Biventricular vs. left univentricular pacing in heart failure: rationale, design, and endpoints of the B-LEFT HF study

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1 Europace (2006) 8, doi: /europace/euj020 Biventricular vs. left univentricular pacing in heart failure: rationale, design, and endpoints of the B-LEFT HF study Christophe Leclercq 1 *, Gerardo Ansalone 2, Fredrik Gadler 3, Giuseppe Boriani 4, Nicasio Perez-Castellano 5, Neil Grubb 6, Stefan Sack 7, and Eric Boulogne 8 on behalf of the B-LEFT HF Investigators 1 Department of Cardiology, Rennes University Hospital, CHU Pontchaillou, 2, rue Henri Le Guilloux,Cedex 9, Rennes, France; 2 Department of Cardiology, Madre G. Vannini Hospital, Rome, Italy; 3 Department of Cardiology, Karolinska Hospital, Stockholm, Sweden; 4 Institute of Cardiology, University of Bologna, San Orsola Malpighi Hospital, Bologna, Italy; 5 Arrhythmias Unit, Hospital San Carlos, Madrid, Spain; 6 Cardiovascular Research Unit, Royal Infirmary, Edinburgh, UK; 7 Department of Cardiology, University Hospital, Essen, Germany; and 8 EMEA Clinical Department, St Jude Medical, Zaventem, Belgium Received 7 January 2005; accepted after revision 21 August 2005 KEYWORDS Heart failure; Cardiac dyssynchrony; Cardiac resynchronization therapy; Left ventricular pacing; Biventricular pacing; Clinical trial Introduction Cardiac resynchronization therapy (CRT) is based on the presence of disorders of electrical impulse propagation, frequently observed in patients with congestive heart failure (CHF), and related to the severity of the left ventricular (LV) systolic dysfunction. 1 In a general population of patients with CHF, the prevalence of QRS.120 ms on the surface electrocardiogram (ECG) is 20 25%, increasing to 50% in patients in New York Heart Association (NYHA) functional class IV. 2,3 These conduction disorders are the cause of atrioventricular, interventricular, and intraventricular * Corresponding author. Tel: þ ; fax: þ address: christophe.leclercq@chu-rennes.fr Aims Cardiac resynchronization therapy (CRT) confers sustained therapeutic benefits to patients suffering from congestive heart failure (CHF) due to systolic dysfunction associated with ventricular dyssynchrony. Biventricular (BiV) pacing has, thus far, been the preferred method, as it corrects both electrical and mechanical dyssynchrony. Left ventricular (LV) only pacing, which has conferred similar benefits in pilot studies, may be an alternative treatment method. Biventricular vs. left univentricular pacing with ICD back-up in heart failure patients (B-LEFT HF) is an international, prospective, randomized, parallel-design, double-blind, clinical trial to examine whether LV only pacing is as safe and effective as BiV pacing in patients suffering from CHF. Methods and results The trial will randomly assign 172 patients to either LV only or BiV pacing. The study has prospectively defined efficacy endpoints to be evaluated at 6 months, which are (i) changes in functional capacity and degree of reverse remodelling (primary) and (ii) changes in the heart failure clinical composite response (secondary). Conclusion Because LV only pacing in CRT is likely to be technically less challenging and costly than BiV, a specifically designed study is needed to compare the safety and effectiveness of the two configurations. B-LEFT HF has been designed to settle this critical issue. mechanical dyssynchrony. By correcting these electrical disorders and their mechanical consequences, CRT significantly improves cardiac function and clinical outcomes. Several clinical studies have demonstrated that this therapy alleviates symptoms, increases exercise tolerance, and improves quality of life in patients with advanced, drug-refractory CHF, a LV ejection fraction (EF),35%, a dilated LV, and intraventricular conduction delays. 4 6 Reduction in the number and duration of hospitalizations and LV reverse remodelling have also been reported. 7,8 All these benefits are durable. On the basis of these observations, BiV pacing has become a class IIA indication in the 2002 ACC/AHA/NASPE guidelines for patients suffering from dilated cardiomyopathy, with advanced, refractory CHF due to systolic dysfunction, and a wide QRS. 9 Recent results & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 LV only vs. BiV pacing in heart failure 77 from the COMPANION trial indicate that CRT combined with optimal drug therapy and an implantable cardioverter defibrillator (CRT-D) significantly decreased both the combined endpoints of all-cause mortality and hospitalization, and death and hospitalization related to CHF, compared with optimal drug therapy alone. 