AIM: Should we lower the bar for CRT in heart failure?

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Cardiac resynchronization therapy (CRT) is beneficial for patients who have a reduced left ventricular ejection fraction (LVEF), a prolonged QRS and less severe symptoms of heart failure, Canadian researchers found during a meta-analysis published in the Feb. 15 issue of the Annals of Internal Medicine.

“[I]mportant questions remain regarding heart failure and CRT,” the authors wrote. These questions include whether CRT is effective in patients with less severe symptoms, whether resynchronization therapy is beneficial in patients with a narrow QRS duration and severe heart failure (HF) symptoms, and whether pacing with an LV lead would provide the same benefit as a three-lead CRT device.

To explore these unanswered questions, Nawaf S. Al-Majed, MBBS, of the University of Alberta and Canadian VICOUR Center in Edmonton, Alberta, Canada, and colleagues assessed the benefits and potential harms of CRT in patients with advanced heart failure and those with less symptomatic disease.

The authors found 25 randomized controlled trials evaluating CRT that included 9,082 patients overall. Three trials compared CRT to usual care, five trials looked at right ventricular pacing, four trials evaluated left ventricular pacing, one trial studied either right or left ventricular pacing, four trials studied backup pacing and eight trials compared CRT plus ICD with ICD alone.

The researchers used all-cause mortality as the review’s primary outcomes and HF hospitalizations, quality of life and functional outcomes as the review’s secondary outcomes.

Al-Majed et al reported that overall, CRT reduced all-cause mortality by 19 percent. In the six trials that included patients with NYHA Class I or II symptoms, CRT reduced the risk of all-cause mortality. Likewise the three trials that studied patients with NYHA Class I or II exclusively showed similar results—407 deaths in 4,054 patients. The same results were true in the 19 trials that enrolled predominantly patients with NYHA Class III or IV patients and the 11 studies that exclusively enrolled those with NYHA Class III or IV symptoms.

The researchers also noted that LV pacing alone did not affect all-cause mortality compared with CRT and the number of events was small, 28 deaths in 677 patients.

In 12 trials, HF-related deaths were reduced, which led to a mortality benefit from CRT. As for the secondary outcome HF hospitalization, CRT was associated with a reduction in the risk of hospitalizations with HF, but no statistical differences were found between the trials that enrolled predominantly patients with NYHA Class III or IV symptoms.

CRT reduced HF hospitalizations in the two studies that exclusively enrolled patients with NYHA Class I or II symptoms—582 events in 3,863 patients—and the eight trials the included patients with NYHA Class III symptoms—635 events in 2,361 patients.

Left ventricular pacing on HF hospitalizations alone was similar to the effects of CRT with three trials, which reported 36 events in 371 patients.

“In this systematic review, we confirm that CRT improves LVEF and reduces all-cause mortality and heart failure hospitalization in patients with milder symptoms of heart failure (NYHA Class I or II), left ventricular systolic dysfunction and prolonged QRS duration,” the authors wrote. “The relative magnitude of these benefits (risk reductions of 17 percent for mortality and 29 percent for heart failure hospitalization) are similar to those seen in patients with NYHA Class III or IV symptoms, left ventricular systolic dysfunction and prolonged QRS duration.”

Patients with QRS durations greater than 150 msec saw the greatest benefit from CRT. “Of note, CRT is the only positive inotropic therapy that has been shown to improve both cardiac systolic function and patient survival,” the authors wrote.

The results of the meta-analysis may support the expansion of CRT indications for less symptomatic patients with HF who have a LVEF less than 30 percent, a QRS duration greater than 120 msec and for those who are in sinus rhythm.

However, the authors offered that one question remains: How generalizable the direct benefits will be when the device is used in clinical practice by less experienced clinicians who work in smaller volume centers?

The authors concluded: “[W]e believe establishing criteria for case selection so that CRT devices are preferentially implanted in the patients who are most likely to benefit is of vital importance for researchers, clinicians and policymakers.”

In an accompanying editorial, Carl R. Reynolds, MD, and Mariell Jessup, MD, of the University of Pennsylvania School of Medicine in Philadelphia, wrote that “the investigators aptly observe that even as we close the book on one important question, we are left with numerous and even more vexing problems threatening the effective translation of this knowledge into responsible clinical practice.”

While Reynolds and Jessup offered that CRT has been “efficacious” in selected HF patients who meet dyssynchrony criteria, 30 percent of patients in early CRT trials were nonresponders. Other questions about other HF subgroups still exist such as evaluating patients with atrial fibrillation, patients with ischemic cardiomyopathy and whether women benefit from CRT more than men.

“Given these complexities, it seems unwise to believe that the response rate to CRT in patients with milder heart failure will be any better than 60 percent if we are not very selective about which patients receive this therapy,” said Reynolds and Jessup.

“The critical lesson is that CRT, an effective therapy, can work in patients with mild heart failure, but it will not do so if it is applied haphazardly or if our current system of cardiac care is not well organized to correctly identify appropriate candidates for it.”

They concluded, “In this field, technology has overrun our ability to use it judiciously and more effective systems of care must be developed to harness the power of evidence-based medicine.”