CRT only or CRT plus ICD?
Division of Cardiology, The Pennsylvania State College of Medicine, Hershey, USA
Received 3 May 2004; accepted 24 May 2004.
* John P. Boehmer, Division of Cardiology, The Pennsylvania State College of Medicine, Room 1511/H047, The Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. Tel.: +1-717-531-7453; fax: +1-717-531-4077
jboehmer{at}psu.edu
Abstract
Aims Cardiac resynchronization therapy (CRT) has been shown in several clinical trials to improve symptoms and exercise capacity in patients with advanced heart failure. The first clinical trials of CRT-D devices were based on populations who already met a standard indication for implantable cardioverter defibrillator (ICD) therapy. In these patients, when CRT is contemplated, a CRT-D device is used. In a broad population of patients with advanced heart failure, the choice of adding ICD therapy is less clear.
Methods and results Results of several clinical trials of CRT and ICD use in heart failure are reviewed. An analysis of data suggests that CRT may reduce death due to progressive heart failure. Recently, the COMPANION trial has reported that CRT can reduce long-term morbidity and mortality. CRT can be delivered as a pacemaker only, or in combination with an ICD. Taken alone, an ICD can improve survival in select groups of patients with left ventricular dysfunction; however, adverse effects have been seen, such as worsening heart failure.
Conclusion There are no clinical trials designed specifically to address the relative merits of CRT delivered by pacemaker versus ICD. Based on our knowledge of the effects of both, along with data from recent clinical trials, it appears as though the preponderance of evidence is in favor of CRT-D. More will be learned from clinical trials currently underway
Key Words: Heart failure • Implantable cardioverter defibrillator • Cardiac resynchronization therapy
Introduction
Heart failure is a common disease in developed countries. It is the most common reason for hospitalization among those over the age of 65 years, and both the incidence and prevalence of heart failure are anticipated to increase as the population ages.1,2 Symptoms of heart failure can become disabling, affecting simple activities of daily living. Despite advances in the treatment of heart failure, many patients remain very symptomatic, and both morbidity and mortality remain high, creating a need for improved therapies.
Cardiac resynchronization therapy (CRT) is a recent addition to therapy for symptomatic heart failure.3 CRT has consistently been shown to improve symptoms and exercise capacity in several randomized clinical trials.4–8 Recently, the Comparison of Medical Therapy, Pacing and Defibrillation (COMPANION) trial has demonstrated a substantial reduction in the combined endpoint of mortality and all-cause hospitalization, thereby expanding the importance of CRT in the treatment of heart failure.9
Implantable cardioverter defibrillators (ICDs) have been shown to reduce mortality in patients at high risk for arrhythmia.10–12 Initially, attention was focused on patients with markers for ventricular arrhythmia, such as nonsustained ventricular tachycardia or inducible sustained ventricular tachycardia during an electrophysiology study.10,12 More recently, attention has been drawn to left ventricular systolic dysfunction as a sole risk factor for arrhythmic death.11
CRT is delivered with devices that are either pacemakers alone, or are combined with ICD therapy (CRT-D). The first clinical trials of CRT-D devices were based on populations who already met a standard indication for ICD therapy. Clearly, in such patients, when CRT is contemplated, a CRT-D device is used. In a broad population of patients with advanced heart failure, the choice of device is less clear. Should we implant CRT devices alone, or add ICD therapy?
In this review, the risks and benefits of CRT devices and ICD therapy alone in heart failure patients will be summarized. The risks of CRT-D devices will be reviewed, along with the benefits observed in randomized clinical trials.
CRT
Conduction system disease is common in patients with advanced heart failure and left ventricular (LV) systolic dysfunction, estimated to occur in 25% of patients with advanced symptoms of heart failure and low ejection fraction.13 Such conduction abnormalities may cause an inefficient left ventricular contraction, uneven LV wall stress, increased myocardial oxygen consumption, and increased mitral regurgitation.14,15 In studies of heart failure patients, conduction system disease is associated with increased symptoms and a poor prognosis. CRT has the potential to normalize these abnormalities, thereby improving patient outcome.
