Clinical Trials Methods and Design

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1 Journal of Cardiac Failure Vol. 11 No Clinical Trials Methods and Design A Comparison of Cardiac Resynchronization by Sequential Biventricular Pacing and Left Ventricular Pacing to Simultaneous Biventricular Pacing: Rationale and Design of the DECREASE-HF Clinical Trial DAVID B. DE LURGIO, MD, 1 ELYSE FOSTER, MD, 2 MICHAEL B. HIGGINBOTHAM, MD, 3 KINLEY LARNTZ, PhD, 4 AND LESLIE A. SAXON, MD 2 Atlanta, Georgia; Durham, North Carolina; Minneapolis, Minnesota; Los Angeles, California; St. Paul, Minnesota ABSTRACT Background: The first generation of cardiac resynchronization therapy (CRT) devices approved for the treatment of heart failure used simultaneous biventricular (BiV) pacing to achieve ventricular resynchronization. Left ventricular pacing alone and sequential BiV pacing also show promise as alternative ways to deliver CRT, but have not been studied together in a large randomized trial. Methods: The Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure (DECREASE-HF) Trial is a randomized, double-blind, 3-arm study of patients in New York Heart Association Class III or IV with an ejection fraction of 35% or less and a QRS duration 150 ms. Patients are randomized to receive either left ventricular pacing, simultaneous BiV pacing, or sequential BiV pacing. Conclusion: The study uses a novel composite endpoint that combines peak oxygen consumption and left ventricular end systolic dimension, thus combining a measure of symptomatic improvement (peak oxygen consumption) with a physiologic measure of ventricular reverse remodeling (left ventricular end systolic dimension) into a single composite score. Additionally, the safety and effectiveness of the CONTAK RENEWAL 2/4/4HE/EASYTRAK 2 system will be evaluated using: heart failure-related adverse events; system-related complications; left ventricular lead-related complications; detection time of induced ventricular fibrillation; and left ventricular lead performance (pacing threshold, pacing impedance, and R-wave amplitude). Key Words: Congestive heart failure, resynchronization therapy, left bundle branch block, implantable defibrillator. Approximately 4.9 million people in the United States have heart failure (HF), with 550,000 new patients diagnosed From the 1 Carlyle Fraser Heart Center, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; 2 Department of Medicine, University of California, San Francisco, California; 3 Department of Medicine, Duke University Medical Center, Durham, North Carolina; 4 School of Statistics, University of Minnesota, Minneapolis, Minnesota; 5 Keck School of Medicine, University of Southern California, Los Angeles, California. Manuscript received January 21, 2004; revised manuscript received June 29, 2004; revised manuscript accepted August 23, Reprint requests: David B. DeLurgio, MD, Carlyle Fraser Heart Center, Division of Cardiology, Emory University School of Medicine, Atlanta, GA Supported in part by Guidant Corporation, St. Paul, Minnesota /$ - see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.cardfail annually. 1 Many of these patients are characterized by a prolonged QRS duration, which indicates abnormal ventricular activation, and is a marker of both worsening cardiac function 2,3 and increased mortality. 4 Device-based treatment for HF (ie, cardiac resynchronization therapy or CRT) improves left ventricular (LV) function, oxygen uptake at peak exercise, 6-minute walk distance, quality of life scores, and change in New York Heart Association (NYHA) Class. 5 8 It has also been reported that CRT reverses the ventricular remodeling process, which has been associated with increased cardiac dimensions and decreased pumping efficiency. 9,10 A meta-analysis of 4 large randomized controlled trials indicates that CRT may also decrease mortality from progressive HF, 11 which is consistent with results reported from the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (ie, COMPANION) trial

