Cardiac Resynchronization Therapy for Treatment of Chronic Heart Failure

Progression of congestive heart failure (CHF), although somewhat slowed by recent therapeutic developments, continues to be a growing problem among men and women age 50–80 years. It afflicts 2–4 million people in the United States and nearly 15 million people worldwide.1–3 There are currently 400,000–700,000 new cases per year. Recent therapeutic advances, such as the use of angiotensin-converting enzyme (ACE inhibitors),4 beta blockers,5 hydralazine in combination with nitrates6 and spironolactone,7 have resulted in decreased mortality rates in patients with CHF.4–7 Despite these pharmacological advances, the true impact of newer innovations in device-based therapy remains to be determined. The overall long-term prognosis and quality of life are still limited in patients with moderate to severe heart failure. Therefore, device-based therapy has been considered in the treatment equation. History. The idea of biventricular pacing (BiV), or cardiac resynchronization therapy (CRT) as it is more commonly known today, most likely came out of a variety of animal studies performed in the late 1980s and early 1990s. Most notable among these studies was the 1986 study of canine pacing in which Burkhoff and colleagues noted that left ventricular pressure decreased linearly as the QRS duration increased.8 It was noted in further studies that there was a high prevalence of left bundle branch block (LBBB) or intraventricular conduction delay in chronic heart failure.9 Interventricular dyssynchrony tends to occur as a result. This leads to a prolonged delay between the onset of left ventricular (LV) and right ventricular (RV) contraction as well as a decrease in the duration of LV diastole and a prolonged isovolumetric relaxation with a shortened LV filling period.8,10–13 The hemodynamic effects of LBBB in chronic heart failure include a reduced left ventricular ejection fraction, reduced cardiac output, reduced mean arterial pressure and reduced dP/dt.14,15 Following the Burkhoff study, Lattuca and colleagues16 hypothesized that by simultaneously pacing the LV along with the RV, a more synchronous ventricular activation (QRS) plus a resultant more synchronous ventricular contraction pattern could be achieved with a reduction in QRS and thereby a reduction in intraventricular asynchrony. In 1995, Foster and colleagues17 compared the acute hemodynamic benefits of atrial, ventricular and biventricular pacing in 18 patients within 18–36 hours of elective coronary artery revascularization surgery. Their study demonstrated that epicardial biventricular pacing increased cardiac index and decreased systemic vascular resistance compared to the other pacing groups, even though this pacing technique failed to significantly shorten QRS duration. More recently, the preliminary results of the Multisite Stimulation in Cardiomyopathies (MUSTIC),18 Multicenter InSync Randomized Clinical Evaluation (MIRACLE),19 Pacing Therapy for Congestive Heart Failure (PATH-CHF),20 InSync,21 Ventak CHF/Contak CD22 and VIGOR CHF22 studies, as well as a small study by Alonso et al,23 have been released and/or published. InSync, MUSTIC and Alonso et al. were uncontrolled, whereas the MIRACLE, PATH-CHF, Ventak CHF/Contak CD and Vigor-CHF studies were randomized or double-blind (MIRACLE) and controlled. All seven of these studies provide promising results. Ongoing studies include the PATH II study,24 CARE-HF, BELIEVE, VecToR, PACMAN, Contak CD (continued access protocol, recently completed enrollment) and one large randomized, controlled study entitled the Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial.²⁵Animal studies. Park and colleagues²⁶ investigated the effects of pacing from the atrium and a variety of ventricular sites on the LV end-systolic pressure-volume relation following autonomic blockade in canines chronically instrumented to measure LV pressure and determine LV volume from three ultrasonic endocardial dimensions. This study found that alterations of the normal activation sequence produced by ventricular pacing depress LV pump function independent of loading conditions, as indicated by a rightward shift of the LV end-systolic pressure-volume curve. The extent of this shift appears to be proportional to the degree of dyssynchronous activation. The 1986 study by Burkhoff et al8 investigated the influence of pacing site on several aspects of LV performance to test the hypothesis that “effective ventricular muscle mass” is reduced with direct ventricular pacing. This study found that with the alteration of the pacing site, there was a linear negative correlation between changes in the LV pressure and the QRS duration. Thus, as LV pressure decreased, the QRS duration increased