The benefits and risks of CRT
Table 1 displays the results of CRT on symptoms, quality of life and exercise capacity in clinical trials. Although the trials used different devices and differed somewhat in methodology, CRT consistently demonstrated a benefit in all these parameters.4–8 Furthermore, the magnitude of benefit is large. In studies of pharmacologic treatment of heart failure, drug therapy known to have long-term benefits is often associated with less improvement or no measurable improvement in some of these metrics.16–18
|
The long-term effect of CRT on morbidity and mortality was not elucidated by these studies. In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, the investigators reported that CRT reduced the composite secondary endpoint of death or heart failure hospitalization (8% CRT, 15% control,
).4 Although the findings were very reassuring, the composite endpoint was fairly narrow and the follow-up was limited, leaving doubt about the long-term effects of CRT. In order to provide more insight into the effects of CRT on mortality, Bradley et al.19 performed a meta-analysis of survival using data from the four of the trials listed in Table 1. Although they were unable to demonstrate an overall mortality benefit (RR 0.77, 95% CI 0.51–1.18), the trend was reassuring and a reduction in death due to progressive heart failure became apparent (RR 0.49, 95% CI 0.25–0.93). The methods used in these trials were to randomize patients after a functioning CRT device was successfully implanted, thus negating any potential adverse effects of the implant in the data analysis. This series of studies of CRT brought this new therapy to clinical practice by providing consistent evidence of substantial improvement in symptoms, exercise capacity and quality of life. The data on morbidity and mortality were clearly trending in the right direction, but were not certain. The risks of CRT implants appear to be relatively low, but certainly deserve attention. The adverse event rates for the Multisite Stimulation in Cardiomyopathies Trial (MUSTIC), MIRACLE, MIRACLE-ICD and CONTAK CD clinical trials are shown in Table 2.4,6–8 Deaths around the time of implant are uncommon, but do occur. The most common adverse events were related to lead dislodgement, followed by coronary sinus trauma.
|
The risks and benefits of ICD therapy in a heart failure population
As mentioned, the study of prophylactic ICD therapy has evolved from evaluating those with markers for ventricular arrhythmias, to evaluating those with severe LV systolic dysfunction and finally those with symptomatic heart failure.10–12,20
The first trial to demonstrate a benefit of prophylactic ICDs in patients with LV dysfunction was the Multicenter Automatic Defibrillator Implantation Trial (MADIT).10 In this study, patients with a history of myocardial infarction, low LVEF (<40%) and nonsustained ventricular tachycardia were screened. If eligible, they underwent electrophysiology (EP) study to determine whether they were inducible for sustained ventricular tachycardia (VT). They were then tested to determine whether procainamide could suppress the arrhythmia, and only if procainamide failed to suppress VT were they enrolled in the study. Patients were randomized to an ICD or no ICD. Medical therapy was prescribed at the investigators' discretion.
A total of 196 patients were enrolled in the study. Mortality, the primary endpoint, was substantially lower for the ICD group, a 54% relative risk reduction at a median follow-up of 27 months. Two issues confounded the study. First, there was only a modest use of drugs known to be beneficial for patients with LV dysfunction, with 50–60% of the cohort being treated with an ACE inhibitor. Furthermore, there was a disparity in the use of ß-blockers, with 31% of patients in the ICD receiving the beneficial effects of ß-blockers compared with only 14% in the control arm at last contact. Although the magnitude of benefit was impressive, the overall small numbers and disparity in medical therapy between the groups left the community of physicians treating heart failure somewhat skeptical.
The Multicenter Unsustained Tachycardia Trial (MUSTT) study was a trial to study the approach of electrophysiologically guided therapy versus no antiarrhythmic therapy for a population at high risk for mortality from sudden death.12 Patients included had a history of a myocardial infarction, a low ejection fraction (<40%) and documentation of nonsustained VT. For the EP guided therapy group, the protocol stipulated a series of therapeutic trials, with the possibility of an ICD as an option if drugs failed to suppress the VT. As the trial progressed and more experience was gained with nonthoracotomy ICD implants, the ICD was used more frequently. The results demonstrated a modest benefit of EP guided therapy for the primary endpoint of cardiac arrest or death from arrhythmia. When the EP guided therapy group was divided into those treated with ICDs and those treated with antiarrhythmic drug therapy, it became apparent that all of the benefit rested with the patients treated with an ICD. If one evaluates those who happened to have received an ICD compared with those in the control group, the result was a 60% reduction in mortality with the ICD (RR 0.40, 95% CI 0.27–0.59). Unfortunately, the primary hypothesis of the trial did not involve an ICD and the patients who received an ICD were not randomized to that therapy, but were selected by their treating physicians, leaving the potential for bias. Accordingly, the results of the trial were left open to other interpretations.
As a result of impressive apparent benefits of prophylactic ICD therapy, the authors of the ACC/AHA guidelines for pacemaker and ICD implant endorsed the use of the prophylactic ICD for patients who would meet either the MADIT or MUSTT criteria.1,2 The authors of the ACC/AHA heart failure guidelines, while acknowledging these studies and recommending physician discretion in the use of these indications, did not strongly endorse these methods and actually recommended against screening for asymptomatic arrhythmia that would identify patients would meet the MADIT or MUSTT criteria. The authors of the ESC guidelines for the treatment of chronic heart failure reviewed some of the above studies, but noted that a broad heart failure population has not been studied.
