Cardiac Resynchronization Therapy: With or without Defibrillation

Abstract

Approximately one-third of patients with cardiomyopathy and heart failure (HF) have intraventricular dyssynchrony that leads to progression of left ventricular (LV) systolic dysfunction and HF symptoms. In these patients, the use of cardiac resynchronization therapy (CRT) can result in improved LV function and favorable cardiac remodeling. These structural changes were found to result in a reduction in mortality. As such, it could be postulated that CRT device, without a defibrillator (CRT-P), may be enough to reduce mortality in these patients. Conversely, defibrillators without CRT have been used for the purpose of mortality reduction in the same group of patients. In an attempt to answer the question about the best device to be used for mortality reduction in these patients, we studied the clinical trials that compared the reduction in mortality benefit in patients with cardiomyopathy and HF with the use of CRT-P, ICD alone, and CRT in combination with ICD (CRT-D).

1. Introduction

Cardiac resynchronization therapy (CRT) is a type of cardiac pacing that was introduced in 1990s with the aim to achieve simultaneous or near simultaneous activation of the left and right ventricles to reduce ventricular dyssynchrony, which has been known to cause progression of LV systolic dysfunction and clinical heart failure (HF) [1]. In normal myocardium, the electrical waveform that travels through the conduction system is uniform and ensures synchronized depolarization of the ventricles. In diseased myocardium, areas of delayed conduction and activation are seen due to damage to the conduction fibers as well as changes to the electrochemical substrate [2]. This delay in conduction will manifest as QRS prolongation on an electrocardiogram and therefore is a clue to the presence of electrical dyssynchrony.

Electrical dyssynchrony can result in mechanical dyssynchrony, which can exhibit in three different ways: interventricular dyssynchrony, intraventricular dyssynchrony, and atrioventricular dyssynchrony. One of the consequences of long-standing dyssynchrony is cardiac remodeling, which often worsens clinical outcomes [3].

There have been multiple observational studies that have demonstrated an association between electrical dyssynchrony and adverse clinical outcomes. Approximately one-third of patients with advanced heart failure have prolonged QRS duration, indicating electrical ventricular dyssynchrony, and these patients have an increased risk of adverse outcomes [4].

In patients with heart failure due to cardiomyopathy and evidence of electromechanical ventricular dyssynchrony, CRT exerts beneficial effects by improving dyssynchrony, thus restoring the physiologic atrioventricular relationship, which in turn results in improved myocardial oxygen consumption, LV function, favorable cardiac remodeling, and reduced severity of mitral regurgitation [3, 4]. These structural changes of CRT translated into clinical benefits noted in appropriately selected patients including functional improvement in exercise capacity, improved quality of life, and a reduction in heart failure admissions and mortality. Therefore, it has been postulated that stand-alone CRT (CRT-P) may be enough to reduce mortality without the need for an added defibrillation therapy. On the other hand, defibrillation therapy using ICDs alone had been used for almost a decade before the introduction of CRT and was proven to reduce mortality in patients with heart failure due to cardiomyopathy, both with and without evidence electromechanical ventricular dyssynchrony.

As noted in the current guidelines, there is significant overlap in the indications for CRT and ICD devices implantations in patients with cardiomyopathy and heart failure [5].

In the guidelines, the CRT indications include patients with left ventricular ejection fraction (LVEF) of 35% or less, who have been treated with goal-directed medical therapy for at least 90 days or 40 days, if cardiomyopathy occurred following myocardial infarction (MI), as potential candidates for CRT.

For patients who are NYHA class I, it is a class IIb recommendation for CRT if LVEF is 30% or less, and the electrocardiogram shows a QRS duration more than 150 msec and LBBB pattern, and the patient has ischemic cardiomyopathy. While in patients with LVEF of 35% or less, with NYHA class II-III symptoms, it is class I indication for CRT if QRS duration is 150 msec or more and there is an LBBB pattern and a class IIa indication for CRT if QRS duration is between 120 and 149 msec and there is an LBBB pattern.

According to the same guidelines, the primary prevention ICD indications bear similarities to the CRT indications as follows. ICD therapy is indicated as a Class I recommendation in patients with LVEF less than or equal to 35% due to prior MI who are at least 40 days post-MI and are in NYHA functional Class I-III. Also, ICD therapy is indicated as a Class I recommendation in patients with nonischemic cardiomyopathy who have an LVEF less than or equal to 35% and who are in NYHA functional Class II or III.

