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: Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013;368: DOI: /NEJMoa

2 Bruise Control Submission to NEJM 6 th March 2013 Bruise Control Submission to NEJM This supplement contains the following items: 1. Original protocol (version13 dated 9 th March 2009) 2. Final protocol (version 14 dated 3. Summary of changes between version 13 and14 4. Original statistical analysis plan is detailed in version 13 and was unchanged during course of study Please contact me if you need anything additional David Birnie dbirnie@ottawaheart.ca

3 Trial. Protocol Version 13 March 9 th 2009 BRUISE CONTROL : BRidge or continue coumadin for device SurgEry randomized CONTROLled Trial Protocol Version 13 9th March 2009 D Birnie (Nominated Principal Investigator) V Essebag (Principal Investigator) A Krahn J Healey C Simpson A Tang D Coyle G Wells S Sivakumaran A Verma J Sapp C Seifer M Sturmer F Philippon F Ayala-Paredes 1

4 Trial. Protocol Version 13 March 9 th THE NEED FOR A TRIAL 1.1 What is the problem to be addressed? Implantation rates of cardiac arrhythmia devices, i.e. pacemakers, implantable cardiac defibrillators (ICD) and cardiac resynchronization therapy (CRT) are steadily increasing by an estimated 10% per year. 1-3 In 2006 there was a total of device implants in Canada (21054 pacemakers, 4812 and 1420 CRT). 1 Figure 1 shows worldwide rates. Figure 1 Worldwide trends in cardiac arrhythmia device implantation (IPG; implantable pacemaker generator, i.e. pacemaker) 1 Many patients (23-24% in a recent pacemaker trial 4 and 32-37% in a recent ICD trial 5 ) requiring cardiac arrhythmia device surgery are on chronic oral anticoagulation (AC) therapy. The peri-procedural management of their AC presents a dilemma to physicians. This is particularly true in the subset of patients with moderate to high risk (e.g. >5% per year) of arterial thrombo-embolic events (ATE). Examples include patients with mitral valve replacement or patients with non-rheumatic atrial fibrillation (AF) and a high CHADS 2 score. 6 The peri-operative risk of ATE (without bridging AC) has been estimated based on a fraction of the annual risk of this outcome. 7, 8 Thus, based on a 17% annual risk 9 of ATE in patients with mechanical MVR without oral AC, the risk for 8 days is 0.4%. 7 For a patient with a CHADS 2 score of 3, the annual risk of ATE without oral AC is estimated to be 5.9% 6 which equates to a risk over 8 days of oral AC interruption of 0.16%. Acronym CHADS2 Risk Criteria Score C Congestive Heart Failure 1 H Hypertension 1 A Age >75 y 1 D Diabetes mellitus 1 S Stroke or TIA 2 Table 1. Description of CHADS2 scoring system for patients with non-valvular AF 10 2

5 Trial. Protocol Version 13 March 9 th 2009 CHADS 2 index Estimated Annual Stroke risk % Table 2. Stroke risk in patients with non-valvular AF not treated with oral AC according to the CHADS 2 index 10 However, it should be noted that these risk estimates assume linear risk, i.e. without any increase in risk due to the pro-thrombotic state of surgery. There are some data to suggest that the pro-thrombotic state of surgery does transiently further increase the risk of ATE. For example, in studies of patients with mechanical valves which compared various strategies of bridging AC, the overall crude risk for peri-operative ATE was 0.83% (95% CI: ). 7 Thus, even with peri-procedural bridging AC, the risk was higher than the modeling data which suggest it should be 0.4%. 7 Similarly, there are some early data that the peri-operative risk of ATE in patients with AF is higher than might be predicted. 11 However, these data are far from conclusive. Furthermore, it is possible that the pro-thrombotic effect maybe lesser with device surgery than with more major surgery. Physicians have responded to concerns about peri-procedural ATE by treating moderate to high risk patients with bridging AC. Oral AC is discontinued a few days before the procedure or surgery and substituted with therapeutic doses of either intravenous unfractionated Heparin (IV UFH) or, more usually, Low Molecular Weight Heparin (LMWH). After surgery the patient is restarted on LMWH or IV UFH for a few days while the oral AC effect is building up to therapeutic levels. High (>10% per year) Moderate (4-10% per year) Mechanical Heart Valve Atrial Fibrillation VTE Any mitral valve prosthesis CHADS 2 score of 5 or 6 Recent (within 3 mo) VTE Older (caged-ball or tilting disc) aortic Recent (within 3 Severe thrombophilia (eg, valve prosthesis mo) stroke or deficiency of protein C, protein transient ischemic S or antithrombin, attack, antiphospholipid antibodies, or Recent (within 6 mo) stroke or Rheumatic valvular multiple abnormalities) transient ischemic attack heart disease Bileaflet aortic valve prosthesis and CHADS 2 score of 3 VTE within the past 3 to 12 mo one of the following: atrial fibrillation, or 4 Nonsevere thrombophilic prior stroke or transient ischemic conditions (eg, heterozygous attack, hypertension, diabetes, factor V Leiden mutation, congestive heart failure, age > 75 yr heterozygous factor II mutation) Low (<4% Bileaflet aortic valve prosthesis CHADS 2 score of 0 per year) without atrial fibrillation and no other risk factors for stroke to 2 (and no prior stroke or transient ischemic attack) Table 3 Risk stratification for recurrent thrombo-embolic events 7 Recurrent VTE Single VTE occurred > 12 mo ago and no other risk factors 3