The MADIT II study represented a departure from prior studies for patient selection. Instead of using markers of arrhythmia for entry, such as nonsustained ventricular tachycardia or the results of EP studies, the major risk criteria were a history of myocardial infarction and a very low ejection fraction (
30%).11 In this respect, the MADIT II study becomes a study of left ventricular systolic dysfunction, rather than ventricular arrhythmia. This study was a prospective, randomized, controlled clinical trial that was not confounded by imbalances in medical therapy or issues with treatment assignment. The study demonstrated an impressive 31% reduction in all-cause mortality at a median follow-up of 20 months. Two issues raised concerns. First, it took more than one year to begin to see a mortality benefit with the ICD. Second, there was an increase in heart failure hospitalization in the ICD group, with an absolute difference of 5.0% (similar to the mortality benefit of 5.6%), and a rate of 9.4 vs. 11.3 hospitalizations per patient month (
) for the control and ICD arms, respectively. The study may have been confounded by right ventricular pacing which appears to have the potential for causing worsening heart failure.21,22 In the MADIT II study, neither the choice of specific device, nor the pacing mode were mandated by protocol, but were left to the investigators' discretion.
When taking these studies together, there is a consistent survival benefit seen with ICDs in patients with LV dysfunction. Concern has been raised about the possibility of adverse effects of ICDs causing unforeseen problems such as worsening heart failure, and there is no proposed mechanism or clinical observation that suggest that ICDs can improve the heart failure condition.
Finally, the Sudden Cardiac Death Heart Failure Trial (SCD-HeFT) was recently reported.24 This, trial was designed to assess the potential of either an ICD or amiodarone to reduce the risk of sudden death in a broad population of heart failure patients (NYHA Class II and III) with low ejection fraction. The trial demonstrated no effect with amiodarone, but a 23% reduction in the risk of all-cause mortality with an ICD (HR 0.77, 97.5% CI 0.62–0.96, 
). This was the first clear demonstration of a benefit of ICD therapy in a broad heart failure population, and will clearly increase the use of ICDs in this group. However, there was a difference in the benefit seen in Class II and Class III heart failure. Patients with Class II heart failure had a dramatic benefit (HR 0.54, 97.5% CI 0.40–0.74), whereas those with Class III heart failure had no clear benefit (HR 1.16, 97.5% CI 0.84–1.61). Caution should be used in interpretation of this subgroup finding and more information will be forthcoming regarding potential reasons for this observation. This finding, in combination with the finding of worsening heart failure in the MADIT II study does raise concern about ICDs in advanced heart failure.
Comparisons of the effects of CRT and CRT-D
There are no randomized, controlled, clinical trials comparing the effects of CRT and CRT-D in a heart failure trial; however, the COMPANION trial is a randomized, controlled clinical trial that compares both CRT and CRT-D to a control population.23 The COMPANION trial results have recently been published.9 The study randomized patients with class III and IV heart failure, low ejection fraction (35%), and a wide QRS duration (>0.12 s) to optimal pharmacologic therapy (OPT) alone, OPT plus CRT or OPT plus CRT-D. The trial was a true intent-to-treat design with a primary endpoint of all-cause mortality and hospitalization. The COMPANION trial demonstrated a 19–20% reduction in the primary endpoint of all-cause mortality and all-cause hospitalization (CRT only HR 0.81, 0.69–0.96, 
; CRT-D HR 0.80, 0.68–0.95, 
) demonstrate a 19% reduction in the primary endpoint for both CRT and CRT-D. In contrast to studies of ICD therapy, there was no evidence of worsening heart failure with either CRT or CRT-D therapy. Mortality was the designated as the most important secondary endpoint. The CRT-D treatment group had a 36% reduction in all-cause mortality that was highly statistically significant (HR 0.64, 0.48–0.86, 
), while the CRT group had a trend towards a survival benefit with a 24% reduction in all-cause mortality (HR 0.76, 0.58–1.01, 
). It appears that the benefit in reduction in hospitalizations was due to CRT, since both groups had a substantial reduction in hospitalizations, while the addition of an ICD conferred a larger survival benefit. By using the point estimates of mortality, approximately two-thirds of the survival benefit was due to CRT and an additional one third of the benefit was due to adding ICD therapy. It should be noted that the statistical plan of the study was to compare both CRT and CRT-D groups with control, and not with each other. Further, there was no difference in the primary endpoint of the study between CRT and CRT-D and the difference in mortality was not statistically significant.