Whether an implantable cardioverter-defibrillator (ICD) should be combined with CRT is dependent on if the patient meets criteria for primary prevention as mentioned above, or secondary prevention in patients who have a history of ventricular arrhythmias without any identifiable reversible causes.

2. Studies that compared device therapy clinical outcomes

Several clinical trials compared the reduction in mortality benefit in patients with heart failure with the use of CRT-P, ICD alone, and CRT-D. In this chapter, we are summarizing the results of some of these trials.

2.1 The multicenter insync randomized clinical evaluation (MIRACLE) and the multicenter insync ICD randomized clinical evaluation (MIRACLE ICD) trial

Published in 2002, the double-blind, randomized MIRACLE trial sought to evaluate the effect of CRT as compared with no CRT on functional capacity and quality of life in patients with existing heart failure and known ventricular dyssynchrony. A secondary goal was to assess the safety of CRT in patients with HF. They hypothesized that CRT would resynchronize contraction of the failing LV and improve cardiac performance [6].

The study enrolled 453 patients; only 32 were female, with an average age of 64 years and NYHA Class III and IV symptoms who were followed for at least 6 months. The patient population had the following characteristics: LVEF <35%, QRS >130 msec, LV end-diastolic dimension >55 mm, and a six-minute walking distance of at least 450 meters. The primary endpoints were defined by a measure of quality of life (determined by the Minnesota Living With Heart Failure Questionnaire), NYHA functional class, and the six-minute hall walk.

After inclusion criteria were met and a baseline assessment completed, the participants underwent device and were randomized to either the control group (no CRT, n = 225) or CRT group (n = 228). They subsequently underwent follow-up at one, three, and six-months. The electrophysiologist was the only unblinded third party, and the rest of the team, which consisted of the heart failure specialist, the managing physician, and the patient, were blinded to study assignment during the six-month period. After the six-month follow-up period, patients in the control arm could go into the resynchronization mode.

Before randomization, all participants were required to be maintained on an angiotensin-converting enzyme inhibitor or ACE inhibitor substitute for 1 month and those on beta-blocker therapy were required to be on a stable regimen for at least 3 months before randomization. Changes to medical therapy were discouraged during the study.

The trial showed that in comparison with placebo, CRT was associated with significant improvement in the quality of life (p = 0.001), time on treadmill during exercise testing (p = 0.001), the six-minute walk distance (p = 0.005), NYHA class (p < 0.001), and EF (p < 0.001). Furthermore, the QRS duration was significantly lower in CRT patients compared with control (p < 0.001), as was the need for hospital admission (p = 0.02) and intravenous medication (p = 0.004). Using the Heart Failure Clinical Composite Outcome Measure, a larger percentage of CRT patients were classified as improved compared to the control group (67 vs. 39%, p < 0.001) and fewer were classified as worsened compared to the control group (16 vs. 27%). Death or worsening heart failure requiring hospitalization occurred less frequently in the CRT arm as well (28 vs. 44%, hazard ratio 0.60, 95% confidence interval 0.37–0.96; p = 0.03).

In conclusion, the MIRACLE trial demonstrated that biventricular pacing was associated with improved quality of life and functional class among patients with HF and ventricular dyssynchrony.

Subsequently, the MIRACLE-ICD trial was published in 2003 and aimed to compare the effect of CRT plus ICD versus ICD alone on the quality of life, functional capacity, and safety in patients with chronic heart failure and ventricular dyssynchrony [7].

The MIRACLE-ICD trial enrolled 369 patients, only 23 participants were female, with a mean age of 67 years with most of them categorized as NYHA class III and a small percentage as NYHA class IV, LVEF ≤35%, a QRS duration ≥130 msec, LV end-diastolic diameter ≥ 55 mm, and a stable drug regimen for at least 1 month. The participants included also had to have a history of cardiac arrest due to ventricular fibrillation or ventricular tachyarrhythmia, or spontaneously sustained ventricular tachyarrhythmia, or inducible ventricular fibrillation or sustained ventricular tachyarrhythmia.

The primary end points included NYHA functional class, quality of life score, and distance covered during the six-minute walking test. All patients underwent device implantation after baseline assessment and were randomized to either the control group (CRT off, ICD on, n = 182) or experimental group (CRT and ICD both on, n = 187) and followed for 6 months. The electrophysiologist served as the unblinded third party, and the rest of the managing team was blinded. Compared with placebo, CRT was associated with a significant improvement in NYHA class by at least one class (median class change −1 vs. 0, p = 0.007) and quality of life (−17.5 vs. −11 points, p = 0.02), but there was no difference in the 6-minute walk distance.