6 Trial. Protocol Version 13 March 9 th 2009 Recently updated guidelines 7 (January 2008) have recommended use of bridging AC in patients with moderate to high risk of ATE or venous thrombo-embolic events (VTE) (See table 3 for details of risk stratification). Specific recommendations from the January 2008 guidelines are as follows: 7 (i) In patients with a mechanical heart valve or AF or VTE at moderate or high risk for thromboembolism, bridging AC with therapeutic-dose LMWH or IV UFH is recommended during temporary interruption of oral AC therapy; Therapeutic dose LMWH is recommended over IV UFH. (ii) In patients with a mechanical heart valve or AF or VTE at low risk for thromboembolism, low-dose LMWH or no bridging over bridging with therapeutic-dose LMWH or IV UFH is suggested. However, there are a number of downsides to bridging AC around device surgery. Firstly, there is a substantial risk of clinically significant device pocket hematoma related to bridging AC. The risk of hematoma with bridging has been shown to be between 8 and 77% (see table 4) The range in reported rates likely relates to the different bridging protocols and heterogeneity in defining significant hematoma. Importantly, hematomas in this situation are not always benign: they can necessitate prolonged cessation of AC with the attendant risk of ATE; they can lead to infection; 17 they can significantly increase hospitalization and cost (by a mean of 3.1 days and US$6995 in one study 18 ); and sometimes re-operation is required. Study Type N Randomization Definition of Significant Hematoma 2007 Observ 74 need for reoperation or Abstract 19 interruption of oral AC Significant Hematoma Rates in bridging group 23% RCT 33 Bridged versus Observ 22 Exerting pressure on RCT 49 in 2007 Not stated 9% Abstract 12 continued oral AC % Abstract 20 suture line and/or requiring intervention 2000 Randomized to Paper 15 RCT time of reinitiation of IV UFH > 2cm mass protruding anterior to pulse generator 6/26 (22%) in 6 hour IVUFH hour group 4/23 (17%) 24 hour IVUFH group 2006 Observ 38 Not defined but 6/ % Paper 16 required reoperation Table 4. Summary of studies reporting device surgery with various heparin bridging regimes The second problem with bridging AC is that there is a phase of normal coagulability (perhaps even hyper-coaguability related to the pro-thrombotic state of surgery) with associated risk of ATE. This period is usually hours, depending on when postoperative bridging is started, and likely explains most of the risk of ATE in bridging trials. For example, in studies of patients with mechanical valves that compared various strategies of 4

7 Trial. Protocol Version 13 March 9 th 2009 bridging AC around non device surgery, the overall crude risk for peri-operative ATE was 0.83% (95% CI: ). 7 The third negative of bridging AC is the cost. LMWH injections are expensive. For example, an eight day course of Enoxaparin costs approximately $ In addition to this is the cost of personnel to organize and teach administration of these injections. Furthermore, a few patients are unable to self inject or do not have someone that can do it for them, and therefore require once or twice daily nursing input. The costliest of all are those patients in whom LMWH is contraindicated and therefore bridging requires prolonged hospitalization for IV UFH. Recently, in response to these issues, a number of centers have explored the option of performing device surgery without cessation of oral AC (see table 5 for a summary of these results). This strategy has the potential to improve on all three of the problems related to bridging AC. Firstly, the observational data would suggest a greatly reduced hematoma rate. Secondly, with a strategy of continued Coumadin there is no period of normal coagulation and thus it is intriguing to speculate that this will result in a reduction in peri-procedural ATE. Thirdly, a strategy of continued AC is likely to be much cheaper than bridging AC. DESIGN N INR Definition of Significant Hematoma Significant Hematoma Rate 2003 paper 21 Observational ( ) Not defined 0% 2004 Paper 22 Observational ± 1.0 Not defined, 7 controlled with pressure dressing and 2 needed reoperation 2.6% 2007 Abstract 23 Observational case control ± 0.2 Causing symptoms and/ or required an unscheduled visit and/or or prolonged hospital stay and /or required surgical revision 8.8% 2007 RCT ± 0.3 Not stated 12% Abstract 12 Observational 35 Not stated Exerting pressure on % Abstract 20 suture line and/or requiring intervention Table 5. Summary of studies reporting device surgery without cessation of oral AC There is of course one possible downside to performing device surgery with continued Coumadin i.e. the potential increased risk of major peri-operative bleeding complications (tamponade and hemothorax). There is a risk of these complications in all device surgeries. Table 5 lists published rates of these complications in patients who were not on Coumadin at the time of surgery. There are 620 patients described in the literature who have had device surgery without cessation of oral AC (see table 4) 12, 20, 22, 23 and there are no reports of either of these complications. Our study will collect data on these complications. 5