linearly. In one of the first animal studies of biventricular pacing, Lattuca and colleagues16 hypothesized that incoordinate contraction pattern might be partly responsible for hemodynamic impairment in heart failure. Pacing was performed in three dogs, comparing pacing right and left ventricles alone with both sides simultaneously in order to determine whether shortening the QRS duration by simultaneously pacing different sites would improve hemodynamics. This study demonstrated that cardiac output increased during biventricular pacing. Cardiac output was 2.44 L/minute with RV pacing and 2.61 L/minute with LV pacing and increased to 2.83 L/minute with biventricular pacing. Aortic pressure increased as well with biventricular pacing. With both independent right and left ventricular pacing, the pressure was 60 mmHg, while it increased to 73.3 mmHg with biventricular pacing. Right atrial pressure decreased from 13.3 mmHg with RV pacing and 12.7 mmHg with LV pacing to 7.7 mmHg with biventricular pacing. The QRS duration showed a decrease as well with biventricular pacing. QRS duration decreased from 100 ms with RV pacing and 109 ms with LV pacing to 76 ms with biventricular pacing. Present system. Initially, pacing systems were implanted via thoracotomy with an epicardial lead system. This approach had significant associated morbidity and a theoretical risk of mortality. Subsequent investigators realized that the coronary sinus can provide a transvenous approach to LV pacing via one of its LV venous branches. Yee and colleagues22 were among the first to realize this approach through their investigation. Figure 1 shows the current design of a system recently approved in the United States. Note the integration of the RV and LV (coronary sinus) leads along with the right atrial lead into the device header. Human investigations. Table 1 shows a summary of the entry criteria for clinical investigation in humans. Tables 2 and 3 show the clinical results of most of these trials (excluding VIGOR CHF, which used the myocardial performance index to measure its endpoint). The following is a description of each of these studies. PATH-CHF.²⁰ The main purpose of this multicenter trial was to determine from invasive hemodynamics the optimal pacing site and atrioventricular delay followed by either one month of pacing in the best univentricular mode or one month of biventricular pacing, randomly selected. After this was determined, a follow-up of no pacing for one month and one month of pacing in the univentricular or biventricular mode was performed. The peak oxygen consumption was measured after each follow-up as well as the distance walked in six minutes, a quality of life assessment and an estimated New York Heart Association class. There were 42 patients enrolled in the trial and all parameters improved or tended to improve during periods of pacing and declined during the month of no pacing. VIGOR-CHF.²² This is the first United States clinical trial of CRT, which used an epicardial lead for LV stimulation. Patient enrollment began in 1996. Before the study began, the average age of 18 patients evaluated was 61 ± 15 years; ten were female. Left ventricular ejection fraction (LVEF) was 27 ± 6% and QRS was 167 ± 29 ms. Fifteen of the patients were functional class III and 3 were class IV. This study measured the myocardial performance index (MPI). MPI has been shown to correlate with simultaneous invasive measures of cardiac function. Improvement in MPI is defined as a reduction in the ratio of isovolumetric contraction and relaxation time relative to ejection time. This was observed in 14 of 18 patients in which MPI decreased overall from 0.77 ± 0.30 pre-implantation to 0.61 ± 0.19 with biventricular pacing. Medtronic InSync.²¹ This multicenter European and Canadian trial examined the safety and efficacy of a multisite pacemaker as a supplemental treatment for refractory congestive heart failure. In order to take part in the study, patients needed to display the following: New York Heart Association functional class III or IV; QRS duration of greater than 150 ms; LVEF of less than 35%; left ventricular end-diastolic diameter (LVEDD) of greater than 60 mm; and the absence of clinical improvement despite stable, standard medical treatment for at least one month. During follow-up in the 68 patients in which a multisite pacemaker was successfully implanted, there was a clinical benefit that was substantiated by a significant improvement in New York Heart Association functional class and in the Minnesota Living with Heart Failure Quality of Life Questionnaire and by a longer distance covered during a 6-minute walk. Along with this improvement, the QRS duration of the patients shortened during pacing and ejection fraction increased. The InSync pacemaker was recently approved by a United States FDA advisory panel as a result of the MIRACLE trial. Ventak CHF/Contak CD.