Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction

Transcription

1 Faculty of Health Sciences, University of Aarhus AARHUS AU UNIVERSITY Doctoral thesis Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction

2 Doctoral thesis Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction Faculty of Health Aarhus University 2012

3 Members of the assessment committee Johan Herlitz, Professor, med.dr., Department of cardiology, Sahlgrenska University Hospital, Göteborg, Sweden Peter Clemmensen, Professor, DmSc, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Kristian Thygesen (Chairman), Professor, DmSc, Department of cardiology B, Aarhus University Hospital, Aarhus, Denmark. Denne afhandling er i forbindelse med de på næste side offentliggjorte artikler af Faculty of Health, Aarhus Universitet antaget til offentligt forsvar for den medicinske doktorgrad. Aarhus Universitet, den 6. juni 2012 Allan Flyvbjerg, Dekan. The Faculty of Health, Aarhus University, Denmark has approved this dissertation for public defense. The public lecture and defense will take place August 31, 2012 at in Auditorium 424, level 4, building 1231, Wilhelm Meyers Allé, Aarhus University.

4 Preface The studies included in this thesis were performed during my employment at Department of Cardiology B, Skejby University Hospital ( ). I would like to express my gratitude to Henning Rud Andersen. He initially introduced me to the research facilities, and he convinced me that use of telemedicine was worth evaluating in a Ph.d. study. During the years he has given me excellent scientific support. I also want to thank Jens Flensted Lassen. He helped me through the Ph.d. study as my project supervisor, and has been a true mentor and friend ever after. Professor Hans Erik Bøtker is thanked for his great support during the years, his personal advice and encouragement. I m grateful to Leif Thuesen who together with Jens facilitated access to the Western Denmark Heart Registry. This registry has become an important source of data for my latest publications. Likewise, I am grateful to Bjarne Linde Nørgaard for his friendship, fruitful discussions, advice, support, and tremendous help during the years. Professor Torsten Toftegaard Nielsen is thanked for his advice and support during many years. Werner Vach, Professor, Ph.d., Department of Statistics, Freiburg Medical Centre, Germany, is thanked for statistical support. I ve always been fascinated by statistics, but Werner makes even complex statistics easy to understand. Søren Paaske Johnsen is likewise thanked for his support and epidemiological advice. Also thanks to my dear colleagues at the catheterization laboratory: Anne, Evald, Lars, Steen and Michael, who not only has helped collecting data to the studies, but also has taught me percutaneous coronary intervention (PCI). Thanks to Steen Hvitfeldt Poulsen and Christian Gerdes for helping me with the Echocardiographic examinations in the early studies. It has been a great experience and true fun to work as supervisor for a number of previous, current, and upcoming Ph.d.-students: Jacob Thorsted Sørensen, Mads Peter Andersen, Carsten Stengaard, Niels Henrik Krarup, Michael Ringborn and Tinne Tranberg. Special thanks should be given to a great number of people without whom the studies would have been impossible to perform: years. I m glad that You always make it clear when it is time to take a break from research and clinical work. Also thanks to my children, Jacob, Jonas, and Sofie. Funding A number of funding sources and public institutions made the studies and/or presentations possible. In alphabetic order: Astra Zenecas travel grant, Aarhus University, Desire and Niels Ydes Foundation, Elin Holms Foundation, Helga and Peter Kornings Foundation, Karl G Andersons Foundation, Kirsten Anthonius Foundation, Mary de Lancy Petersens Foundation, Murermester Lauritz Peter Christensen and wife Kirsten Sigrid Christensens Foundation, Lægernes forsikringsforening af 1891 I samarbejde med Tryg, Snedkermester Sophus Jacobsen and wife Astrid Jacobsens Foundation, The Arvid Nilsson foundation, The A.P. Møller Foundation for the Advancement of Medical Science, The Bønnelykke Foundation, The Danish Heart Foundation, The Health Research Fund of Central Denmark Region, The John and Birthe Meier Foundation, The Laerdal Foundation of acute Medicine, The Research Foundation at Skejby University Hospital, and The Riisfort Foundation. September 2011 Skejby University Hospital: Nurses at the catheterization laboratory and Department of Cardiology B1 are thanked for their outstanding patience and help with collection of data during the years. Randers and Silkeborg County Hospital: Frode Kirketerp Rømer, Liv Bjørn-Hansen Gøtzsche and Tage Jensen, as well as doctors and nurses at the departments of medicine are thanked for their support and help. Falck, Denmark: Sven Trautner and Jens Peter Ankersen are thanked for their support, help and enthusiasm. Finally I want to thank Louise for her never-ending support and faith in me, and for her patience through the Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 3

5 Table of Contents Preface... 3 Funding List of Papers... 5 Abbreviations, acronyms, and definitions Introduction Aims Methodological aspects Study designs and populations Statistics Methods for sampling and analysing continuous ECG monitoring data and 12-lead ECGs Mortality in patients with AMI Delay to reperfusion Earlier reperfusion therapy with PPCI: impact on mortality Earlier reperfusion therapy with PPCI: impact on readmission due to heart failure The time-window for PPCI: PCI-related delay Mortality reduction achieved by field-triage of patients with STEMI directly to invasive centers Statistical considerations in observational studies Interaction between covariates Overadjustment Continuous ECG-monitoring for pre- and per-interventional risk-stratification of patients Spontaneous ST-resolution and the ST-peak phenomenon during PPCI Accelerated idioventricular rhythm during PPCI The optimal reperfusion strategy Future perspectives Summary and conclusions Danish summary and conclusions PAPER I...22 PAPER II...38 PAPER III...46 PAPER IV...55 PAPER V...64 PAPER VI...70 PAPER VII...79 PAPER VIII

6 List of Papers The present dissertation is based on the following original peer reviewed papers. The papers and related studies are referred to by their Roman numerals in the text. The papers are arranged according to the year of publication. I. Terkelsen CJ, Lassen JF, Nørgaard BL, Gerdes JC, Jensen T, Gøtzsche LBH, Nielsen TT, Andersen HR. Mortality rates in patients with ST-elevation versus non-st-elevation acute myocardial infarction. Observations from an unselected cohort. Eur Heart J 2005, 26: II. Terkelsen CJ, Lassen JF, Nørgaard BL, Gerdes JC, Poulsen SH, Bendix K, Ankersen JP, Gøtzsche LBH, Rømer FK, Nielsen TT, Andersen HR. Reduction of treatment delay in patients with ST-elevation myocardial infarction: impact of prehospital diagnosis and direct referral to primary percutanous coronary intervention. Eur Heart J 2005, 26:770-7 III. Terkelsen CJ, Norgaard BL, Lassen JF, Poulsen SH, Gerdes JC, Sloth E, Gøtzsche LBH, Romer FK, Thuesen L, Nielsen TT, Andersen HR. Potential significance of spontaneous and interventional ST-changes in patients transferred for primary percutaneous coronary intervention: observations from the ST-MONitoring in Acute Myocardial Infarction study (The MONAMI study). Eur Heart 2006;27: IV. Terkelsen CJ, Kaltoft AK, Nørgaard BL, Bøttcher M, Lassen JF, Clausen K, Nielsen SS, Thuesen L, Nielsen TT, Bøtker HE, Andersen HR. ST changes before and during primary percutaneous coronary intervention predict final infarct size in patients with ST elevation myocardial infarction. J Electrocardiol 2009; 42: V. Terkelsen CJ, Sørensen JT, Kaltoft AK, Nielsen SS, Thuesen L, Bøtker HE, Lassen JF. Prevalence and significance of accelerated idioventricular rhythm in ST-Elevation myocardial infarction patients treated with primary percutaneous coronary intervention. Am J Cardiol 2009; 104: VI. Terkelsen CJ, Sørensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S, Vach W, Johnsen SP, Thuesen L, Lassen JF. Health Care System Delay and Mortality among patients with ST-Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention. JAMA 2010;304: VII. Terkelsen CJ, Jensen LO, Tilsted HH, Trautner S, Johnsen SP, Vach W, Bøtker HE, Thuesen L, Lassen JF. Health Care System Delay and Heart Failure in Patients with ST-Elevation Myocardial Infarction. Annals of Int Med 2011;155(6): VIII. Terkelsen CJ, Jensen LO, Tilsted HH, Thaysen P, Ravkilde J, Johnsen SP, Trautner S, Andersen HR, Thuesen L, Lassen JF. Primary Percutaneous Coronary Intervention implemented as a national reperfusion strategy in patients with ST-Elevation Myocardial Infarction. Circ Cardiovasc Intervention 2011; 4(6): Paper I & II have previously been included in the Ph.d. thesis with the title: Telemedicine in the prehospital evaluation of patients with acute myocardial infarction, Aarhus University, 2004, public defence The papers numbered III- VIII have not been included in a previous thesis. Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 5