10 CRT and optimal drug therapy were also superior to drug therapy alone, though the difference did not reach statistical significance. In most studies, CRT was delivered by pacing simultaneously the right and left ventricles. In most cases, the LV was paced with a lead inserted into a tributary vein of the coronary sinus over the free wall. However, experimental observations suggest that pacing limited to the LV, which usually increases electrical dyssynchrony, may significantly mitigate mechanical dyssynchrony. 11 Furthermore, short-term haemodynamic studies performed in candidates for CRT showed similar or greater benefits with LV only pacing compared with BiV pacing. 12,13 Longterm LV only pacing has been evaluated in small non-controlled studies, which demonstrated a functional improvement compared with no pacing. 14,15 The biventricular vs. left univentricular pacing with ICD back-up in heart failure patients trial has been designed to examine whether the safety and efficacy of LV only and BiV pacing are equivalent. Study design The biventricular vs. left univentricular pacing with ICD back-up in heart failure patients (B-LEFT HF) trial has been designed to test the hypothesis that LV only pacing is as safe and effective as BiV pacing in recipients of CRT-D systems. The primary, composite efficacy endpoint, including NYHA functional class and change in LV end-systolic diameter (ESD), and the primary safety endpoint are detailed subsequently. B-LEFT HF is a multicentre, European, prospective, randomized, double-blind, parallel-design trial. An 18 months enrolment period and 6 months of post-implant follow-up have been planned. All patients included in this study will undergo implantation of Epic HF, Epic þ HF, or Atlas þ HF, CRT-D devices (St Jude Medical, Sylmar, CA, USA), with right atrial, right ventricular (RV) and LV leads. The latter will be placed transvenously in a tributary vein of the coronary sinus. After successful implantation of the system, and before discharge, the patients will be randomly assigned in a 1:1 ratio to BiV CRT or to LV only CRT (Fig. 1). To obtain two study groups as similar as possible with respect to known and unknown risk factors, and to eliminate patient biases, a table with permuted blocks will be used for the randomization procedure. To guarantee the Figure 1 B-LEFT HF study design. double-blind study design, an investigator unaware of the randomization assignment will be designated at each centre. This investigator will be in charge of all the nondevice-based tests and evaluations for the duration of the study. The criteria for inclusion and exclusion from the study are listed in Table 1. Study endpoints The main objective of B-LEFT HF is to test whether LV only pacing is as effective as BiV pacing in improving functional capacity, expressed as NYHA functional class, and in promoting reverse remodelling, measured by LVESD, in patients with indications for CRT-D systems. Primary The efficacy of the CRT-D systems will be measured by the proportion of patients improved after 6 months of CRT compared with baseline. Patients will be considered improved if their NYHA functional class has decreased by 1 and echocardiographic LVESD by 5 mm. The safety of the CRT-D systems will be measured by the survival-free from CRT-D system-related complications. They will be considered safe if this event-free survival is.70% at 6 months. Secondary The secondary objective of this trial is to compare the proportion of patients clinically improved at 6 months of follow-up in each group, using the heart failure clinical composite response. 16 This scheme classifies each patient as improved, unchanged, or worse, depending on the clinical response and status during and at the end of follow-up. Table 1 Study inclusion and exclusion criteria Inclusion Criteria Class I or II indication for implantation of an ICD NYHA functional class III or IV despite stable, optimal drug therapy QRS width 130 ms Left ventricular end-diastolic diameter 55 mm Left ventricular EF 35% Exclusion criteria Prior CRT device implant Conventional pacing indication History of atrial fibrillation lasting.1 month within 1 year prior to enrolment or cardioversion in the past month Ability to walk.450 m during a 6-min walk test Uncorrected primary valvular disease Recent myocardial infarction, unstable angina, or coronary revascularization within 1 month of enrolment Cerebrovascular accident or transient ischaemic attack within 3 months of enrolment Life expectancy,1 year Inability to comply with the follow-up schedule and tests Age,18 years Pregnant state or pregnancy planned in the next 6 months