In addition, multiple secondary end points were improved in the CRT arm, although not all with significant p-values, including time on the treadmill during exercise testing, improved end-diastolic and end-systolic volumes, and ejection fraction. There was also a trend for a higher percentage of CRT patients to be classified as improved using the change in overall clinical status. There was no difference in mortality or the composite of death or repeat hospitalization for worsening HF.

2.2 The comparison of medical therapy, pacing, and defibrillation in heart failure (COMPANION) trial

The COMPANION trial was published in 2004 and was the first randomized, controlled trial that compared optimized pharmacological therapy, CRT delivered with a biventricular pacemaker (CRT-P), and CRT with defibrillator (CRT-D) in patients with advanced chronic heart failure. The trial was conducted at 128 U.S. centers between early 2000 and end of 2002 and included 1520 patients with New York Heart Association (NYHA) class III or IV heart failure (which could be ischemic or nonischemic in etiology), LVEF <35%, and a QRS duration of more than 120 msec [8].

These patients were randomized in a 1:2:2 ratio to receive optimized medical therapy (diuretics, angiotensin-converting-enzyme inhibitor, beta-blocker, and mineralocorticoid receptor antagonist) alone or in combination with CRT or CRT-D. The primary composite end point was the time to death from any cause or hospitalization for any cause. Secondary outcome was death from any cause. The median follow-up duration was about 14 months. Of the enrolled patients, mean age was 67 years, about one-third were female, 85% had NYHA class III heart failure, and mean EF was 22%.

Compared to the arm where patients where receiving optimized medical therapy only, patients with CRT and CRT-D had improved primary end point by 34% and 40%, respectively. CRT reduced the risk of the secondary end point of death from any cause by 24%, and CRT-D reduced the risk by 36%. All data was statistically significant. There was an even larger reduction in the outcome of death from or hospitalization for heart failure. It is noteworthy that in both CRT and CRT-D arms, lowering of the hazard ratio was directly proportional to an increasing QRS interval.

2.3 The multicenter automatic defibrillator implantation (the MADIT-CRT) trial

The MADIT-CRT was published in 2009 and was designed to determine whether CRT would improve clinical outcomes (specifically death and heart failure events) in patients with LVEF <30% (ischemic or nonischemic cardiomyopathy), QRS duration of at least 130 ms, but with milder cardiac symptoms (NYHA I and II) [7]. Patients were randomized in a 3:2 ratio to receive CRT-D (1089 patients) or ICD alone (731 patients). All patients were on goal-directed medical therapy (diuretics, angiotensin-converting-enzyme inhibitor, beta-blocker, mineralocorticoid antagonist). The primary end point was death from any cause or a nonfatal heart-failure event. During an average follow up of 2.4 years, the patients in the CRT-D group had a lower rate of the primary outcome with 35% relative reduction in all-cause mortality (p = 0.048) and a 63% relative reduction in first heart failure event (p < 0.001).

Echocardiography was performed at baseline and at the 1-year follow-up to assess changes in LV volumes and ejection fraction in the two study groups. There was reduction in LV volumes and significant increment in the ejection fraction in patients in the CRT-D group as compared to the those in the ICD group.

When subgroup analysis of the primary outcome was performed, it revealed that women benefitted more than men from CRT-D and that the benefit of CRT-D over ICD was seen only in patients who had QRS duration of more than 150 msec.

The median age of patients enrolled in the COMPANION and MADIT-CRT trials was 67 and 65 years, respectively. Therefore, the benefit of CRT in older patients with heart failure with reduced ejection fraction (HFrEF) was not adequately assessed.

A recently published retrospective study has looked at whether CRT benefited patients with HFrEF who were older than 65 years [9]. Patients were categorized by age (65–74, 75–84, and 85+ years), and they had undergone implantation of CRT-D or ICD device between 2008 and 2015. The risk of death was lower in the CRT-D group by 10% and 18% in the age groups of 75–84 and 85 + years, respectively. This supports the use of CRT in older patients undergoing ICD implantation.

2.4 Resynchronization reverses remodeling in systolic left ventricular dysfunction (REVERSE trial)

In the large multicenter, randomized, double-blind REVERSE trial, which was published in 2008, participants were randomized to have their CRT-D turned on for 1 year and then CRT-D turned off for 1 year or vice versa [10].