2 234 Journal of Cardiac Failure Vol. 11 No. 3 April 2005 The first generation of CRT devices approved in the United States used simultaneous biventricular (BiV) stimulation to resynchronize the left and right ventricles. It has been proposed that pacing the left ventricle is the key to providing CRT, with or without right ventricular pacing. 13 Preliminary studies suggest that LV pacing is equivalent to BiV pacing terms of hemodynamics, ventricular reverse remodeling, and long-term clinical effect At least 2 studies indicate that LV pacing provides a small but statistically significant improvement over simultaneous BiV pacing in LV dp/dt. 14,15 Other reports indicate that BiV pacing may be superior to LV pacing in reducing LV end-diastolic diameter 21 and increasing peak endocardial acceleration. 22 Data from a large randomized trial are needed to evaluate the use of LV pacing for the treatment of HF. Sequential BiV pacing has also been proposed as an alternative to simultaneous BiV pacing. Sequential BiV pacing allows decoupling of the ventricular pacing pulses to provide prestimulation of 1 ventricle, thus compensating for a conduction delay on that side. Several reports indicate that compared with simultaneous BiV pacing, sequential BiV pacing provides many patients with narrower QRS intervals, 23 increased LV function, 24,25 and increased 6-minute walk distance. 26 The Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure (DECREASE-HF) clinical investigation is the first large randomized controlled trial to compare both LV pacing and sequential BiV pacing with simultaneous BiV pacing. Study Design and Goals The DECREASE-HF trial is a prospective, multicenter, randomized, double-blind trial designed to determine if LV pacing and sequential BiV pacing are equivalent to simultaneous biventricular pacing after 6 months of therapy. The primary endpoint for assessing therapy equivalence combines peak oxygen consumption (VO 2 ) and LV end-systolic dimension (LVESD), which represent measures of functional capacity and cardiac reverse remodeling, respectively. Secondary and ancillary therapy endpoints include 6-month change in NYHA Class, quality of life (based on the Minnesota Living with Heart Failure Questionnaire), peak VO 2, LVESD, and other echocardiographic measures. The overall safety and effectiveness of the device system will also be evaluated by assessing: (1) freedom from HFrelated adverse events; (2) freedom from system-related complications; (3) freedom from LV lead-related complications; (4) ventricular fibrillation detection time; (5) ability to deliver continuous appropriate CRT pacing; and (6) electrical performance of the LV lead (pacing threshold, pacing impedance, and R-wave amplitude). All patients will undergo an implant procedure for the CONTAK RENEWAL 2/4/4HE/EASYTRAK 2 system. Between implant and a 2-week follow-up visit, devices will be programmed to provide antitachycardia therapy, but not to deliver CRT. At the 2-week visit, patients complete baseline testing and receive a randomization assignment (LV pacing, simultaneous BiV pacing, or sequential BiV pacing) in a 1:1:1 ratio. Patients who are unable to complete baseline testing will not be given a randomization assignment, but will be followed throughout the study for safety data. These patients, along with patients who cannot be programmed according to their randomization assignment because of recommendations made by the device, are considered to be in a separate safety arm, as shown in Fig. 1. All patients have an equal chance of being placed in the safety arm, regardless of randomization assignment. Patients in the safety arm do not undergo special testing, but are otherwise followed normally and counted toward safety endpoints. Patient Population To participate in the study, patients must be 18 years of age or older, have moderate or severe HF (NYHA Class III or IV) despite optimal pharmacologic therapy (OPT), QRS duration of 150 ms or greater, ejection fraction of 35% or less, and a life expectancy of longer than 6 months. Patients must not have had previous CRT or currently have indications for antibradycardia pacing. The definition of OPT includes 30 days of stable angiotensin-converting enzyme inhibitor and β-blocker therapy. 27,28 Additionally, patients must have been prescribed to a β-blocker for 90 days. All DECREASE-HF enrollment criteria are listed in Table 1. Endpoints The DECREASE-HF study is designed to evaluate 3 different CRT modalities for equivalence and to evaluate safety and effectiveness of the device system. The primary endpoint used to compare the treatment arms (LV pacing and sequential BiV) with the control arm (simultaneous BiV pacing) Fig. 1. Device Evaluation of CONTAK RENEWAL 2 and EASY- TRAK 2: Assessment of Safety and Effectiveness in Heart Failure randomization arms and follow-up testing. BiV-CRT, simultaneous biventricular pacing; LV offset, sequential BiV pacing; LV-CRT, LV pacing.

