CRT Survival Gains in Mild HF Durable at Seven Years: MADIT-CRT

March 30, 2014

WASHINGTON, DC (updated) — Cardiac-resynchronization therapy (CRT) can be a long-term fix for patients with mild heart failure, provided that they have left-bundle-branch block (LBBB) along with their reduced LV ejection fractions and other indications for the pacing therapy, suggests a seven-year follow up analysis from a major randomized trial[1].

Patients with LBBB who received CRT with a defibrillator (CRT-D) compared with those getting a defibrillator alone showed a steep 55% reduction in seven-year risk of nonfatal heart-failure events or death from any cause in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) long-term follow-up analysis. Both parts of the composite end point also improved on their own, and just as significantly.

But there were no such benefits from CRT among the trial's patients without LBBB, and in fact they may have shown a signal of harm, with an increase in all-cause mortality, according to the investigators, led by Dr Ilan Goldenberg (Sheba Medical Center and Tel Aviv University, Israel). The finding "should be interpreted with caution, since it was obtained only after multivariate adjustment and is therefore sensitive to covariate selection," the group writes in a report published today in the New England Journal of Medicine. Goldenberg also presented the analysis here today at the American College of Cardiology 2014 Scientific Sessions .

Question Nailed at Last

Dr Ilan Goldenberg

But others heard a stronger message in the poor outcome of non-LBBB patients. Speaking at a media briefing on Goldenberg's presentation, Dr Allan S Jaffe (Mayo Clinic, Rochester, MN), who wasn't involved in the study, observed that long-term follow-ups are a good way to study subgroups. That's because in primary analyses, usually their numbers are too small and endpoints too few for reliable conclusions. And although the special effectiveness of CRT in LBBB patients has been appreciated for years now and has made its way into guidelines, some non-LBBB patients are thought to gain from the treatment. "I think this long-term follow-up has nailed the question down at last. At least for now, the way we do [the procedure], LBBB is where the [CRT] benefit is."

Dr Prediman K Shah (Cedars-Sinai Medical Center, Los Angeles, CA), also not connected with MADIT-CRT, agreed. "I think this study puts it in perspective: not only is it important to limit this technique to those with LBBB, it is important to avoid it in patients without it, because they can perhaps fare worse. And that's an important message that otherwise gets lost." Guidelines that still make room for CRT in some patients without LBBB should be changed, he said, to strengthen cautions against it.

Special Benefit in LBBB Seen Before

In the study's primary analysis, as reported by heartwire in 2009, CRT was associated with a 34% reduction in the primary end point of death by any cause or HF events over about two-and-a-half years. A 41% drop in HF-event risk accounted for most of the CRT benefit, which was predominantly in patients with LBBB, according to a later analysis of the trial.

The current analysis traced outcomes for the 1820 randomized patients, including 1691 patients who survived the MADIT-CRT study period over a median follow-up of 2.4 years and 854 who were further followed in a registry for a median of 5.6 years.

At seven years, by intention-to-treat analysis, 18% of patients with LBBB treated by CRT-D had died, compared to 29% of similar patients who received only a defibrillator. The improvements for the composite end point and its components were all significant, at p<0.001, in multivariate analysis.

Adjusted HR (95% CI) for Seven-Year Outcomes in MADIT-CRT Patients With LBBB, Intention-to-Treat Analysis

End points HR (95% CI)
Death from any cause 0.59 (0.43–0.80)
Nonfatal HF events 0.38 (0.30–0.48)
Nonfatal HF events or death 0.45 (0.37–0.56)

Adjusted for age at enrollment, serum creatinine, smoking status at enrollment, diabetes, etiology of cardiomyopathy, LV end-systolic volume index, body surface area, baseline QRS duration, NYHA class 3-4 heart failure within three months before enrollment

For none of those end points was there a significant improvement with CRT-D among the patients without LBBB, but possible harm was seen for all-cause mortality (HR 1.57, 95% CI 1.03–2.39; p=0.04) in adjusted analysis.

In patients with LBBB, "the reported 41% reduction in mortality, with an absolute reduction of 11 percentage points, is particularly impressive when added to the therapeutic benefit of the background therapy of beta-blockers and ACE inhibitors or angiotensin-receptor blockers [ARBs], each of which already has substantial effects to improve survival," writes Dr Jeffrey J Goldberger (Northwestern University, Chicago) in an accompanying editorial[2].

"Equally important is the demonstration that patients with a wide QRS complex without left bundle-branch block do not benefit from CRT and may even be harmed."

MADIT-CRT was funded by Boston Scientific. Goldenberg reports grant support from Boston Scientific. Disclosures for the coauthors are available at nejm.org. The Path to Improved Risk Stratification, directed by Goldberger, is a not-for-profit think tank that has received unrestricted educational grants from Boston Scientific, Medtronic, and St Jude Medical; he has received fees for lecturing and/or consulting from Medtronic and GE Healthcare. Jaffe discloses receiving consulting fees or honoraria from Radiometer, Abbott, Ortho Diagnostics, Beckman-Coulter, Trinity, ET Healthcare, Alere, Amgen, Roche, Critical Diagnostics. Shah discloses receiving research grants from CardioVax.

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