Introduction. CLINICAL RESEARCH Clinical Trial Design. Mohammad Saeed 1 *, Mehdi Razavi 1, Curtis G. Neason 2, and Simona Petrutiu 2. Aims.

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1 Europace (2011) 13, doi: /europace/eur195 CLINICAL RESEARCH Clinical Trial Design Rationale and design for programming implantable cardioverter defibrillators in patients with primary prevention indication to prolong time to first shock (PROVIDE) study Mohammad Saeed 1 *, Mehdi Razavi 1, Curtis G. Neason 2, and Simona Petrutiu 2 1 Texas Heart Institute, St Luke s Episcopal Hospital, Houston, TX , USA; and 2 St Jude Medical, Sylmar, CA, USA Received 2 March 2011; accepted after revision 26 May 2011; online publish-ahead-of-print 21 July 2011 Aims Shock therapy delivery by implantable cardioverter defibrillators (ICD) can be painful and may have negative psychological consequences. Reducing shock burden for patients with ICDs and cardiac resynchronization therapy defibrillators (CRT-Ds) may have beneficial consequences. This may be achieved by avoiding inappropriate for supraventricular tachycardia (SVT) and by limiting appropriate to only those that are necessary to convert ventricular arrhythmias.... Methods The programming implantable cardioverter defibrillators in patients with primary prevention indication to prolong and results time to first shock study (PROVIDE) is a prospective, randomized, multicentre study that will test the hypothesis that a combination of pre-selected ventricular tachyarrhythmia detection, anti-tachycardia pacing, and SVT discriminator parameters will prolong the time to first shock without increasing arrhythmic syncope in patients receiving ICDs for primary prevention. Patients receiving St Jude Medical ICDs and CRT-Ds for primary prevention will be randomized 1:1 to one of two arrhythmia detection and therapy approaches. The study will enroll and follow 1600 patients for at least 1 year or until 226 first have been documented in the total study population. The primary endpoint of the study is the mean time to first shock and the safety endpoint is the rate of arrhythmic syncope.... Conclusion The PROVIDE trial is a randomized controlled study, designed to assess if a pre-selected combination of programming parameters can reduce shock burden among patients receiving ICDs/CRT-Ds for primary prevention Keywords Implantable cardioverter defibrillator Anti-tachycardia pacing Ventricular tachycardia Ventricular fibrillation Sudden cardiac death Introduction Implantable cardioverter defibrillators (ICD) have been shown to improve survival in patients with life-threatening ventricular arrhythmias, coronary artery disease, and left ventricular dysfunction. 1 3 Shock therapy is effective in terminating ventricular tachycardia (VT) but it can be painful, and repetitive have the potential to impact quality of life. 4 6 A number of studies have investigated the efficacy and safety of anti-tachycardia pacing (ATP) as a painless method to terminate both slow and fast VT. 7 9 Most studies, including PainFREE Rx II (Pacing Fast Ventricular Tachycardia Reduces Shock Therapies II) and EMPIRIC (Comparison of Empiric to Physician Tailored Programming of Implantable Cardioverter Defibrillators trial), have evaluated ATP therapies in a population of patients receiving ICDs for pre-dominantly secondary prevention of sudden cardiac death. 7,8 The PROVE trial 9 was the first large, multicentre clinical trial that showed the efficacy of using ATP in the primary prevention population. The avoidance of unnecessary is an important consideration when programming device therapy, especially in patients with primary prevention indication for ICD and CRT-D. Most efforts have focused on reducing inappropriate for * Corresponding author Fannin, Suite 2480, Houston, TX , USA. Tel: ; fax: , hallgar@hgcardio.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Shock reduction in ICD patients 1649 supraventricular tachycardia (SVT), which make up a significant percentage of in the primary prevention population. 7 However, further reduction in could be achieved by also preventing for slower haemodynamically stable ventricular arrhythmias as well as those that might terminate spontaneously. The PREPARE study 10 proposed a set of rate-based parameters to minimize shock therapy without increasing the risk of syncope or untreated VT in primary prevention patients. The study suggested that these parameters may reduce the total number of in primary prevention patients without exposing them to other risks. However, there were limitations to the PREPARE trial design: it was non-randomized, used a historical control, and the historical control included a large percentage of patients with cardiac resynchronization therapy defibrillator (CRT-D) devices. 