8 Trial. Protocol Version 13 March 9 th 2009 Study/database Number of pts Tamponade Hemothorax CRT CARE-HF % 0 CRT Medicare % not stated ICD Medicare % not stated Pacemaker MOST % not stated Table 6. Reported rates of significant intra-operative device surgical complications (all procedures performed off AC). 1.2 Why is a trial needed now A trial is needed now because there are suggestive data from observational studies that the hematoma rate is less with a strategy of continued oral AC compared to bridging. Despite these encouraging results, most physicians are reluctant to move to a strategy of operating on continued Coumadin in the absence of confirmatory data from RCTs and because of concerns of acute life threatening bleeding complications. Furthermore, current clinical practice in Canada varies widely. We recently surveyed 62 Clinical Electrophysiologists across Canada. The results of the survey have been presented at the Canadian Cardiovascular Congress in October The survey posed 4 clinical scenarios of patients on oral AC undergoing device implantation. The questions collectively presented a gradient of perceived risk of ATE based on the presence of a mechanical heart valve, AF, previous stroke and the remainder of the CHADS 2 risk factors. Respondents were offered 3 options: discontinuing oral AC without heparin bridging; discontinuing oral AC with heparin bridging; or continuing therapeutic dose oral AC. The results are shown in Table 7. Clinical equipoise is clearly evident, and supports the need for comparative studies to identify optimal patient care strategies. CHADS 2 Score Mechanical Valve AF Previous stroke Device Surgery Stop AC/no bridge Stop AC and Bridge Continue oral AC Case 1 1 No Yes No pacemaker 83% 3% 13% Case 2 4 No Yes No pacemaker 32% 38% 30% Case 3 1 Aortic No No pacemaker 0% 64% 36% Bileaflet Case 4 4 No Yes Yes CRT-ICD 5% 73% 22% Table 7. Results of survey of peri-operative oral AC management practice of patients on chronic coumadin undergoing arrhythmia device surgery There are 2 recently published reviews. The first review was published by Jamula et al. in October These authors ended their review by concluding The optimal perioperative anticoagulation management of patients who require pacemaker or ICD implantation is not established but a strategy involving bridging is associated with a high risk for bleeding, whereas perioperative continuation of warfarin appears to confer a lower risk for bleeding. Randomized trials are needed to compare the efficacy and safety of different perioperative anticoagulation strategies in this increasing patient population. The second review was published by our group in January The paper also outlines this clinical trial. 6

9 Trial. Protocol Version 13 March 9 th 2009 None of the recent guideline documents make any comment on the practice of device 6, 7, 29 surgery on continued Coumadin. 1.2 What is/are the principal research question(s) to be addressed? Efficacy Does a strategy of continued Coumadin at the time of device surgery, in patients with moderate to high risk of thrombo-embolic events, lead to a reduction in the incidence of clinically significant hematoma in comparison to the current practice standard of bridging AC? Safety Is a strategy of continued Coumadin at the time of device surgery safe? Cost Analysis What are the potential cost savings from a strategy of continued Coumadin? 2. THE TRIAL 2.1 Trial design Prospective, single blind randomized controlled trial (1:1 randomization). 2.2 Planned trial interventions 1. Conventional Arm (Bridging AC). Discontinue oral AC 5 days before procedure. Start full therapeutic doses of subcutaneous LMWH (for example Enoxapirin 1mg per kg twice daily) or IV Heparin 3 days before procedure. The final dose of LMWH will be given in the morning of the day prior to the procedure (i.e. >24 hours prior to procedure). IV Heparin will be discontinued 4 hours prior to surgery Oral AC will be resumed on the evening of the procedure. Patient will be started back on full dose LMWH injections or full dose IV Heparin 24 hours after surgery. Investigators will be encouraged to use only LMWH. If they do chose IV Heparin initially then the patients should be switched to LMWH as soon as possible Full dose LMWH injections or full dose IV Heparin will be continued until INR is above the lower limit of the prescribed therapeutic range for the patient (usually 2; 2.5 for some valve patients) 2. Experimental Arm (Continued Coumadin). The INR on the day of surgery will be the upper limit of the prescribed therapeutic range for the patient (usually 3; 3.5 for some valve patients) 7

10 Trial. Protocol Version 13 March 9 th 2009 Meet eligibility Criteria Bridging anti-coagulation Discontinue oral anti-coagulation 5 days before procedure. Start full therapeutic doses of subcutaneous LMWH 3 days before procedure. The final dose of LMWH will be given in the morning of the day prior to the procedure (i.e. >24 hours prior to procedure). Oral anti-coagulation will be resumed on the evening of the procedure. Patient will be started back on full dose LMWH injections or full dose IV Heparin 24 hours after surgery. Continued Coumadin Patients will continue on oral anticoagulation. The INR on the day of surgery will be the upper limit of the prescribed therapeutic range for the patient (usually 3; 3.5 for some valve patients) Figure 2 Randomization 2.3 Practical arrangements for allocating participants to trial groups Eligible and consenting patients will be equally randomized to control or experimental groups. The randomization will be blocked using blocks of varying sizes. Once activated, each participating center will be allotted a certain number of sealed envelopes. Determination of the treatment assignment will be conducted by the Study Coordinator opening the sealed envelope that will run in consecutive order. 2.4 Investigator blinding Patient blinding is not possible because of the very different nature of the two treatment arms. For the purpose of investigator blinding, each centre will be required to identify two teams for each patient. 1) The unblinded team will have knowledge of treatment allocation and will be responsible for device implantation and follow-up. They will not be allowed to make decisions about the clinical relevance of a hematoma. 2) The blinded team will have no knowledge of treatment allocation. The blinded team will review the patient each day during hospital admission, at 1-2 week follow-up, and during any unscheduled hospital visits/admissions. Also, they will perform a telephone follow-up on post-op day 3 or 4. In addition, an adjudication committee blinded to treatment allocation will review all endpoints. 8

