomly selected by the Institut für Herzinfarktforschung. Monitors will have to ensure that in every individual case informed consent is available before they request access to the patient s files. Additional monitoring can be carried out if indicated after evaluation of the steering committee in case of insufficient data quality or delayed ecrf input. In context of these specific monitoring visits all data relevant for the study will be controlled and eventually updated. To ensure the capability for inspections the investigators will provide access to the study-related facilities and to all files of every study participant to guarantee a complete source data verification. The exact planning and execution of the monitoring is based on the eligible SOPs of the Institut für Herzinfarktforschung and will be delineated in a monitoring manual Audits As part of this study no regular audits are planned. However, to ensure correct execution of the study, audits may be conducted if necessary Inspections As the current study is not linked to the German pharmaceutical or medicinal product act (AMG 82, 83 or MPG), no inspections of higher federal authorities are scheduled Independent surveillance of the study To ensure the safety interests of the participants, an independent DMSB will regularly evaluate the safety and efficacy of the study treatment, as well as the integrity and validity of the collected data. Additionally, the DMSB should make recommendations concerning further execution of the study (e.g. termination or modification) based on the recorded data and the planned interim analysis Data protection and confidentiality The recorded information include personal data (e.g. date of birth and gender) as well as data on medical treatment and the course of treatment (medical findings, treatment strategies, administered medication, etc.) of the study participants. These data will be electronically stored and analyzed in pseudonymized form (i.e. unrelated to the name of the patient) using an electronic identification number. Data processing will be carried out at the Institut für Herzinfarktforschung. Based on a security model, protection against unauthorized access and protection against data loss in accordance with data protection acts will be guaranteed. Data will be stored electronically and evaluated in anonymized form and any inferences in respect of the actual persons will not be possible. All data are protected from external unauthorized access as only members of the research team are permitted and enabled to access these data. In case of withdrawal of a prior given consent it will be assessed to what extent the data are still required. If data are no longer necessitated they will be erased immediately. The recorded personal data will be erased/anomyzed after completion of all study related projects, at the latest after 10 years in case no legal, statutory or contractual regulations oppose. Stiftung Institut für Herzinfarktforschung and University of Lübeck 31

76 CULPRIT-SHOCK Study Protocol Version 1.2, Administrative regulations 6.1 Study execution in accordance with the protocol The trial is planned, executed and analyzed according to ICH-GCP requirements. Protocol violations are all deviations from the directives and procedures described in this protocol. Only violation of in- and exclusion criteria are defined as major protocol violations. After inclusion of a patient, the investigator has the responsibility to avoid protocol violations, to ensure patients further participation in the study. Major protocol violations must be reported immediately to the principal investigator and the sponsor. All protocol violations will be documented and discussed with the responsible biometrician prior to analysis. The investigator has to ensure that all recorded data are documented according to the study protocol. Minor deviations can certainly not be eliminated completely; nevertheless this has to be documented including an explanatory statement. 6.2 Publishing agreement and registration After the database has been closed, the Institut für Herzinfarktforschung Ludwigshafen will hand a final report of the study to the steering committee. The steering committee owns the data that has been collected with the CULPRIT-SHOCK trial and decides on the further use of the data. It is aimed to publish the results of this clinical trial in a renowned international medical journal. In this context the study will be registered at ClinicalTrials.gov ( Authorship will be selected according to the requirements of the New England Journal of Medicine ( These indicate that every author provided such contribution to the clinical trial and the subsequent publication that he can take public responsibility for the integrity of the entire work. Therefore the credit for authorship requires substantial contributions to: 1. The conception and design or analysis and interpretation of the data. 2. The drafting of the article or critical revision for important intellectual content. 3. Final approval of the version to be published. Authors must have fundamentally taken part in all of the 3 aspects. In the Acknowledgement- Section of the publication, the names of all responsible investigators of the regional participating centers will be listed. The local centers are entitled to use the recorded data for additional scientific exploitation. Following the consultation of the steering committee the local centers may work on other scientific questions and may publish the results under their own name. For the main publication each of the 10 main centers will obtain at least 1 authorship, if the above mentioned requirements 1-3 are met. Prior to sub-publication consultation and agreement of the coordinating investigator and the steering committee are mandatory. For publications of any kind the study acronym CULPRIT-SHOCK will be used. Stiftung Institut für Herzinfarktforschung and University of Lübeck 32

77 CULPRIT-SHOCK Study Protocol Version 1.2, Definitions Death Death of all cause. Death cardiovascular Death due to cardiovascular causes, such as heart failure, cardiac arrhythmias, myocardial infarction, sudden cardiac death or all deaths of unknown cause. Severe renal failure requiring renal replacement therapy Any indication for renal replacement therapy such as dialysis, hemofiltration or hemodiafiltration such as renal failure with one of the following criteria: - Otherwise untreatable volume overload - hyperpotassemia (>6.0 mmol/l) - severe uremia (BUN >50 mg/dl or >8.4 mmol/l) - persistent severe metabolic acidosis (ph <7.2) Myocardial reinfarction The definition of myocardial reinfarction in the CULPRIT-SHOCK trial is based on the universal definition of myocardial infarction. 84 Thus, myocardial reinfarction is defined according to the specific situation (see Table 4). Re-MI <24 h Symptoms, such as angina pectoris for 20 minutes, most likely due to myocardial ischemia and or new ST-elevation 1 mm in 2 contiguous leads or new left bundle branch block or angiographic evidence of reocclusion of a previously open coronary artery or graft Re-MI 24 h 7 days Symptoms, such as angina pectoris for 20 minutes, most likely due to myocardial ischemia and or if cardiac markers are still elevated, new increase >20% from the last non-normalized measurement or if cardiac markers are normalized, application of the universal definition for myocardial infarction (see next column) Re-MI >7 days Universal definition for myocardial infarction 1. Rise and/or fall of cardiac biomarkers above the 99 th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following: Symptoms of ischemia ECG changes indicative of new ischemia Development of pathological Q waves in ECG Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 2. Sudden, unexpected cardiac death with ST-elevation and presumably new LBBB or evidence of fresh thrombus by coronary angiography, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood. 3. Peri-PCI myocardial infarction: increases of biomarkers > 3 of the upper reference level 4. Peri-CABG myocardial infarction: increases of biomarkers > 5 of the upper reference level plus new pathological Q waves or new LBBB or angiographically documented new graft or native coronary artery occlusion 5. Pathological findings of acute myocardial infarction Stiftung Institut für Herzinfarktforschung and University of Lübeck 33