3 Table 1. DECREASE-HF Patient Enrollment Criteria DECREASE-HF Trial Design De Lurgio et al 235 Inclusion criteria Meet the general indications for an implantable cardiac device Moderate or severe heart failure, defined as New York Heart Association class III-IV despite optimal pharmacologica heart failure therapy A 12-lead electrocardiogram (ECG) obtained no more than 90 days before enrollment documenting a sinus rate 50 bpm, QRS duration 150 ms, and PR interval 320 ms measured from any 2 leads, and a P-wave duration 150 ms measured from lead V 1 Creatinine 2.5 mg/dl obtained no more than 14 days before enrollment Left ventricular ejection fraction 35% (measured by echo, multiple gated acquisition scan, cardiac catheterization) no more than 14 days before enrollment Willing and capable of undergoing a device implant and participating in all testing associated with this clinical investigation Have a life expectancy of more than 180 days, per physician discretion Age 18 or older, or of legal age to give informed consent specific to state and national law Exclusion criteria Right bundle branch block morphology (per World Health Organization Guidelines, Appendix C) on a 12-lead ECG obtained no more than 90 days before enrollment Have had previous cardiac resynchronization therapy, a previous coronary venous lead, or meet the general indications for antibradycardia pacing Have a neuromuscular, orthopedic, or other noncardiac condition that prevents normal, unsupported walking Have an atrial tachyarrhythmia that is permanent (ie, does not terminate spontaneously and cannot be terminated with medical intervention) or persistent (ie, can be terminated with medical intervention, but does not terminate spontaneously) within 180 days before enrollment Have a hypersensitivity to a 0.7 mg does of dexamethasone acetate Have surgically uncorrected primary valvular heart disease Undergoing dialysis Have chronic obstructive pulmonary disease, defined as forced expiratory volume at 1 second/forced vital capacity 60% Have had a myocardial infarct, unstable angina, percutaneous coronary intervention, or coronary artery bypass graft during the 30 days before enrollment Have hypertrophic obstructive cardiomyopathy or infiltrative cardiomyopathy (eg, amyloidosis, sarcoidosis) Have a mechanical tricuspid prosthesis Enrolled in any concurrent study, without Guidant written approval, that may confound the results of this study is a composite score combining peak VO 2 and LVESD; secondary comparisons will be made in quality of life, NYHA Class, LVESD, and peak VO 2. Other primary endpoints that will be used to evaluate system safety and effectiveness include: HF-related adverse event-free rate; systemrelated complication-free rate; lead-related complication free rate; ventricular fibrillation detection time; lead electrical performance (pacing thresholds, pacing impedance, and R-wave amplitudes) in the tip-to-ring pacing, and sensing configuration. Secondary system safety and effectiveness endpoints include continuous appropriate CRT pacing, as evaluated through a Holter substudy, and lead electrical performance in all alternate pacing/sensing configurations. Primary Endpoints Composite Score Therapy. Effectiveness will be assessed by a composite score that scales 6-month changes in peak VO 2 and LVESD such that approximately equal weight is given to each measure. Previous HF studies have shown that a change in peak VO 2 of 1 ml kg min and LVESD of 5 mm are achievable and clinically meaningful. 5 8 Based on these estimations, a scaling factor of 5 is used to calculate the score, as follows: score (5 change in peak VO 2 ) (change in LVESD). The change in LVESD is subtracted because an improvement is represented as a reduction in LVESD and is, therefore, a negative number. For example, a patient exhibiting an increase of 1.2 ml kg min in peak VO 2 and reduction of 4 mm in LVESD would receive a score of 10 points, as would a patient with an increase of 0.8 ml kg min in peak VO 2 and reduction of 6 mm in LVESD. By combining these relatively independent (Table 2) and objective (Table 3) measures, the score represents improvement in both functional capacity and cardiac reverse remodeling. Thus the score captures both change in symptomatic status and prevention of disease progression, which have been discussed as independent benefits of CRT. 29 A retrospective analysis of CONTAK CD patients who meet DECREASE-HF inclusion criteria and have paired data was performed to determine the mean patient scores in the CRT and no CRT arms (Table 3) and visualize the distribution of scores in each arm (Figure 2). The mean scores demonstrate that the score may be an effective means by which to distinguish patients receiving a clinical benefit from resynchronization therapy. Figure 2 demonstrates a generally random dispersion in the no-crt arm and a clear trend toward improvement in the CRT arm; importantly, the improvement seen in the CRT arm did not appear to be caused disproportionately by either peak VO 2 or LVESD. Table 2. Correlation Coefficients Between Peak Oxygen Consumption and Left Ventricular End-Systolic Dimension in a Subset of Patients From the VENTAK CHF/CONTAK CD Biventricular Pacing Study Who Meet the Eligibility Criteria for DECREASE-HF Correlation P value CONTAK CD patients who meet DECREASE-HF eligibility criteria (n 18)* *Includes only biventricular cardiac resynchronization therapy patients with paired 6-month data.

