Does Coenzyme Q10 Have the Energy to Change Heart Failure Therapy?

Could a nutritional supplement be the “magic bullet” in heart failure therapy?  Coenzyme Q10 (CoQ10), or ubiquinone, is an electron carrier in mitochondria and plays a key role in ATP synthesis. It is also thought to have antioxidant effects and may stabilize LDL molecules. All of which would, theoretically, help the failing heart.^1-3

Previous studies using CoQ10 in HF have suggested it may, indeed, have clinical benefits.^4-6 Several meta-analyses have reported that CoQ10 improves ejection fraction (EF), but this benefit was largely seen in patients who were not using an angiotensin-converting enzyme inhibitor (ACEI) and in patients with less advanced HF.^5,7-8  Further, CoQ10 has also been reported to improve exercise capacity, which is considered a predictor of positive prognosis.⁹  Most trials had small sample sizes and did not provide data regarding mortality and cardiovascular event rates.⁷   Given the limitations of these trials, few can agree if and when CoQ10 should be used. Many have raised significant concerns that the observed benefits may be overestimated.

Current HF guidelines note that some evidence exists to suggest that CoQ10 may reduce hospitalization, dyspnea, and edema.  However, given the inconsistency of the evidence, the American College of Cardiology and American Heart Association recommend against the routine use of nutritional supplements for the management of HF.¹⁰

The Q-SYMBIO trial sought to study the effects of CoQ10 supplementation in the setting of chronic HF – not only its impact on symptoms but also biomarkers and long-term cardiovascular outcomes. The study was a randomized, prospective, double-blind, placebo-controlled, multicenter trial that enrolled patients 18 and older with NYHA functional class II – IV HF resulting from ischemic heart disease, dilated cardiomyopathy, or valvular heart disease.  Patients were included if they were on “appropriate medical treatment for HF” which was defined as a diuretic, ACEI or angiotensin-receptor blocker (ARB), beta-blocker, aldosterone antagonist, and digoxin at stable doses for at least one month prior to study enrollment.  Major exclusion criteria included myocardial infarction, unstable angina, percutaneous coronary intervention, cardiac resynchronization device, cardiac surgery, or stroke in the prior 6 weeks, congenital heart disease, implanted mechanical assist devices, inotropic support, and those with anticipated problems with adherence.

This trial was divided into two phases in which specific endpoints were assessed at 16 and 106 weeks.  The primary short-term 16-week endpoints were NYHA functional class, 6-minute walk test, and NT-proBNP.  The primary long-term 106-week endpoint was a composite of major adverse cardiovascular events (MACE), consisting of unplanned hospital stay due to worsening HF, cardiovascular death, mechanical assist implantation, or urgent cardiac transplantation.  The primary outcome was analyzed using a time to first event analysis.  Secondary long-term outcomes included NYHA functional class, NT-proBNP, echocardiography, and all-cause mortality.   All patients completed a 2-week run-in period with placebo prior to randomization.

The Q-SYMBIO study enrolled 420 patients from 17 centers between 2003 and 2010.  Patients were randomly assigned to CoQ10 (N=202) 100 mg three times daily or placebo (N=218).  Of note, Q-SYMBIO did not reach target enrollment of 550 participants. Baseline characteristics between the groups were similar. The majority of patients were classified as NYHA functional class III (88%), treated with an ACEI or ARB (90%), and receiving a beta-blocker (75%) at baseline.  A significant proportion (34%) were taking an aldosterone antagonist.  The “average” patient in the study was approximately 62 years old, had a mean duration of HF of roughly 3 years, and a mean left ventricular ejection fraction (LVEF) of 31%.  The trial did not exclude patients with HF with preserved ejection fraction (HFpEF) but only 7% of the study participants had an EF > 45%. 

After 16 weeks, no statistically significant differences in the short-term endpoints were noted. At 106 weeks there was a significant improvement in NYHA functional class by at least one grade in 58% of participants receiving CoQ10.  In addition, there was a 43% relative reduction in the primary outcome (HR 0.5; 95% CI 0.32-0.80, P=0.003) in the CoQ10 group compared with placebo.  After two years of follow-up, hospital stays for HF, cardiovascular death, and all-cause mortality were also significantly reduced in the CoQ10 group.  Changes in echocardiographic parameters and NT-ProBNP were not statistically different.  The authors noted a lower incidence of adverse effects in the CoQ10 group (13% vs. 19%) but this was not statistically different.

Such robust findings demonstrating significant reductions in cardiovascular outcomes in the setting of a double-blind RCT are certainly promising.  BUT several issues must be considered prior to directing all HF patients to their local OTC aisle. First, the relatively small population size raises concern about reproducibility and generalizability.   Although the authors attribute slow enrollment to lack of funding and competition for enrollment with other large RCTs, the difficulties with recruitment over a seven-year period were not discussed in detail. While the authors claim that CoQ10 is “safe and well-tolerated,” the small study population makes elucidation of safety and the potential for infrequent but serious adverse effects with more widespread use difficult to discern.

Surprisingly, patient race was not reported, which makes examining the study results in specific patient populations impossible.  African Americans have the highest HF prevalence and age-adjusted incidence of developing HF compared with Hispanic, Caucasian, and Chinese Americans.¹¹ Subgroup analysis stratified by race would have been helpful to more clearly understand the benefit of CoQ10 on MACE in specific patient populations.  Moreover, given that CoQ10 is found in a variety of common foods (i.e. meat, fish, some oils), evaluation of dietary intake through a food frequency questionnaire may have been helpful in determining potential interactions between diet and the outcomes studied.¹² Perhaps advising patients to improve dietary intake of CoQ10-rich foods would provide the same benefits without requiring supplementation. 

The fact that CoQ10 is not regulated as a pharmaceutical agent is a practical obstacle to its widespread use.  There are inconsistencies in the amount of active ingredient in neutraceuticals and this may lead to inconsistent benefits. Further, while CoQ10 is a nonprescription product, it is not necessary inexpensive. Procurement of CoQ10 at study doses from reputable sources costs approximately $50 per month without insurance.¹³ Additionally, in patients already on complex regimens requiring strict adherence to evidence based medications, is the addition of another medication which must be taken three times daily feasible?  Unfortunately, there is little incentive for funding from pharmaceutical companies to development a prescription product or for additional large-scale RCTs to be completed.   

Although the authors of Q-SYMBIO indicate that HF medications were utilized at “evidence-based” doses, the actual doses were not reported.  The mean heart rate (HR) in the Q-SYMBIO trial was approximately 80 beats per minute (BPM), similar to the baseline HR in the COMET trial prior to initiation of beta-blocker therapy.¹⁴  COMET reported an average reduction in HR of 12 to 13 BPM in the carvedilol and metoprolol groups after four months of treatment.   Additionally, baseline use of evidence-based therapies such as beta-blockers and aldosterone antagonists were considerably lower than in other contemporary HF trials.¹⁵ Use of ICDs at baseline was also low in this trial (3%), especially given most patients were classified as class III-IV HF with an average EF approximately 31%.  Therefore, it is unclear at present whether established therapies were appropriately utilized and titrated, which may have impacted mortality outcomes in the Q-SYMBIO trial.¹⁵  While the majority of patients were classified with NYHA class III at baseline, the authors later report that HF severity may have been overestimated. 

Lastly, current evidence-based treatment guidelines differ significantly in their recommendations for pharmacotherapy in HFrEF vs. HFpEF.  However, no differentiation was made between these patients in Q-SYMBIO.  As patients were not stratified based on baseline EF, it is unclear whether a similar benefit from CoQ10 was seen in both preserved and reduced EF.

So where does this leave us? Should the results of the Q-SYMBIO trial add CoQ10 to the list of evidence-based therapies that most patients with HFrEF should receive? What do you think? The results of this study are certainly compelling, but its limitations beg the question whether Q-SYMBIO has the energy to influence clinical practice guidelines.