Updated Analyses and Insights from Cardiac Resynchronization Therapy Clinical Trial

Cardiac Resynchronization Therapy Pacemaker vs Medical Therapy
Cardiac Resynchronization Therapy Pacemaker vs Medical Therapy
Updated analyses and insights from the first cardiac resynchronization therapy-heart failure mortality/morbidity trial comparing defibrillator or pacemaker with pharmacologic therapy alone.

Investigators of the COMPANION (Comparison of Pharmacologic Therapy, Pacing, and Defibrillation in Heart Failure) trial recently reported updated analyses and insights from their experience in JACC: Heart Failure.

COMPANION was the first cardiac resynchronization therapy-heart failure mortality/morbidity controlled trial that compared resynchronization therapy delivered via biventricular pacemaker or defibrillator device with optimal pharmacologic therapy alone.

The trial was a collaboration between heart failure clinicians and electrophysiologists. They noted that the trial was not blinded due to ethical concerns related to the implantation of a nonfunctional pharmacologic device for at least 1 year in the optimal pharmacologic therapy arm.

Patients who were included had advanced chronic heart failure with QRS prolongation ≥120 ms and reduced left ejection fraction (HFrEF). They were classified as New York Heart Association Class III or IV and had an average 6-minute walk test of 262 meters.

Time to first occurrence of the composite of all-cause mortality and all-cause hospitalization or its equivalent served as the primary outcome.

“The conduct of COMPANION was challenged by important issues that arose during the trial, the most important of which was FDA approval of cardiac resynchronization therapy devices,” researchers explained. “Hypothesis-generating new findings are that in patients receiving beta-blocker therapy the mortality reduction advantage of cardiac resynchronization therapy-defibrillator vs cardiac resynchronization therapy-pacemaker may be minimized or eliminated, and that there may be adverse effects of cardiac resynchronization therapy-defibrillator shocks on pump failure-related outcomes.”

During the course of the trial, the US Food and Drug Administration (FDA) approved cardiac resynchronization therapy devices, both in pacemaker and defibrillator form. These approvals slowed down the enrollment for COMPANION, as well as a higher crossover rate in the optimal pharmacologic therapy arm to receive one of the approved devices.

As the crossover rate increased, the Steering Committee, trial sponsor (Boston Scientific), and FDA attempted to enforce a particularly strict regulatory practice to curb withdrawals. Instead, the practice actually increased incentive for withdraw consent prior to crossover. Therefore, the primary outcome could not be obtained for subsequent follow-up.

“The lesson here is that consent forms can be constructed prospectively to deal with various levels of withdrawal, obviating the need to re-consent,” researchers wrote. “A 3-part document can and should be structured for different levels of withdrawal.”

However, they conceded that this issue could not have been prevented by traditional means because the first device was introduced by a competitor. “Possible solutions for this dilemma in future trials include competing sponsors cooperating in ‘multi-arm’ trials deploying devices from each sponsor that would share a control group and regulatory solutions, such as FDA delaying approval based on surrogate markers if a clinical end point driven Phase 3 trial with the same or a comparable device is underway.”

In November 2015, investigators released what they consider the final updated database and study results. The optimal pharmacologic therapy alone group had a primary end point event rate above the predicted rate (67.5% vs 40%) and a secondary end point rate of all-cause mortality less than expected (18.5% vs 24%). After the entire trial event rates were normalized to 12 months follow-up, however, all-cause mortality was 25%. The effect sizes for the primary end point were somewhat less as well, in both device arms (18 to 19% vs 25%), but the all-cause mortality was greater in the cardiac resynchronization therapy defibrillator arm than predicted (36% vs 25%).

“In terms of statistical power, for the primary end point slightly lower than expected effect sizes were balanced by a higher than expected control arm event rate leading to a slightly higher than expected absolute event rate reduction in both device arms,” researchers wrote. “For the all-cause mortality secondary end point a slightly lower than expected optimal pharmacologic therapy arm 12-month event rate was overcome by a higher than expected effect size in the cardiac resynchronization therapy defibrillator arm.”

In the cardiac resynchronization therapy defibrillator vs optimal pharmacologic therapy comparisons, the primary end point and mortality were significant (P=.014 and P=.003, respectively). In the cardiac resynchronization therapy pacemaker arm vs optimal pharmacologic therapy comparisons, the primary outcome was also significant (P=.016) but with mortality having a non-significant beneficial trend (P=.059).

Additionally, investigators analyzed the affects of taking multiple neurohormonal inhibitors, which was defined as a regimen of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) plus a beta-blocker. Both devices were deemed highly effective in the presence of these standard HFrEF pharmacologic classes with “hazard ratios numerically lower and effect sizes that were higher than the entire cohort.” In addition, in a subpopulation of patients who received “triple neurohormonal inhibitors” (ACEI/ARB plus beta-blocker and spironolactone), mortality end points and cardiovascular hospitalization and mortality were even lower (56% mortality in the defibrillator group alone).

“That is, cardiac resynchronization therapy may be more effective on a background of maximal neurohormonal inhibitors than in the absence of such therapy,” the authors noted. “The most general explanation for this is that cardiac resynchronization therapy is operating through a mechanism separate from neurohormonal inhibitors, and its effects are therefore additive.”

Investigators concluded that the “COMPANION indication” (ie, the FDA-approval of the device for both intermediate functional outcomes and mortality plus hospitalization for any cause and mortality) is for HFrEF patients with the specific COMPANION inclusion criteria who remain symptomatic despite stable, optimal pharmacologic therapy.

They added that current optimal therapy may need to be revised to include ivabradine for patients on beta-blockers with persistently higher heart rates or sacubitril-valsartan instead of an ACEI, but neither agent should compromise cardiac resynchronization therapy effectiveness.


Bristow MR, Saxon LA, Feldman AM, Mei C, Anderson SA, DeMets DL. Lessons learned and insights gained in the design, analysis, and outcomes of the COMPANION trial. JACC Heart Fail. 2016. doi:10.1016/j.jchf.2016.02.019.