²² This study began initial enrollment in 1998 and involved 581 patients. Patients were implanted with the Contak CD triple-chamber biventricular ICD and the Guidant coronary sinus lead for LV stimulation (EASYTRAK™). Qualifications for participation in the study included New York Heart Association functional class >= II, ejection fraction = 120 ms. Patients in the study were randomized to receive a three-month period of either atrial synchronous ventricular pacing or no pacing. A second three-month period followed with the pacemaker in the alternative therapy mode. Of the 501 patients who were evaluated, the mean age was 66 ± 10.5 years in the BiV group with 84.3% male and 66.3 ± 10.5 years in the no BiV group. In the BiV group, 32.3% were New York Heart Association class II, 59.7% were class III and 8.1% were class IV. In the no BiV group, 32.8% were class II, 56.9% were class III and 10.3% were class IV. The study found that after 6 months of BiV, the quality of life improved an average of 7.2 ± 2.0 points, while the no BiV group improved 5.1 ± 2.0 points, suggesting a slight placebo effect. After six months, 11.8% of the BiV group had decreased 2 or more New York Heart Association classes, 22.6% had decreased 1 class and 52.7% had no change. In the no BiV group, 2% decreased 2 or more classes, 27.6% decreased 1 class, and 54.1% demonstrated no change. Peak oxygen consumption showed continual improvement in the treatment group after 6 months, whereas the control group showed a slight decline from its 3 month point. Six-minute walk distance improved in both groups over 6 months. More improvement was shown in the treatment group. The results of this study were recently presented to a United States Food and Drug Administration advisory panel, which did not recommend the approval of the Guidant device used in this study because it did not meet its primary endpoints. However, the FDA has permitted an additional 240-patient enrollment as part of a continued access protocol. This study is still under review. Alonso et al.²³ Twenty-six patients age 66 ± 7 years with drug refractory heart failure and a wide QRS were implanted with biventricular DDD pacemakers. The patients were divided into group I: responders; and group II: non-responders. Responders were defined as patients who had a significant improvement in class status and exercise tolerance while implanted with the biventricular pacemaker. All other patients were classified as non-responders (group II). Inclusion criteria for the study included: severe congestive heart failure rated as New York Heart Association class III or IV, refractory to optimized drug treatment involving diuretics with converting enzyme inhibitors at the maximum tolerable dose; LV systolic dysfunction defined by an ejection fraction 60 mm on electrocardiogram; and a prolongation of intraventricular conduction time as reflected by a QRS duration of > 120 ms. The mean LVEF was 23 ± 8% and mean LV end-diastolic diameter was 65 ± 9 mm. Before implantation, eight patients were class IV and 18 were class III. The mean QRS interval was 178 ± 24 ms. After implantation, the class rating in group I went from 3.3 ± 0.5 to 2.0 ± 0.5 at six months. The maximum oxygen consumption (V02) increased from 12.2 ± 5.0 ml/kg/minute to 18.0 ± 4.0 ml/kg/minute. In group II, class rating had no significant change (3.3 ± 0.5 versus 2.7 ± 0.8). VO2 increased from 14.2 ± 1.0 ml/kg/minute to 16.7 ± 15.0 ml/kg/minute. The QRS duration decreased from 179 ± 22 ms to 154 ± 17 ms in group I and increased from 176 ± 30 ms at baseline to 177 ± 26 ms in group II. MUSTIC.¹⁸ Sixty-seven patients with class III New York Heart Association heart failure, normal sinus rhythm and a QRS interval of > 150 ms received transvenous atrio-biventricular pacemakers. This study compared the responses of the patients during two periods: a 3-month inactive pacing period and a 3-month active pacing period. The primary endpoint of this study was the distance walked in 6 minutes; secondary endpoints were the quality of life as measured by a questionnaire, peak oxygen consumption, hospitalizations related to heart failure, the patient’s treatment preference (active versus inactive), and mortality rates. At 3-month follow-up, a significant improvement in exercise tolerance and quality of life was shown in the biventricular pacing group. MIRACLE.