11 Trial. Protocol Version 13 March 9 th Inclusion/exclusion criteria Inclusion Criteria 1. Any patient undergoing elective device surgery (i.e. de novo device implantation or pulse generator change or lead replacement or pocket revision) 2. Patient at moderate or high risk of ATE 7 or high risk of VTE 7 (defined as one or more of following): 2.1 Prosthetic mitral valve replacement 2.2 Caged ball or tilting disc aortic valve prosthesis 2.3 Bileaflet aortic valve prosthesis and one or more of AF Prior stoke or TIA Hypertension DM CHF age > AF associated with rheumatic valvular heart disease 2.4 Non-rheumatic AF and CHADS 2 SCORE > Non-rheumatic AF and stroke or TIA within 3 months 2.6 Recent (within 3 months) VTE 2.7 Severe thrombophilia 7 (Protein C or S deficiency or anti-thrombin or antiphospholipid antibodies or multiple abnormalities 3. Willing to self-inject or have a relative or friend or nurse inject LMWH Exclusion Criteria 1. Unable or unwilling to provide informed consent 2. History of noncompliance of medical therapy 3. Prior Heparin induced thrombocytopenia 4. Active device infection 5. Included in another clinical trial Management of Plavix/Aspirin in patients with coronary stents Patients on Plavix for more than one year since their bare metal stent will have their Plavix stopped 5 days before the procedure. Those with drug eluting stents will be done on Plavix. Aspirin will be continued in all patients. 2.6 Duration of treatment period The treatment period is peri-procedural. Patients in the conventional arm will discontinue oral AC 5 days before the procedure and will start therapeutic dosages of LMWH 3 days before the procedure. They will restart injections or IV UFH 24 hours after the procedure to be continued until therapeutic INR is achieved. 2.7 Frequency and duration of follow up All follow-up will be performed by the blinded team. Patients will be seen daily throughout their inpatient stay. All patients will have telephone follow-up on day 3 or 4 or the next 9

12 Trial. Protocol Version 13 March 9 th 2009 business day if this falls on the weekend. They will be asked if they have developed progressive swelling over their device. A positive response will lead to a same day visual assessment by the blinded team. All patients will also be seen at their first routine postoperative outpatient visit (one to two weeks after discharge). Patients developing clinically significant hematoma will be followed until resolution of their hematoma. 2.8 Primary and secondary outcome measures The primary outcome is Clinically significant hematoma defined as: 1. Hematoma requiring re-operation or 2. Hematoma resulting in prolongation of hospitalization or 3. Hematoma requiring interruption of AC Hematoma requiring re-operation is defined as a hematoma that continues to expand despite all appropriate non-operative measures, or is producing impending or actual wound breakdown or skin necrosis. Minor hematomas that are evacuated at the time of other reoperation (e.g. for lead repositioning) are not considered as a primary outcome. Hematoma resulting in prolongation of hospitalization is defined as extended hospitalization or rehospitalization for >24 hours, post index surgery, primarily due to hematoma. Hematoma requiring interruption of AC, is defined as reversal or intentional withholding of all AC, in response to wound hematoma, resulting in sub-therapeutic AC for >24 hours. If the patient is taking Coumadin sub-therapuetic AC will be defined as two consecutive daily INRs < the lower limit of the prescribed therapeutic range for the patient (usually <2; <2.5 for some valve patients) All potential primary outcomes will require completion of detailed case report forms by the blinded observing team. These reports will be reviewed by the event adjudication committee to determine if they meet the criteria for clinically significant hematoma. Considerations in choosing and defining the primary outcome There is no agreed definition of clinically significant hematoma and investigators have used various definitions (see table 8). In selecting our definition we took the following into consideration: what has been previously used; that the hematoma leads to sequelae, i.e. is truly clinically significant; and that the definition is as objective as possible. Secondary Outcomes 1. Each of the components of the primary outcome 2. Composite of all other major peri-operative bleeding events defined as follows: 2.1 Hemothorax: 2.2 Cardiac tamponade: typical hemodynamic +/- echocardiographic features leading to and confirmed by pericardiocentesis or surgical exploration. 10

13 Trial. Protocol Version 13 March 9 th Significant pericardial effusion: a new effusion diagnosed by echocardiography (> 0.5cm) and not meeting definition of tamponade. 3. Thrombo-embolic events defined as follows: 3.1 Transient ischemic attack: presence of a new focal neurologic deficit thought to be vascular in origin, with signs or symptoms lasting <24 h.* 3.2 Stroke: presence of a new focal neurologic deficit thought to be vascular in origin, with signs or symptoms lasting >24 h.* *These diagnoses should be confirmed by an imaging procedure such as a computed tomography or magnetic resonance imaging and by a neurologist. 3.3 Deep venous thrombosis diagnosed by ultrasound 3.4 Pulmonary embolism diagnosed by high-probability VQ scan or CT scan or pulmonary angiography 3.5 Peripheral embolus to limb(s).** 3.6 Peripheral embolus to other major organ.** 3.7 Valve thrombosis** **These diagnoses should be confirmed by appropriate imaging procedures and/or and /or expert opinion and/or surgical exploration. 4. All cause mortality 5. Number of days with sub-therapeutic AC 6. Cost utilization 7. Patient quality of life, peri-operative pain, and satisfaction (see appendix i) Patients will be asked at the 1-2 week follow-up to grade their Quality of Life, since the start of the study, using EQ-5D. 30 They will also be asked to grade their most severe perioperative pain on the Visual Analogue Scale. 31 Patient satisfaction at the management of their peri-operative AC will be assessed using a 7 point Likert scale (0= very satisfied to 7 very dissatisfied). All these assessments will be performed by the blinded team. 2.9 Sample size The combined hematoma rate with bridging AC in five studies is 26.9% (Table 8). Hence, we have estimated the rate to be 25%. We polled 25 implanting physicians (including members of the steering committee) and the consensus was that the minimal clinically important difference was 30%. In order to detect a 30% relative risk reduction in the primary 11

14 Trial. Protocol Version 13 March 9 th 2009 endpoint under the experimental group (continued oral AC), at alpha = (two-sided) and 80% power, using the chi-square test, a sample size of 984 patients will be needed (492 in the Bridging AC arm and 492 in the Continued Coumadin arm). We do not anticipate significant rates of non-compliance and loss to follow-up. CONTINUED COUMADIN REF pts Hematoma N Hematoma definition Hematoma Rate Not defined, 7 controlled with pressure dressing and 2 needed re-operation 2.6% Causing symptoms and/or 8.8% required an unscheduled visit and/or prolonged hospital stay and /or required surgical revision Not stated 12% Exerting pressure on suture 2.9% line and/or requiring intervention Not defined 0 TOTAL % Bridging AC need for reoperation or 23.0% interruption of oral AC Not stated 9% Exerting pressure on suture 77% line and/or requiring intervention > 2cm mass protruding 20.4% anterior to pulse generator Not defined but 6/ % required re-operation TOTAL % Table 8. Reported rate of significant hematoma 2.10 Planned recruitment rate We have a total of 13 committed centres (the 7 centres of the steering committee and 5 additional centres). See table 9 for estimation of potentially eligible patient numbers. Potentially eligible for BRUISE CONTROL is based on data from 2 of our centres. At Hamilton Health Science Centre, 1282 device surgeries were performed in a 2 year period, and of these patients, 196 (15.3%) required peri-operative bridging. 19 At University of Ottawa Heart Institute, we reviewed the charts of all device surgery patients for a 6-month period Feb - July 2008; 16.1% of these patients would have been eligible for this study. Based on these data we used 15% to calculate the potentially eligible patients. 12

15 Trial. Protocol Version 13 March 9 th 2009 Centre 2008 volumes Number University of Ottawa Heart London Health Science Center McGill University Health Center Hamilton Health Science Center Mazankowski Alberta Heart Institute Kingston General Royal Jubilee Hospital, Victoria Halifax Infirmary, NS Hôpital Sacré-Coeur de Montréal Hôpital Laval Southlake Hospital, Newmarket St. Boniface Gen Hospital, Winnipeg Sherbrooke University Hospitals TOTALS Potential Eligible for BRUISE CONTROL* Table 9. Annual device volumes at participating centres ( volumes are projected based on an anticipated annual 5% growth). Between patients per year at our 13 centres will potentially be eligible for the study. We plan to complete the study in three years and anticipate recruitment of 250 patients in year 1, 400 patients in year 2, and the remaining 334 patients in year 3 If we find that we are lagging behind in recruitment there are a number of other centres in Canada and in Europe which have expressed an interest in joining our study Planned analyses. Descriptive statistics including 95% confidence intervals will be calculated for all baseline variables using means, medians, standard deviations and interquartile ranges for continuous outcomes, and rates and proportions for discrete outcomes for each treatment arm. For the 13

16 Trial. Protocol Version 13 March 9 th 2009 primary outcome, clinically significant hematoma, the treatment arms Bridging AC versus Continued Coumadin will be compared using the chi-square test. Baseline characteristics of the treatment arms will be compared. If any clinically significant differences are identified, a logistic regression analysis will be conducted to compare clinically significant hematoma between the two treatment arms adjusting for these differences. The same analysis plan for the primary outcome will be followed for the secondary outcomes: each of the components of clinically significant hematoma, composite of all bleedings events and thrombo-embolic events Planned subgroup analyses The planned subgroup analyses include comparison of: Taking Clopidogrel (Plavix) compared to not taking Clopidogrel (Plavix). (Patients who have temporarily discontinued the drug peri-operatively will be included on the latter group.) Taking any anti-platelet agent compared to not De novo implants compared to subsequent surgeries 2.13 Frequency of analyses Two interim analyses are planned when 33% and 66% of the patients have been recruited and assessed. The O Brien-Fleming group sequential method 32 will be followed with the p- values of , and for the first interim, second interim and final analysis respectively Economic issues A key component of the study will be an analysis of the costs associated with the two comparators within the trial. Medical resource use will be assessed for each patient. Resource consumption to be recorded will include costs directly related to the two treatments (e.g. cost of bridging medications and administration of bridging medications, costs of teaching bridging, costs of INRs, etc.). In addition, we will collect data on length of hospitalization and costs related to complications of the two treatment strategies (e.g. costs of tamponade or re-operation related to hematoma). The costs of the initial surgery will not be counted, as these will be identical in each arm. We postulate that the experimental treatment will be dominant in that it is likely to be cost saving and reduce the incidence of the primary outcome. Primary analysis will focus on identifying the mean cost savings per patient. These savings can be extrapolated on an annual basis to Canada as a whole. Secondary analyses will focus on relating the incremental costs to incremental secondary outcomes, and in assessing the uncertainty around these estimates using non-parametric bootstrapping. We are postulating that our experimental treatment (continued Coumadin) will be dominant, 33 i.e. both cheaper and more effective than the control arm. Hence strictly a sample size calculation is not required. 14