78 CULPRIT-SHOCK Study Protocol Version 1.2, Repeat revascularization Any revascularization procedure (PCI or CABG) after the initial intervention. Chronic total occlusion (CTO) Complete obstruction of a coronary artery, described as 99% stenosis of >3 months duration with poor or no antegrade blood flow (TIMI 0-1). Stent thrombosis Stent thrombosis is classified in definite, probable and possible stent thrombosis according to the Academic Research Consortium (ARC) definition: 85 Definite Probable Possible Acute coronary syndrome and angiographic OR pathological confirmation of stent thrombosis Unexplained death within the first 30 days OR acute ischemia in the territory of an implanted stent without angiographic confirmation of stent thrombosis in the absence of another culprit lesion Unexplained death >30 days Bleeding complications Bleeding complications will be classified according to 3 different definitions (for further evaluation which one best predicts outcome in cardiogenic shock patients). BARC bleeding definition: 79 Type Bleeding definition Type 0 Type 1 Type 2 Type 3 Type 3a Type 3b Type 3c Type 4 no bleeding bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional (2) leading to hospitalization or increased level of care, or (3) prompting evaluation Overt bleeding plus hemoglobin drop of 3 to <5 g/dl* (provided hemoglobin drop is related to bleed) Any transfusion with overt bleeding Overt bleeding plus hemoglobin drop 5 g/dl* (provided hemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) Bleeding requiring intravenous vasoactive agents Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal) Subcategories confirmed by autopsy or imaging or lumbar puncture Intraocular bleed compromising vision CABG-related bleeding Perioperative intracranial bleeding within 48 h Reoperation after closure of sternotomy for the purpose of controlling bleeding Stiftung Institut für Herzinfarktforschung and University of Lübeck 34

79 CULPRIT-SHOCK Study Protocol Version 1.2, Type 5 Type 5a Type 5b Transfusion of 5 U whole blood or packed red blood cells within a 48-h period Chest tube output 2L within a 24-h period Fatal bleeding Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation GUSTO-definition: 86 Severe/life-threatening bleeding complications Intracranial hemorrhage or bleeding that causes hemodynamic compromise requiring intervention Moderate bleeding Bleeding that requires blood transfusion but does not result in hemodynamic compromise Mild bleeding Bleeding that does not meet criteria for either severe or moderate bleeding. TIMI definition: 87 Classification Description TIMI major Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of 5 g/dl Fatal bleeding (bleeding that directly results in death within 7 d) TIMI minor Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dl Stroke Stroke will be classified in hemorrhagic (cranial CT, MRI, or autopsy) or non-hemorrhagic Stroke is defined as an acute new neurological deficit ending in death or lasting longer than 24 hours, and classified by a physician as a stroke. 1. Primary hemorrhagic - defined as an intracerebral hemorrhage or subdural hematoma a. Intracerebral hemorrhage - Stroke with focal collections of intracerebral blood seen on brain imaging (CT or MRI) or a post-mortem examination, not felt to represent hemorrhagic conversion. Subarachnoid hemorrhage should be included in this category. b. Subdural hematoma - High density fluid collection in subdural space on brain images or blood in the subdural space on autopsy. 2. Non-hemorrhagic cerebral infarction - Stroke without focal collections of intracerebral blood on brain imaging. 3. Non-hemorrhagic infarction with hemorrhagic conversion - Cerebral infarction with blood felt to represent hemorrhagic conversion and not a primary hemorrhage. 4. Uncertain - Any stroke without brain imaging (CT or MRI) or autopsy documentation of type, or if tests are inconclusive. New congestive heart failure Occurrence of congestive heart failure after hospital discharge: Defined as; Re-hospitalization due to new or worsening heart failure >24 h after hospital discharge. Stiftung Institut für Herzinfarktforschung and University of Lübeck 35

80 CULPRIT-SHOCK Study Protocol Version 1.2, Infarct artery/culprit vessel Artery responsible for acute myocardial infarction. In general its identification is based on 1) ECG 2) Wall motion abnormalities 3) Angiographic morphology of the lesion (e.g. ulceration and/or thrombus consistent with plaque rupture). Patency of culprit vessel and additional major vessels before and after PCI (TIMI-Flow) The TIMI-flow is visually assessed according to the following grading system: 88 Grade Perfusion Characterization 0 No Perfusion No antegrade flow beyond the point of occlusion 1 Penetration without perfusion Contrast material passes beyond the area of obstruction but fails to opacify the entire coronary distal bed 2 Partial reperfusion Contrast material passes across the obstruction with delayed entry and clearance from the distal bed 3 Complete reperfusion Normal flow Hemodynamic stability criterion Sustained (> 60 min) systolic blood pressure >90 mmhg WITHOUT requirement for catecholamines AND WITHOUT signs of peripheral endorgan hypoperfusion Sepsis Sepsis is defined according to the ACCP/SCCM Consensus-conference plus additional 89, 90 elevated pro-calcitonin ( 2 pg/ml). I) Signs of infection Diagnosis of infection via microbiological evaluation or by clinical criteria II) Systemic Inflammatory Response Syndrome (SIRS) ( 2 criteria required) Body temperature >38 C or <36 C Tachycardia: Heart rate >90/min Tachypnoe: ventilation rate >20/min or hyperventilation (PaCO 2 <4,3 kpa or 33 mmhg) White blood cell count (>12.000/mm 3 ) or (<4.000/mm 3 ) or >10 % premature neutrophil granulocytes SAPS II-Score The severity of cardiogenic shock and concomitant organ dysfunction will be assessed by the SAPS II-Score. 91 This score is evaluated on a routine basis in all hospitals in Germany. The calculation of the SAPS II-Score can be done using the following link: The individual parameters of the SAPS-II-score can be found in Figure 5. Stiftung Institut für Herzinfarktforschung and University of Lübeck 36