4 236 Journal of Cardiac Failure Vol. 11 No. 3 April 2005 Table 3. Peak VO 2 and LVESD* in a Subset of Patients From the VENTAK CHF/CONTAK CD Biventricular Pacing Study Who Meet the Eligibility Criteria for DECREASE-HF CRT No CRT n Estimate SE n Estimate SE p value Peak VO LVESD VO 2, oxygen consumption; LVESD, Left ventricular end-systolic dimension; SE, standard error. *Using a longitudinal modeling method. n refers to the number of patients with a measurement at a minimum of 1 visit. Estimates and standard errors are presented. HF-Related Adverse Event Free Rate. Therapy safety will be assessed by the HF adverse event free rate observed between initiation of CRT at the 2-week visit and 6 months thereafter. The HF adverse event free rate is defined as the number of patients who do not experience a HF-related adverse event divided by the total number of patients who do not receive implants. The lower one-sided 95% confidence bound for the HF adverse event free rate will be compared with 50%. This comparison is based on the adverse event free rate reported for NYHA III/IV patients who received CRT in the VENTAK CHF/CONTAK CD Biventricular Pacing Study (95% CI: 53%-77%). Ventricular Fibrillation Detection Time. Ventricular fibrillation detection time will be used to assess whether CRT as delivered by the investigational device system affects the time required to detect induced ventricular fibrillation. Detection time at implant will be compared with an historical standard based on commercially available Guidant implantable cardioverter defibrillator (ICD) devices and clinical expectations for detection times. The upper one-sided 95% confidence bound for ventricular fibrillation detection time will be compared with 6 seconds. LV Lead-Related Complication-Free Rate. Lead safety will be assessed by the LV lead-related complication free rate over the 6-month follow-up period. All complications associated with the use of the LV lead or the procedure (including attempted implants) will count toward the safety endpoint. Lead-related complications are defined as leadrelated adverse events (eg, conductor failure, dislodgment, extracardiac stimulation, insulation breach, loss venous vasculature, undersensing) that result in permanent loss of CRT, invasive intervention, injury, or death; the complication-free rate is defined as the number of patients who do not experience a complication divided by the total number of patients who undergo an LV lead implant. The lower onesided 95% confidence bound for lead-related complication free rate will be compared with 80%, which is derived from predicate device data. System-Related Complication-Free Rate. System safety will be assessed by the system-related complicationfree rate observed through the 6-month follow-up period. The system-related complication-free rate is defined as the number of patients who do not experience a system-related complication divided by the total number of patients who undergo an implant. The lower one-sided 95% confidence bound for the system-related complication-free rate of the will be compared with 70%. LV Lead Measurements in Tip-to-Ring Configuration. EASYTRAK 2 lead effectiveness will be evaluated through pacing thresholds, pacing impedance, and R-wave amplitudes in the tip-to-ring bipolar pacing and sensing configurations at 6 months. For thresholds, the upper one-sided 95% confidence bound of the mean will be compared with Fig. 2. Distribution according to composite score of patients in the VENTAK CHF/CONTAK CD Biventricular Pacing Study who meet the Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure enrollment criteria.

