Overview of Clinical Trials on Resynchronization and Combined Internal Cardiac Defibrillator-Resynchronization in Heart Failure
Ayesha Hasan
Cardiac resynchronization therapy (CRT) has become a standard of care in advanced chronic heart failure refractory to optimal drug therapy. In fact, CRT alone or in combination with an internal cardiac defibrillator (ICD) has been shown to reduce morbidity and mortality in selected patients.1,2 Resynchronization expands on traditional dualchamber pacemakers, where transvenous leads are right sided, and also applies left-sided pacing through coronary sinus cannulation and placement of a lead in a lateral or posterior branch, ideally avoiding diaphragmatic stimulation. CRT is based upon the presence of ventricular dyssynchrony, as evidenced by a left bundle branch block or other imaging documenting delayed mechanical contraction.3,4,5 The physiology and response mechanisms of CRT are the focus of the first chapter. However, for review purposes, interventricular dyssynchrony refers to the delayed contraction between the right and left ventricles, whereas intraventricular dyssynchrony refers to the abnormal segmental contraction within the left ventricle. An abnormal contraction pattern results in poor pump function, with increased left ventricular (LV) end-systolic volumes, the presence of mitral regurgitation (both diastolic and systolic), and reduced diastolic function, with higher end-diastolic volumes and reduced left ventricular filling.
Early pacing studies in chronic heart failure were comprised of dual chamber devices (traditional right atrium and right ventricle placement); however, no clinical benefit was substantiated.5,6,7,8 In fact, findings in the DAVID (Dual Chamber and VVI Implantable Defibrillator) trial proposed that chronic right ventricular (RV) stimulation in heart failure worsened heart failure progression,9 leading to the first randomized controlled CRT trials in the 1990s, which compared left ventricular and biventricular pacing to right ventricular pacing.10 Subsequent early clinical trials also focused on clinical primary end-points including functional capacity (6-minute walk distance), quality of life (QOL) score, and New York Heart Association (NYHA) functional class,11,12,13 but a survival benefit and improved morbidity have been established in more recent CRT trials.1,2 Although clinical parameters, such as QOL and NYHA class, are more subjective, they represent conventional end-points in heart failure evaluation, and have consistently improved in large CRT trials. More objective echocardiographic measurements of reverse remodeling have also been shown in CRT studies, with improved LV ejection fraction (LVEF) in most studies and reduced enddiastolic/end-systolic volumes and mitral regurgitation.2 Reverse remodeling has been documented within three months of CRT, with an incremental decline after discontinuation of biventricular pacing.14 Despite the risk of sudden cardiac death in chronic heart failure, advanced heart failure mortality (NYHA Class III and IV) is often the outcome of worsening pump failure.15 The purpose of CRT is to improve both systolic and diastolic ventricular performance through biventricular pacing and subsequent resynchronization of the interventricular and intraventricular contraction. Thus far, eight randomized trials have been conducted in moderatesevere heart failure and have established both clinical and survival benefits of CRT, either alone or in combination with an implantable cardioverter-defibrillator (Tables 11.1 and 11.2). This chapter will review the clinical trial data on CRT and CRT plus ICD, and will also review recently published CRT trials in nonstandard indications.
PATH-CHF
The Pacing Therapies in Congestive Heart Failure (PATH-CHF) trial was the earliest randomized CRT trial and focused on acute hemodynamic benefits using invasive LV dP/dt measurements. Left ventricular and biventricular pacing
produced significant immediate hemodynamic improvement when compared to right ventricular pacing.10,16 The study also found further hemodynamic benefit at a patient-specific optimal AV delay. This was a smaller trial of 27 patients using epicardial LV leads; later trials were larger and directed toward intermediate and long-term effects.
produced significant immediate hemodynamic improvement when compared to right ventricular pacing.10,16 The study also found further hemodynamic benefit at a patient-specific optimal AV delay. This was a smaller trial of 27 patients using epicardial LV leads; later trials were larger and directed toward intermediate and long-term effects.
TABLE 11.1 Major Clinical Trials of Cardiac Resynchronization and Enrollment Criteria* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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MUSTIC STUDY
The Multisite Stimulation in Cardiomyopathy (MUSTIC) study was a randomized, controlled, single-blind, crossover study in the 1990s designed to evaluate the safety and clinical efficacy of transvenous biventricular pacing in severe heart failure patients without a standard indication for a pacemaker.12,17,18 Patients had evidence of intraventricular conduction delay with a QRS duration >150 ms and NYHA Class III heart failure. It consisted of two arms, and enrolled 58 patients in the MUSTIC-SR (sinus rhythm) arm and 41 in the MUSTIC-AF (atrial fibrillation) arm. Patients in the SR arm were randomized to either 3 months of biventricular pacing or no pacing, followed by a 3-month crossover period; patients in the AF arm were randomized to a crossover of 3 months of biventricular pacing versus 3 months of RV pacing (VVIR mode, or ventricular inhibited pacing). Both groups were programmed at the end of the 6-month period to their preferred mode of pacing (active CRT pacing versus inactive). In terms of LV lead location, the lateral wall was the preferred site based on coronary sinus venogram, midway between the base and apex, with the RV lead positioned as far from the LV lead as possible. Other lateral and posterior positions were suitable, but the middle cardiac vein was used only when other sites were not satisfactory. There was a 92% success rate of LV lead placement with 88% of patients having a functional lead at the end of the crossover period. The primary end-point of exercise capacity (distance walked in 6 minutes) and secondary end-point of QOL were significantly improved in both the sinus rhythm and the atrial fibrillation groups. All patients in MUSTIC-SR and most of those in MUSTIC-AF preferred biventricular pacing. Both groups had fewer hospitalizations with biventricular pacing during follow-up in the first crossover period; although a short period to assess the effects of CRT on morbidity, these results were encouraging. As a relatively small study, it was not designed to assess morbidity and mortality. A sustained clinical benefit was seen with CRT when the follow-up was extended to 12 months in a substudy of patients.17 This was the first randomized CRT study with positive long-term clinical outcomes.
TABLE 11.2 Primary and Secondary End-points of the Major Randomized Clinical Trials in Cardiac Resynchronization Therapy | |||||||||||||||||||||||||||||
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MIRACLE TRIALS
The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial was the first prospective, double-blind randomized controlled clinical trial evaluating CRT and was much larger than PATH-CHF and the MUSTIC trials, enrolling 454 patients.13,
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