81 CULPRIT-SHOCK Study Protocol Version 1.2, Figure 5: Parameters of the SAPS-II Score 91 Quality of life Quality of life will be assessed using the Euroqol 5D-questionnaire ( Euroqol 5D: Quality of life Mobility Self-Care Usual Activities (e.g. work, study, housework, family or leisure activities) Pain/Discomfort Anxiety/Depression In comparison to the general health state (GHS) in the past 12 months, today s GHS of the patient is Pat. has no problems in walking about Pat. has some problems in walking about Pat. is confined to bed Pat. has no problems with self-care Pat. has some problems washing or dressing himself Pat. is unable to wash or dress himself Pat. has no problems with performing his usual activities Pat. has some problems with performing his usual activities Pat. is unable to perform his usual activities Pat. has no pain or discomfort Pat. has moderate pain or discomfort Pat. has extreme pain or discomfort Pat. is not anxious or depressed Pat. is moderately anxious or depressed Pat. is extremely anxious or depressed better overall similar worse How does the patient scales his GHS today? Best imaginable GHS: 100% Worst imaginable GHS: 0% % Stiftung Institut für Herzinfarktforschung and University of Lübeck 37

82 CULPRIT-SHOCK Study Protocol Version 1.2, References 1. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med 1999;341: The TRIUMPH Investigators. Effect of Tilarginine Acetate in patients with acute myocardial infarction and cardiogenic shock. The TRIUMPH Randomized Controlled Trial. JAMA 2007;297: Thiele H, Lauer B, Hambrecht R, Boudriot E, Cohen HA, Schuler G. Reversal of cardiogenic shock by percutaneous left-atrial-to-femoral arterial bypass assistance. Circulation 2001;104: Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intraaortic balloon support versus a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005;26: Thiele H, Schuler G, Neumann FJ, et al. Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: Design and rationale of the intraaortic balloon pump in cardiogenic shock II trial (IABP-SHOCK II). Am Heart J 2012;in press. 6. Barron HV, Every NR, Parsons LS, et al. The use of intra-aortic balloon counterpulsation in patients with cardiogenic shock complicating acute myocardial infarction: data from the National Registry of Myocardial Infarction 2. Am Heart J 2001;141: Goldberg RJ, Samad NA, Yarzebski J, Gurwitz J, Bigelow C, Gore JM. Temporal trends in cardiogenic shock complicating acute myocardial infarction. N Engl J Med 1999;340: Hochman JS, Buller CE, Sleeper LA, et al. Cardiogenic shock complicating acute myocardial infarction--etiologies, management and outcome: a report from the SHOCK Trial Registry. J Am Coll Cardiol 2000;36: Thiele H, Allam B, Chatellier G, Schuler G, Lafont A. Shock in acute myocardial infarction: the Cape Horn for trials? Eur Heart J 2010;31: Zeymer U, Vogt A, Zahn R, et al. Predictors of in-hospital mortality in 1333 patients with acute myocardial infarction complicated by cardiogenic shock treated with primary percutaneous coronary intervention (PCI). Eur Heart J 2004;25: Sanborn TA, Sleeper LA, Webb JG, et al. Correlates of one-year survival in patients with cardiogenic shock complicating acute myocardial infarction: angiographic findings from the SHOCK trial. J Am Coll Cardiol 2003;42: Webb JG, Sanborn TA, Sleeper LA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK Trial Registry. Am Heart J 2001;141: Wong SC, Sanborn T, Sleeper LA, et al. Angiographic findings and clinical correlates in patients with cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. J Am Coll Cardiol 2000;36: Goldberg RJ, Gore JM, Alpert JS, et al. Cardiogenic shock after acute myocardial infarction. Incidence and mortality from a community-wide perspective, 1975 to 1988 [see comments]. N Engl J Med 1991;325: Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Gruppo Italiano per lo Studio della Streptochi-nasi nell'infarto Miocardico (GISSI). Lancet 1987;2: In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. The International Study Group [see comments]. Lancet 1990;336: Bengtson JR, Kaplan AJ, Pieper KS, et al. Prognosis in cardiogenic shock after acute myocardial infarction in the interventional era. J Am Coll Cardiol 1992;20: Disler L, Haitas B, Benjamin J, Steingo L, McKibbin J. Cardiogenic shock in evolving myocardial infarction: treatment by angioplasty and streptokinase. Heart Lung 1987;16: Stiftung Institut für Herzinfarktforschung and University of Lübeck 38

