MADIT-CRT: Resynchronization Ups Survival in Patients with Mild Heart Failure and LBBB

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Among patients with mild heart failure, only those who have left bundle branch block (LBBB) stand to gain better long-term survival from receiving cardiac resynchronization therapy (CRT) in addition to a defibrillator. In contrast, those without the conduction abnormality may be at risk of harm, according to late-breaking results presented March 30, 2014, at the American College of Cardiology/i2 Scientific Session and simultaneously published online in the New England Journal of Medicine.

For the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), researchers enrolled 1,820 patients with:

• Cardiomyopathy (NYHA functional class I or II for ischemic and class II for nonischemic)
• Left ventricular dysfunction (LVEF ≤ 30%)
• Prolonged QRS duration (≥ 130 msec)

Patients were randomized in a 3:2 ratio to CRT plus defibrillator or defibrillator alone. In the original trial, early intervention with CRT reduced the relative risk of heart failure events by 41% over a median follow-up of 2.4 years.

Conduction Abnormality Must Be Present

The current analysis, presented by Ilan Goldenberg, MD, of Sheba Medical Center (Tel Aviv, Israel), was based on post-trial follow-up (median of 5.6 years) for the 1,691 surviving patients from MADIT-CRT and subsequent registry data for 854 trial participants.

Kaplan-Meier analysis estimated that the cumulative rate of death from any cause in patients with LBBB at 7 years was 18% for those who received CRT and 29% for those who did not (P = 0.002). The number needed to treat to avoid 1 death was 9. No mortality difference was observed over the same time frame for patients without the conduction abnormality (P = 0.205).

Multivariable analysis confirmed that the benefit of CRT was restricted to the LBBB subgroup when considering either death or nonfatal heart failure events with the non-LBBB subgroup showing a higher adjusted risk of death with CRT (P for interaction < 0.001 for both; table 1).

Table 1. Long-Term Outcomes: CRT plus Defibrillator vs Defibrillator Alone

Among patients with LBBB, the long-term effect of CRT on mortality did not differ by sex, cause of cardiomyopathy, or QRS duration. Moreover, the lack of survival benefit in the absence of LBBB also was consistent across these subgroups.

Data Make the Case for CRT

These data fill a gap in the literature, Dr. Goldenberg and colleagues note in NEJM. MADIT-CRT and REVERSE, the 2 studies supporting CRT in patients with asymptomatic or mildly symptomatic heart failure, had relatively short-term mean follow-up durations of 2 to 3 years, whereas RAFT provided evidence of a survival benefit but included patients with more advanced heart failure.

In an editorial accompanying the paper, Jeffrey J. Goldberger, MD, MBA, of Northwestern University (Chicago, IL), agrees that the continued follow-up for MADIT-CRT provides valuable information that “solidifies the role” of CRT in offering long-term protection against morbidity and mortality in patients with mild heart failure and reduced ejection fraction and LBBB.

For such patients, the decreased mortality amounts to “an absolute reduction of 11 percentage points,” he notes, and “is particularly impressive when added to the therapeutic benefit of the background therapy of beta-blockers and angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, each of which already has substantial effects to improve survival.”

Possible Harm a ‘Cautionary Flag’

Dr. Goldberger says that the demonstrated lack of benefit and possible harm in patients without LBBB is just as important. “These findings should provide a cautionary flag that CRT, as currently implemented, is not necessarily beneficial when used in groups of patients without the primary abnormality that is remedied by CRT,” he writes.

Exactly how LBBB figures into the picture “is not clear,” the researchers say. And while CRT plus defibrillator therapy is not beneficial among patients lacking the conduction abnormality, “the finding regarding a possible harmful effect [of treatment] in this population should be interpreted with caution, since it was obtained only after multivariate adjustment and is therefore sensitive to covariate selection,” they stress.

According to Dr. Goldberger, “the synergy between heart failure with reduced ejection fraction and [LBBB] myopathy may produce substantial functional and clinical decline over time that is ameliorated by CRT (or isolated left ventricular pacing). Better understanding of the pathophysiology of this process and its ‘antidote’ could inform the development of new pacing strategies that may be helpful in the setting of other conduction abnormalities.”

 

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Sources:
1. Goldenberg I, Kutyifa V, Klein HU, et al. Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med. 2014;Epub ahead of print.

2. Goldberger JJ. Left bundle-branch block myopathy in heart failure. N Engl J Med. 2014;Epub ahead of print.

 

• Dr. Goldenberg reports no relevant conflicts of interest.
• Dr. Goldberger reports serving as a lecturer or consultant for Medtronic and as a consultant to GE Healthcare; he also reports unrestricted educational grants from Boston Scientific, Medtronic, and St. Jude to Path to Improved Risk Stratification, a not-for-profit think-tank of which he is director.

 

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