7 Abbreviations, acronyms, and definitions AAR Area At Risk ACC American Colleges of Cardiology ACS Acute Coronary Syndrome AHA American Heart Association AIVR Accelerated Idioventricular Rhythm AMI Acute Myocardial Infarction BBB Bundle Branch Block BBBMI Bundle Branch Block Myocardial Infarction CCU Coronary Care Unit CHF Congestive Heart Failure DANAMI-2 DANish trial in Acute Myocardial Infarction 2 D2B delay Door-to-Balloon delay = Time from arrival at the invasive center to first balloon inflation D2N delay Door-to-Needle delay = Time from arrival at the hospital to initiation of fibrinolysis ECG Electrocardiogram EHS-ACS European Heart Survey of Acute Coronary Syndromes EMS Emergency Medical Services ER Emergency Room ESC European Society of Cardiology Field-triage Triage of patients from the scene of event directly to the invasive center FIS Final Infarct Size GRACE Global Registry of Acute Coronary Events Health care system delay Time from contact to the health care system to reperfusion therapy ICU Intensive Care Unit IS Infarct Size IQR Inter-Quartile Range LBBB Left Bundle Branch Block LVEF Left Ventricular Ejection Fraction MI Myocardial Infarction MONAMI The ST-MONitoring in AMI patients registry MONICA MONItoring of trends and determinants in CArdiovascular disease NRMI National Registry of Myocardial Infarction NSTEMI Non-ST-Elevation Myocardial Infarction NonSTEMI NSTEMI On scene At the scene of event = at the location where the patient is picked up Patient delay Time from symptom onset to contact with the health care system PCI Percutaneous Coronary Intervention PCI-related delay The extra delay associated with performing PPCI instead of administering fibrinolysis PPCI Primary Percutaneous Coronary Intervention Primary PCI Primary Percutaneous Coronary Intervention Prehospital delay Time from symptom onset to admission to a hospital Prehospital system delay Time from contact with the health care system to admission to a hospital RA Reperfusion Arrhythmias RBBB Right Bundle Branch Block SPECT Single Photon Emission Computerized Tomography SpontSTR Spontaneous ST-Resolution before PPCI STEMI ST-Elevation Myocardial Infarction STM ST level at J+ 1/16 of the average RR interval ST-peak Increase in ST-elevation during PPCI System delay Time from contact with the health care system to reperfusion therapy Telemedicine centre Centre where prehospital diagnoses are established with the use of telemedicine TIMI Thrombolysis In Myocardial Infarction TnT Troponin T Treatment delay Time from symptom onset to reperfusion therapy UAP Unstable Angina Pectoris VF Ventricular Fibrillation VT Ventricular Tachycardia 6

8 1. Introduction Ischemic heart disease is the leading cause of death in the western world. The incidence of acute myocardial infarction (AMI) is approximately per year in Denmark, of whom 25%-30% dies in the prehospital phase 1-3. Approximately Danish patients are being hospitalized with their first AMI each year. Among the latter one-year mortality is around 20% 4. In patients with AMI, the presenting electrocardiogram (ECG) is used to distinguish between three subtypes of AMI: ST-Elevation Myocardial Infarction (STEMI) in case of ST-elevation in two or more contiguous leads, Bundle Branch Block Myocardial Infarction (BBBMI) in case of newly developed Bundle Branch Block (BBB), and Non-ST-segment Elevation Myocardial Infarction (NSTEMI) in the remaining cases 5. This classification is used to stratify therapy 6-9. In patients with STEMI and BBBMI urgent reperfusion therapy is crucial, with either fibrinolysis 10 or primary percutaneous coronary intervention (PPCI) 9. Ten years ago there was limited evidence regarding the impact of time to reperfusion on outcome, as well as the potential benefit achieved if diagnoses were established already in the prehospital phase. At that time, the diagnosis and choice of reperfusion therapy was determined after patients were admitted to a local hospital. 3. Methodological aspects 3.1. Study designs and populations Study I: A historical follow-up study 11. The aim was to determine mortality in an unselected cohort of patients with AMI admitted to a local hospital (Randers County hospital). Records were reviewed for all patients admitted to the coronary ward at the local hospital (any diagnoses), patients assigned a final diagnosis of AMI at other medical departments, and patients transferred to the remote invasive center (Aarhus University Hospital, Skejby) for PPCI (Figure 1). In patients with a rise in coronary biochemical markers indicative of myocardial necrosis, patients receiving reperfusion therapy, patients with a hospital tentative diagnosis of STEMI or BBBMI, and patients with a hospital discharge diagnosis of AMI, the final diagnosis was adjudicated by an endpoint committee. 2. Aims The overall purpose of this thesis was to evaluate the benefit achieved from early diagnosis, triage, reperfusion, and risk stratification in patients with STEMI. The specific aims were: 1. To estimate the mortality in an unselected cohort of Danish patients with AMI. 2. To evaluate the association between delay to reperfusion and mortality in patients with STEMI treated with PPCI. 3. To assess the association between delay to reperfusion and readmission with congestive heart failure (CHF) following PPCI in patients with STEMI. 4. To assess to which extent prehospital diagnosis combined with triage of patients from the scene of event directly to an invasive center for PPCI (fieldtriage) is associated with earlier reperfusion and improved outcome. 5. To assess whether simple ECG parameters obtained before and during PPCI are useful for riskstratification in patients with STEMI. Figure 1. Selection of patients for study I. Study II: A follow-up study evaluating whether prehospital diagnosis is associated with earlier reperfusion in patients with STEMI treated with PPCI. The study included all patients with STEMI transferred from two local hospitals (Silkeborg and Randers county hospital) to the invasive center (Aarhus University Hospital, Skejby) for PPCI 12. Study III: A prospective study assessing the prevalence and clinical significance of dynamic ECG changes before and during PPCI, i.e. spontaneous ST-resolution before PPCI and increase in ST-elevation (the ST-peak Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 7

9 phenomenon) during PPCI. The study included patients with STEMI in whom continuous ST-monitoring was performed during the prehospital phase and continued until 90 minutes after PPCI 13. Study IV: A prospective study with the purpose of evaluating whether spontaneous ST-resolution before PPCI or the ST-peak phenomenon occurring during PPCI is associated with the myocardial area at risk (AAR) and final infarct size (FIS). The study included patients with STEMI who had continuous STmonitoring initiated before PPCI and continued until 90 minutes after PPCI. Single Photon Emission Computerized Tomography (SPECT) scan was performed in the acute phase and after one month, respectively 14. Study V: A prospective study with the aim to describe the prevalence and clinical significance of Accelerated Idio-Ventricular Rhythm (AIVR) occurring during PPCI. Inclusion criteria as in study IV, but comprising a larger study population 15. Study VI: A historical follow-up study with the aim to evaluate the association between health care system delay (time from first contact to the health care system to PPCI) and mortality in patients with STEMI treated with PPCI. The setting was Western Denmark, and the study period was 2002 to The study included patients admitted with their first STEMI during the study period, who were treated with PPCI within 12 hours of symptom onset, and with a system delay of 6 hours or less. Only patients with available data from the Emergency Medical Service (EMS) provider were included. Study VII: A historical follow-up study assessing the association between system delay and the risk of readmission or an outpatient visit due to CHF in patients with STEMI treated with PPCI. Selection of patients was similar as for study VI, however the study period was extended from 1999 to Study VIII: A historical follow-up study with the purpose of describing the gradual implementation of fieldtriage for PPCI in Western Denmark, and assessing the associated outcome. The study population was the same as for study VI, however, the study period was extended from 1999 to 2009, and patients without EMS data were also included Statistics Categorical variables are expressed as % (n) or n (%), and continuous variables as medians (25 th -75 th percentiles) or means (standard deviation or variance). The chi square test, Fisher Exact test, Kruskal-Wallis test and Mann Whitney test were used as appropriate for comparison of variables. Unadjusted survival data were plotted as Kaplan Meier curves, and comparison between subgroups performed using log rank statistics (study I,VI,VII,VIII) 11, Associations between covariates and mortality at follow-up were evaluated using Cox regression analyses (study I,VI,VIII) 11, 16, 18. Competing risk regression analysis was used to study the association between covariates and readmissions or an outpatient visit with CHF during follow-up, with mortality as the competing risk (study VII) 17, 19. The proportional hazard assumption was checked for each categorical variable through visual inspection and by the method described by Grambsch and Therneau 20, using the Shoenfeld residuals (study I,VI and VIII). In study VII the proportional hazard assumption was checked by evaluating whether the hazard ratio for each covariate was time-varying. For continuous variables the linearity assumption was checked graphically using the Martingale residuals. Variables associated with outcome in univariable analysis were implemented in multivariable analysis (study I,VI,VII,VIII) 11, 16, 18. In study I variable selection was performed in the multivariable Cox regression analysis as a stepwise backward elimination method, each time excluding the one variable with the highest P-value according to Wald statistics. Likelihood Ratio test (LRtest) was used for comparison of models. In study VI, VII and VIII all covariates associated with outcome in univariable analysis was implemented in the multivariable model. Complete cases analyses were performed replacing missing values with imputed values. In study I,VI and VIII single imputation was performed 11, 16, 18, whereas multiple imputation was introduced in study VII 17. In single imputation imputed values were obtained as predictions from a regression model or logistic model using all non-missing covariates in each subject 21, 22. In multiple imputation missing values among covariates were replaced using multiple imputation of chained equations by the Stata ICE command 23. Logistic regression modeling was used for binary covariates, ordinal logistic regression modeling for Killip class, and linear regression modeling for continuous covariates. We imputed 10 datasets. Statistical significance was defined as 2P Software packages SPSS version 10.0 and STATA 8,10 and 11 were used for statistical analyses Methods for sampling and analysing continuous ECG monitoring data and 12- lead ECGs For study III, IV and V a commercial monitordefibrillator (LIFEPAK 12, Medtronic Emergency Response Systems, USA) was used for 12-lead ECG acquisition and sampling of continuous ST-monitoring 8

