Author + information
- Justin A. Ezekowitz, MBBCh, MSc∗ ()
- ↵∗Division of Cardiology, Department of Medicine, University of Alberta, 2-132 Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta T6G 2E1, Canada
Dr. Mortensen raises a number of points that need clarification and context.
First, the references to current therapeutics (angiotensin-converting enzyme inhibitor and beta-blocker) success in smaller clinical trials are taken out of context. A practice change and recommendations occurred after the confirmatory adequately powered randomized controlled trials (RCTs) were complete. Other therapies have not made it by this necessary hurdle as a result of lack of efficacy or safety. On the basis of Dr. Mortensen’s rationale, many nonefficacious and potentially toxic medications would be on the market and in patient pill bottles had the adequately powered RCT not been done.
Second, although promising, safety is not established (1). Lack of reporting to regulatory authorities does not mean lack of safety events, because coenzyme Q10 (CoQ10) is not subject to any rigorous reporting such as post-marketing surveillance. Clinical trials are only 1 method to review safety and an imperfect one given the narrow inclusion and broad exclusion criteria. In the PubMed search of the same articles mentioned, which includes many single-arm noncontrolled studies, safety assessment is of mixed reporting quality.
Third, other nonpatentable intervention trials have been completed and successfully changed clinical practice, so as originally stated, it behooves the clinical and scientific community to seek appropriate funding for the adequately powered RCT. Much like the trials of statins that were said to be “unethical” because of fixed beliefs that statins improve outcomes in patients with HF, it was ethical, and statins did not reduce clinical events (2). Perhaps the ethical dilemma of recommending a therapy without proven benefit outside of the context of clinical research should be considered.
Fourth, the trial was not about supplementing a “deficiency” because the inclusion criteria did not require a baseline CoQ10 level to be below a set threshold (3). Any statements to the contrary are not supported by data.
Finally, the authors should be cautious of overestimation for trials that are truncated, especially when there are fewer than 200 events, as this can lead to a large overestimation of efficacy (4). Indeed, the Q-SYMBIO trial (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/mortality]) was truncated at 420 of 550 expected patients, interestingly without data safety and monitoring board involvement. Thus, in the current example and using the data from the only other trial in patients with HF reporting all-cause mortality to 1 year, we have <100 events in ∼1,000 patients—too few for definitive guidance for our patients and clinicians. We should not drop the rigor of the scientific process to accommodate a new pharmacological agent, no matter how appealing.
- American College of Cardiology Foundation
- Ezekowitz J.A.
- Krum H.,
- McMurray J.J.
- Mortensen S.A.,
- Rosenfeldt F.,
- Kumar A.,
- et al.