3 78 C. Leclercq et al. A heart failure clinical composite response is classified as follows:. Worse if the patient (i) has died, (ii) was hospitalized for management of CHF, or (iii) has crossed-over from the assigned to the other randomization group because of CHF progression;. Improved if the patient has not worsened, and either the NYHA functional class or the patient global assessment has improved;. Unchanged if the patient has neither worsened nor improved. Additional data collected at baseline and during follow-up to be compared between the two study groups are listed in Table 2. Concomitant medical therapy At the time of enrolment, the patients must have been on a stable, optimal drug regimen for 30 days. This regimen should include, unless contraindicated or not tolerated, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, a beta-adrenergic blocker, diuretics, and spironolactone. Patients treated with a beta-adrenergic blocker must have been on treatment for 90 days prior to enrolment. Beta-adrenergic blockade may be absent from the medical regimen if contraindicated or limited by hypotension or bradycardia. Beta-adrenergic blockade should not be initiated during the trial if it was not being prescribed at the time of enrolment. Antiarrhythmic drug therapy should be stable prior to patient enrolment. Furthermore, a stable drug regimen will be maintained during the 6 months of follow-up. Patients not on a stable drug regimen at the time of enrolment will be stabilized for a period of up to 30 days after device implantation, and the randomization procedure postponed until medical therapy is stable. During that period, the CRT function of the device will be disabled. Cross-over Patient cross-over from the assigned study group to the alternate is prohibited before 6 months of follow-up visit, unless mandated by progression of CHF. Table 2 Details of tests and data collection 6 min walk test New York Heart Association heart failure functional class Quality of Life score by Minnesota Living with Heart Failure questionnaire w Cross-over from assigned to alternate group because of CHF progression Hospitalizations For all causes For CHF Mortality Ventricular mechanical (echocardiographic) and electrical (QRS morphology) remodelling Incidence of supraventricular and ventricular tachycardia or fibrillation Arrhythmia detection and redetection times Appropriate and inappropriate device interventions Device description The Epic HF (model V-339), Epic þ HF (model V-350), and Atlas þ HF (model V-341) St Jude Medical CRT devices (or new St Jude Medical CRT-D devices with equivalent similar function) will be implanted. These devices, which provide resynchronization and antiarrhythmic therapies, enable the programming of either BiV or LV only pacing for CRT. The pulse generators will be interfaced with a bipolar pace/sense right atrial lead, a true or integrated bipolar pace/sense/defibrillation lead in the right ventricle, and a unipolar or bipolar transvenous pacing lead in the left ventricle. An integrated bipolar RV lead will be used to minimize the risk of RV anodal pacing during LV only pacing from a unipolar lead. When unipolar LV and true bipolar RV leads have been implanted, the RV anodal threshold will be measured and recorded at implant and during all postimplant follow-up visits. Recipients of epicardial LV leads will be classified as unsuccessful implants. The AV and VV delays will be optimized before discharge of the patients from the hospital. The methods of AV and VV delays optimization will be left to the discretion of the investigators, although Ritter s method for optimization of the AV delay 17 and LV outflow tract velocity time integration for optimization of the VV delay (Ref.) are recommended. Patient follow-up The date of successful system implantation will be day 0 of follow-up. Patients will be examined within 30 days before CRT system implantation, within 7 days after implantation, at 6 weeks, and 3 and 6 months, and every 6 months thereafter, until study termination. Complete evaluations, including echocardiographic examination, 6 min walk test, quality of life questionnaire, NYHA functional class classification, global assessment, and detailed CRT system interrogation will be performed at 6 months follow-up. Sample size and statistical analyses The calculation of study sample size was based on an estimate of the proportion of patients who would benefit from 6 months of CRT with a BiV vs. LV only pacing system. The estimated minimum number needed to reject the null hypothesis with an 80% power, when the proportion of patients improved is the same in each group, is 73 in each group. 18 This conservative estimate assumed that 50% of the patients derive the same benefit in each group, producing the largest sample size. Assuming a 7% implant failure rate (QuiskSite K evaluation within Rhythm US study) and an 8% loss to follow-up, 172 patients will be recruited. Since the same assumptions could be made for the Heart Failure Clinical Response endpoint, this sample size is sufficient to show equivalence between the 2 groups. The expected survival from system-related complications at 6-months is 81%. 19 The number of patients required for an 80% power to reject the null hypothesis with an 81% system-related complication-free survival is 100. This sample size was calculated by simulations, using conservative confidence interval methods for a binomial probability. Statistical significance will be considered when P The primary analyses will be performed according to the intention-to-treat principle, including all randomized patients, regardless of protocol violations or deviations,