¹⁹ Two hundred and sixty-six patients were implanted with the Medtronic InSync device and were then randomized to CRT or placebo therapy. Patients were older than 18 years. All were New York Heart Association class III–IV, with a QRS interval of > 130 ms. LVEF was 55 mm. Primary efficacy endpoints were the quality of life, New York Heart Association functional class, and 6-minute walk distance. Primary safety endpoints were freedom from InSync system-related complications (i.e., device, lead, and pacing threshold). Secondary efficacy endpoints were metabolic evaluation (peak VO2, exercise duration); electrocardiographic evaluation (LVEF, LV size); neurohormonal evaluation (norepinephrine, brain natriuetic peptide); and a composite response (patient improved, unchanged or worse). During follow-up, six-minute walk times improved in the CRT arm by an average of 39 meters, whereas the placebo arm did not show improvement. Quality of life scores improved in the CRT group. The treatment arm showed greater improvement than the placebo group (average, 19 points). New York Heart Association classification also improved. Thirty percent of the placebo group improved to class II or above at 6 months and 65% of the treatment group were in New York Heart Association class II or above. Peak VO2 improved from baseline in the CRT arm with a 100 second improvement in exercise time. LVEDD and LVEF improved by 0.5 cm and 6%, respectively, whereas there was no improvement seen in the placebo group. The study concludes that CRT is safe and well tolerated; it improves quality of life, functional class and exercise capacity, cardiac geometry (LVEDD) and function (LVEF), and the composite clinical response. These results prompted the FDA to approve the InSync device. This was the first BiV system approved in the U.S. Ongoing human investigations. COMPANION.²⁵ This randomized, open-label, 3-arm study conducted by Bristow and colleagues plans to determine whether optimal pharmacological therapy used with ventricular resynchronization therapy alone or ventricular resynchronization therapy combined with ICD capability is superior to drug therapy in: decreasing mortality and hospitalizations; reducing cardiac morbidity; improving functional capacity, cardiac performance, and quality of life; and increasing total survival. In order to qualify for the study, patients need to demonstrate New York Heart Association class III or IV, an ejection fraction of 35% or less and a QRS duration of PATH II.²⁴ This ongoing, randomized crossover study will determine the potential benefits of biventricular or left ventricular resynchronization therapy in patients with advanced heart failure. This study plans to enroll 64 patients split into 2 separate groups: one including patients with a QRS 150 ms. This study will test functional capacity as the primary endpoint and improvement in quality in life, and improvements in prognostic and hemodynamic parameters as secondary endpoints. Discussion. Over the past two decades, cardiac resynchronization therapy has evolved from concept to clinical application. The myriad of studies described in this review show the evolution of biventricular pacing into the newly coined term of “cardiac resynchronization therapy”. Most recently, the MIRACLE trial has paved the way for the approval of the InSync device by the United States Food and Drug Administration. However, Guidant’s similar product showed a trend toward meeting its clinical endpoints of slowing the progression of heart failure by 25%. The authors of this manuscript anticipate the approval of the Guidant system as well as other manufacturers’ comparable devices in the near future. A market analysis of the projected clinical implants in the United States can be seen in Table 4.28 Only time will tell the true clinical value and market penetration for these newer therapies. Conclusion. Cardiac resynchronization therapy has been approved for use in the U.S. and is a reality. All major manufacturers are on the precipice of testing and releasing clinical devices for cardiac resynchronization therapy. Future devices will not only incorporate this type of therapy, but may vary the timing sequences of the left and right ventricles and incorporate other adjunctive therapies (atrial fibrillation suppression algorithms and therapies, SVT detection and therapeutic algorithms) and perhaps even drug-delivery systems. The recent acquisition of MiniMed by Medtronic Inc. has further shown their commitment to exploring the potential of such therapies in implantable heart rhythm management devices. In addition, these companies have been investigating long-term implantable physiologic sensors for the monitoring of the patient’s physiologic state (i.e., increasing heart failure or hemodynamic compromise) with the goal of providing appropriate electrical and/or pharmacological intervention to optimize myocardial performance. Additional studies are necessary to show the feasibility and viability of hybrid therapy.

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