They studied a total of 610 patients with NYHA functional class I or II heart failure, a QRS >120 msec, and an LVEF <40% who were randomly assigned to active CRT (CRT-ON; n = 419) or control (CRT-OFF; n = 191) for 12 months. The primary end point was the HF clinical composite response and was scored as improved, unchanged, or worsened based on how the patients did over 12 months. In the CRT-ON group, there was only 16% worsening in the HF clinical composite response as compared with 21% in the CRT-OFF group (p = 0.10).

In addition, patients assigned to CRT-ON experienced a greater improvement in LV end-systolic volume index (p < 0.0001) and other measures of LV remodeling, and they had a significantly delayed time-to-first HF hospitalization (hazard ratio: 0.47, p = 0.03).

The concept of reverse remodeling by CRT has been described in small studies with a 6-month follow-up prior to the REVERSE trial, but it was reinforced with the much larger REVERSE trial with a longer follow-up period [11, 12].

Overall, the REVERSE trial demonstrated that CRT, in combination with optimal medical therapy (with or without defibrillator), reduced the risk for heart failure hospitalizations and improved ventricular structure and function in patients with mild HF symptoms or those who were asymptomatic, that is, NYHA functional class II and I, respectively.

2.5 Resynchronization-defibrillation for ambulatory heart failure (RAFT) trial

Published in 2010, the multicenter RAFT trial studied 1798 patients with NYHA class II or III heart failure, intrinsic QRS duration ≥120 msec or a paced QRS duration ≥200 msec, and LVEF ≤30% (ischemic or nonischemic etiology). These patients were randomized to receive either CRT-D or ICD alone. The primary outcome was mortality and hospitalization for HF with a mean follow-up duration of 40 months. The primary outcome occurred in 25% lesser patients in the CRT-D group than in the ICD group. The number needed to treat was exceptionally low at only 14. However, patients in the CRT-D group had a significantly higher adverse event rate as compared to the ICD group [13].

The probability of event-free survival at 5 years was 8.9% more in the CRT-D group than in the ICD group, while the probability of survival at 5 years was 6% more in the CRT-D group than in the ICD group.

Only 20% of patients in this trial had NYHA class III heart failure; however, on subgroup analysis, similar reductions in the risk of death or hospitalization for heart failure were observed in the two study arms. Approximately 70% of the patients had LBBB type of QRS morphology, and these patients benefitted at a greater degree than those with nonspecific interventricular conduction delay. Furthermore, CRT-D was found to be more beneficial for patients with intrinsic QRS duration >150 msec.

The RAFT Long-Term Study followed the patients in the RAFT trial for a mean 7.7 years to study the effect of CRT on long-term survival [14]. 1050 patients of the total 1798 patients were included in this trial. Among these patients with reduced EF, widened QRS complex, and NYHA class II or III HF, the survival benefit associated with CRT-D as compared with ICD was sustained during a median of nearly 14 years of follow-up [14].

2.6 Cardiac resynchrnization therapy upgrade in heart failure with right ventricular pacing (budapest CRT upgrade trial)

The Budapest CRT Upgrade trial, presented at ESC Congress 2023, showed that upgradation to CRT-D from pacemaker or ICD in patients with ejection fraction (EF) less than 35%, QRS duration ≥150 msec, and RV pacing burden of ≥20% resulted in decreased all-cause mortality, hospitalization from heart failure, and decreased end-systolic volume.

A total of 360 patients with EF ≤ 35% (NYHA heart failure symptoms II-Iva) on goal-directed medical therapy who had undergone implantation of a pacemaker or ICD ≥ 6 months prior and had a wide QRS duration ≥150 msec with pacing burden of ≥20% were randomized in 3:2 ratio to a CRT-D upgrade group and an ICD group. During a median follow-up of more than a year, the primary outcome of a composite of hospitalization from heart failure, all-cause mortality and decreased reverse LV modeling occurred in 32.4% patients in the CRT-D arm and 78.9% patients in the ICD arm, p < 0.0001. The number needed to treat was incredibly low at 2.2. Notably, the occurrence of ventricular arrhythmia was substantially lower in the CRT-D group. Procedure or device-related complications were comparable in the 2 groups.

3. For patients with cardiomyopathy and heart failure, which device to implant: ICD, CRT, or CRT-D?

Meta-analysis of the studies discussed above provided strong evidence that CRT reduces mortality and hospitalization and improves cardiac function and structure in symptomatic HF patients on OPT with severely depressed LVEF (i.e., ≤35%) and complete LBBB. In these patients, CRT was superior either to optimal medical therapy or to ICD alone. Also, analysis of these studies demonstrated that CRT-D provided a slightly better degree of reduction in mortality with a trade-off of higher cost and to some degree higher procedural complications (Table 1) [15].