17 Trial. Protocol Version 13 March 9 th DETAILS OF TRIAL TEAM 3. TRIAL MANAGEMENT 3.1 What are the arrangements for day to day management of the trial? E.g. randomization, data handling, and who will be responsible for coordination. The University of Ottawa Heart Institute (UOHI) Clinical Trials Centre will function as the coordinating centre for all aspects of this trial. UOHI will be responsible for the randomization process and for receiving, editing, processing, analyzing, and storing data generated in this trial. The centre is responsible for implementing and maintaining quality assurance procedures related to data generation. The coordinating centre has developed clinical manual of operations, study data forms and related materials and will serve as the payment centre for the general study needs. The Clinical Trials Centre at UOHI has coordinated several multi-centre clinical trials. One current example is the Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT). This is a 35 centre, multinational, 7 year, 1800 patient study commenced in 2003 (CIHR Grant Number ). A trial Project Manager has already been identified for BRUISE CONTROL. She will be responsible for the day to day running of the study including liaising with the individual study sites and study research co-coordinators. This individual will supervise the activities of the Study Nurses with respect to patient eligibility, data accumulation and transmission, and patient follow-up 3.2 What will be the role of each principal applicant and co-applicant proposed? The nominated principal applicant (Birnie) will be responsible for direct supervision of the project manager. He will also chair the steering committee. The co-pi (Essebag), CIHR Clinician Scientist and PhD in epidemiology and biostatistics, will assist the nominated principal applicant in trial supervision and coordination. The Director of the Cardiovascular Methods Center at UOHI (Wells) is a co-applicant and he will be involved in all aspects of trial management. Krahn, Healey and Tang all have extensive experience with clinical trials and will assist with trial direction. Coyle is a health economist and will be responsible for all aspects of the cost utilization analysis. Birnie, Essebag and 5 of the other co-applicants (Krahn, Healey, Simpson, Tang, Sivakumaran, Verma) are all implanting electrophysiologists and will each be principal investigators at their individual sites. They will supervise research nurses in recruiting patients to the study. The Canadian electrophysiology/pacing clinical research community has a long history of successfully completing large scale clinical trials (e.g. CIDS, 34 VPS, 35 CTOPP, 35 AF-CHF 36 ) which attests to the capacity to complete this trial successfully. 3.3 Describe the trial steering committee and if relevant the data safety and monitoring committee. The steering committee consists of all applicants on this grant. There is also a separate data safety and monitoring committee (DSMC). The DSMC consists of three people. The chair is Dr Lyall Higginson, an experienced General Cardiologist and immediate past President of 15

18 Trial. Protocol Version 13 March 9 th 2009 the Canadian Cardiovascular Society. The other members, both from University of British Columbia, are Dr Stanley Tung (an implanting electrophysiologist), and Dr Rollin Brant (a bio-statistician). All members of the DSMC have extensive clinical trials experience and were invited on the basis of their expertise and independence. Dr Tung s centre will not be involved in patient recruitment. There will also be an events adjudication committee. The committee (blinded to treatment allocation) will be responsible to review the data of the primary outcome events, i.e. clinically significant hematoma. The committee will also be responsible for reviewing reports prepared by the data coordinating centre to detect deficiencies in data collection or intake processes and recommend alternate action if required. 16

19 Trial. Protocol Version 13 March 9 th 2009 Appendix: Patient quality of life, peri-operative pain, and satisfaction All assessments will be performed by blinded team at the 1-2 week follow-up 1. Patients will be asked to grade their Quality of Life, since the start of the study, using EQ- 5D. 30 MOBILITY I have had no problems in walking about since I started the study I have had some problems in walking about since I started the study I have been confined to bed since I started the study SELF-CARE I have had no problems with self-care since I started the study I have had some problems washing or dressing myself since I started the study I have been unable to wash or dress myself since I started the study USUAL ACTIVITIES (e.g. work, study, housework family or leisure activities) I have had no problems with performing my usual activities since I started the study I have had some problems with performing my usual activities since I started the study I have been unable to perform my usual activities since I started the study PAIN / DISCOMFORT I have had no pain or discomfort since I started the study I have had moderate pain or discomfort since I started the study I have had extreme pain or discomfort since I started the study ANXIETY / DEPRESSION I have not been anxious or depressed since I started the study I have been moderately anxious or depressed since I started the study I have been extremely anxious or depressed since I started the study Tick one answer in each section 17

20 Trial. Protocol Version 13 March 9 th Patients will also be asked to grade their most severe peri-operative pain on the Visual Analogue Scale. 31 To help people say how good or bad their state of health has been on average since starting the study, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0. We would like you to indicate on this scale how good or bad your health has been on average since starting the study in your opinion. Please do this by drawing a line on the scale. 18

21 Trial. Protocol Version 13 March 9 th Patient satisfaction at the management of their peri-operative AC will be assessed using a 7-point Likert scale (1 = very dissatisfied = to 7 very satisfied). 1. very dissatisfied 2. somewhat dissatisfied 3. slightly dissatisfied 4. Neither dissatisfied or satisfied 5. slighly satisfied 6. somewhat satisfied 7. very satisfied 19

22 Trial. Protocol Version 13 March 9 th 2009 Bridging AC Baseline Evaluation Randomization 5-14 days pre-op Day 5 preop stop Oral AC Day 3 pre-op Start Bridging Surgery Day 0 Evening of surgery Restart oral AC Day 1 Post-op Restart Bridging Daily while in-patient assessment by blinded team Day 3/4 Telephone FU by blinded team One to two weeks post-op assessment by blinded team Continued Coumadin 5-14 days pre-op Day 0 assessment by blinded team Telephone FU by blinded team assessment by blinded team Table 10 BRUISE CONTROL summary 20