5 DECREASE-HF Trial Design De Lurgio et al V, because the maximum output voltage of the investigational device family is 7.5 V. This value will ensure that patients have at least a 100% safety margin. For sensing, the lower one-sided 95% confidence bound of the mean left ventricular R-wave amplitude will be compared with 3 mv because the investigational device family is capable of detecting R-wave amplitudes down to 3 mv when programmed to its least sensitive value. For impedance, the lower one-sided 95% confidence bound of the mean will be compared with 300 Ω, which has been used as a criteria for the evaluation of predicate leads. Secondary Endpoints Secondary and ancillary therapy effectiveness endpoints include 6-month change in NYHA Class, quality of life, peak VO 2, LVESD, and other echocardiographic measures. Improvement in the therapy arms will be assessed by 6- month change from baseline and compared with 0 using the lower bound of a 1-sided confidence interval. The percent of patients that improve at least 1 NYHA Class between the preimplant visit (pretherapy) and 6-month visit (posttherapy) will be computed in each treatment arm and compared with 0%. Additional analyses will be performed to evaluate which patients show the greatest improvement with LV pacing, sequential BiV pacing, or simultaneous BiV pacing. In the longitudinal modeling of endpoint variables (such as composite score, peak VO 2, and echo measures), interactions between treatment and baseline variables (such as etiology, QRS duration, intrinsic PR interval, lead location, and echocardiography measures) will be examined. Secondary therapy safety endpoints include continuous appropriate pacing during exercise and during a 24-hour period, as recorded with a Holter monitor at the 3-month visit. The lower 1-sided 95% confidence bound of the mean time paced will be compared with 90%. Holter data will also be compared with the data saved on the device histogram for validation of device histograms; the percentage of paced beats seen on the Holter monitor should be consistent (within 10%) with the percentage of paced beats counted by the device. Secondary lead effectiveness endpoints and acceptance criteria are the same as described for the primary LV lead endpoints (pacing thresholds, pacing impedance, and R-wave amplitudes), but are taken in the alternate pacing and sensing configurations. Follow-Up Testing The randomization assignment will be assigned at the 2- week visit after successful completion of the baseline cardiopulmonary exercise and echocardiography testing. Patients in the treatment and control arms will be followed at hospital discharge, 2 weeks, 3 months, and 6 months after implant, and then at quarterly intervals thereafter until study closure. In addition to the treatment arms and the control arm, there will be a safety arm including patients who cannot complete both cardiopulmonary exercise and echocardiography testing at baseline and patients who receive a simultaneous BiV pacing recommendation from the Expert Ease feature in CONTAK RENEWAL 2/4/4HE CRT-D family. Expert Ease is a feature that recommends AV delay and, in some cases, a pacing chamber. Patients in the safety arm will be followed for routine testing at all required visits. Electrical performance the investigational lead will be evaluated at each scheduled visit. Cardiopulmonary Exercise Methods Maximal exercise testing will be conducted at the 2-week baseline visit the 3-month visit and the 6-month visit using a modified Naughton treadmill protocol. The protocol includes a 2-minute resting period followed by increasing workloads every 2 minutes and finally a 10-minute recovery period. The duration of the test is limited by patient symptoms (eg, fatigue, shortness of breath). Breath-by-breath ventilation, oxygen uptake, and carbon dioxide production will be continuously measured through a mouthpiece connected to a metabolic cart. Blood pressure, heart rate, and Borg scale of perceived exertion 30 will be collected throughout the test at the end of each stage. A blinded cardiopulmonary exercise core laboratory will analyze all data, including peak VO 2. Echocardiographic Methods Echocardiograms will be recorded at the 2-week visit without pacing and at the 3-month and the 6-month visits with CRT pacing and assessed by a blinded echocardiography core laboratory. Left ventricular internal dimensions will be measured using the leading edge technique on the 2- dimensionally guided m-mode echocardiogram or directly from the 2-dimensional echocardiogram. LV volumes and ejection fraction will be obtained by tracing the endocardium at end-diastole and end-systole in the 2- and 4-chamber views and derived according to Simpson s rule (biplane method of disks). Doppler measurements of systolic function include: LV stroke volume measured as product of