4 LV only vs. BiV pacing in heart failure 79 comparing the two groups according to assigned therapy. Secondary per protocol analyses will be performed, excluding major protocol violators or deviators, comparing the two groups by therapy actually received. The primary analyses will be performed after collection of all data. Differences between the two groups will be expressed as odds ratio and 95% confidence interval. If the lower confidence limit is.0.8, the two groups will be considered equivalent. System-related complications System-related complications will be analysed by Kaplan Meier actuarial methods, up to 6 months after CRT system implantation. The survival of patients who experience a system-related complication will be calculated as the number of days from implant to the date of the reported complication. For patients who exit the study before the time of analysis, the survival time will be calculated as the number of days from implant to the date of drop-out. For patients who have not experienced a system-related complication at the time of analysis, the survival time will be the number of days from implant to the last follow-up date. Secondary endpoint The secondary endpoint will be analysed similarly to the primary endpoint. Study organization Steering committee The study steering committee is responsible for developing the protocol and monitoring its implementation. It is also responsible for ensuring the timely publication of the study results. Adverse events committee An independent adverse events committee will review all serious adverse events and cross-overs at regular intervals until study completion. Echocardiography core laboratory Before enrolling their first patient in the study, centres must obtain the approval of the core laboratory by sending a qualification tape/optical disc. The laboratory is responsible for assessing the echocardiographic parameters specified in the echo protocol (primary endpoint and additional data) at baseline and at 6 months post-implant. Discussion The results of several controlled and prospective trials have confirmed the effectiveness of CRT as adjunctive therapy in patients suffering from advanced CHF and intraventricular conduction delays. 4 6 Furthermore, recent results from the COMPANION trial suggest that, when added to optimal drug therapy, CRT-D improves survival in this very high-risk population. 10 Several questions regarding CRT remain in need of answers. The main issue, currently, pertains to a sharper definition of selection criteria, in order to decrease the rate of non-responders, estimated between 20 and 30%. 6 Whether BiV pacing can be replaced by LV only pacing is another important question in need of an answer. In a canine model of CHF with left bundle branch block, Leclercq et al. 11 showed that both LV only and BiV pacing improved LV function significantly, increasing dp/dt max and aortic pulse pressure by 25% compared with atrial pacing and that this improvement correlated with mechanical resynchronization. However, electrical dispersion, from electrical epicardial activation map of the whole heart,increased by 13% with LV only and decreased by 23% with BiV pacing. In short-term clinical studies, LV only pacing produced similar, sometimes greater, haemodynamic improvements than BiV when compared with spontaneous rhythm. In patients with severe CHF, Blanc et al. 12 found that both LV only and BiV pacing produced similar, significant improvements in systolic BP, pulmonary capillary wedge pressure, and mitral regurgitation when compared with spontaneous rhythm baseline measurements or RV pacing alone. A trend towards a greater increase in dp/dt max and pulse pressure at a lower energy cost by LV only pacing when compared with BiV pacing has also been reported by Kass et al. 13 and Auricchio et al. 20 Long-term LV only pacing has been tested in noncontrolled studies. 14,21 At 6 months, alleviation of symptoms, improvement in functional capacity, and amount of LV remodelling all tended to be greater with BiV than with LV only pacing. In another comparison of the effects of LV vs. BiV pacing in permanent atrial fibrillation patients during exercise with measurements of peak endocardial acceleration, BiV was superior to LV only pacing. 