23 Trial. Protocol Version 13 March 9 th 2009 Reference List (1) John Crysler Inc.Market Statistics. Cardiac Arrythmia Device Implant Market Jan. (2) Birnie D, Williams K, Guo A et al. Reasons for escalating pacemaker implants. Am J Cardiol 2006 July 1;98(1):93-7. (3) Mond HG, Irwin M, Morillo C, Ector H. The world survey of cardiac pacing and cardioverter defibrillators: calendar year Pacing Clin Electrophysiol 2004 July;27(7): (4) Greenspon AJ, Hart RG, Dawson D et al. Predictors of stroke in patients paced for sick sinus syndrome. J Am Coll Cardiol 2004 May 5;43(9): (5) Bardy GH, Lee KL, Mark DB et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005 January 20;352(3): (6) Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006 August 15;48(4): (7) Douketis JD, Berger PB, Dunn AS et al. The Perioperative Management of Antithrombotic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008 June 1;133(6_suppl):299S-339. (8) Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997 May 22;336(21): (9) Baudet EM, Oca CC, Roques XF et al. A 5 1/2 year experience with the St. Jude Medical cardiac valve prosthesis. Early and late results of 737 valve replacements in 671 patients. J Thorac Cardiovasc Surg 1985 July;90(1): (10) Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001 June 13;285(22): (11) Garcia DA, Regan S, Henault LE et al. Risk of Thromboembolism With Short-term Interruption of Warfarin Therapy. Arch Intern Med 2008 January 14;168(1):63-9. (12) Tolosana JM, Berne P, Mont L et al. Heparin Vs Acenocomarol in device implant/replacement: A propsective, randomized Trial. HRS Ref Type: Abstract (13) Slotwiner D. The Pocket Protecotr Study: Use of D Stat Flowable Hemostat in pulse Gnerator Pectoral pockets reduces the rate of clnically relevant hematomas. Circulation 116[II], Ref Type: Abstract (14) Robinson M, Healey J, Eikelboom J et al. Development of an improved strategy for peri-operative bridging of AC: predictors of wound hematoma following surgery for permanent pacemakers and ICDs. CCS Ref Type: Abstract (15) Michaud GF, Pelosi F, Jr., Noble MD, Knight BP, Morady F, Strickberger SA. A randomized trial comparing heparin initiation 6 h or 24 h after pacemaker or defibrillator implantation. J Am Coll Cardiol 2000 June;35(7):

24 Trial. Protocol Version 13 March 9 th 2009 (16) Marquie C, De GG, Klug D et al. Post-operative use of heparin increases morbidity of pacemaker implantation. Europace 2006 April;8(4): (17) de Oliveira JCM, Martinelli MM, D'Orio Nishioka SAP et al. Efficacy of Antibiotic Prophylaxis Before the Implantation of Pacemakers and Cardioverter-Defibrillators: Results of a Large, Prospective, Randomized, Double-Blinded, Placebo-Controlled Trial.[Article]. Circulation: Arrhythmia and Electrophysiology 2009 February;2(1): (18) Reynolds MR, Cohen DJ, Kugelmass AD et al. The frequency and incremental cost of major complications among medicare beneficiaries receiving implantable cardioverter-defibrillators. J Am Coll Cardiol 2006 June 20;47(12): (19) Robinson M, Healey J, Eikelboom J et al. Postoperative Low-Molecular-Weight Heparin Bridging is Associated with an Increase in Wound Hematoma Following Surgery for Pacemakers and Implantable Defibrillators. Pacing Clin Electrophysiol 2009 January 3;32: (20) Sivakumaran S, Paradon K, Pantano A, Kimber S, Hrczkowski T. Continuous Warfarin maybe superior to interuppted Heaprin in preventing large pocket hematomas in pacemaker and ICD patients. HRS AHA Ref Type: Abstract (21) al-khadra AS. Implantation of pacemakers and implantable cardioverter defibrillators in orally anticoagulated patients January. (22) Giudici MC, Paul DL, Bontu P, Barold SS. Pacemaker and implantable cardioverter defibrillator implantation without reversal of warfarin therapy. Pacing Clin Electrophysiol 2004 March;27(3): (23) Tischenko A, Yee R, Skanes AC, Klein GJ, Gula LJ, Krahn AD. Implantation of cardiac thythm managment devices without interruption of oral AC therapy. CCS Ref Type: Abstract (24) Gras D, Bocker D, Lunati M et al. Implantation of cardiac resynchronization therapy systems in the CARE-HF trial: procedural success rate and safety. Europace 2007 July;9(7): (25) Ellenbogen KA, Hellkamp AS, Wilkoff BL et al. Complications arising after implantation of DDD pacemakers: the MOST experience. The American Journal of Cardiology 2003 September 15;92(6): (26) Krahn AD, Jeffrey S.Healey, Christopher S.Simpson, Vidal Essebag, Soori Sivakumaran, David H.Birnie. Peri-operative Anti-coagulation of Patients on Chronic Warfarin Undergoing Arrhythmia Device Surgery: Wide Variability of Practice in Canada. CJC Ref Type: Abstract (27) Jamula E, Douketis JD, Schulman S. Perioperative anticoagulation in patients having implantation of a cardiac pacemaker or defibrillator: a systematic review and practical management guide. J Thromb Haemost 2008 October;6(10): (28) Birnie D, Healey JS, Krahn A et al. Bridge or continue Coumadin for device surgery: a randomized controlled trial rationale and design. Curr Opin Cardiol 2009 January;24(1):82-7. (29) Bonow RO, Carabello BA, Chatterjee K et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006 August 1;48(3):e

25 Trial. Protocol Version 13 March 9 th 2009 (30) EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol Group. Health Policy 1990 December;16(3): (31) Price DD, McGrath PA, Rafii A, Buckingham B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 1983 September;17(1): (32) O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35: (33) O'Brien BJ, Drummond MF, Labelle RJ, Willan A. In search of power and significance: issues in the design and analysis of stochastic cost-effectiveness studies in health care. Med Care 1994 February;32(2): (34) Connolly SJ, Gent M, Roberts RS et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000 March 21;101(11): (35) Connolly SJ, Sheldon R, Thorpe KE et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA 2003 May 7;289(17): (36) Roy D, Talajic M, Nattel S et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008 June 19;358(25):

26 Trial. Protocol Version 1 4 July 2 nd 2010 BRUISE CONTROL : BRidge or continue coumadin for device SurgEry randomized CONTROLled Trial Protocol Version 14 2 nd July 2010 D Birnie (Nominated Principal Investigator) V Essebag (Principal Investigator) A Krahn J Healey C Simpson A Tang D Coyle G Wells S Sivakumaran A Verma K Rajappan Page 1 of 27

27 Trial. Protocol Version 1 4 July 2 nd THE NEED FOR A TRIAL 1.1 What is the problem to be addressed? Implantation rates of cardiac arrhythmia devices, i.e. pacemakers, implantable cardiac defibrillators (ICD) and cardiac resynchronization therapy (CRT) are steadily increasing by an estimated 10% per year. 1-3 In 2006 there was a total of device implants in Canada (21054 pacemakers, 4812 and 1420 CRT). 1 Figure 1 shows worldwide rates. Figure 1 Worldwide trends in cardiac arrhythmia device implantation (IPG; implantable pacemaker generator, i.e. pacemaker) 1 Many patients (23-24% in a recent pacemaker trial 4 and 32-37% in a recent ICD trial 5 ) requiring cardiac arrhythmia device surgery are on chronic oral anticoagulation (AC) therapy. The peri-procedural management of their AC presents a dilemma to physicians. This is particularly true in the subset of patients with moderate to high risk (e.g. >5% per year) of arterial thrombo-embolic events (ATE). Examples include patients with mitral valve replacement or patients with non-rheumatic atrial fibrillation (AF) and a high CHADS 2 score. 6 The peri-operative risk of ATE (without bridging AC) has been estimated based on a fraction of the annual risk of this outcome. 7, 8 Thus, based on a 17% annual risk 9 of ATE in patients with mechanical MVR without oral AC, the risk for 8 days is 0.4%. 7 For a patient with a CHADS 2 score of 3, the annual risk of ATE without oral AC is estimated to be 5.9% 6 which equates to a risk over 8 days of oral AC interruption of 0.16%. Acronym CHADS2 Risk Criteria Score C Congestive Heart Failure 1 H Hypertension 1 A Age >75 y 1 D Diabetes mellitus 1 S Stroke or TIA 2 Table 1. Description of CHADS2 scoring system for patients with non-valvular AF 10 Page 2 of 27

28 Trial. Protocol Version 1 4 July 2 nd 2010 CHADS 2 index Estimated Annual Stroke risk % Table 2. Stroke risk in patients with non-valvular AF not treated with oral AC according to the CHADS 2 index 10 However, it should be noted that these risk estimates assume linear risk, i.e. without any increase in risk due to the pro-thrombotic state of surgery. There are some data to suggest that the pro-thrombotic state of surgery does transiently further increase the risk of ATE. For example, in studies of patients with mechanical valves which compared various strategies of bridging AC, the overall crude risk for peri-operative ATE was 0.83% (95% CI: ). 7 Thus, even with peri-procedural bridging AC, the risk was higher than the modeling data which suggest it should be 0.4%. 7 Similarly, there are some early data that the peri-operative risk of ATE in patients with AF is higher than might be predicted. 11 However, these data are far from conclusive. Furthermore, it is possible that the pro-thrombotic effect maybe lesser with device surgery than with more major surgery. Physicians have responded to concerns about peri-procedural ATE by treating moderate to high risk patients with bridging AC. Oral AC is discontinued a few days before the procedure or surgery and substituted with therapeutic doses of either intravenous unfractionated Heparin (IV UFH) or, more usually, Low Molecular Weight Heparin (LMWH). After surgery the patient is restarted on LMWH or IV UFH for a few days while the oral AC effect is building up to therapeutic levels. High (>10% per year) Moderate (4-10% per year) Low (<4% per year) Mechanical Heart Valve Atrial Fibrillation VTE Any mitral valve prosthesis CHADS 2 score of 5 or 6 Older (caged-ball or tilting disc) Recent (within 3 mo) aortic valve prosthesis stroke or transient ischemic attack, Recent (within 6 mo) stroke or Rheumatic valvular transient ischemic attack Bileaflet aortic valve prosthesis and one of the following: atrial fibrillation, prior stroke or transient ischemic attack, hypertension, diabetes, congestive heart failure, age > 75 yr Bileaflet aortic valve prosthesis without atrial fibrillation and no other risk factors for stroke heart disease CHADS 2 score of 3 or 4 CHADS 2 score of 0 to 2 (and no prior stroke or transient ischemic attack) Table 3 Risk stratification for recurrent thrombo-embolic events 7 Recent (within 3 mo) VTE Severe thrombophilia (eg, deficiency of protein C, protein S or antithrombin, antiphospholipid antibodies, or multiple abnormalities) VTE within the past 3 to 12 mo Nonsevere thrombophilic conditions (eg, heterozygous factor V Leiden mutation, heterozygous factor II mutation) Recurrent VTE Single VTE occurred > 12 mo ago and no other risk factors Page 3 of 27