10 Furthermore, the decision to programme an increased number of detection intervals in the ventricular fibrillation (VF) detection zone may have contributed to the higher frequency of syncope in this study. 10 The programming implantable cardioverter defibrillators in patients with primary prevention indication to prolong time to first shock (PROVIDE) study is a randomized, multicentre trial designed to investigate a combination of parameters that may increase the time to first shock in these patients. It aims to prospectively study the effect of higher detection rates, 7 prolonged detection intervals, 7 aggressive SVT discriminators, 11,12 and extensive ATP therapy on the time to first shock and incidence of arrhythmia-related syncope in patients receiving ICD/CRT-D for primary prevention of sudden cardiac death. Methods Hypothesis The PROVIDE study will test the hypothesis that the specific preselected VT/VF detection, ATP, and SVT discriminator parameters will prolong the mean time to first shock compared with the control settings without increasing arrhythmic syncope in patients receiving an ICD/CRT-D for primary prevention. Study design This is a prospective, randomized, multicentre study sponsored by St Jude Medical Cardiac Rhythm Management Division (SJM; Sylmar, CA, USA) registered with (#NCT ). The study will enroll 1600 patients and each patient will be followed until 1 year after the last patient enrollment or until 226 first have been documented. Patients will be enrolled at up to 100 centres in the USA and each centre may enroll up to 80 patients. The study must be approved by the institutional committee on human research at each participating site. At enrollment, informed consent is obtained, and enrolled patients are randomized to either a control or an experimental group. Follow-up visits are conducted in-clinic or remotely and will occur every 3 months until study closure. The programmed parameters in the control group are based on the PROVE study. The programmed parameters in the experimental group include a combination of higher detection rates, prolonged detection intervals, aggressive SVT discriminators, and ATP therapy and are designed specifically to attempt to increase the time to first shock in primary prevention patients. Table 1 Study inclusion/exclusion criteria Inclusion criteria (i) Patient is enrolled within 30 days of implant with a market-released SJM Current TM, Promote TM, or a newer market released SJM device for a primary prevention indication for ICD/CRT-D (ii) Patient is willing to comply with the study procedure (iii) Patient is able to be programmed to their assigned set of programmed parameters specified in the protocol Exclusion criteria (i) Patient had spontaneous VT or VF episode prior to the implant. VT is considered an exclusion if: (a) VT lasted for 30 s (b) VT was haemodynamically unstable (c) VT required external cardioversion (ii) Patient had inducible sustained VT,181 bpm during an electrophysiology test (iii) Patient had an ICD or CRT-D device prior to their currently implanted device (iv) Patient is enrolled in any other clinical investigation that includes an active treatment arm (v) Patient s life expectancy is,24 months (vi) Patient is a candidate for cardiac transplant (vii) Patient is pregnant (viii) Patient s age at enrollment is,18 years SJM, St Jude Medical; ICD, implantable cardioverter defibrillators; CRT-D, cardiac resynchronization therapy device; VT, ventricular tachycardia; VF, ventricular fibrillation. Study endpoints The primary endpoint of the study is the mean time to first shock. The safety endpoint is the rate of arrhythmic syncope. Additional data will be collected including: all-cause, inappropriate therapies, inappropriate SVT detections, untreated sustained VT/VF episodes, VT episodes accelerated to VF by ATP or shock therapy, success of ATP therapies, health care utilization due to ICD-related events, and adverse events. Inclusion and exclusion criteria Any patient who meets the primary prevention ICD/CRT-D criteria 13 and is implanted