10 data. The analog ECG signals were digitized at a sample rate of 500 Hz for processing by the GE/Marquette Medical Systems 12SL ECG interpretive algorithm. Sampling of continuous ST-monitoring data was initiated automatically when the first 12-lead ECG was acquired in the ambulance vehicle or on arrival at the catheterization laboratory. At 30-second intervals the ST-monitoring software generated a signal-averaged QRST-complex (median beat) for all 12 leads based on a 10-second epoch of ECG data. From each of these QRST-complexes the level of ST-deviation at STM (ST level at J+ 1/16 of the average RR interval) was established automatically by the software and stored. In the event of a 0.1 mv change in STM lasting 2.5 minutes the software automatically acquired and stored a 10- second 12-lead ECG waveform. During transport to the invasive center ambulance staff replaced traditional electrodes with radiolucent carbon fiber lead wire electrodes (Ambu Blue Sensor QR electrodes, Ambu A/S, Denmark), enabling ST-monitoring to be continued during PCI (study III). In study IV and V radiolucent carbon fiber lead wire electrodes were mounted on arrival at the invasive center. ST-monitoring was terminated 90 minutes following first balloon inflation. All 12- lead ECG waveforms and continuous ST-monitoring data were transferred to a computer and stored with a random key for subsequent blinded analysis. Pre-interventional ST-monitoring data, i.e. data acquired before any coronary intervention (wire, distal protection device, suction device, balloon inflation, stent) were analyzed to detect spontaneous resolution of ST-elevation before coronary intervention (resolution of ST-elevation to a level <0.1 mv in leads I,II,III,aVF, avl,v4-v6 and <0.2 mv in leads V1-V3). The cumulated level of ST-elevation before PPCI was estimated by summating the maximal pre-interventional level of ST-elevation in each anterior leads ( 0.1 mv ST-elevation required in I,aVL,V4-V6 and 0.2 mv required in V1-V3) and non-anterior leads ( 0.1 mv STelevation required in II,III,aVF,V5-V6), respectively. Per-interventional ST-monitoring data, i.e. data acquired during the coronary intervention, were analyzed for the presence of the ST-peak phenomenon. The ST-peak phenomenon was defined as a 0.1 mv increase in ST-elevation in any lead (except for avr) during coronary intervention (compared with the level of ST-elevation in the same lead immediately before coronary intervention), and lasting 2.5 minutes. This classification was determined by the ST-change required for automatically acquisition of ECGs by the LIFEPAK-12 software. Accordingly, any significant increase in ST-elevation was documented by both continuous ST-monitoring data and a snapshot 12-lead ECG waveform. A similar approach has been implemented by other investigators evaluating the value of continuous ST-monitoring during the prehospital phase 24. Post-interventional ST-monitoring data were evaluated to estimate: time from first wire placement to achievement of 70% ST-resolution (minutes) and complete ST-resolution (minutes), as well as achievement of 70% and complete ST-resolution (yes/no) 30, 60 and 90 minutes following first wire placement. Complete ST-resolution implied that there was no significant ST-elevation present (previous described criteria for significant ST-elevation were no longer fulfilled). 4. Mortality in patients with AMI In 1999 data on mortality in patients with STEMI, NSTEMI and BBBMI mainly originated from voluntarily reporting to registries 25, and from trials with numerous inclusion and exclusion criteria, hence inherently data may have been hampered by selection bias. We aimed to evaluate the mortality in an unselected cohort of patients with AMI admitted to a local hospital (study I) 11. The main findings of this study in comparison with previous studies were a higher median age, a larger proportion of patients classified as having NSTEMI, and a lower mortality in patients with STEMI than in those with NSTEMI and BBBMI, respectively (Figure 2) 26. Figure 2. Mortality in an unselected cohort of patients with ST- Elevation Myocardial Infarction (STEMI), Non-ST-Elevation Myocardial Infarction (NSTEMI) and Bundle Branch Block Myocardial Infarction (BBBMI). Reproduced from Paper I by permission of Oxford University Press. We believe that this study was unique because an unselected cohort of patients admitted with AMI was identified. Moreover, the diagnosis of AMI was accepted according to the year 2000 European Society of Cardiology (ESC) / American College of Cardiology (ACC) criteria of AMI 27, with the modifications that a diagnosis of AMI was accepted also in patients dying prior to blood sampling or before a possible rise in coronary biochemical markers could be detected, if typical symptoms and ECG signs of AMI were present on admission. Recently, similar modifications were implemented in Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 9

11 the universal definition of MI in A diagnosis of aborted MI was also accepted in patients presenting with typical symptoms and an ECG consistent with STEMI, however, without a rise in biochemical markers and resolution of ST-elevation after early reperfusion therapy. The presence of AMI was adjudicated by an endpoint committee. The implementation of an endpoint committee is a clear strength when compared to previous registry studies, as it has been documented that case-fatality is clearly misjudged when based on epidemiological criteria only 29. Overall selection and information bias should be limited in study I. In comparison, the MONICA registry has claimed to identify unselected patients 25 to 75 years of age, but only 7101 patients were identified in a 20-year period, corresponding to 355 per year, from a catchment area of inhabitants. This is one-third of the number of patients per year per inhabitants compared to our study, hence even the MONICA registry is most likely hampered by selection bias 30. The age criteria (<75 years), the survival criteria (only patients surviving the initial 24 hours were included) and the transfer criteria (transfer patients excluded) potentially contributed to the low recruitment numbers per year in the MONICA registry. Our study was also performed in the same period as the Global Registry of Acute Coronary Events (GRACE) 31, the Euro Heart Survey of Acute Coronary Syndromes (EHS-ACS) 25, and the third national Registry of Myocardial Infarction (NRMI-3) 32. These registries obviously were hampered by selection bias as 52% and 63% of patients with AMI were categorized as having STEMI in GRACE and EHS-ACS. The inhospital mortality rates of 14% observed in our study was also considerably higher than those observed in the GRACE (5%), EHS-ACS (5%) and NRMI-3 (9%) registries. Most likely, the voluntarily reporting of cases, the exclusion of patients dying within 24 h of admission from the GRACE registry, the high proportion of interventional centres including patients in EHS-ACS registry, and the requirement of patient consent for participation in the GRACE and EHS-ACS registry, explain at least partially the lower mortality in these registries. Moreover, it is evident that octogenarians were less likely to be included in the above mentioned registries. Furthermore, in the GRACE registry the category STEMI included patients with BBBMI. This may potentially explain the higher mortality observed in patients with STEMI compared with patients with NSTEMI. Finally, none of the three registries relied on an endpoint committee to adjudicate the final diagnosis. Mortality in our study was also higher than the mortality observed in large-scale clinical trials 33, 34. It is well-known that the large number of inclusion and exclusion criteria implemented in clinical trials results in selected cohorts with low mortality, not only because the patients are in a condition allowing them to give informed consent, but also because they are selected for reperfusion therapy There is no reason to believe that the median age in patients admitted with AMI has declined after conduction of our study (study I). On the other hand, introduction of the refined criteria for AMI in year , and the redefinition in , have increased the number of patients classified as having AMI 4. Those patients identified after lowering the biomarker discriminator level for AMI may have lower mortality. This, together with improved treatment, pharmacologically as well as interventional, most likely contributes to the overall reduction in mortality observed during the last 2 decades 32, 39, 40. Still, despite advances in therapy, mortality in patients with AMI is high, i.e. the prehospital mortality is most likely unchanged, with 20-30% of patients dying in the prehospital phase 1. Our findings of a comparable or even higher mortality among NSTEMI-patients compared with STEMI patients (Figure 2), has been confirmed by others 41, 42. There have been improvements in therapy since this trial was conducted. Certainly, a higher proportion of patients with NSTEMI are treated with PCI. Whether more than 70% of STEMI patients are treated with reperfusion therapy is uncertain, and even though some countries claim to initiate reperfusion therapy in nearly 100% of patients 43, an updated sampling of an unselected cohort would probably document that the true proportion of patients given reperfusion therapy is considerably lower. 5. Delay to reperfusion Time to reperfusion in patients with STEMI is dependent on diagnostic strategy (prehospital diagnosis versus in-hospital diagnosis), reperfusion strategy (prehospital fibrinolysis, hospital fibrinolysis, field-triage for PPCI, transfer for PPCI), and logistical challenges at the hospital, i.e. are patients triaged for PPCI admitted directly to the catheterization laboratory, or are they initially seen in the Emergency Room (ER), at the Coronary Care Unit (CCU) or at the Intensive Care Unit (ICU). In the following, the association between delay to PPCI and outcome will be addressed. Furthermore, the timewindow for PPCI, i.e. the extra delay acceptable to perform PPCI instead of fibrinolysis (PCI-related delay) will be assessed Earlier reperfusion therapy with PPCI: impact on mortality Previous studies evaluating the association between delay to reperfusion with PPCI and mortality in patients with STEMI has presented conflicting results. Zijlstra and colleagues demonstrated a horizontal association between treatment delay (time from symptom onset to PPCI) and mortality 44. Cannon and colleagues also 10

