September 3. 2013
A once promising indication for cardiac resynchronization therapy (CRT) in selected heart failure patients with narrow QRS intervals has suffered a major blow with the premature termination of the Biotronik sponsored multicenter EchoCRT trial reported today at the European Society of Cardiology in Amsterdam.
Cardiac resynchronization therapy was developed in the late 1990s as a treatment in patients with systolic heart failure. A series of seminal trials including MUSTIC, MIRACLE and COMPANION firmly established biventricular pacing as an effective treatment for advanced systolic congestive heart failure by the early 2000s. The patients in all of these early trials had LVEF <= 35% and wide electrocardiographic QRS complexes (>120msec or more) as a marker intraventricular dyssynchrony that could be improved with CRT.
Later trials including MADIT CRT and REVERSE showed benefit of CRT in patients with milder symptomatic classes of heart failure, but the study populations still required wide QRS complexes and severe LV dysfunction.
Analysis of these and other studies has suggested that the treatment benefit of CRT may be confined to the left bundle branch block population and the most recent US society guidelines for CRT now reflect this, assigning less weight to the non-LBBB wide QRS population.
For years, investigators have suggested that there may be an unmet need for CRT in patients with systolic heart failure who do not have wide QRS complexes, but appear to have treatable dyssynchrony by echo. Small studies, commonly single center, have shown CRT benefit in this population when pre-procedure screening echocardiography has shown evidence of dyssynchrony. A larger randomized study RETHINQ, reported in 2007, however, failed to show any benefit in a heart failure population with echocardiographic dyssynchrony and narrow QRS. Some criticized the study for its design, with particular attention to the type of echo parameters used to define dyssynchrony. This past February, however, another randomized trial of CRT in patients with narrow QRS, LESSER-EARTH was terminated prematurely without benefit. This trial, however, did not have any echocardiographic enrollment requirements and was also limited by very slow enrollment (85 patients over 8 years).
One isolated recent bit of supporting evidence for narrow QRS CRT came from the NARROW-CRT trial that was reported this past April. This trial showed benefit of CRT in a small, randomized sample of heart failure patients with narrow QRS and echo criteria for dyssnchrony. They were randomized to CRT-D vs. D-ICD with minimal pacing. The biventricular paced group had a significantly higher proportion of patients that improved their heart failure clinical composite score. (41% vs. 16%) and exhibited a trend toward improvement in survival and heart failure hospitalization.
The best, and possibly last remaining hope for the CRT in the narrow QRS population has rested on the EchoCRT trial, which was reported today at the European Society of Cardiology meeting in Amsterdam and simultaneously published in New England Journal of Medicine. Biotronik sponsored this investigator-initiated randomized, multicenter trial, which began enrollment in August 2008 with projected enrollment of 2330 patients. Study patients had Class III or IV heart failure with LVEF <= 35%, diastolic LV dimension greater than 5.5cm and QRS duration < 130 msec. Prior to enrollment, all patients had echocardiography with modern, advanced dyssynchrony measurements including tissue doppler and speckle tracking imaging. A single core lab at the University of Pittsburgh reviewed all echoes, and patients were enrolled in the trial only if they met predetermined indices for dyssynchrony. Once determined eligible, all patients underwent placement of a biventricular ICD with blinded randomization to active CRT=ON versus CRT=OFF. The primary endpoint was a composite of time to first hospitalization for heart failure or all-cause mortality over a minimum of one year. Duration of the trial was event driven and had been expected to have been completed in December 2012.
On March 13, 2013, the EchoCRT data safety and monitoring committee notified the trial sites that the trial would be terminated prematurely due to futility. There had not been a public disclosure of this news until April of this year when this was discussed in an ACC summary of the NARROW-CRT trial publication and later reported by Cardiobrief. No details of the trial results were available until this week’s report.
The Echo CRT trial enrolled 809 patients over mean 19.4 months. The composite outcome of death or heart failure admission was reached in 28.7% patients getting CRT vs. 25.2% of the blinded controls. There were 45 deaths in the CRT group and 26 in the control group. Although neither of these values reached statistical significance, it is worth noting that the trial was terminated for futility before comparative power could be reached, and the death data appears to show ongoing curve divergence upon termination of the trial. When analyzed specifically for cardiovascular death, the CRT group did have statistically significant excess death (37 vs. 17, P=0.004). None of the nine pre-specified subgroups showed benefit from CRT, and more procedural harm was demonstrated in the CRT group.
After this extremely discouraging, but well run trial, it seems unlikely that there will be a future for CRT in the narrow QRS heart failure population. Given the current strict regulatory environment, off label implants are likely to be heavily scrutinized and discouraged. It also seems unlikely that another large-scale trial in this population will be carried out.
Although the results of EchoCRT likely eliminates the promise of CRT as a primary treatment for narrow QRS systolic heart failure, the overall field of biventricular pacing continues to advance. The positive findings of the BLOCK HF trial published earlier this year may lead to an indication for CRT as a preferred pacing therapy in patients with heart block and LV dysfunction. BIOPACE has a similar design as BLOCK HF and is reported to be in follow up. In addition, the recently initiated MIRACLE EF trial will look at CRT as a primary treatment in heart failure patients with LBBB and mild LV dysfunction. The ongoing PROMPT trial is evaluating LV or biventricular pacing as a treatment to prevent adverse myocardial remodeling early after myocardial infarction.