with a market-released SJM Current TM, Promote TM, or a newer ICD/CRT-D will be eligible for participation in the study up to 30 days post-implantation of the device. The main exclusion criteria include: (i) patient has history of spontaneous sustained VT or VF prior to the implant, (ii) patient had inducible sustained VT, 181 bpm. during an electrophysiology test, or (iii) patient had an ICD or CRT-D device prior to their currently implanted device. The complete list of inclusion and exclusion criteria is shown in Table 1. Randomization and data collection Randomization will be assigned in a 1:1 ratio between the control and experimental arm at the enrollment visit, and will be stratified according to cardiac disease classification (i.e. ischaemic or non-ischaemic aetiology) and implanted device type (i.e. single chamber, dual chamber, or CRT-D). Randomization assignments will be distributed to participating centres, as stratified, via an automated telephone randomization system. Tachycardia detection and treatment parameters will be programmed according to their assigned randomizations and the programming parameters outlined in the Device Programming

3 1650 M. Saeed et al. Table 2 Supraventricular tachycardia discriminator settings for single chamber devices Control arm Experimental arm... Diagnosis If any If 2 of 3 % Match 60% 60% Interval stability ON ON with SIH Stability delta 80 ms 40 ms Sudden onset ON ON Onset delta 100 ms 16% VT timeout OFF OFF SVT discrimination timeout OFF OFF VT, ventricular tachycardia; SVT, supraventricular tachycardia; SIH, sinus interval history. Table 3 Supraventricular tachycardia discriminator settings for dual chamber and cardiac resynchronization therapy defibrillator devices Control arm Experimental arm... V,A If any If all % Match 60% 60% Interval stability ON ON Stability delta 80 ms 40 ms V¼A If any If all % match 60% 60% Sudden onset ON ON Onset delta 100 ms 16% VT timeout OFF OFF SVT discrimination timeout OFF OFF V,A, ventricular events are less than atrial events in number; V¼A, ventricular events are equal in number to atrial events; VT, ventricular tachycardia; SVT, supraventricular tachycardia; CRT-D, cardiac resynchronization therapy device. section (see Tables 2 and 3). Programmable parameters not specified in the protocol and programming of the device prior to randomization are left to the individual investigator s discretion. All enrolled patients will be followed until the study comes to a close. Follow-up visits are conducted in-clinic or remotely at 3, 6, 9, 12, and every 3 months thereafter (see Figure 1). A minimum of one in-clinic follow-up per year is required. During the follow-up visits, device data, including stored electrograms and episode diagnostics will be collected; this includes remote follow-up using Merlin.net. Information about syncopal episodes will also be collected at each follow-up. Patients followed remotely will be contacted by the investigating centre after each remote follow-up to collect information about syncopal episodes, hospitalizations, and adverse events. Device programming Control group All patients randomized to the control group will be programmed to similar detection criteria and therapy zones as those programmed in the PROVE study; the settings in PROVE were based on the PainFREE II trial and aimed to reflect the empiric programming of a primary prevention patient. Specifically, a monitor only zone will be programmed from 150 to 180 bpm. A VT therapy zone will be set from 180 to 214 bpm, where two rounds of ATP will be attempted followed by high-output defibrillation. Supraventricular tachycardia discriminators at nominal values will be activated for the VT zone as shown in Table 2 for single chamber devices and Table 3 for dual chamber and CRT-D devices. A VF therapy zone will be set for all rates.214 bpm, where all therapies will be high-output. For both the VT and VF zones, a total of 12 beats are required for detection and delivery of therapy (see Figure 2). Experimental group In experimental group patients, two VT zones will be programmed: a slow VT zone from 180 to 214 bpm, where two ATPs are attempted prior to high-output, and a fast VT zone from 214 to 250 bpm, where one ATP is attempted prior to high-output. The slow VT zone requires 25 beats to detection and will have empirically-based SVT discriminator settings active as shown in Table 2 for single chamber devices and Table 3 for dual chamber and CRT-D devices. 