Conclusion
The decision to use a CRT only or a CRT-D device will be left to clinical judgment. Many patients who are eligible for CRT may already have an indication for ICD therapy, such as the criteria used for the MADIT II trial, thus making the choice of device obvious. In situations where an ICD is already indicated the choice to use a CRT device is simple. The COMPANION trial has reported data on an important, combined, morbidity and mortality endpoint in a long-term clinical trial in which the use of both types of devices are associated with significant benefit. We have evidence of a mortality benefit for CRT-D along with a trend towards a mortality benefit with CRT. There are other clinical trials, particularly SCD-HeFT, which may shed further light on the use of ICDs in patients with nonischemic dilated cardiomyopathy, and CARE-HF, which may provide important mortality data for CRT alone. If the results of the COMPANION trial are supported in the final analysis, the preponderance of evidence seems to support the use of a CRT-D device, although the results of clinical trials already in the follow-up phase may further elucidate the role of CRT only devices.
References
- Remme WJ, Swedberg K. Task force for the D: treatment of chronic heart failure ESoC. Guidelines for the diagnosis and treatment of chronic heart failure. Eur. Heart J. 2001;22(17):1527–1560
[Free Full Text] - Hunt SA, Baker DW, Chin MH, et al. 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). J. Am. Coll. Cardiol. 2001;38(7):2101–2113
[Free Full Text] - Boehmer JP. Device therapy for heart failure. Am. J. Cardiol. 2003;91(6A):53D–59D[Web of Science][Medline]
- Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N. Engl. J. Med. 2002;346(24):1845–1853
[Abstract/Free Full Text] - Auricchio A, Stellbrink C, Sack S, et al. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am. J. Cardiol. 1999;83(5B):130D–135D[CrossRef][Web of Science][Medline]
- Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay [comment]. N. Engl. J. Med. 2001;344(12):873–880
[Abstract/Free Full Text] - Higgins SL, Hummel JD, Niazi IK, 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;42:1454–1459
[Abstract/Free Full Text] - Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial [comment]. JAMA. 2003;289(20):2685–2694
[Abstract/Free Full Text] - Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N. Engl. J. Med. 2004;350:2140–2150
[Abstract/Free Full Text] - Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N. Engl. J. Med. 1996;335(26):1933–1940
[Abstract/Free Full Text] - Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N. Engl. J. Med. 2002;346(12):877–883
[Abstract/Free Full Text] - Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N. Engl. J. Med. 1999;341(25):1882–1890
[Abstract/Free Full Text] - Doval HC, Nul DR, Grancelli HO, et al. Randomised trial of low-dose amiodarone in severe congestive heart failure. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Lancet. 1994;344(8921):493–498[CrossRef][Web of Science][Medline]
- Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation. 1999;99(12):1567–1573
[Abstract/Free Full Text] - Nelson GS, Berger RD, Fetics BJ, et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation. 2000;102(25):3053–3059
[Abstract/Free Full Text] - Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA Cooperative Studies Group. Circulation. 1993;87(6 Suppl):VI5–VI16
- Ziesche S, Cobb FR, Cohn JN, et al. Hydralazine and isosorbide dinitrate combination improves exercise tolerance in heart failure. Results from V-HeFT I and V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation. 1993;87(6 Suppl):VI56–VI64
- Colucci WS, Sonnenblick EH, Adams KF, et al. Efficacy of phosphodiesterase inhibition with milrinone in combination with converting enzyme inhibitors in patients with heart failure. The Milrinone Multicenter Trials Investigators. J. Am. Coll. Cardiol. 1993;22(4 Suppl A):113A–118A
- Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials [comment]. JAMA. 2003;289(6):730–740
[Abstract/Free Full Text] - Bardy G, Lee K, Mark D. The sudden cardiac death in heart failure trial: pilot study [abstract]. PACE. 1997;20:1148
- Silvet H, Amin J, Padmanabhan S, et al. Prognostic implications of increased QRS duration in patients with moderate and severe left ventricular systolic dysfunction. Am. J. Cardiol. 2001;88(2):182–185 A6[CrossRef][Web of Science][Medline]
- Shamim W, Francis DP, Yousufuddin M, et al. Intraventricular conduction delay: a prognostic marker in chronic heart failure. Int. J. Cardiol. 1999;70(2):171–178[CrossRef][Web of Science][Medline]
- Bristow MR, Feldman AM, Saxon LA. Heart failure management using implantable devices for ventricular resynchronization: Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators. J. Card. Fail. 2000;6(3):276–285[CrossRef][Web of Science][Medline]
- Bardy G. Sudden Cardiac Death Heart Failure Trial Results, The American College of Cardiology Annual Scientific Sessions, New Orleans, LA, March 8, 2004
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||