Download Why We Respect Randomized Controlled Clinical Trials in Heart

JACC: HEART FAILURE
VOL. 3, NO. 7, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2015.05.001
EDITOR’S PAGE
Why We Respect Randomized
Controlled Clinical Trials in
Heart Failure
Christopher M. O’Connor, MD, FACC, Editor-in-Chief, JACC: Heart Failure
“A few observations and much reasoning lead
to error; many observations and a little
—Dr. Alexis Carrel,
heart failure therapy, such as phosphodiesterase in-
French surgeon and 1912 Nobel Prize
hibitors, calcium channel blockers, and the antiarrhy-
in Medicine recipient (1)
thmic agents to name a few, that resulted in increased
his month, we have learned a surprising
finding through a company press release
of the results of a large-scale clinical trial
SERVE-HF (Treatment of Predominant Central Sleep
Apnoea by Adaptive Servo Ventilation in Patients
With Heart Failure) in which the primary endpoint
of this trial was not met (2). The investigators and
sponsors had equipoise but held the common belief
in the hypothesis that active therapy for central sleep
apnea would improve clinical outcomes in heart failure patients. The rationale had been elucidated and
detailed in Phase I studies, nonrandomized registries,
cohort studies, and numerous mechanistic investigations. Small-scale randomized controlled trials
showed important positive signals on certain endpoints. However, when the trial was completed with
an appropriate sample size, meaningful endpoints
that were relevant and reproducible, and conducted
in a multicenter fashion to avoid bias, the results
were not positive. More surprisingly, there was an
adverse signal with an increased risk of cardiovascular mortality.
This was a trial that wasn’t required to be done, but
the sponsors and investigators asked an important
question and answered it with the correct equipoise.
This, of course, is not unprecedented and should
be the basis for doing important research.
When I was a resident at Duke, I remember
administering encainide and flecainide to control
post-myocardial
How could suppression of PVCs be bad?
Subsequently, we have witnessed clinical trials of
reasoning lead to truth”
T
out (3), turning the world of cardiology upside down.
infarction
premature
mortality in heart failure patients. We have also seen
the case where devices have been shown to be associated with adverse events such as the atherectomy
catheter in coronary artery disease patients, despite
better surrogate outcomes. With a device that was
believed to be as innocuous as adaptive servoventilation therapy in heart failure with reduced ejection
fraction patients showing an increased cardiovascular
mortality, it reminds us that once again pathophysiological reasoning cannot replace well-conducted,
large-scale randomized controlled clinical trials.
To this end, we must commend the sponsors, the
investigators, and most importantly, the patients for
participating and ensuring a well-conducted clinical
trial. Although the results are disappointing to all, the
findings have provided an enormous advancement in
knowledge, and allow correction of our direction and
understanding and how to pursue research in this
field going forward. I remain humbled and grateful
for the simple process of well-conducted randomized
controlled clinical trials, of which I believe there is
no greater way that we can advance our understanding of therapeutic interventions, and no better
method to correct our often overstated pathophysiologic reasoning and bias.
We need to find a way to do these trials faster,
cheaper, more efficiently, and larger: a goal our
community should be committed to accomplish.
ADDRESS FOR CORRESPONDENCE: Dr. Christopher M.
ventricular
O’Connor, Editor-in-Chief, JACC: Heart Failure, American
contractions (PVCs). Then suddenly, the CAST trial
College of Cardiology, Heart House, 2400 N Street NW,
(Cardiac Arrhythmia Suppression Trial) results came
Washington, DC 20037. E-mail: [email protected].
O’Connor
JACC: HEART FAILURE VOL. 3, NO. 7, 2015
JULY 2015:576–7
Editor’s Page
REFERENCES
1. BrainyQuote. Alexis Carrel quotes. Available at:
http://www.brainyquote.com/quotes/quotes/a/
alexiscarr158390.html. Accessed May 19, 2015.
2. ResMed Provides Update on Phase IV SERVE-HF
Study of Adaptive Servo-Ventilation Therapy.
Resmed news release. May 13, 2015. Available at:
www.resmed.com. Accessed May 19, 2015.
3. Echt DS, Liebson PR, Mitchell LB, et al.
Mortality and morbidity in patients receiving
encainide, flecainide, or placebo. The Cardiac
Arrhythmia Suppression Trial. N Engl J Med
1991;324:781–8.
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