	CRT-D	CRT-P
Mortality reduction	Similar level of evidence but CRT-D slightly better	Similar level of evidence but CRT-P slightly worse
Complications	Higher	Lower
Costs	Higher	Lower

Table 1.

Comparative results of CRT-D vs. CRT-P in primary preventions.

CRT-D = cardiac resynchronization therapy and defibrillator; and CRT-P = cardiac resynchronization therapy and pacemaker.

In patients indicated for CRT, defibrillation therapy is typically deferred in patients with life expectancy less than a year, NYHA Class IV, severe renal disease and other severe comorbidities, cachexia, and frailty (Table 2) [15].

Factors favoring CRT-P	Factors favoring CRT-D
Advanced heart failure	Life expectancy >1 year
Severe renal insufficiency or dialysis	Stable heart failure, NYHA II
Other major co-morbidities	Ischaemic heart disease (low and intermediate MADIT risk score)
Frailty	Lack of comorbidities
Cachexia

Table 2.

Clinical guidance to the choice of CRT-P or CRT-D in primary prevention.

CRT-D = cardiac resynchronization therapy and defibrillator; CRT-P = cardiac resynchronization therapy and pacemaker; MADIT = Multicentre Automatic Defibrillator Trial; and NYHA = New York Heart Association.

4. Pacing site-dependent arrhythmia

This phenomenon was described by Medina-Ravell et al. in 2003 and was defined as an arrhythmia due to simultaneous pacing of right ventricle (RV) endocardium and LV epicardium [16]. Normally, ventricle activation starts at the endocardium and spreads through the myocardium to the epicardium. Therefore, LV epicardial pacing alters ventricular activation and repolarization dynamics, which leads to QT interval prolongation rendering the ventricle vulnerable to extrasystoles that result in R on T phenomenon, Torsades des Pointes, or non-sustained or sustained polymorphic ventricular tachycardia. The incidence of this condition was reported to be about 4% and mostly occurred in ischemic cardiomyopathy patients [17].

Because about 4% of CRT implant patients could die soon after device implantation due to the device-related arrhythmia described above if left untreated, CRT-D is preferably selected instead CRT-P when a patient meets CRT indications.

5. Future prospective

None of the randomized controlled trials for either CRT or CRT-D had the patients on goal-directed medical therapy optimized as per present day guidelines. These trials had majority of patients on beta-blockers, but the proportion of patients on mineralocorticoid receptor antagonist or angiotensin convertase inhibitors/angiotensin receptor blockers was much less. The role of angiotensin receptor/neprilysin inhibitor and SGLT-2 inhibitors in heart failure treatment were yet not established when these trials were conducted. Hence, there is a scope for newer trials to be conducted with patients on optimized goal-directed medical therapy as per present day guidelines.

Also, left ventricular scarring may lead to ineffective CRT. Cardiac MRI is the current gold standard for detecting myocardial scarring. With the use of cardiac MRI, it may be helpful in guiding LV lead deployment. The strategy of avoiding myocardial scar during LV lead implantation has not been studied in a multicenter, randomized, controlled trials because of the difficulty in including a control group not treated with CRT. Cardiac MRI can also provide measurements of global and segmental cardiac function and permit localization and quantification of myocardial perfusion. These measures provide important information on the cause and prognosis of patients with heart failure. Therefore, further studies regarding the use of cardiac MRI to select appropriate candidates for CRT and to achieve the maximum benefit from it are needed [18].

Another potential benefit of cardiac MRI use in selection of the device relates to myocardial scar as a possible predictor of arrhythmic events. Some studies showed that scar burden is a more powerful predictor of SCD than LVEF. For example, in the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) trial, the extent of fixed perfusion defects on nuclear imaging was a strong predictor of lethal arrhythmias over a follow-up of 30 months [19]. As such, the presence of extensive myocardial scarring in patients eligible for CRT may be a good reason to favor the use of CRT-D over CRT-P in these patients.

6. Conclusion

In the presence of QRS duration of ≥150 msec and LBBB in patients with cardiomyopathy and reduced ejection fraction LVEF of ≤35%, and in the absence of contraindications for defibrillation therapy, it is suggested that the maximum reduction of mortality benefit may be achieved with the use of CRT-D device, possibly due to decreased risk of death due to arrhythmia with this combination.

Nevertheless, CRT-P has proven benefits that do not only include improvement in heart failure symptoms and quality of life, but include significant mortality reduction benefit as well and therefore can still be used when defibrillation therapy is contraindicated.