83 CULPRIT-SHOCK Study Protocol Version 1.2, Eltchaninoff H, Simpfendorfer C, Franco I, Raymond RE, Casale PN, Whitlow PL. Early and 1-year survival rates in acute myocardial infarction complicated by cardiogenic shock: a retrospective study comparing coronary angioplasty with medical treatment. Am Heart J 1995;130: Ellis SG, O'Neill WW, Bates ER, et al. Implications for patient triage from survival and left ventricular functional recovery analyses in 500 patients treated with coronary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1989;13: Gacioch GM, Ellis SG, Lee L, et al. Cardiogenic shock complicating acute myocardial infarction: the use of coronary angioplasty and the integration of the new support devices into patient management [see comments]. J Am Coll Cardiol 1992;19: Hibbard MD, Holmes DR, Jr., Bailey KR, Reeder GS, Bresnahan JF, Gersh BJ. Percutaneous transluminal coronary angioplasty in patients with cardiogenic shock [see comments]. J Am Coll Cardiol 1992;19: Lee L, Bates ER, Pitt B, Walton JA, Laufer N, O'Neill WW. Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by cardiogenic shock. Circulation 1988;78: Lee L, Erbel R, Brown TM, Laufer N, Meyer J, O'Neill WW. Multicenter registry of angioplasty therapy of cardiogenic shock: initial and long-term survival. J Am Coll Cardiol 1991;17: Meyer P, Blanc P, Baudouy M, Morand P. [Treatment of primary cardiogenic shock by coronary transluminal angioplasty during the acute phase of myocardial infarction]. Arch Mal Coeur Vaiss 1990;83: Moosvi AR, Khaja F, Villanueva L, Gheorghiade M, Douthat L, Goldstein S. Early revascularization improves survival in cardiogenic shock complicating acute myocardial infarction [see comments]. J Am Coll Cardiol 1992;19: O'Keefe JH, Jr., Bailey WL, Rutherford BD, Hartzler GO. Primary angioplasty for acute myocardial infarction in 1,000 consecutive patients. Results in an unselected population and high-risk subgroups. Am J Cardiol 1993;72:107G-15G. 28. Seydoux C, Goy JJ, Beuret P, et al. Effectiveness of percutaneous transluminal coronary angioplasty in cardiogenic shock during acute myocardial infarction. Am J Cardiol 1992;69: Verna E, Repetto S, Boscarini M, Ghezzi I, Binaghi G. Emergency coronary angioplasty in patients with severe left ventricular dysfunction or cardiogenic shock after acute myocardial infarction. Eur Heart J 1989;10: Hochman JS, Sleeper LA, White HD, et al. One-year survival following early revascularization for cardiogenic shock. JAMA 2001;285: Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction. JAMA 2006;295: Urban P, Stauffer JC, Bleed D, et al. A randomized evaluation of early revascularization to treat shock complicating acute myocardial infarction. The (Swiss) Multicenter Trial of Angioplasty for Shock-(S)MASH. Eur Heart J 1999;20: Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction - executive summary. Circulation 2004;110: Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008;29: Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010;31: Hamm CW, Bassand J-P, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2011;32: Kushner FG, Hand M, Smith SC, Jr., et al Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 39 Stiftung Institut für Herzinfarktforschung and University of Lübeck

84 CULPRIT-SHOCK Study Protocol Version 1.2, Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009;120: Babaev A, Frederick PD, Pasta DJ, Every N, Sichrovsky T, Hochman JS. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005;294: Goldberg RJ, Spencer FA, Gore JM, Lessard D, Yarzebski J. Thirty-year trends (1975 to 2005) in the magnitude of, management of, and hospital death rates associated with cardiogenic shock in patients with acute myocardial infarction: a population-based perspective. Circulation 2009;119: Jeger RV, Radovanovic D, Hunziker PR, et al. Ten-year incidence and treatment of cardiogenic shock. Ann Intern Med 2008;149: Hochman JS, Sleeper LA, Godfrey E, et al. SHould we emergently revascularize Occluded Coronaries for cardiogenic shock: an international randomized trial of emergency PTCA/CABG-trial design. The SHOCK Trial Study Group. Am Heart J 1999;137: Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;epub ahead of print:doi: /eurheartj/ehs Werdan K, Ruß M, Buerke M, et al. [German-Austrian S3-guideline: Diagnosis, monitoring, and therapy of cardiogenic shock due to myocardial infarction]. Intensivmed 2011;48: Werdan K, Ruß M, Buerke M, Delle-Karth G, Geppert A, Schöndube FA. Cardiogenic shock due to myocardial infarction: diagnosis, monitoring and treatment - A German- Austrian S3 Guideline. Dtsch Arztebl Int 2012;109: Bauer T, Zeymer U, Hochadel M, et al. Use and outcomes of multivessel percutaneous coronary intervention in patients with acute myocardial infarction complicated by cardiogenic shock (from the EHS-PCI Registry). Am J Cardiol 2012;109: White HD, Assmann SF, Sanborn TA, et al. Comparison of percutaneous coronary intervention and coronary artery bypass grafting after acute myocardial infarction complicated by cardiogenic shock: Results from the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) Trial. Circulation 2005;112: Webb JG, Lowe AM, Sanborn TA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol 2003;42: van der Schaaf RJ, Claessen BE, Vis MM, et al. Effect of multivessel coronary disease with or without concurrent chronic total occlusion on one-year mortality in patients treated with primary percutaneous coronary intervention for cardiogenic shock. Am J Cardiol 2010;105: Cavender MA, Milford-Beland S, Roe MT, Peterson ED, Weintraub WS, Rao SV. Prevalence, predictors, and in-hospital outcomes of non-infarct artery intervention during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (from the National Cardiovascular Data Registry). Am J Cardiol 2009;104: Zeymer U, Hochadel M, Mudra H, Brachmann J, Hoffmann S, Zahn R. Impact of immediate multivessel intervention on outcome of patients with multivessel disease undergoing primary PCI for cardiogenic shock. Clin Res Cardiol 2012;101 (Suppl): Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360: Mehta RH, Lopes RD, Ballotta A, et al. Percutaneous coronary intervention or coronary artery bypass surgery for cardiogenic shock and multivessel coronary artery disease? Am Heart J 2010;159: Toma M, Buller CE, Westerhout CM, et al. Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial. Eur Heart J 2010;31: Stiftung Institut für Herzinfarktforschung and University of Lübeck

