AIM: Should CRT guidelines be revised if many patients don't see benefit?

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Striking data have shown that four of 10 patients who receive cardiac resynchronization therapy (CRT) may not benefit, according to a meta-analysis published in the June 13 issue of the Archives of Internal Medicine. In fact, the authors noted that CRT in heart failure (HF) patients with moderate QRS durations—120 msec to 150 msec—may be unnecessary. These results call into question whether the clinical practice guidelines for CRT should be revised.

CRT, or biventricular pacing, has been shown "to improve hemodynamics, promote reverse remodeling and reduce clinical events including death in patients with prolonged QRS duration on the electrocardiogram,” the authors wrote.

Current treatment guidelines endorsed by American Heart Association (AHA), American College of Cardiology (ACC) and the European Society of Cardiology (ESC) recommend CRT for patients with a QRS duration greater than 120 msec. While nearly one-third of systolic HF patients have QRS duration above the 120 msec cutoff, recent research has found that an estimated one-third to one-half of patients receiving CRT according to the guidelines may benefit from the therapy.

Is the current 120 msec QRS duration cutoff sufficient?
To investigate this question, Ilke Sipahi, MD, of the University Hospitals Case Medical Center in Cleveland, and colleagues combed the MEDLINE, SCOPUS and Cochrane databases and identified five CRT trials—COMPANION, CARE-HF, REVERSE, MADIT-CRT and RAFT—to assess whether the effect of CRT on adverse clinical events (death and hospitalization) varied in patients with moderately (120 msec to 149 msec) versus severely (more than 150 msec) prolonged QRS duration.

He and his colleagues found CRT to be very beneficial in patients with QRS duration of 150 msec or greater. In fact, the risk of hospitalization and death was reduced by 40 percent in these patients with a longer QRS duration. However, “patients who had a QRS duration that was only moderately prolonged [120 msec to 150 msec] had absolutely no benefit whatsoever in terms of mortality or other clinical events reduction with CRT,” Sipahi told Cardiovascular Business.

“These findings are extremely important,” he noted. “Forty percent of the patients receiving devices according to the current treatment guidelines have QRS duration between 120 msec and 150 msec and will not benefit from CRT.”

Sipahi noted that four of 10 CRT implants are “unnecessary,” and urged that current clinical practice guidelines be reworked.

“We must further examine whether a subset of patients with a moderately prolonged QRS might benefit from CRT, like an increased risk subset perhaps,” Sipahi said. Sipahi offered that conducting an individual patient level analysis could help. “Before revising the guidelines right away and changing them to 150 msec, further analyses will be necessary to become confident with the recommendations.”

Sipahi does not recommend CRT therapy for patients with QRS duration between 120 msec and 150 msec. At this point, patients with a moderate QRS duration should remain on medical therapy—beta-blocker, ACE inhibitor or aldosterone antagonists. As for high-risk patients with only a moderately prolonged QRS who are at risk for repeat hospitalizations or kidney failure, more advanced techniques such as heart pump transplants or heart transplantation may be necessary.

“It is really unfortunate to see guidelines recommending CRT for moderately prolonged QRS durations of 120 msec,” Sipahi offered. “These guidelines are incorrect and must be fixed.

"We are seeing no benefit from CRT in these patients [those with a moderate QRS duration],” Sipahi said. “How many more negative subgroup analyses do we have to wait for before we fix the guidelines?”

In an accompanying editorial, Lynne Warner Stevenson, MD, of Brigham and Women’s Hospital in Boston, wrote that Sipahi et al provided a "vivid demonstration of how we may be intoxicated by the enthusiastic presentations of new trials and how we may be rendered sober again by deeper analysis of the collective experience as we seek to translate those trials for the patients who rely on our wisdom.”

In fact, Stevenson called it “remarkable” that these lessons are exemplified even in relation to CRT, “one of the most effective therapies for heart failure in terms of quality of life, freedom from hospitalization and survival.”

She offered that inclusion criteria for CRT trials was a required QRS duration of 120 msec (or 130 msec or greater in MADIT-CRT), however, the median QRS duration in the major trials was more than 150 msec. “Because the overall result was positive, the trials were translated into CRT approval and recommendation for patients with QRS intervals of 120 to 150 milliseconds as well as those with QRS intervals greater than 150 milliseconds,” Stevenson wrote.

Stevenson told Cardiovascular Business that “issues such as these highlight a major challenge, which is how to take information from clinical trials and make sure that it is applied carefully to individual patients.”

Even though previous studies have shown a clear benefit of CRT in HF patients, this trial did not “specifically identify what patients would benefit within the subgroup of patients within the trial. There is very clear evidence that there are a substantial proportion of people who are recommended to get this therapy but in fact are unlikely to benefit from it,” Stevenson noted.

These results have major implications on patient care. Despite the limitations of combining different trials, the results of this meta-analysis are robust enough to anchor a growing suspicion that the patients with QRS in the 120- to 150-millisecond range do not improve after CRT,” she wrote. The current meta-analysis confirms clinical impressions that specific patients with moderate QRS durations are not benefiting, Stevenson said.

The majority of patients who receive CRT derive major benefit in terms of quality of life; however, the current guidelines recommendations also includes a subgroup of patients who are unlikely to benefit from this therapy.

“It’s a complex issue because on the one hand we want to make sure that guidelines keep pace with new progress, however, at the same time as we keep up with progress we have to make sure that the guidelines are nimble enough to be revised when there is new evidence,” Stevenson offered.

Currently, she said more energy is being thrust into what new therapies should be used as opposed to what therapies should not be used.

“We must remain humble about what we know and what we don’t know and realize even that when we acquire new knowledge that there is a vast amount that we don’t yet know and we have to remain ready to learn it,” Stevenson concluded.