Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Cardiac resynchronization therapy reduced all-cause death and hospitalization in chronic heart failure

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ACP J Club. 2004 Nov-Dec;141:60. doi:10.7326/ACPJC-2004-141-3-060

Related Content in this Issue
• Companion Abstract and Commentary: A prophylactic cardioverter–defibrillator prevented sudden death from arrhythmia in nonischemic cardiomyopathy


Clinical Impact Ratings

Hospitalists: 6 stars

Cardiology: 6 stars


Source Citation

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;350:2140-50. [PubMed ID: 15152059]


Abstract

Question

In patients with advanced chronic heart failure (HF), is cardiac resynchronization therapy (CRT) with a biventricular pacemaker with or without a defibrillator in addition to optimal pharmacotherapy (OPT) better than OPT alone for reducing death and hospitalization?

Methods

Design: Randomized controlled trial (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure [COMPANION]).

Allocation: Concealed.*

Blinding: Unblinded.*

Follow-up period: 12 months.

Setting: 128 centers in the United States.

Patients: 1520 patients (mean age 67 y, 68% men) with advanced New York Heart Association (NYHA) class III or IV HF resulting from either ischemic or nonischemic cardiomyopathy, left ventricular (LV) ejection fraction ≤ 0.35, QRS interval ≥ 120 ms and PR interval > 150 ms, sinus rhythm, no clinical indication for a pacemaker or implantable defibrillator, and hospitalization for the treatment of HF or equivalent in the previous 12 months.

Intervention: All patients received OPT (diuretics, if needed); angiotensin-converting enzyme inhibitors (or angiotensin-receptor blockers, if not tolerated); β-blockers, if tolerated or not contraindicated; and spironolactone, if tolerated), and digoxin or other medications for HF. Patients were allocated to OPT (n = 308), OPT plus CRT with a biventricular pacemaker (n = 617), or OPT plus CRT and a pacemaker-defibrillator (n = 595).

Outcomes: Composite endpoint of all-cause death or hospitalization. Unscheduled intravenous inotropic or vasoactive drugs for > 4 hours in the emergency department or on an outpatient basis was considered an instance of the primary endpoint with respect to hospitalization. Secondary endpoints included all-cause death, and death from or hospitalization for cardiovascular (CV) causes or HF.

Patient follow-up: 97% (intention-to-treat analysis).

Main results

Compared with OPT alone, CRT with or without a defibrillator reduced risk for the composite endpoint (Table). Fewer patients who received CRT and a pacemaker–defibrillator died from all causes than did those who received a pacemaker alone (Table). Compared with OPT, death from or hospitalization for CV causes or HF were reduced in CRT groups with a defibrillator (hazard ratio [HR] 0.72, 95% CI 0.60 to 0.86) and without a defibrillator (HR 0.75, CI 0.63 to 0.90). More moderate or severe all-cause adverse events occurred in the CRT defibrillator group than the OPT group (69% vs 61%, P = 0.03).

Conclusion

In patients with advanced chronic heart failure, cardiac resynchronization therapy with a biventricular pacemaker with or without a defibrillator reduced all-cause death or hospitalization.

*See Glossary.

Source of funding: Guidant.

For correspondence: Dr. M.R. Bristow, University of Colorado Health Sciences Center, Denver, CO, USA. E-mail michael.bristow@uchsc.edu.


Table. Cardiac resynchronization therapy with a pacemaker (P) or pacemaker–defibrillator (PD) vs optimal pharmacologic therapy (OPT) for advanced chronic heart failure at mean 12 months†

Outcomes P PD OPT RRR (95% CI) NNT (CI)
Composite endpoint 56% 68% 11% (2 to 20) 13 (8 to 68)
56% 68% 12% (3 to 21) 13 (8 to 54)
All-cause death 15% 19% 22% (−0.9 to 39) Not significant
12% 19% 34% (13 to 49) 16 (11 to 42)

†Composite endpoint = all-cause death or hospitalization. Other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Despite major improvements in treating HF, mortality remains high. Newer therapeutic approaches have focused on the benefits of such electrical therapies as CRT and ICDs. CRT is aimed at restoring the desynchronization that is usually associated with conduction delays (characterized by left-bundle branch block), and ICDs primarily prevent arrhythmic deaths.