85 CULPRIT-SHOCK Study Protocol Version 1.2, Cardarelli F, Bellasi A, Ou FS, et al. Combined impact of age and estimated glomerular filtration rate on in-hospital mortality after percutaneous coronary intervention for acute myocardial infarction (from the American College of Cardiology National Cardiovascular Data Registry). Am J Cardiol 2009;103: Lee JH, Park HS, Chae SC, et al. Predictors of six-month major adverse cardiac events in 30-day survivors after acute myocardial infarction (from the Korea Acute Myocardial Infarction Registry). Am J Cardiol 2009;104: Kornowski R, Mehran R, Dangas G, et al. Prognostic impact of staged versus "one-time" multivessel percutaneous intervention in acute myocardial infarction: Analysis from the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial. J Am Coll Cardiol 2011;58: Hannan EL, Samadashvili Z, Walford G, et al. Culprit vessel percutaneous coronary intervention versus multivessel and staged percutaneous coronary intervention for STsegment elevation myocardial infarction patients with multivessel disease. JACC Cardiovasc Interv 2010;3: Bauer T, Zeymer U, Hochadel M, et al. Prima-vista multi-vessel percutaneous coronary intervention in haemodynamically stable patients with acute coronary syndromes: Analysis of over patients in the EHS-PCI registry. Int J Cardiol Khattab AA, Abdel-Wahab M, Rother C, et al. Multi-vessel stenting during primary percutaneous coronary intervention for acute myocardial infarction. A single-center experience. Clin Res Cardiol 2008;97: Di Mario C, Sansa M, Airoldi F, et al. Single vs multivessel treatment during primary angioplasty: results of the multicentre randomised HEpacoat for culprit or multivessel stenting for Acute Myocardial Infarction HELP AMI Study. Int J Cardiovasc Intervent 2004;6: Politi L, Sgura F, Rossi R, et al. A randomised trial of target-vessel versus multi-vessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up. Heart 2010;96: Vlaar PJ, Mahmoud KD, Holmes Jr DR, et al. Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: A pairwise and network meta-analysis. J Am Coll Cardiol 2011;58: Bangalore S, Kumar S, Poddar KL, Ramasamy S, Rha S-W, Faxon DP. Meta-analysis of multivessel coronary artery revascularization versus culprit-only revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease. Am J Cardiol 2011;107: Navarese E, De Servi S, Buffon A, Suryapranata H, De Luca G. Clinical impact of simultaneous complete revascularization vs. culprit only primary angioplasty in patients with ST-elevation myocardial infarction and multivessel disease: a meta-analysis. J Thromb Thrombolysis 2011;31: Santa-Cruz RA, Cohen MG, Ohman EM. Aortic counterpulsation: a review of the hemodynamic effects and indications for use. Cath Cardiovasc Inter 2006;67: Sjauw KD, Engstrom AE, Vis MM, et al. A systematic review and meta-analysis of intra aortic balloon pump therapy in ST-elevation myocardial infarction: should we change the guidelines? Eur Heart J 2009;30: Thiele H, Schuler G, Neumann F-J, et al. Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: Design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. Am Heart J 2012;163: Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;epub ahead of print. 69. Lowel H, Meisinger C, Heier M, Hörmann A, von Scheidt W. [Myocardial infarction and coronary mortality in Southern Germany]. Deutsches Ärzteblatt 2006;103: Thom T, Haase N, Rosamund W, et al. Heart disease and stroke statistics-2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcomittee. Circulation 2006;113:e85-e151. Stiftung Institut für Herzinfarktforschung and University of Lübeck 41

86 CULPRIT-SHOCK Study Protocol Version 1.2, Thiele H, Schuler G. Cardiogenic shock: To pump or not to pump? Eur Heart J 2009;30: Ambrose JA, Weinrauch M. Thrombosis in ischemic heart disease. Arch Intern Med 1996;156: Thiele H, Hildebrand L, Schirdewahn C, et al. Impact of high-dose N-acetylcysteine versus placebo on contrast-induced nephropathy and myocardial reperfusion injury in unselected patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol 2009;in press. 74. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006;354: Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44: Allen LA, Hernandez AF, O'Connor CM, Felker GM. End points for clinical trials in acute heart failure syndromes. J Am Coll Cardiol 2009;53: Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012;367: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation 2011;123: Prondzinsky R, Lemm H, Swyter M, et al. Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock - the prospective, randomized IABP SHOCK Trial for attenuation of multi-organ dysfunction syndrome. Crit Care Med 2010;38: O Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35: Gesetz über Verkehr mit Arzneimitteln (Arzneimittelgesetz AMG) in der Fassung der Bekanntmachung vom 05. August BGBI I 2004: Verordnung über die Anwendung der Guten Klinischen Praxis bei der Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen (GCP-Verordnung - GCP-V) in der Fassung der Bekanntmachung vom 12.August BGBI I 2004: Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Circulation 2007;116: Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. Circulation 2007;115: The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991;115: The TIMI Research Group. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI II A results. JAMA 1988;260: ACCP/SCCM Consensus Conference Committee. Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20: S-2 Leitlinien der Deutschen Sepsis-Gesellschaft e.v. (DSG) und der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI). Diagnose und Therapie der Sepsis. Clin Res Cardiol 2006;95: Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993;270: Stiftung Institut für Herzinfarktforschung and University of Lübeck 42

87 CULPRIT-SHOCK Study Protocol Version 1.2, Signature Page Prof. Dr. med. Holger Thiele Medizinische Klinik II, Universität Lübeck, Germany Lübeck, Place, Date Prof. Dr. med. Uwe Zeymer Institut für Herzinfarktforschung, Ludwigshafen, Germany Ludwigshafen, Place, Date Stiftung Institut für Herzinfarktforschung and University of Lübeck 43

88 STATISTICAL ANALYSIS PLAN CULPRIT-SHOCK TRIAL Version: 1.0 Date SAP last modified: March 18 th 2015 Authors: Dr. Tobias Limbourg Statistician IHF GmbH Stiftung Institut für Herzinfarktforschung GmbH (IHF GmbH) Bremserstr Ludwigshafen am Rhein, Germany IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 1

89 Approvals The undersigned have reviewed the GSR SAP draft, and agree with its contents. Prof. Dr. Holger Thiele, Lübeck, Principal Investigator Prof. Dr. Uwe Zeymer, Ludwigshafen, Co-Principal Investigator PD Dr. Steffen Desch, Lübeck, Co-Principal Investigator Dr. Tobias Limbourg, Ludwigshafen, Study Statistician IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 2

90 Content 1. The CULPRIT-SHOCK trial and statistical analysis plan (SAP) Aim of the CULPRIT-SHOCK trial Inclusion criteria Exclusion criteria Sample size calculation Aim of the statistical analysis plan Data handling & General considerations Statistical software and responsibilities Statistical tables Handling of missing values Definition of primary and secondary endpoints, events, event periods and time-to-event analysis Event rates Event periods Survivor-only analyses Primary endpoint Secondary endpoints Event rate endpoints Clinical events and measurements Safety aspects Definition of study populations Safety population ITT-population PP population As-treated population Statistical analysis Interim analysis Final analysis IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 3

91 1. The CULPRIT-SHOCK trial and statistical analysis plan (SAP) 1.1. Aim of the CULPRIT-SHOCK trial The CULPRIT-SHOCK trial is a prospective, randomized, international, multicenter, open-label study to compare immediate multivessel revascularization by percutaneous coronary intervention (PCI) to culprit lesion only PCI with potentially staged non-culprit lesion revascularization in patients with cardiogenic shock complicating acute myocardial infarction presenting with multivessel disease. Despite aggressive treatment modalities such as PCI as well as mechanical and inotropic support, mortality of cardiogenic shock complicating acute myocardial infarction remains at a very high level. The majority of patients with cardiogenic shock present with multivessel coronary artery disease and the mortality of these patients is higher than in patients with single vessel disease. From a pathophysiological standpoint, it might be beneficial to reperfuse all relevant coronary arteries with significant stenosis in addition to the culprit lesion to improve myocardial perfusion. On the other hand, immediate multivessel PCI might pose additional risk for the patients. However, there are no randomized clinical trials assessing the optimal reperfusion strategy. This trial examines if culprit vessel only PCI with potentially subsequent staged revascularization in comparison to immediate multivessel revascularization by PCI in patients with cardiogenic shock complicating acute myocardial infarction reduces the incidence of 30-day mortality or severe renal failure requiring renal replacement therapy. In addition, it aims to confirm a potential advantage at long-term follow-up. Therefore, a 6- and 12-month follow-up will be performed which will also encompass rehospitalization for congestive heart failure and recurrent infarction among other clinical endpoints Inclusion criteria All patients with cardiogenic shock complicating acute myocardial infarction (STEMI or NSTEMI) will be included if they fulfill the following criteria. Cardiogenic shock complicating acute myocardial infarction (STEMI or NSTEMI) with obligatory: Planned early revascularization by PCI Multi essel oro ary artery disease defi ed as > 0% ste osis i at least 2 ajor essels ( 2 mm diameter) with identifiable culprit lesion Systolic blood pressure <90 mmhg for >30 min or catecholamines required to maintain pressure >90 mmhg during systole and Signs of pulmonary congestion Signs of impaired organ perfusion with at least one of the following criteria: o Altered mental status o Cold, clammy skin and extremities IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 4

92 Informed consent o Oliguria with urine output <30 ml/h o Serum lactate >2.0 mmol/l 1.3. Exclusion criteria Patients will be excluded if they meet one of the following exclusion criteria. Resuscitation >30 minutes No intrinsic heart action Cerebral deficit with fixed dilated pupils (not drug-induced) Need for primary urgent bypass surgery (to be determined after diagnostic angiography) Single vessel disease Mechanical cause of cardiogenic shock Onset of shock >12 h Massive lung emboli Age >90 years Shock of other cause (bradycardia, sepsis, hypovolemia, etc.) Other severe concomitant disease with limited life expectancy <6 months Pregnancy Known severe renal insufficiency (creatinine clearance <30 ml/min) 1.4. Sample size calculation The sample size is defined in the study protocol. The primary endpoint of the CULPRIT-SHOCK trial is a composite of all-cause death and severe renal failure requiring renal replacement therapy, both within 30 days after randomization. The 30-day mortality of patients with multivessel disease and cardiogenic shock undergoing immediate multivessel PCI is approximately 50% as indicated in several registries (see Table 1 in study protocol for details). The 30-day death rate in the culprit lesion only group is supposed to be 39% based on reported mortality rates from registries. These assumptions are at the lower end of the estimated difference in mortality reduction by culprit lesion only PCI with current registry data suggesting an absolute mortality reduction of 7-35% and the most recent data suggesting 11%. It should, however, be taken into account that registry data might overestimate treatment effects and therefore a conservative estimate is justified. The incidence of severe renal failure requiring renal replacement therapy is estimated to be absolutely 2% lower in the culprit lesion only group. Based on these data and with regard to the combined primary endpoint of death and renal replacement therapy, event rates of 50% in the multivessel PCI group vs. 38% in the culprit lesion IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 5

93 only group were used for sample size calculation. A total of 684 patients are needed to test the null hypothesis of no difference between groups (test criterion: two-sided test Chi 2 test; power: 80%, alpha: for final analysis). Allowing for a 3% dropout rate, 706 patients will be recruited. Based on previous clinical trials a higher dropout rate is not expected. The software used for sample size calculation was nquery Advisor 7.0, Statistical Solutions, Cork, Ireland Aim of the statistical analysis plan This statistical analysis plan (SAP) aims to describe in detail the definitions and statistical methods to be implemented for the primary and secondary endpoint analysis in the CULPRIT- SHOCK trial. Specifically, the plan has the purpose to prospectively define the study populations and endpoints and outline the types of analyses and presentations of data used. The SAP is based on the relevant sections of the CULPRIT-SHOCK study protocol, version 1.2., December 1 st Data handling & General considerations 2.1. Statistical software and responsibilities The statistical analyses will be performed at the Institut für Herzinfarktforschung (IHF GmbH), Bremserstr. 79, D Ludwigshafen a. Rh., Germany. Dr. Tobias Limbourg, will process the data, perform all statistical analyses and prepare the interim and final analysis of endpoints, as well as statistical tables and reports. The statistical analysis system SAS, release 9.3 (Cary, NC, U.S.A.) will be used for the statistical calculations. This package is in widespread use and is accepted as valid by national and international agencies Statistical tables All items shown in the CULPRIT-SHOCK electronic Case Report Form (ecrf) at baseline and at each follow-up will be presented in a descriptive fashion in tabulated form. Categorical variables will be shown as counts and percentages of patients in each category. Continuous variables will be presented as means with standard deviation (SD), median with interquartile range, range (minimum value and maximum value), and number of known values. Rates for events and complications (only the first event or complication for each type is counted) are shown at each follow-up in a cumulative fashion and will be presented as Kaplan-Meier plots. The presentation of variable and tables will follow the order in which the sections are shown in the ecrf. Values recorded in more than one SI unit (e.g. lab units) will be converted into a single appropriate SI unit. IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 6

94 2.3. Handling of missing values For the majority of variables no imputation of missing values will be performed. However, data needed for the calculation of time to first event rates that are relevant for primary or secondary endpoints (e.g. randomization date, date of event) will be imputed by randomly choosing a survival time that follows the distribution of survival times in the CULPRIT-SHOCK population. 3. Definition of primary and secondary endpoints, events, event periods and time-to-event analysis The aim of the CULPRIT-SHOCK trial is to test whether culprit lesion only PCI with potentially subsequent staged revascularization is beneficial over immediate multivessel revascularization by PCI in patients with acute myocardial infarction and cardiogenic shock. This will be achieved by comparing the event rates of the primary endpoint, i.e. the composite of all-cause death and severe renal failure requiring renal replacement therapy within 30 days after randomization, between the group with immediate multivessel revascularization and the group with culprit lesion only PCI Event rates Event rates for death at 30 days, 6 and 12 months severe renal failure requiring renal replacement therapy until 30 days rehospitalization for congestive heart failure and recurrent infarction until 30 days, 6 and 12 month and any combination of the above mentioned events as composite endpoints are being determined by means of time to first event calculation, defined as the time in days between randomization date and the date of the first event related to a given primary or secondary endpoint or safety related event. IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 7

95 3.2. Event periods The event periods of interest for which event rates will be calculated are 30 days, 6 months (183 days) and 12 months (365 days). Any patient with an event related to one of the endpoints will count for that event when the days to the first event are smaller or equal 30 for the 30 days period, smaller or equal 183 for the 6 months period and smaller or equal 365 for the 12 months period. If the patient is event free or the number of days to first event is greater than the upper border of the observation period, then the patient will not count for that event and will only add to the denominator of the event rate. Patients without information on vital status or with no observations post discharge will not be analyzed Survivor-only analyses A number of analyses will be performed for survivors only. Survivors are defined as patients who survive throughout a given period, i.e. the 30-day period, the 6 months period and the 12 months period. Thus, a patient may be a survivor for the 30-day period, but not for the 6 and 12 months period. Survivor-only analyses are specified in the chapter for secondary endpoints Primary endpoint The primary endpoint of the study is the composite of all-cause death or severe renal failure requiring renal replacement therapy within 30 days after randomization. Severe renal failure requiring renal replacement therapy is defined as any indication for renal replacement therapy such as dialysis, hemofiltration or hemodiafiltration such as renal failure with one of the following criteria: Otherwise untreatable volume overload hyperpotassemia (>6.0 mmol/l) severe uremia (BUN >50 mg/dl or >8.4 mmol/l) persistent severe metabolic acidosis (ph <7.2) Death and renal failure requiring renal replacement therapy and the date of occurrence are part of the CULPRIT-SHOCK ecrf. IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 8

96 3.5. Secondary endpoints There are a number of event rates and clinical events and measurements that are relevant as secondary endpoints Event rate endpoints 30-day all-cause mortality. 30-day renal failure with requirement of renal replacement therapy. Survivor-only analysis. All-cause death at 6 months and 12 months post randomization Recurrent infarction within 30 days, 6 and 12 months follow-up. Survivor-only analysis. Death or recurrent infarction at 6 and 12 months follow-up Rehospitalization for congestive heart failure within 30 days, 6 and 12 months follow-up. Survivor-only analysis. Death or recurrent infarction or rehospitalization for congestive heart failure within 30 days, 6 and 12 months Need for repeat revascularization (PCI or CABG) within 30 days, 6 and 12 months followup. Survivor-only analysis. Death, severe renal failure requiring renal replacement therapy, rehospitalization for congestive heart failure and repeat revascularization (PCI or CABG) are part of the CULPRIT-SHOCK ecrf, together with the respective date for each event, and can thus be used to calculate event rates according to this SAP Clinical events and measurements All secondary endpoints related to clinical events are analyzed only for patients that survive until discharge. Procedural success, defined as TIMI 3 patency and no remaining stenosis >70% in major vessels Time to hemodynamic stabilization, defined as number of days between randomization (PCI) date and the date of sustained (> 60 min) systolic blood pressure >90 mmhg without requirement for catecholamines and without signs of peripheral endorgan hypoperfusion. Time to hemodynamic stability in days and catecholamine requirement as start and end times per day of treatment are separate parts of the ecrf, while information on signs of peripheral end organ hypoperfusion is not being collected. The time to hemodynamic stabilization will be thus being re-defined as the earliest time by which the patients is hemodynamic stable and receives no catecholamines. Duration of catecholamine therapy, in days treated with catecholamines between randomization and hospital discharge. A day treated with catecholamines is any day IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 9

