More than a decade after reporting that cardiac resynchronization therapy (CRT) — with either a pacemaker or defibrillator — lowered death rates in patients with heart failure, the investigators behind COMPANION shared the lessons they learned from that trial.
Michael Bristow, MD, PhD, of University of Colorado Hospital in Aurora, and colleagues, in an article online in JACC: Heart Failure, broke down the challenges that almost derailed their randomized controlled trial.
“Moving forward, collaborations with trialists, patients, clinical experts, device manufacturers, and regulatory bodies may broaden our quest to apply the lessons learned from COMPANION to the evolution of a nimble and adaptable cardiovascular device clinical trial paradigm which values transparency both from external validation of results as well as honest reporting of challenges faced by trial insiders,” noted Emily P. Zeitler, MD, and Eric D. Peterson, MD, MPH, both of Duke University Medical Center, in an accompanying editorial.
Lesson #1: Anticipate Patient Withdrawal
“One of the major challenges to successful completion of COMPANION was FDA approval of both [pacemaker and defibrillator] devices during the trial … The impact of these approvals was that recruitment for COMPANION was slowed in mid-2001, decreasing from a peak of 100 patients/month to less than 10 patients/month by mid-2002.”
Importantly, this meant more crossover from the medical therapy control arm to receive the approved devices and a differing patient withdrawal rate among the study groups — ultimately, the control group was followed at least 4 months shorter than the CRT comparators, according to Bristow’s group.
“The lesson here is that consent forms can be constructed prospectively to deal with various levels of withdrawal, obviating the need to re-consent,” they suggested.
To mitigate uneven withdrawal rates among participants, “a three part document can and should be structured for different levels of withdrawal, i.e. from the intervention only but continuing in the trial for full follow-up, from the intervention and study visits but allowing subsequent patient or family contact for determination of vital status or other important clinical events, and complete withdrawal with no further contact by study personnel.”
Lesson #2: Stay Vigilant For Safety
Early days of the COMPANION trial saw many inexperienced operators placing the left ventricular lead through the coronary sinus, causing various adverse events.
The Steering Committee resolved the issue by recommending “additional training in the Sponsor’s laboratories, increased proctoring of cases performed by first time implanting physicians, and limitations on procedure duration,” the authors wrote. “The alertness of the Data and Safety Monitoring Committee and the Sponsor to early operational issues was important to the successful completion of the trial, which would have been discontinued if the serious adverse event rate had not been brought quickly down to acceptable levels.”
Lesson #3: The Event Rate Is Key…
“A major reason for COMPANION’s success was the very high event rate for the primary and other composite mortality/hospitalization endpoints,” according to its investigators.
“An event rate for all-cause mortality or hospitalization as high as COMPANION’s, 67.5% at 12 months in the optimal pharmacological therapy alone group, is somewhat remarkable and indicates that the protocol was able to identify an advanced heart failure with reduced ejection fraction [HFrEF] population at high risk for morbidity and mortality, and that the investigators adhered to the protocol.”
COMPANION included 1,634 patients with advanced chronic heart failure and QRS lasting greater than 120 ms.
Lesson #4: … So Pick Your Patients Carefully
Bristow and colleagues emphasized “the successful selection of a HFrEF subpopulation expected to be more responsive to the tested intervention.”
“If COMPANION had been conducted in a generalized HFrEF population without the lengthened QRS inclusion criterion it almost certainly would have been a negative trial,” they wrote. “Enrichment of clinical trial populations through the use of biomarkers that identify responsive subpopulations is something that is highly desirable but difficult to attain, and COMPANION and CARE-HF demonstrate that this approach can be successful.”
The trial was funded by Boston Scientific.
Bristow, Zeitler, and Peterson declared no relevant conflicts of interest.
JACC: Heart Failure
Bristow MR, et al “Lessons learned and insights gained in the design, analysis and outcomes of the COMPANION trial” JACC Heart Fail 2016.
JACC: Heart Failure
Zeitler EP and Peterson ED “Promoting transparency in trials: lessons from the COMPANION investigators” JACC Heart Fail 2016.