12 found a horizontal association between treatment delay and mortality, whereas a modest positive association was observed between door-to-balloon delay (D2B delay = time from arrival at the invasive center to PPCI) and mortality 45. The latter study included consecutive patients admitted at 667 invasive hospitals in the United States during a 3.7 year study period. The mean number of patients treated at each center was 11 per year, with a median D2B delay of 1 h 56 minutes, and with only 8% of patients having a D2B delay of 60 minutes or less 45. The long D2B delays were observed despite the fact that 87% of patients were admitted directly at a hospital with invasive facilities. Moreover, the cohort treated with PPCI only comprised 4% of the population with AMI during the study period (N= ). Accordingly, the general performance of the invasive hospitals and the prehospital diagnostic program may not have been optimal. Finally, the study only focused on in-hospital and not long-term mortality, and used logistic regression rather than Cox regression, thus not taking into account the extra information derived from the observation time. Based on the findings by Zilstra and colleagues and Cannon and colleagues, it has been claimed that the importance of the timing of treatment for myocardial salvage may be less with PPCI as compared to treatment with fibrinolysis One major limitation to most previous studies addressing the association between delay to reperfusion therapy and mortality is the implementation of the overall treatment or patient delay as covariates in the analyses, i.e. intervals of delay to reperfusion that indeed are hampered by uncertainty, as they are based on symptom onset. The major problems with these delays are: 1. Recall bias: Patients are uncertain of the exact onset of symptoms. 2. Measurement error: Onset of symptoms may not be identical to time of coronary vessel occlusion because the event of AMI may have been preceded by hours of unstable angina pectoris (UAP), including spontaneous opening and closure of the vessel, and/or recruitment of collaterals. 3. Survivor cohort effect: From the prefibrinolytic era it is known that early incomers untreated have the highest risk 1. However, these patients also achieve the largest benefit from PPCI. The benefit of PPCI is reduced in late incomers. On the other hand late incomers a priori have lower mortality, because they already survived the most critical phase, i.e. the prehospital phase. This survivor cohort effect most likely explains the neutral association observed between treatment delay and mortality in the study by Cannon and colleagues as early and late presenters may end up with comparable mortality (Figure 3) 44, 45, 51. Paradoxically, this phenomenon implies a timedependent benefit of PPCI, and further support that the reduction in mortality achieved by earlier reperfusion therapy is underestimated when evaluated from observational data 52. Figure 3. Patients presenting late are survivors of the most critical prehospital phase (survivor cohort effect) but gain less from PPCI and therefore may end up with the same mortality as early incomers. Despite the aforementioned limitations, we decided to perform an observational study evaluating the association between delay to reperfusion and mortality. However, our focus was on the total health care system delay (Figure 4), i.e. the time from contact to the health care system to PPCI, in the following just termed system delay (study VI) 16. System delay is defined for all patients contacting the health care system. Accordingly, system delay is not hampered by recall bias, and less hampered by selection bias. Our studies (study VI,VII,VIII) demonstrated an extreme variance observed for patient delay. Even though the median patient delay and system delay were comparable (around hours), the variance was more than 5 times higher for patient delay compared with system delay. This again resulted in a large variance for treatment delay (Table 1), because the variance for treatment delay is given by the equation: σ 2 Treatment delay = σ 2 Patient delay + σ 2 System delay Whether patient delay is merely hampered by recall bias or measurement error, or whether individual variation contributes to the larger variance observed for patient delay compared to system delay, is of less importance. The overall implication is that it is more difficult to demonstrate an association between patient delay or treatment delay and mortality, when analyses are based on observational data. It doesn t mean that patient delay and treatment delay are not associated with mortality, and neither this observation or the lack of any longlasting effect of media campaigns on patient or treatment delays, should deter us from encouraging patients to seek medical help as soon as possible after the onset of symptoms 53, 54. Intuitively, each interval of delay to Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 11

13 reperfusion therapy must have nearly the same impact on mortality, whether the delay is before or after contact to the health care system. One exception is of course when delay in the prehospital phase results in ventricular fibrillation (VF), because the chance of surviving inhospital VF is higher than the chance of surviving prehospital VF. This is yet another example supporting that patient delay may indeed affect mortality. The fact that patients dying in the prehospital phase from VF are not included in the majority of registry studies contributes to a potential underestimation of the association between delay to reperfusion and mortality when based on observational data from registries. Our findings also indicate that it may not be appropriate just to rely on symptom duration as a criterion to withheld PPCI 49. When some authors state that after 2-3 hours the delay to reperfusion therapy is less critical this is not consistent with observations from meta-analyses documenting a benefit of PPCI compared with fibrinolysis also after 2-3 hours 55. Table 1. Various delays observed in study VIII. Treatment delay Patient delay Health care system delay Mean delay, µ 4.2 h 2.3 h 2.2 h Variance, σ h 5.2 h 1.0 h De Luca and colleagues have also evaluated the association between treatment delay and mortality, based on observational data, however, from a single centre 48, 56. They found that treatment delay was associated with mortality, with a 7.5% relative increase in mortality per half hour increase in treatment delay. They were able to document a clear association between treatment delay and mortality, even though their cohort was considerable smaller than the cohort in our study VI and the cohort presented by Cannon and colleagues 45. De Luca argued that their study included high-risk patients, however, with a one-year mortality of only 5.8%, and all patients being selected from randomized controlled trials, this is hardly the case. Given that randomized trials are unethical to conduct in order to evaluate the association between delay to PPCI and mortality, our registry study (study VI) seems to be the best alternative for evaluating the association between delay to reperfusion and mortality. Our study demonstrates that system delay is independently associated with mortality, with a 10% relative increase in mortality per hour increase in system delay (Figure 5). Figure 4. Various delays to reperfusion with primary percutaneous coronary intervention (PPCI) in patients with ST-elevation myocardial infarction. Delays presented only for patients transported by the Emergency Medical Service (EMS) from the scene of event. Stratified according to triage of patients. Reproduced from paper VI by permission from The American Medical Association. 12

