Cardiac Resynchronization Therapy

Preclinical Trial Era

Although in the early 1980s there was some attempt to use biventricular pacing for assessing arrhythmia mechanism or LV pacing in patients with atrioventricular (AV) block and left bundle branch block (LBBB), there was little interest in abandoning the traditional RV site. In 1987, Mower devised and was granted a patent for the concept of “biventricular pacing” explicitly aimed at HF treatment. Mower conceived biventricular pacing as a method of pacing both ventricles after a predetermined AV interval. Two electrodes would be connected in series, one in the RV and another one on the LV free wall. Bakker's group used a dual-chamber pacemaker with a Y adapter to treat 12 patients with advanced HF, most of whom were on transplant list, and showed that biventricular pacing improves functional capacity and LV function. Cazeau et al subsequently described a four-chamber pacing system that increased cardiac mechanics and significantly improved functional capacity. This group later described a wholly transvenous CRT implant that, coupled with the innovative over-the-wire technique of Auricchio et al, began a new era for CRT.

Cardiac Resynchronization Therapy in Sinus Rhythm Patients with Normal QRS Duration

Since the introduction of CRT into clinical practice, there has been a great deal of interest in the possibility of using CRT in patients with normal QRS duration (<120 msec), a population that represents the vast majority of patients with HF. Although this group of patients has been usually addressed as having “narrow” QRS duration, in contrast to patients with LBBB or right bundle branch block (RBBB) and wide QRS complex, we prefer to refer to them as patients with normal QRS duration by implementing recommendations of the European Society of Cardiology (ESC) and the American Heart Association, the American College of Cardiology Foundation, and the Heart Rhythm Society (HRS) for the standardization and interpretation of the electrocardiogram (ECG).

A significant number of the patients with normal QRS duration also display some degree of mechanical dyssynchrony as measured by different advanced echocardiographic techniques, which has been considered an abnormality correctable by CRT. In contrast to very promising initial results of small, observational clinical trials, all recent prospectively conducted studies have provided consistent evidence that CRT neither improves clinical symptoms nor reduces hospitalization or deaths in those patients with normal QRS duration ( Tables 18-3 and 18-4 ). A recent meta-analysis not only emphasized the futility of CRT in patients with QRS duration ≤130 msec but also pointed to a potential adverse outcome of higher all-cause mortality. When Shah et al performed subgroup analysis of three clinical trials involving patients with LV mechanical dyssynchrony and QRS duration ≤130 msec, they found that there was higher all-cause mortality in these patients as compared with the control group ( Fig. 18-1 ). Until future research provides robust measures of dyssynchrony and clear insights into how to improve outcomes of CRT in patients with HF with narrow QRS complex, its use should be strongly discouraged in this population, as emphasized by current clinical guidelines (see Table 18-2 ).

Echo-CRT Study

The Echo-CRT was a randomized trial involving 115 centers. It was designed to evaluate the effect of CRT in patients with NYHA class III or IV HF, an LVEF ≤35%, a QRS duration <130 msec, and echocardiographic evidence of LV dyssynchrony (opposing wall delay in the peak systolic velocity ≥80 msec or delay in the anteroseptal to posterior wall ≥130 msec). All patients underwent device implant and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death due to any cause or first hospitalization for worsening HF. The study was stopped for futility on the recommendation of the Data and Safety Monitoring Board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.92-1.57; P = 0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; HR, 1.81; 95% CI, 1.11-2.93; P = 0.02). The observed excess mortality with CRT in this trial was of clinical concern. The excess mortality was due to a significant increase in the rate of death from cardiovascular causes among patients receiving CRT. There was a nonsignificant trend toward an increase in mortality related to HF, which was paralleled by a nonsignificant increase in hospitalization for HF. However, the interpretation of secondary outcomes in trials that fail to confirm the primary hypothesized outcome should be approached with great caution ( Fig. 18-2 ).

A recent prespecified subgroup analysis of Echo-CRT showed no benefit of CRT in patients with a QRS duration of 120 to 130 msec ( Fig. 18-3 ). These data further question the usefulness of CRT in this specific patient population. These data, together with the consistent data from other large-scale randomized trials, provide the most compelling evidence to suggest that CRT can worsen or provoke dyssynchrony in patients with little or no dyssynchrony to begin with.

Cardiac Resynchronization Therapy in Sinus Rhythm Patients with Abnormal QRS Duration

When CRT was clinically introduced, the inclusion criteria for clinical trials of CRT were relatively narrow: stability of proven medical therapy before enrollment, LVEF <0.35, NYHA class III or IV HF, normal sinus rhythm, and wide QRS duration. Table 18-5 summarizes the design, inclusion criteria, and results of the early controlled clinical trials of CRT with pacemaker (CRT-P) and CRT-D devices. Only two early trials used epicardial LV leads, placed through limited thoracotomy for LV stimulation. The Multisite Stimulation in Cardiomyopathy (MUSTIC) trial investigators used a stylet-driven coronary sinus lead; researchers in the other trials used over-the-wire leads to achieve LV stimulation through a coronary sinus branch vein. In the two early U.S. trials that were the basis for attaining the initial approvals from the U.S. Food and Drug Administration (FDA) for CRT-D, patients with NYHA Class II HF were included, but FDA labeling was not requested for this patient subset and was granted only for patients with NYHA class III or IV HF. Exclusion criteria included the presence of an implanted device and requirement for bradycardia pacing support or permanent atrial fibrillation (AF). The early U.S. trials used parallel designs; devices were implanted in all patients, who were then randomly assigned to “CRT-on” or “CRT-off” status for 6 months. Two principal investigators at each enrolling center were designated in most trials, so the physician managing the medical therapies (HF) was blinded to the treatment assignment, and the implanting physician (electrophysiologist) followed the device performance.