velocity time interval of left ventricular flow and the LV outflow tract area; cardiac output measured as the product of LV stroke volume and heart rate; and myocardial performance index measured as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time. Doppler measures of diastolic function include mitral E deceleration time, E/ A ratio, and the pulmonary venous flow systolic to diastolic ratio. The severity of mitral regurgitation will be estimated and graded on a 1 to 3 scale of increasing severity. Pulmonary artery pressure will be derived using the modified Bernoulli equation from the peak velocity of the tricuspid regurgitant jet and a derived right atrial pressure. Statistical Considerations The sample size requirement was calculated using the normal theory methods, 80% power, and an α level of 0.027,

6 238 Journal of Cardiac Failure Vol. 11 No. 3 April 2005 as calculated from the Dunnett method for multiple comparisons. 31 Each of the 2 primary effectiveness endpoints (composite score comparisons of LV pacing and sequential BiV pacing to the simultaneous BiV pacing- control arm) will be tested for equivalence at a significance level of α A longitudinal analysis will be performed to estimate the 3- and 6-month SCORE for all 3 treatment groups. However, the endpoint will be based on the change at 6 months. The difference in the estimates (simultaneous BiV pacing minus LV pacing) and (simultaneous BiV pacing minus sequential BiV pacing) will be compared with 10 points using the upper bound of a 1-sided 97.3% confidence interval. The difference in the estimates (simultaneous BiV pacing minus LV pacing) and (simultaneous BiV pacing minus sequential BiV pacing) will be compared with 0 points using the upper bound of a 2-sided 97.3% confidence interval. The null hypotheses state that the treatment arms are inferior to the control arm; the alternative hypotheses state that the treatment arms are not inferior (ie, equivalent). Each component of the primary endpoint will be summarized individually using descriptive statistics. To ensure that the simultaneous BiV pacing arm provides an adequate control group for the LV pacing and sequential BiV pacing arms, the mean change in peak VO 2 in the simultaneous BiV pacing arm must be at least 0.75 ml kg min and the mean change in LVESD must be at least 4 mm. If the control arm does not meet these standards, each patient s measure will be adjusted by the amount of deficit so that the means are at a level of at least 0.75 ml kg min and 4 mm for change in peak VO 2 and LVESD, respectively. Patients who are included in the safety arm will not contribute toward the therapy effectiveness endpoints, but will contribute toward all safety endpoints and all LV lead effectiveness endpoints. The 360 patient enrollment target was set to assure composite score data from 165 patients (55 patients per arm) at 6 months. Device Descriptions The EASYTRAK 2 lead and the CONTAK RENEWAL 2/4/4HE CRT-D devices used in this study are not commercially available in the United States and are limited by federal law to investigational use. The implanted system may include any Guidant endocardial right ventricular cardioversion/defibrillation lead and any commercially available atrial pace/sense lead. The CONTAK RENEWAL 2/4/4HE CRT-D family provides cardiac resynchronization therapy for the treatment of HF by using either simultaneous or sequential biventricular or univentricular electrical stimulation to synchronize ventricular contractions. The EASYTRAK 2 Lead (Guidant Corp) is an over-the-wire coronary venous lead with a 5.4 Fr distal lead body diameter and dual electrodes to allow bipolar sensing and pacing. Summary The first generation of CRT devices approved for the US market for the treatment of HF used simultaneous BiV pacing to resynchronize the ventricles. Both LV pacing and sequential BiV pacing show promise as CRT delivery, but these 2 modalities previously had not been studied together in a large randomized trial. DECREASE-HF will compare both LV pacing and sequential BiV pacing with a simultaneous BiV pacing control arm in a prospective, randomized, double-blind, controlled investigation of patients with NYHA Class III/IV HF and a QRS interval of 150 ms or greater. The study will use a novel composite score as the primary endpoint; this score combines a measure of symptomatic improvement (peak VO 2 ) with a physiologic measure of disease progression (LVESD). Information from this and other concurrent trials will contribute to better understanding the roles of different CRT delivery in everyday clinical practice. References 1. American Heart Association. Heart Disease and Stroke Statistics 2003 Update. Dallas (TX): American Heart Association, Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block: the effect of interventricular asynchrony. Circulation 1989;79: Murkofsky