14 Figure 5. Association between the delay from emergency medical service call to primary percutaneous coronary intervention (System delay) and mortality in patients with ST-elevation myocardial infarction. Reproduced from Paper VI by permission from The American Medical Association. System delay is defined in all patients surviving until contact with the health care system, and hence studying its effect is not affected by selection bias from survival. It can be studied in all patients contacting the health care system. Furthermore it is an objective parameter not prone to recall bias. Most importantly system delay (and its components) appears to be the only risk factors that can be modified in the acute phase, by optimizing pre-hospital and in-hospital triage (study VI). 12, 57 In contrast, the generally accepted risk factors in patients with STEMI, i.e. age, Killip class, infarct location, history of AMI, diabetes, hypertension, angina, left ventricular ejection fraction (LVEF), renal failure, current blood pressure, number of diseased vessels, biomarker levels, ECG changes (ST-segment elevation, STsegment depression, BBB), heart rate, infarct location, etc., are not modifiable in the acute phase if modifiable at all Earlier reperfusion therapy with PPCI: impact on readmission due to heart failure Because shorter time to reperfusion with PPCI is associated with reduced mortality and smaller infarct size, intuitively the risk of CHF in those surviving STEMI should also depend on delay to reperfusion. However, there are limited data to support this. Lambert and colleagues recently found that timely reperfusion therapy with PPCI was associated with a tendency towards lower risk of readmission with CHF. In their cohort of 1440 patients with STEMI, a system delay of 90 minutes or more versus less than 90 minutes was associated with an OR (95% CI) of 2.02 ( ) for readmission with CHF within one year 59. In our study (study VII) 17 the risk of readmission or an outpatient visit with CHF at one year was comparable to the findings by Lambert and colleagues (Figure 6). However, our study cohort was considerable larger, and with a longer follow-up. Furthermore, we also included visits in the outpatient clinic with a diagnosis of CHF as a proxy for development of congestive heart failure. Hitherto study VII is the largest study evaluating the association between system delay and the risk of CHF in patients with STEMI. With coronary heart disease being the initiating cause in 70% of CHF cases, CHF being responsible for 5% of all hospital admissions, 4% of the population having CHF, and 2% of the national expenditure on health being used on CHF, we should focus on any initiatives that may reduce CHF 60. Figure 6. Association between delay from emergency medical service call to primary percutaneous coronary intervention (system delay) and re-admissions or outpatient contacts with congestive heart failure. Reproduced from paper VII with permission from The American Medical Association. The present findings, that each hour of increase in system delay is associated with a 10% increase in the risk for hospital readmission or an outpatient visit with CHF further support the need of an optimal health care system performance in the acute phase in patients with STEMI. Thus, a one-hour reduction in system delay, by prehospital diagnosis and field-triage of STEMI-patients to invasive centres 12, may have a considerable impact on not only mortality, but also on morbidity among those surviving their STEMI. Notably, in study VII system delay again was the only among the risk factors studied that is modifiable in the acute phase. Future studies are needed to clarify whether the expected benefit of earlier reperfusion therapy on development of CHF also translates into reduced sick leave and later retirement from work. Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 13

15 5.3. The time-window for PPCI: PCIrelated delay The acceptable time-window for PPCI in patients with STEMI is controversial. Previous European and the 2004 ACC/AHA guidelines 61 recommended PPCI only if the delay in performing PPCI instead of administering fibrinolysis (PCI-related delay) was less than 60 minutes, and the presentation delay was more than 3 h. Otherwise fibrinolysis was recommended as a an equal therapy. The ACC/AHA and ESC recommendation of a maximum acceptable PCI-related delay of 60 minutes was based on a meta-analysis by Nallamothu and colleagues introducing the term PCI-related delay 62, 63. For each of 21 randomized trials the absolute mortality benefit achieved by PPCI when compared with fibrinolysis (Y-axis) was plotted against the observed PCIrelated delay (X-axis). In a linear regression analysis an X-axis intercept of approximately 60-minutes was observed. The authors considered this value to be the maximal acceptable PCI-related delay. This finding was implemented in previous guidelines 50, A critical review of the original published data from the 21 randomized controlled trials, however, revealed that the Nallamothu regression analysis was hampered by inaccuracies in extraction of tabulated data 52, e.g. the PCIrelated delay for the PRAGUE-1 and PRAGUE-2 studies were interpreted to be 10 and 32 minutes, respectively, whereas the delays were 70 and 85 minutes according to the original publications 9, 62,68, 69 (Figure 7). The authors acknowledged this in a later publication 63, as also documented by Betriu and colleague 70. However, there were additional inaccuracies in extraction of data in the publications by both Nallamothu and colleagues 62, 63 and Betriu and colleagues 70 : They considered the PCI-related delay to be seven minutes for a study by Ribicini and colleagues, 15 minutes for a study by Garcia and colleagues, 25 minutes for a study by Gibbons and colleagues, and 15 minutes for a study by Vermeer and colleagues 9, 62, 63, 70. According to the original papers the correct delays were 16, 47, 45, and 90 minutes, respectively (Figure 7). The latest meta-analysis, by Asseburg and colleagues also misinterpreted data for PCI-related delay, i.e. estimating the PCI-related delay in the PRAGUE-1 trial to be six minutes instead of 70 minutes 75, which may also have affected the costbenefit analysis by Vergel and colleagues based on the same data 76. All the aforementioned meta-analyses, including our own review 52, 62, 70, 75, were performed at a trial level, i.e. based on published summary statistics rather than individual data. Accordingly, only estimates of the relation between PCI-related delay and mortality were implemented in the regression analyses. Such analyses ignore an important source of information on the relation between PCI-related delay and mortality, namely the heterogeneity between centers within each trial. It is evident that the PCI-related delay is dependent on the distance from the scene of event to the PCIcenter, dependent on prehospital triage (field-triage to a PCI-center or admission to local hospital and transfer), dependent on in-hospital logistics (admission to ER, CCU, ICU or directly at the catheterization laboratory), and dependent on the alternative fibrinolytic strategy (prehospital or in-hospital fibrinolysis). Figure 7. PCI-related delay (extra delay used to perform primary percutaneous coronary intervention = PPCI instead of fibrinolysis) for various randomized controlled trials comparing fibrinolysis with PPCI in patients with ST-elevation myocardial infarction. Reproduced from: "Primary PCI as the preferred reperfusion therapy in STEMI: it is a matter of time, Terkelsen et al, Heart 2009;95:362-9, with permission from BMJ Publishing Group Ltd. A more optimal meta-analysis has been performed by Boersma and colleagues, who collected patient-specific data for the majority of the above-mentioned trials, and defined PCI-related delay at the hospital level 55. Accordingly, the Boersma analysis of the association between PCI-related delay and mortality was not only based on the correct data (provided by the primary investigators), but also were based on 153 estimates (at the hospital-level) of the relationship between PCIrelated delay and mortality. In the Boersma analysis there was a beneficial effect of PPCI even at PCI-related delays of minutes. Notably, 76% of fibrinolytictreated patients were given fibrin-specific drugs, whereas only 40% of patients treated with PPCI received stents and less than 30% of PPCI-treated patients received glycoprotein IIb/IIIa inhibitors. It is unsettled whether improvements in both reperfusion strategies have had any impact on the maximal acceptable PCIrelated delay. Registry data also have been used to evaluate the maximal acceptable PCI-related delay. Based on data from the NRMI-registry 77 Pinto and colleagues found an x-axis intercept of 114 minutes, when evaluating the association between PCI-related delay and mortality benefit achieved from PPCI. A subgroup analyses also indicated that treatment delay, age and infarct location may have an impact on the acceptable PCI-related delay. Major limitations to the latter study were: 1) Observational data are prone to selection bias, and from previous publications we know that the PPCI-treated group in the NRMI-registry comprised three times as many patients with cardiogenic shock, which leads to an underestimation of the acceptable PCI-related delay 78, 14