97 during the hospital period on which a start and end time for the catecholamines epinephrine, norepinephrine, dobutamine or dopamine was entered in the ecrf. Creatinine-clearance (calculated by the Cockcroft-Gault-Formula) 78 until stabilization, presented as the median of all measurements between randomization and the date of hemodynamic stabilization. SAPS-II score until stabilization, presented as the median of all measurements between randomization and the date of hemodynamic stabilization. Length of mechanical ventilation. Defined as the number of days any start- and end-time for mechanical ventilation was entered in the ecrf. Length of ICU-stay. Defined as the number of days between randomization date and the date of ICU discharge. Peak creatine kinase, creatine kinase-mb and troponin level during hospital stay. Only the highest value of all available measurements of the aforementioned variables is taken into account. Quality of life at 6 and 12 months assessed using Euro QOL 5D (EQ-5D-3L) questionnaire. The EQ5D Index will be calculated for patients with complete EQ5D data Safety aspects The safety of the two procedure variants is assessed by the rate of patients with occurrence of bleeding and stroke. Both endpoints will be analyzed for survivors only, as time to first event analyses. Bleeding is defined as bleeding events with BARC-definition types 2-3 and 5. Stroke is defined as any new neurological symptom in association with signs of ischemia or hemorrhage in a cranial CT or MRI. 4. Definition of study populations There are a number of pre-defined study populations in the CULPRIT-SHOCK trial. The intentionto-treat population (ITT population) is the population of interest from which the relevant results will be derived. Other populations may be analyzed with lower importance, for instance to test whether the results from the ITT population are repeatable or for safety reasons Safety population All patients included in the study are part of the safety population. IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 10

98 4.2. ITT-population All data will be analyzed according to the intention-to-treat principle. All randomized patients that do not violate the in- or exclusion criteria are part of the ITT population. However, patients with no information on vital status at 30 days will be excluded from ITT analyses, except those with documented renal failure requiring renal replacement therapy PP population The per-protocol (PP) population is defined by pts. fulfilling the in- and exclusion criteria and non-cross over patients undergoing successful or unsuccessful revascularization. Cross-over patients are any ITT subjects that undergo a different treatment than the defined treatment for the group it has been allocated to by the randomization. Patients who die before the start of revascularization or who do not undergo any revascularization attempt for other reasons will not be included in the PP analysis. In addition, patients with significant deviations from the study protocol will be excluded from the PP population. The decision of a significant deviation from the study protocol will be made by the steering committee of the CULPRIT-SHOCK trial. A sensitivity analysis according to the PP population evaluating the robustness of the data will be performed As-treated population The as-treated population contains all patients from the PP population grouped according to treatment actually received (i.e. cross-over patients will be counted towards the treatment actually received). 5. Statistical analysis 5.1. Interim analysis Since the presumed event rates in both groups are derived from registry data, these might be prone to error. Therefore, a group sequential statistical design with one interim analysis will be chosen. The interim analysis will be performed using the O'Brien-Fleming method without any specified alpha spending function. Thus, the analysis will be equally spaced in terms of the numbers of patients involved at the interim analysis and will be performed after 50% (342) of all analyzable patients have completed 30-day follow-up. The global type I error level is set at The trial will be discontinued if the null hypothesis of equal event rates can be rejected with a IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 11

99 significance level of at the interim analysis. In case of trial discontinuation at the interim analysis, secondary endpoints will be analyzed before finalization of the trial Final analysis All data will be analyzed according to the ITT principle. A sensitivity analysis according to the PP population evaluating the robustness of the data will also be performed. Event rates for the primary and secondary endpoints will be tested by means of the Chi 2 tests. Secondary endpoints based on continuous/numerical variables will be performed with the Wilcoxon test. The analysis of the primary endpoint will e perfor ed ith α=0.0 i order to eet the o erall significance level. Secondary endpoints will be analyzed ith a α of 0.0. Prior to the analysis of the primary endpoint a number of univariate analyses will be performed, comparing all items from the following ecrf chapters between the treatment groups: Admission Clinical and laboratory parameters Medical history Cardiovascular risk factors ECG If no variable differs significantly between treatment groups (i.e. all p >0.05) Chi 2 tests will be performed to test for differences between the treatment groups. However, the primary endpoint will be tested by means of stepwise logistic regression analysis in case that one or more variables turn out to be significantly different between the treatments groups. All variables with a p <0.05 in the previously described univariate comparison will be entered in the stepwise logistic regression model, which will be adjusted for all variable remaining in the model after the stepwise selection process. Additionally, Kaplan-Meier curves will be calculated to visualize the cumulative events in both groups during the 30-day follow-up period. A Forest plot with odds ratios resulting from univariate comparisons between the treatment groups will be shown for the predefined subgroups as defined below. Finally, to determine independent predictors for the primary endpoint a logistic regression analysis will be performed. Variables for the model will be chosen by a univariate comparison between patients that reached the primary endpoint at 30 days versus patients that did not reach the endpoint. All significant variables will be entered in the model from which the final model will be chosen by stepwise selection. Predefined subgroup analyses will be performed for gender, age groups <50 years versus years versus >75 years, diabetes versus no diabetes, arterial hypertension versus none, STEMI IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 12

100 versus NSTEMI, anterior myocardial infarction versus infarct at another location, previous infarction vs none, and 2- versus 3-vessel disease. Also, patients with complete revascularization will be compared to patients that did not underdo complete revascularization. IHF GmbH and University of Lübeck Statistical Analysis Plan Final CULPRIT-SHOCK trial 13

101 STATISTICAL ANALYSIS PLAN CULPRIT-SHOCK TRIAL Version: 1.1 Date SAP last modified: August 3 rd 2017 Author: Dr. Steffen Schneider Stiftung Institut für Herzinfarktforschung Bremserstr Ludwigshafen am Rhein, Germany IHF GmbH and University of Lübeck Statistical Analysis Plan CULPRIT-SHOCK trial 1

102 Approvals The undersigned have reviewed the Culprit-Shock SAP, and agree with its contents. Prof. Dr. Holger Thiele, Lübeck, Principal Investigator Date Prof. Dr. Uwe Zeymer, Ludwigshafen, Co-Principal Investigator Date PD Dr. Steffen Desch, Lübeck, Co-Principal Investigator Date Dr. Steffen Schneider, Ludwigshafen, Study Statistician Date IHF GmbH and University of Lübeck Statistical Analysis Plan CULPRIT-SHOCK trial 2