11,12 The fast VT zone requires 18 beats to detection, and no active SVT discriminators. A VF therapy zone will be programmed for all rates.250 bpm, where 12 beats will be required for detection and all therapies will be high-output (see Figure 2). The detection intervals were based in part on the PREPARE trial. However, to reduce the rate of syncope observed in PREPARE, the number of detection intervals was not increased as drastically in the PROVIDE study. In addition, a second round of ATP was added to the slow VT zone to attempt to terminate the rhythm with a less painful therapy and avoid unnecessary. Sample size The primary efficacy endpoint is the mean time to first shock. The sample size calculation is based on the PROVE trial, 9 where patients experienced a shock rate of 10% per year. Therefore, it is expected that the shock rate at 1 year is 10% in the control group. A 30% reduction of the shock rate at 1 year is expected in the experimental group. The sample size is calculated as the number of first required to have 80% power to detect a 30% reduction in the shock rate at the 5% significance level. 14 Assuming a patient accrual period of 2 years and an additional follow-up time of 1 year, the total number of patients required to achieve 226 first is Assuming an overall attrition of 15%, the total number of patients required to be enrolled is 1600 patients (800 per group). The study will enroll patients until 226 first have been documented in the study or 1600 patients have been enrolled and the last patient has been followed for 1 year (whichever occurs first). Data analysis The primary analysis will be conducted according to the principles of intent-to treat. All episodes of syncope will be evaluated for correlation to arrhythmias based on device diagnostics. The rate of arrhythmic syncope will be compared between the control and experimental groups using a log-rank test.

4 Shock reduction in ICD patients 1651 In-clinic or remote ICD implant SR DR CRT-D R 1:1 Experiment Control 3 month 3 month 6 month 6 month Randomization of the patient is 30 days maintained throughout the duration of the study. Figure 1 PROVIDE study design. Randomization scheme and data collection intervals. SR, single chamber; DR, dual chamber; CRT-D, cardiac resynchronization therapy device. Experimental VT-1 zone 2x ATP (25 beats) VT-2 zone 1x ATP (18 beats) VF zone SVT Discriminators Control VT-1 zone [MONITOR] VT-2 zone 2x ATP VF zone SVT discriminators 150 b.p.m. 181 b.p.m. 214 b.p.m. 250 b.p.m. Figure 2 Overview of programmed therapy. Device programming including the therapy zones and respective rate cut-offs. Each zone lists the therapy available (e.g. monitor, anti-tachycardia pacing, or ), the use of supraventricular tachycardia discriminators and the number of beats to detection. VT, ventricular tachycardia; VF, ventricular fibrillation; ATP, anti-tachycardia pacing; SVT, supraventricular tachycardia. A Cox proportional hazards model will be used to analyse the potential effects of certain baseline variables on shock rate. The following variables will be analysed: age, gender, left ventricular ejection fraction per cent, New York Heart Association class, intrinsic QRS duration, cardiac disease aetiology, history of myocardial infarction, history of atrial fibrillation, hypertension, renal disease, medications, and implanted device type. Data safety, monitoring, and adjudication committees The data and safety monitoring board (DSMB) consists of two electrophysiologists and one statistician who are independent of the study and the study sponsor. The DSMB will meet quarterly, or as needed, in order to evaluate adverse events related to the protocol. The DSMB will periodically review the available data and provide recommendations about the early termination of the trial based on the safety and efficacy data provided during the trial. All episodes will be adjudicated by an Adjudication Committee consisting of electrophysiologists. Conclusion The PROVIDE trial is a multicentre randomized study designed to test the ability of a combination of programming parameters to reduce the total burden of shock therapy without increasing arrhythmic syncope in patients with primary prevention indication for an ICD/CRT-D. Conflict of interest: C.G.N. and S.P. are employees of St. Jude medical.

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