16 and 2) Pinto and colleagues compared an optimal fibrinolytic strategy (92% given fibrin-specific drugs with door-to-needle time of 40 minutes) with a suboptimal PPCI-strategy (PPCI at low-volume centers performing less than one PPCI a month in mean, and with a mean DTB times of 116 minutes) 77. Another registry study (The Vienna registry) found a comparable mortality in PPCI and fibrinolytic treated patients (8.1 versus 8.2 %) 79 even at a PCI-related delay of 138 minutes. In the FINESSE trial the PCI-related delay was 90 minutes, and no significant difference was observed in outcome 46. The Swedish RIKS-HIA registry found a lower mortality in patients treated with PPCI compared to patients treated with pre-hospital fibrinolysis, despite a PCI-related delay of 90 minutes 80. Overall, the previous recommendation of a maximal acceptable PCI-related delay of 60 minutes is not evidence-based, and it may be at least minutes. Also, the recent guidelines on revascularization may underestimate the time-window for PPCI when recommending fibrinolysis if PPCI is not possible within 90 minutes in patients <75 years of age, with anterior infarctions and presenting within 2 hours of symptom onset. If accepting that fibrinolysis is not initiated instantaneously, but often with a delay of 30 minutes, such recommendations correspond to a maximum acceptable PCI-related delay of 60 minutes 81. There is no evidence to support this. Even if accepting 90 minutes as the acceptable PCI-related delay, such a statement is based on comparable outcome with a median PCIrelated delay of 90 minutes, which imply that even if 50% of patients have longer delay the outcome is expected to be comparable in the complete cohort Mortality reduction achieved by field-triage of patients with STEMI directly to invasive centers Until 1999 no prehospital diagnosis was performed in Denmark. After publication of the DANAMI-2 trial it seemed logical to combine prehospital diagnosis with triage directly to the PCI-centers. The first case was presented in , and early after the initial experience with use of telemedicine for triage of patients with STEMI were published (study II) 12. In the first years, it was decided only to field-triage patients in whom the distance from the scene of event to the interventional center was no longer than the distance to the local hospital. Even though comparable distances were observed from the scene of event to the interventional centre in patients field-triaged and patients transferred (study II), those being field-triaged directly to the PCI-center were treated 80 minutes faster than patients in whom the diagnosis was established after admission to the local hospital (study II). After the initial experience, it was decided to implement telemedicine equipment in all ambulances, and to field-triage the majority of patients directly to the invasive hospital. If long transportation (more than minutes) were expected, then an ambulance physician was dispatched to meet the primary ambulance (rendez-vouz). The general use of telemedicine with rendez-vouz logistics has resulted in approximately 90% of patients with STEMI being field-triaged directly to the invasive center at Skejby University Hospital 83. If focusing on all patients with STEMI transported from the scene of event in the Western Denmark region, the proportion of patients field-triaged directly to a PCI-center have increased from 33% (34/103) in 1999 to 72% (616/851) in year (study VIII) (Figure 8). This corresponds to an 18-fold increase in the absolute number of patients field-triaged for PPCI. However, even though the majority of patients are now triaged directly to the invasive center, there is still room for improvement. Figure 8. Gradual change in triage of patients with STEMI. Reproduced from paper VIII with permission from Circulation Cardiovascular Intervention. To evaluate the mortality reduction achieved with prehospital diagnosis and field-triage directly to invasive centers, a randomized study design would have been optimal but unethical. Observational data from the Western Denmark heart registry documents that patients field-triaged directly to invasive hospitals have a lower mortality compared with patients transferred from local hospitals (study VIII) (Figure 9) 18. Even though the latter finding was significant in multivariable analysis, we cannot exclude residual confounding or selection bias. Certainly, patients in cardiogenic shock, with repetitive VF or being unconscious were referred to the nearest hospital, if rendez-vouz with an ambulance physician was not possible. On the other hand patients field-triaged had larger cumulated ST-elevation, and thus in theory a larger myocardial area at risk (AAR). From the pre-fibrinolytic era we also know that early presenters untreated have the highest risk 1. Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 15

17 5.5. Statistical considerations in observational studies When performing multivariable analyses based on observational data, the results must be interpreted with caution. In the following some issues not mentioned above, i.e. interaction between covariates and overadjustment in the analyses will be addressed Interaction between covariates Figure 9. Mortality in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Arranged according to triage of patients. Reproduced from paper VIII with permission from Circulation Cardiovascular Intervention. If accepting the observed 1-year mortality of around 10% in patients with STEMI treated with PPCI 11 (study I), if accepting a 10% relative mortality reduction in mortality per hour reduction in system delay (study VI), and if accepting a 1-hour reduction in treatment delay by prehospital diagnosis combined with field-triage directly to the PCI-centers (study II+VIII), then the expected mortality reduction is around 1%. This corresponds to 10 extra lives saved per 1000 treated, when combining prehospital diagnosis with field-triage of directly to invasive centers. This benefit is achieved on top of all the previous improvements in pharmacologic and interventional therapies in patients with STEMI (Table 2). Table 2. Mortality reduction achieved by various therapies in patients with ST-elevation myocardial infarction. Strategy No of extra lives saved per 1000 treated Fibrinolysis instead of placebo Aspirin instead of placebo PPCI instead of fibrinolysis hour earlier PPCI 10 1-hour earlier fibrinolysis In study I we found that levels of Troponin T (TnT) did not provide independent prognostic information in the complete cohort of patients with AMI, but within the categories of AMI. The reason was that mortality was lower but the TnT levels higher in patients with STEMI when compared to the other groups. Thereby level of TnT ended up being associated with lower mortality in unadjusted analyses. The prognostic information achieved from biochemical markers therefore needs to be interpreted according to the category of AMI. The smoker paradox is another example, i.e. the observation that smokers in univariable analysis may have a lower mortality. Smokers, however, are younger compared to non-smokers, which again means that smoking may be associated with improved outcome in unadjusted analyses. The women paradox is also worth mentioning, i.e. the mortality is higher among women admitted with AMI in univariable analysis. This observation has received lots of attention, however is at least partially explained by the fact that women are older when admitted with their AMI, and when correcting for age and other confounders, there may not be any difference in mortality (study VII) Overadjustment If implementing variables that are highly correlated in the multivariable analysis, one may end up underestimating the effect of one or both variables. This is the reason that we only implemented systolic blood pressure in the multivariable analysis and not diastolic blood pressure (study VI, VII, VIII). It is also the reason that we in our initial study (study I) did not implement both TnT and LVEF, as they are highly correlated and both being associated with mortality and of course infarct size. Killip class, LVEF and TnT are often considered as mandatory covariates in the multivariable analyses when focusing on mortality as outcome. For instance, in study I we wanted to study the prognostic significance of AMI category. In this setting Killip class may be considered a consequence of the AMI category, and thus highly correlated both with the AMI category and outcome, in which case implementation of both Killip class and AMI category would give the risk of overadjustment. The same may apply to AMI category and LVEF, and AMI category and TnT. 16

18 6. Continuous ECG-monitoring for pre- and per-interventional risk-stratification of patients Mortality has steadily decreased during the last decades in patients with STEMI. Still, however, there are patients that despite early reperfusion therapy and successful restoration of epicardial blood flow have a poor outcome. Even among patients achieving Thrombolysis In Myocardial Infarction (TIMI) flow grade 3, more than one-third have impaired myocardial tissue perfusion and an unfavorable outcome Therefore, angiographically assessed parameters may not be sufficient for acute risk assessment and tailoring of adjunctive pharmacological and mechanical treatment 95 at the time of PPCI. Other methods proposed for acute risk-assessment such as: rise of markers indicative of myocardial damage or increased wall tension 96-98, evaluation of myocardial tissue perfusion by myocardial contrast echocardiography 99 or single photon emission computerized tomography (SPECT) 100, or traditional ST-resolution analysis minutes following balloon inflation , may also have limited value, because prognostic information is only available at a time when irreversible myocardial damage may have occurred, or because the methods are not generally available on a 24- hour basis. In clinical practice it would be ideal if a noninterventional and easy applicable method was available for acute risk-assessment at the time of PCI. In the following the value of pre- and perinterventional continuous ECG-monitoring for early risk-assessment in patients with STEMI will be addressed, with the focus on spontaneous ST-resolution before PPCI, increase in ST-elevation during PPCI (STpeak) (Figure 10), and presence of Accelerated Idio- Ventricular Rhythms (AIVR) during PPCI (Figure 12). 3) The exact timing of achievement of complete STresolution 4) The comparison of concomitant ST-changes and TIMI-flow changes. The analysis of pre-interventional ST-monitoring data showed that one fourth of STEMI-patients transferred to an interventional hospital for PPCI achieved spontaneous ST-resolution before coronary intervention. Despite the use of very conservative ECG-criteria for classification of spontaneous ST-resolution (absolute resolution of ST-elevation required compared with 50% relative resolution of ST-elevation required in a previous study 108 ), this number is considerable higher than expected. Spontaneous ST-resolution was associated with less myocardial damage as indicated by lower levels of biochemical markers of myocardial damage, such as Troponin-T (TnT) and Creatinin kinase MB (CKMB), and a higher LVEF, thus supporting that these patients should be considered at low-risk (study III) 96-98, The observation that spontaneous ST-resolution is associated with a favorable prognosis is well established 13, 108, 112. Future studies should clarify whether patients with spontaneous ST-resolution are eligible for deferred PCI or at least deferred coronary stenting, or on the other hand, whether they are eligible for prompt referral back to the local hospital and early discharge if PPCI is performed Spontaneous ST-resolution and the ST-peak phenomenon during PPCI ECG parameters are widely used as surrogates of outcome in PPCI studies, but often evaluation of ECGchanges during PPCI is based either on snapshot ECG acquisition, or restricted to anterior wall infarction, patients with an occluded LAD, or patients who have achieved TIMI flow 3 following reperfusion therapy 90, 106, 107. In comparison study III included patients with all types of STEMI, any culprit lesion, and any TIMI flow grade on admission. Moreover, study III was the first study to combine prehospital and in-hospital continuous ST-monitoring (instead of single ECG acquisition) to achieve a comprehensive evaluation of ST-changes occurring in the pre-, per- and post-interventional phase. This enabled: 1) Evaluation of spontaneous ST-resolution before PPCI 2) The detection of short-lasting ST-peaks Figure 10. Examples of spontaneous ST-resolution and ST-peak (increase in ST-elevation) during Primary Percutaneous Coronary Intervention (PPCI). A: Spontaneous ST-resolution before PPCI and no ST-peak during PPCI. B: Spontaneous ST-resolution before PPCI with ST-peak during PPCI. C: ST-elevation on arrival at the catheterization laboratory and no ST-peak during PPCI. D: ST-elevation on arrival at the catheterization laboratory and ST-peak during PPCI. Reproduced from Paper IV with permission from Elsevier. It has been suggested that the ST-peak phenomenon observed during PPCI is primarily seen in patients with severely ischemic damage before reestablishment of vessel patency (ST-peak as a marker of injury before reperfusion) 91, 113. The latter would render the appearance of the ST-peak phenomenon unavoidable and irreversible 114. Our study (study IV) questions the findings Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 17

19 by Miida and colleges, as we found that the ST-peak phenomenon was associated with IS also when correcting for infarct location and pre-procedural maximum cumulated ST-deviation (e.g. expected markers of myocardium at risk at time of coronary occlusion). Others have suggested that the ST-peak phenomenon during PPCI merely is a marker of injury induced by reperfusion (ST-peak as a marker of reperfusion induced injury), hence potentially modifiable by adjunctive pharmacological or interventional therapies. Due to the timing and location of the ST-peak, i.e. temporarily coincident with the coronary intervention, and most often restricted to leads related to the infarct related region 95, 115, it may be hypothesized that unsuccessful epicardial or microvascular re-perfusion or distal embolisation of thrombus or atherosclerotic debris from unstable plaques may contribute to the phenomenon. In the present studies an increase in ST-elevation during coronary intervention was found to be associated with higher levels of biochemical markers of myocardial damage (TnT, CKMB) and N-terminal pro-brain natriuretic peptide (Nt-pro-BNP), and delayed resolution of STelevation, hence indicating a greater extent of myocardial damage and a compromised microvascular perfusion (Study III,IV). Furthermore, no improvement in LVEF during follow-up was observed in patients presenting with ST-elevation and developing ST-peaks during PPCI, thus indicating irreversible myocardial damage in these patients. In previous studies the analysis of ST-changes in relation to PPCI most often was based on the acquisition of snapshot ECGs acquired at various fixed intervals following balloon inflation 87, 89-91, 107, Any increase in ST-elevation at time of PPCI therefore may have been underestimated or even missed. Moreover, previous studies have been small in sample size and the cohorts highly selected, i.e. primarily including patients with anterior myocardial infarction, presenting with TIMI flow 0 or 1 and achieving TIMI flow 3 during coronary intervention 107, 116, 117. No previous studies have implemented continuous ST-monitoring for the evaluation of per-interventional ST-changes. Previous studies have focused on ST-resolution 60 or 90 minutes after PPCI for risk assessment. The latter strategy may not be ideal because: 1. Often the studies were based on single ECG acquisition; hence the exact timing of complete STresolution was impossible. 2. When evaluating ST-resolution 60 or 90 minutes after PPCI the information is of no support to the PPCI operator. 3. The use of continuous 12-lead ECG-monitoring allowed us to evaluate the exact time of achievement of complete ST-resolution. Study IV documented that complete ST-resolution is achieved within 30 minutes of the first coronary intervention in most patients with STEMI treated with PPCI (Figure 11). This explain why there were no differences in the categorical parameters 70% ST-resolution 60 and 90 minutes after PCI (study IV) despite the fact that significant differences were observed in time to complete ST-resolution between patients with and without ST-peaks. Therefore, evaluation of STresolution as a categorical variable and evaluation 60 or 90 minutes after PPCI is not ideal. Figure 11. Time from first coronary intervention (wire) until complete ST-resolution in patients with spontaneous STresolution and no ST-peak during primary percutaneous coronary intervention (PPCI) (A), patients with spontaneous STresolution and ST-peak during PPCI (B), patients with STelevation before PPCI and no ST-peak during PPCI (C) and patients with ST-elevation before PPCI and ST-peak during PPCI (D). Reproduced from paper IV with permission from Elsevier. In conclusion, both spontaneous ST-resolution and the presence of the ST-peak during PPCI are simple parameters that may provide prognostic information. However, larger studies are needed to confirm that these two distinct features are associated with outcome. Furthermore studies are needed to clarify whether the ST-peak phenomenon is a marker of injury before reperfusion or a marker of reperfusion induced injury (study IV). In the former case the ST-peak phenomenon may have prognostic implication only; in the latter case it may add as a target for intervention and may be of value in tailoring peri-procedural adjunctive therapy in patients with STEMI Accelerated idioventricular rhythm during PPCI Accelerated idioventricular rhythm (Figure 12) has been considered as a marker of successful reperfusion in fibrinolytic treated patients, but there has been conflicting reports regarding its significance in patients with STEMI treated with PPCI. Ilia and colleagues studied reperfusion arrhythmias (RA) in patients with STEMI treated with PPCI. They classified RA as AIVR, ventricular tachycardia (VT) or multiple premature ventricular complexes appearing 18

20 within one minute of balloon inflation, and found that 29-38% of patients experienced RA being associated with a favourable outcome 119, 120. However, in the latter study patients in whom arrhythmias occurred before balloon inflation were excluded 119, 120, thus assuming that reperfusion occurs instantaneously at the time of balloon inflation. Bonnemeier and colleagues defined RA as arrhythmias occurring before, during, or within 24 hours following PPCI 121. Both time-windows seems extreme. Certainly, one minute after balloon inflation is to narrow a time-window, because 1) a considerable proportion of patients treated with PPCI actually achieves epicardial reperfusion before first balloon inflation, 2) more than one-third of patients achieves microvascular reperfusion defined as STR before first balloon inflation 14, and 3) even after achievement of epicardial patency 30 minutes may elapse before successful microvascular reperfusion is achieved as evaluated by time to complete STR 14. We observed AIVR in 42% of patients, and AIVR was associated with larger AAR, larger FIS, more often TIMI flow 0 on admission, delayed ST-resolution, and higher levels of biochemical markers indicative of myocardial necrosis (study V) 15. Consequently, we found no evidence to support AIVR as a marker of successful reperfusion in patients with STEMI treated with PPCI. Our findings also are in accordance with the observations by Majid and colleagues showing that reperfusion bursts of VES is positively associated with FIS 122. The observation that AIVR was inversely associated with TIMI-flow on admission and spontaneous STresolution before PPCI may explain why AAR and FIS is larger in patients with AIVR. It would be of interest to evaluate whether AIVR occurs with the same frequency in the prehospital or local hospital phase in patients who experience spontaneous ST-resolution before arrival at the catheterization laboratory. If this is the case, AIVR may end up as a phenomenon appearing at the time of pharmacological or mechanical opening of the infarct-related artery, without being associated with successful reperfusion at the microvascular level. Figure 12. Example of accelerated idioventricular rhythm (left side of figure) and non-sustained ventricular tachycardia (right side of figure). Reproduced from Paper V with permission from Elsevier. Overall, it remains unsettled whether AIVR appearing at time of epicardial reperfusion with PPCI is a marker of mechanical opening of the vessel, whether it reflects extensive myocardial injury before reperfusion, whether it reflects reperfusion induced injury, or whether it is a marker of failed microvascular reperfusion. However, there is no evidence to support that AIVR is a marker of successful reperfusion in patients with STEMI treated with PPCI. 7. The optimal reperfusion strategy Based on the previous chapters, PPCI is recommended as the preferred reperfusion strategy for all patients with STEMI if initiated timely. The assumption of a superior effect of fibrinolysis in the early incomers is not supported by evidence, thus, in the early incomers also PPCI should be the preferred reperfusion strategy 55. Evidently, there is a delay to PPCI beyond which the beneficial effect of PPCI compared with fibrinolysis is lost. This delay may among other parameters depend on infarct location and age 77, but a 60 minute limit as previously proposed 62 and also indirectly supported in current guidelines seems not justified. More likely, the acceptable PCI-related delay is 2-3 hours 52, 55, 80. For patients in whom a strategy of PPCI is associated with a PCI-related delay of more than 2-3 hours, prehospital fibrinolysis seems to be the ideal alternative, but also combined reperfusion strategies have been proposed. For many years facilitated PCI was thought to be a valuable alternative to PPCI 49. The ASSENT-IV trial evaluated whether full-dose tenecteplase combined with delayed PCI was superior to conventional PPCI in patients with less than 6 hour symptom duration. The study, however, documented that facilitated PCI was associated with a higher mortality 123. Study enrollment was stopped by the safety monitoring board because of a higher in-hospital mortality in the facilitated than in the standard PPCI group (6% versus 3%, P=0.011). Notably, in the latter study median time from randomization to first balloon was similar in both groups, thus documenting that it was not delayed PCI in the facilitated group that was responsible for the higher mortality, but the combination therapy alone 123. It has been questioned whether the lower use of glycoprotein IIb/IIIa inhibitors and lower doses of heparin in the facilitated group contributed to the worse outcome. However, in the Finesse trial all patients were pre-treated with unfractionated heparin and were given abciximab after PCI, but no differences in outcome was observed. The comparable outcome was observed despite a PCI-related delay of 90 minutes 46. The GRACI-2 trial also compared facilitated PCI with PPCI, however, the study was underpowered including only 212 patients 124. The Capital AMI study compared facilitated PCI with fibrinolysis alone, and found facilitated PCI to be associated with improved outcome 125. So at best, facilitated PCI conveys similar outcome as PPCI at a PCI-related delay of 90 minutes, but it may even be harmful. It is still debated whether routine early postfibrinolytic interventional therapy can provide similar outcome as PPCI. There are authors that consider this Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 19