21 At 12 months of follow-up, Blanc et al. 15 found LV only pacing to be safe and reported a significant increase in exercise capacity, improvements in quality of life and LV function, and decrease in degree of mitral regurgitation and concentrations of circulating catecholamines. The PATH-CHF II trial evaluated the effects of LV only pacing in patients with LV systolic dysfunction and advanced CHF. The patients were divided into a group with baseline QRS widths on surface ECG between 120 and 150 ms and a group with QRS widths.150 ms. 22 A significant alleviation of symptoms and increase in exercise tolerance was observed, although limited to the group of patients with QRS.150 ms. The results of the BELIEVE pilot trial, a parallel study including 74 patients to compare the effects of LV vs. BiV pacing in recipients of CRT-D systems, were recently presented by Gasparini et al. 23 Both configurations similarly and significantly increased LVEF, alleviated symptoms, and decreased LV end-diastolic volume. Because LV only pacing for CRT is likely to require simpler devices than BiV pacing, an improvement in cost-effectiveness would be expected if LV pacing alone is shown as effective and safe as BiV pacing. 24 Conclusions It is currently legitimate to hypothesise that LV only pacing may be as safe and effective as BiV pacing, the most commonly used configuration, to treat patients with indications for CRT. Thus far, equivalence of the two configurations has been observed in a single pilot study including a small

5 80 C. Leclercq et al. number of patients. Because LV only pacing is likely to be technically simpler and less costly, larger trials are needed to address this critical issue. The B-LEFT HF trial should provide useful information regarding the efficacy and the safety of LV only compared with the currently widely used BiV pacing configuration. References 1. Shenkman HJ, Pampati V, Khandelwal AK et al. Congestive heart failure and QRS duration: establishing prognosis study. Chest 2002;122: Aaronson KD, Schwartz JS, Chen TM et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95: Baldasseroni S, Opasich C, Gorini M et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 2002;143: Auricchio A, Stellbrink C, Block M et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation ;99: Cazeau S, Leclercq C, Lavergne T et al. Multisite Pacing in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344: Abraham WT, Fisher WG, Smith AL et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: Linde C, Leclercq C, Rex S et al. Long-term benefits of biventricular pacing in congestive herat failure: results from the MUSTIC study. J Am Coll Cardiol 2003;40: St John Sutton M, Plappert T, Abraham W et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107: Gregoratos G, Abrams J, Epstein AE et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee on Pacemaker Implantation). (2002). 10. Bristow MR, Saxon LA, Boehmer J et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced heart failure. N Engl J Med 2004;350: Leclercq C, Faris O, Tunin R et al. Systolic improvement and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left bundle-branch block. Circulation 2002;106: Blanc JJ, Etienne Y, Gilard M et al. Evaluation of different ventricular pacing sites in patients with severe heart failure. Circulation 1997;96: Kass D, Chen CH, Curry C et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99: Touiza A, Etienne Y, Gilard M et al. Long-term left ventricular pacing: assessment and comparison with biventricular pacing in patients with severe congestive heart failure. J Am Coll Cardiol 2001;38: Blanc JJ, Bertault-Valls V, Fatemi M et al. Midterm benefits of left univentricular pacing in patients with congestive heart failure. Circulation 2004;109: Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail 2001;7: Kindermann M, Frohlig G, Doerr T, Schieffer H. Optimizing the AV delay in DDD pacemaker patients with high degree AV block: mitral valve Doppler versus impedance cardiography. Pacing Clin Electrophysiol 1997;20(10 pt 1): Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. StatMed 1988;17: Medtronic InSync ICD Cardiac Resynchronization System FDA Advisory Panel presentation, 5 March Auricchio A, Stellbrink C, Sack S et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002;39: Garrigue S, Bordachar P, Reuter S et al. Comparison of permanent left ventricular and biventricular pacing in patients with heart failure and chronic atrial fibrillation: prospective haemodynamic study. Heart 2002;6: Auricchio A, Stellbrink C, Butter C et al. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 2003;42: Gasparini M, Bocchiardo M, Lunati M et al. Left ventricular pacing alone significantly increased ejection fraction at 1 year follow-up: preliminary results from the BELIEVE multi-center randomized study. Heart Rhythm 2004;1: S69 A Nichol G, Kaul P, Huszti E et al. Cost-effectiveness of cardiac resynchronization therapy in patients with symptomatic heart failure. Ann Intern Med 2004;141: