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.
577
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.
577