21 so-called pharmacoinvasive strategy valuable in patients with STEMI, i.e. fibrinolysis is followed by late PCI 126. In the West trial the median time from symptom onset to balloon inflation was 15 hours in the pharmacoinvasive group 127. It is hard to understand that such delayed PCI in combination with fibrinolysis should result in improved outcome when PPCI alone is superior to fibrinolysis. The ongoing STREAM trial compares prehospital fibrinolysis with PPCI in early incomers, and may provide additional evidence 128. Presently, field-triage of patients for PPCI seems to be the ideal reperfusion strategy, and when the expected PPCI-related delay is more then 2-3 hours prehospital fibrinolysis seems a valuable alternative. However, except for patients self-presenting at rural hospitals with long transfer time to the PCI-centers, hospital fibrinolysis seems obsolete. 8. Future perspectives During the last 10 years prehospital diagnosis of patients with STEMI combined with field-triage to PPCI centers has successfully been implemented in Denmark. Some of the goals within the next 10 years should be: 1. To ensure that at least 90% of patients with STEMI are diagnosed in the prehospital phase. 2. To ensure that at least 90% of patients with STEMI who are diagnosed in the prehospital phase are field-triaged directly to a PCI-center. 3. To improve prehospital diagnosis in patients with NSTEMI. 4. To improve prehosptial diagnosis in patients with BBBMI. 5. To ensure that the majority of patients with BBBMI receive reperfusion therapy 6. To evaluate whether PPCI improves outcome in patients with NSTEMI. 7. To clarify to which extent contact with primary care physicians before admission has an impact on system delay and outcome 8. To find a way to successfully identify patients that may benefit from adjunctive therapy in the acute phase. 9. To identify methods to further reduce infarct size. 10. To identify methods to predict reperfusion injury and therapies to reduce reperfusion injury. 20

22 9. Summary and conclusions Ischemic heart disease is the leading cause of death in the western world. The incidence of acute myocardial infarction (AMI) is approximately per year in Denmark, with an estimated 25%-30% of patients dying in the prehospital phase, around being hospitalized with their first AMI each year, and a one-year mortality among hospitalized patients of around 20%. In patients with large myocardial infarctions, socalled ST-elevation myocardial infarction (STEMI) or bundle branch block myocardial infarction (BBBMI), reperfusion therapy is essential, using either fibrinolysis or primary percutaneous coronary intervention (PPCI). Only ten years ago, the diagnosis and decision regarding reperfusion therapy was initiated after patients were admitted to a local hospital, and the majority of patients were treated with fibrinolysis. There was limited experience with prehospital diagnosis, and no evidence regarding the potential benefit of combining prehospital diagnosis with field-triage of patients directly to invasive centers for PPCI. During the last 10 years a dramatic change has occurred in the diagnosis, triage, and choice of reperfusion strategy in patients with STEMI. First and foremost PPCI has replaced fibrinolysis as the recommended reperfusion therapy. This in itself has been estimated to result in 25 extra lives saved per 1000 treated. Furthermore, prehospital diagnosis, especially with the use of telemedicine, has emerged, and the majority of Danish patients with STEMI are now diagnosed prehospitally. Prehospital diagnosis combined with field-triage directly to invasive centers is estimated to result in a one-hour reduction in delay to reperfusion. Based on experience from the Western Denmark Heart registry, a one hour reduction in delay to reperfusion is estimated to result in a 10% relative reduction in mortality, and a 10% relative reduction in the risk of congestive heart failure among survivors. Overall, the prehospital diagnostic program when combined with field-triage to invasive centers is estimated to save another 10 lives per 1000 treated. Still a subgroup of patients has a high mortality despite successful triage and timely therapy. This may be caused by reperfusion induced injury. To further improve outcome in these patients, we need methods to risk stratify patients in the acute phase, and pharmacologically or interventional therapies to further reduce infarct size and hopefully reduce reperfusion induced injury. Certain ECG-parameters, such as spontaneous normalization of the electrocardiogram (spontaneous ST-resolution) and worsening of the electrocardiographic pattern (increase in ST-elevation during PPCI) may be helpful to risk stratify patients in the acute phase. Further studies are needed to clarify this. 10. Danish summary and conclusions Iskæmisk hjertesygdom er den primære årsag til dødsfald I den vestlige verden. Incidencen af blodprop i hjertet er omkring per år i Danmark, hvoraf omkring 25-30% dør præhospitalt, omkring indlægges med deres første blodprop hvert år, og 1-års dødeligheden blandt hospitaliserede er omkring 20%. Blandt patienter med store blodpropper i hjertet, såkaldt ST-elevations myokardie infarkt (STEMI) eller grenbloks myokardie infarkt (BBBMI), er blodpropsopløsende behandling med enten medicin (fibrinolyse) eller akut ballonudvidelse (primær perkutan coronar intervention = PPCI) essentiel. For 10 år siden blev diagnosen stillet efter patienten var blevet indlagt på lokalt sygehus, og de fleste patienter blev behandlet med fibrinolyse. Der var begrænsede erfaringer med præhospital diagnostik, og ingen erfaring med at kombinere præhospital diagnostik med visitering af patienter direkte til et invasivt center med henblik på PPCI. Gennem de sidste 10 år er der sket en dramatisk ændring hvad angår diagnostik og behandling af patienter med STEMI. For det første har PPCI erstattet fibrinolyse som rutinebehandling, hvilket i sig selv resulterer i at yderligere 25 liv reddes per 1000 behandlede. Endvidere er præhospital diagnostik, specielt ved anvendelse af telemedicin, blevet udbredt i hele landet. Hovedparten af danske patienter med STEMI bliver nu diagnosticeret præhospitalt. Dette kombineret med visitation direkte til et invasivt center medfører mere end én times reduktion i forsinkelsen til behandling. Baseret på data fra Vestdansk Hjerte-database kan det estimeres at én times tidligere behandling medfører 10% relativ reduktion i dødelighed og ydermere 10% relativ reduktion i risikoen for udvikling af hjertesvigt. Sammenlagt vurderes det at præhospital diagnostik kombineret med visitation af patienterne direkte til hjertecenter mhp. PPCI resulterer i at yderligere 10 liv reddes per 1000 behandlede. Stadig er der dog en subgruppe af patienter som på trods af præhospital diagnostik og hurtig behandling har en høj mortalitet. Dette kan være betinget af skade opstået i forbindelse med reperfusion, d.v.s. genåbning af kranspulsårene (reperfusions skade). For at forbedre prognosen yderligere for disse patienter er der behov for metoder til at risiko-stratificere patienter i den akutte fase, og medicinske eller interventionelle metoder til yderligere at reducere dødeligheden, infarkt-størrelsen og forhåbentligt hindre reperfusions skade. Specielle EKG-fund, såsom spontan normalisering af EKGforandringerne (spontan ST-resolution) og forværring af EKG-forandringerne i forbindelse med PPCI (tiltagende ST-elevationer) kan formentlig bruges til at risikostratificere patienter i den akutte fase. Yderligere studier er nødvendige for at afklare dette. Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 21

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30 Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 29

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32 Timely diagnosis, triage, reperfusion, and risk stratification in patients with ST-elevation myocardial infarction. 31