RL, Dangas G, Diamond JA, Mehta D, Schaffer A, Ambrose JA. A prolonged QRS duration on surface electrocardiogram is a specific indicator of left ventricular dysfunction. J Am Coll Cardiol 1998;32: Baldasseroni S, Opasich C, Gorini M, Lucci D, Marchionni N, Marini 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: Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al. Multisite Stimulation 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: Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, et al. Long term benefits of biventricular pacing in congestive heart failure: Results from the MUltisite STimulation In Cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40: Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al, for the MIRACLE Study Group. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42: Saxon LA, De Marco T, Schafer J, Chatterjee K, Kumar UN, Foster E, for the VIGOR Congestive Heart Failure Investigators. Effects of longterm biventricular stimulation for resynchronization on echocardiographic measures of remodeling. Circulation 2002;105: Stellbrink C, Breithardt O-A, Franke A, Sack S, Bakker P, Auricchio A, et al. Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodelling in patients with congestive heart failure and ventricular conduction disturbances. JACC 2001;38: Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 2003;289: Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al; Comparison of Medical Therapy, Pacing, and Defibrillation

7 DECREASE-HF Trial Design De Lurgio et al 239 in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350: Blanc JJ, Etienne Y, Gilard M, Mansourati J, Munier S, Boschat J, et al. Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study. Circulation 1997;96: Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 1999;99: Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99: Breithardt OA, Stellbrink C, Franke A, Balta O, Diem BH, Bakker P, et al, for the Pacing Therapies for Congestive Heart Failure Study Group, for the Guidant Congestive Heart Failure Research Group Acute effects of cardiac resynchronization therapy on left ventricular Doppler indices in patients with congestive heart failure. Am Heart J 2002;143: Hamdan MH, Zagrodzky JD, Joglar JA, Sheehan CJ, Ramaswamy K, Erdner JF, et al. Biventricular pacing decreases sympathetic activity compared with right ventricular pacing in patients with depressed ejection fraction. Circulation 2000;102: Stellbrink C, Breithardt O-A, Franke A, Sack S, Bakker P, Auricchio A, et al. Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances. J Am Coll Cardiol 2001;38: Etienne Y, Mansourati J, Touiza A, Gilard M, Bertault-Valls V, Guillo P, et al. Evaluation of left ventricular function and mitral regurgitation during left ventricular-based pacing in patients with heart failure. Eur J Heart Failure 2001;3: Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, 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: Touiza A, Etienne Y, Gilard M, Fatemi M, Mansourati J, Blanc JJ. Long-term left ventricular pacing: assessment and comparison with biventricular pacing in patients with severe congestive heart failure. J Am Coll Cardiol 2001;38: Garrigue S, Bordachar P, Reuter S, Jaïs P, Kobeissi A, Gaggini G, et al. Comparison of permanent left ventricular and biventricular pacing in patients with heart failure and chronic atrial fibrillation: prospective haemodynamic study. Heart 2002;87: O Cochlain B, Delurgio D, Leon A, Langberg J. The effect of variation in the interval between right and left ventricular activation on paced QRS duration. PACE 2001;24: Sogaard P, Egeblad H, Pedersen AK, Kim WY, Kristensen BO, Hansen PS, et al. Sequential versus simultaneous biventricular resynchronization for severe heart failure: evaluation by tissue Doppler imaging. Circulation 2002;106: Abraham WT, Leon AR, Liang C, Shih A, Odryzynski NL. Sequential biventricular pacing provides significant hemodynamic benefit for heart failure patients with ventricular dyssynchrony. J Cardiac Failure 2002;8:S Abraham WT. Does sequential biventricular pacing contribute incremental benefit to patient well-being? Results from the INSYNC III Study. J Cardiac Failure 2002;8:S Heart Failure Society of America. HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction pharmacological approaches. J Cardiac Failure 1999;5: ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task force on practice guidelines (Committee to revise the 1995 guidelines for the evaluation and management of heart failure). Circulation 2001;104: Saxon LA, De Marco T. Cardiac resynchronization: a cornerstone in the foundation of device therapy for heart failure. J Am Coll Cardiol 2001;38: Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14: Woolson RF. Statistical methods for the analysis of biomedical data. New York: John Wiley & Sons, 1987.