The study endpoints in CRT trials have evolved over time. Although all trials have included safety and efficacy endpoints, the initial trials assessed only measures of HF functional status, then included measurement of ventricular function and reverse remodeling, and finally considered morbidity (mostly HF hospitalization) and mortality ( Table 18-6 ). The use of these multiple endpoints is standard for HF trials evaluating medical therapies and has highlighted the issue of defining “benefit” from CRT. One can define “response” as consisting only of symptom improvement, or one can require that all three measures of HF show benefit, as outlined in Table 18-6 . To complicate the issue further, no one-to-one correlation seems to exist between these measures of response, as recently discussed by Daubert et al ( Fig. 18-4 ).

Effect of Cardiac Resynchronization Therapy on Soft Endpoints

The first studies that included patients with severe HF with NYHA class III or IV used as study endpoints change in NYHA functional class, exercise tolerance as evaluated by the 6-minute walk test, QOL, and occasionally, change in peak oxygen consumption assessed by cardiopulmonary exercise test. The first randomized studies—namely PATH-CHF, MUSTIC, and MIRACLE —found consistent results, with a mean decrease in NYHA by one class with CRT. The exercise capacity was improved with CRT in each of these studies, with a mean increase in the 6-minute walk test of 10% to 20% as well as a significant improvement in QOL, measured as reduction in the Minnesota Living with Heart Failure Questionnaire score of 20 points on average. These findings were finally confirmed by the results of two very large randomized controlled studies: CARE-HF and COMPANION. A meta-analysis that included both randomized trials and observational studies definitively confirmed the positive effect of CRT on each of the soft endpoints. Of note, few prospective controlled studies assessed the impact of CRT on peak V o ₂ . Peak V o ₂ was modestly but significantly improved by 1 to 2 mL/min/kg from a mean value of 12 to 14 mL/min/kg compared with a nearly unchanged peak oxygen consumption in the non-CRT-treated group.

Effect of Cardiac Resynchronization Therapy on Surrogate Endpoints of Mortality: Left Ventricular Volumes and Ejection Fraction

The knowledge of dissociation between functional capacity and ventricular function in patients with HF rapidly moved the interest of the clinical research community to assess the effect of CRT on ventricular function and ventricular remodeling. Cardiac remodeling is generally accepted as a determinant of the clinical course of HF. Defined as genome expression resulting in molecular, cellular, and interstitial changes and manifested clinically as changes in size, shape, and function of the heart resulting from cardiac load or injury, cardiac remodeling is influenced by hemodynamic load, neurohormonal activation, and other factors still under investigation. Although patients with significant remodeling demonstrate progressive worsening of cardiac function, slowing or reversing remodeling has only recently become a goal of HF therapy. LV end-diastolic and end-systolic volume and EF data provide support for the beneficial effects of therapeutic agents such as angiotensin-converting enzyme inhibitors and β-adrenergic blocking agents on the remodeling process. These agents also provide benefits in terms of morbidity and mortality.

The first report on LV reverse remodeling derived from a substudy of the PATH-CHF and MUSTIC trials. Both studies showed, in an independent manner, a significant reduction in LV end-systolic and diastolic diameters and a significant increase in LVEF. An observation was also made that these changes were slightly more pronounced in patients with nonischemic cardiomyopathy. These results were confirmed by an echocardiographic study conducted in the MIRACLE trial ( Fig. 18-5 ). In 323 patients randomized to CRT or medical treatment, CRT was associated at 6-month follow-up with a significant reduction in LV end-systolic volume (LVESV) and LV end-diastolic volume (LVEDV) by 10% and at 1-year follow-up by 16% and 10%, respectively. The same trial found an absolute increase in LVEF of 7% from the baseline value at 24% at 6-month and 1-year follow-up examinations (see Fig. 18-5 ). These data were confirmed later by the CARE-HF trials with an impressive effect of CRT on LV reverse remodeling over time up to 29 months of follow-up. Interestingly, the CARE-HF data showed that the magnitude of the benefit of CRT on LV reverse remodeling was significantly higher in the nonischemic population than in the ischemic population. Moreover, all trials observed a significant reduction in mitral valve regurgitation with CRT.

More recently, results from CRT clinical trials conducted in patients with mild HF (NYHA class I-II) led to similar conclusions (see Fig. 18-5 ). The REVERSE trial assessed the effect of CRT in 610 NYHA class II patients (see Table 18-1 ). In contrast to a nearly unchanged NYHA functional class, there was a marked reduction of both end-systolic and end-diastolic volumes by about 20% in the treated arm, and a significant absolute increase in LVEF by 6% at 6-month follow-up. Notably, a continuous and sustained reduction of ventricular volumes accompanied by an increase in LVEF was observed in the 5 years of follow-up after CRT ( Fig. 18-6 ). These impressive results were confirmed by the 1-year echocardiographic results of the MADIT-CRT trial comparing CRT and no CRT in 1372 patients, mainly in NYHA class II, with a more pronounced effect in nonischemic patients. Of major importance was the correlation between the magnitude of the LV reverse remodeling and the reduction of the occurrence of death or of HF events ( Fig. 18-7 ).