The COMPANION trial by Bristow and colleagues further supports and extends the beneficial effects of CRT in patients with advanced HF and QRS > 120 ms and reinforces the importance of OPT. In addition, all-cause mortality was reduced by 36% when CRT and an ICD were combined (HR 0.64, 95% CI 0.48 to 0.86). A limitation of this study was the disproportionately high rate of withdrawal from the OPT group, which was reported once the Multicenter Automatic Defibrillator Implantation II (MADIT-II) trial results became available (1). It remains unclear whether the reduction in mortality is solely attributable to the ICD or the combination of CRT and ICD.

The extent of benefit derived from CRT with or without an ICD was similar in both ischemic and nonischemic patients. Interestingly, in patients with nonischemic cardiomyopathy, CRT combined with an ICD was associated with a lower risk for all-cause mortality than with OPT (HR 0.50, CI 0.29 to 0.88). These findings support the use of CRT with or without an ICD also in patients with advanced HF secondary to nonischemic cardiomyopathy.

The main issue related to electrical therapy of HF remains its cost-effectiveness. Although not reported, the 20% reduction in the composite endpoint in both groups may indicate a reduction in health costs (primarily driven by hospitalizations). The 13 patients needed to treat to prevent 1 primary outcome is comparable to the treatment cost of other chronic conditions (2). However, in the COMPANION trial, the effect on all-cause mortality was only seen in the group that received both CRT and an ICD.

Despite the major effect of CRT on quality of life, hospital admissions, and mortality secondary to the progression of HF, 20% to 40% of patients do not respond to this therapy (3−5). Similarly, not all patients with an LV ejection fraction < 30% will benefit from insertion of an ICD. Better methods of identifying CRT responders as well as patients with higher risk for sudden death are needed to reduce unnecessary costs (6, 7). Treatment decisions may depend on whether the purpose of therapy with CRT is primarily for symptomatic relief, prolongation of life, or both. The critical question is whether all patients with poor LV function (associated with some degree of desynchrony, regardless of cause) should undergo the insertion of CRT with an ICD.

The DEFINITE trial by Kadish and colleagues showed a trend toward reducing all-cause mortality in patients with nonischemic cardiomyopathy who received an ICD. Conversely, an impressive reduction in sudden death from arrhythmia was reported in the group that received ICD. Aggressive medical therapy in patients with depressed LV function secondary to nonischemic cardiomyopathy should be reinforced. The recently presented Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) randomized patients with poor LV function (ejection fraction < 35%) and moderate-to-severe HF (NYHA II-III) to placebo, amiodarone, or an ICD. SCD-HeFT showed that an ICD reduced all-cause mortality regardless of cause by 23% (HR 0.77, 97.5% CI 0.62 to 0.97) (8). These studies support prophylactic insertion of an ICD in patients with moderate-to-severe LV dysfunction.

The COMPANION and DEFINITE trials expand the indications of CRT and ICDs in high-risk patients with LV dysfunction regardless of cause. Further risk stratification is needed to appropriately select responders to either therapy. Given the impact of electrical therapy for HF on health economics, judicious use of these technological advances is warranted.

Carlos A. Morillo, MD, FRCPC
McMaster University
Hamilton, Ontario, Canada


References

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3. Bradley DJ, Bradley EA, Baughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA. 2003;289:730-40. [PubMed ID: 12585952]

4. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. 2003;289:2685-94. [PubMed ID: 12771115]

5. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845-53. [PubMed ID: 12063368]

6. Abraham WT. Cardiac resynchronization therapy: a review of clinical trials and criteria for identifying the appropriate patient. Rev Cardiovasc Med. 2003;4 Suppl 2:S30-7 [PubMed ID: 12776011]

7. Hohnloser SH, Ikeda T, Bloomfield DM, Dabbous OH, Cohen RJ. T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation. Lancet. 2003;362:125-6. [PubMed ID: 12867114]

8. Shah SH, Dery JP, Fischi MC, et al. Highlights from the American College of Cardiology Annual Scientific Sessions 2004: March 9-12. Am Heart J. 2004;148:254-62.