Effect of Coenzyme Q10 on Morbidity and Mortality in Chronic Heart Failure
Introduction
Optimal treatment of heart failure (HF) remains a considerable challenge. Standard treatment approaches are designed to block cellular processes rather than stimulate them (1), making it impossible to meet some important myocardial requirements. Although HF has numerous causes, impaired bioenergetic function resulting in an energy deficit in cardiac myocytes may represent an important additional mechanism (2, 3).
Coenzyme Q10 (CoQ10) is a potent fat-soluble antioxidant (4) and a central component of the oxidation-reduction reactions of the electron transport chain and adenosine triphosphate synthesis (5). Myocardial CoQ10 levels have been found to be reduced in patients with HF, and this has been associated with worsening symptoms and left ventricular dysfunction (6). Low plasma CoQ10 has been shown to be an independent predictor of mortality in HF (7), although another observational study did not confirm this finding (8). Published meta-analyses of randomized controlled trials evaluating CoQ10 therapy in patients with HF have generally emphasized a beneficial effect on left ventricular ejection fraction, with or without improvement in New York Heart Association (NYHA) functional class (9–11).
This article presents data from Q-SYMBIO, a randomized, double-blind, placebo-controlled, multicenter trial investigating adjunctive CoQ10 therapy in chronic HF. The study focused primarily on changes in symptoms, biomarker status, and long-term outcomes.
Methods
Between 2003 and 2010, patients were invited to participate in the Q-SYMBIO trial at 17 centers in Europe, Asia, and Australia. The study was conducted in accordance with Good Clinical Practice guidelines. Previous controlled trials investigating the effects of CoQ10 therapy in HF aimed to achieve serum CoQ10 levels of at least 2 mg/ml when administering daily doses of 100–200 mg to obtain a beneficial clinical effect. CoQ10 administered at 100 mg twice daily provided better absorption and higher serum levels than a single daily dose of 200 mg, probably because of saturation resulting in delayed absorption of the substance in the small intestine (14).
In the Q-SYMBIO trial, the active-treatment group received CoQ10 at a dose of 100 mg three times daily in the form of the Bio-Quinone Q10 dietary supplement manufactured by Pharma Nord, with the aim of ensuring a significant increase in serum levels.
Clinical trial data were submitted to the Data Safety Monitoring Committee, which blindly assessed all potential adverse events in the two treatment groups. Study endpoints were assessed blindly by the Endpoint Committee. All analyses at the end of the study were performed by an independent statistician. The study was approved by the Institutional Review Board and regional ethics committee of each participating institution, as well as the relevant national ethics committees, and complied with the ethical guidelines of the Declaration of Helsinki.
The patients participating in the study were divided into two groups. One group was treated for 16 weeks. The aim was to assess patients’ symptoms according to NYHA functional class and functional status using the Visual Analog Scale (VAS), the 6-minute walk test, and echocardiographic findings. Serum samples were collected to determine CoQ10 and N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker of HF (15).
The other group was treated for 106 weeks. The aim was to investigate whether CoQ10 could reduce cardiovascular morbidity and mortality associated with HF. The endpoints in this group included VAS assessment of symptoms such as dyspnea, fatigue, and changes in symptoms. The primary long-term endpoints were cardiovascular events, comprising unplanned hospitalization due to worsening HF, cardiovascular death, implantation of a cardiac pacemaker, or the need for urgent heart transplantation. Secondary long-term endpoints included NYHA functional class, NT-proBNP, echocardiographic findings, and mortality.
Patients were eligible for the study if they had chronic HF and were classified as NYHA functional class III or IV. Patients with typical signs and symptoms of HF were also included (Table 1).
Table 1. Baseline Patient Characteristics
| Characteristic | CoQ10 Treatment (N=202) | Placebo (N=218) |
|---|---|---|
| Age, years | 62.3±12 | 62.3±11 |
| Male/female ratio | 154/48 | 151/67 |
| Weight, kg | 77.1±17 | 77.9±18 |
| BMI, kg/m² | 28±5 | 28±6 |
| Heart rate, beats/min | 80±16 | 82±14 |
| Systolic blood pressure, mm Hg | 125±18 | 122±16 |
| Diastolic blood pressure, mm Hg | 78±11 | 77±11 |
| Sinus rhythm | 148 (73) | 161 (74) |
| Atrial fibrillation | 33 (16) | 41 (19) |
| Smoking, yes (current) | 21 (10) | 16 (7) |
| Ischemic heart disease | 137 (68) | 156 (72) |
| Dilated cardiomyopathy | 54 (27) | 59 (27) |
| Valvular heart disease | 11 (5) | 3 (1) |
| Duration of HF, months | 38±47 | 35±36 |
| NYHA functional class II | 6 (3) | 8 (4) |
| NYHA functional class III | 178 (88) | 189 (87) |
| NYHA functional class IV | 18 (9) | 21 (10) |
| Left ventricular EF, % | 31±10 (10–65) | 31±10 (10–70) |
| Left ventricular EDD, mm | 66±8 | 64±9 |
| Left ventricular ESD, mm | 55±11 | 54±11 |
| 6MWT, m | 287±99 (25–525) | 286±92 (90–490) |
| Serum CoQ10, μg/ml* | 1.14±0.08 | 0.91±0.06 |
| NT-proBNP, pg/ml† | 1,883±271 (50–7,999) | 1,692±229 (50–7,735) |
| Medications | ||
| ACE inhibitor / ARB | 178 (90) | 195 (90) |
| Beta-blockers | 141 (72) | 164 (76) |
| Digoxin | 90 (46) | 97 (45) |
| Diuretics | 155 (79) | 176 (81) |
| Aldosterone antagonists | 66 (34) | 74 (34) |
| Statins | 74 (38) | 77 (35) |
| Anticoagulants | 49 (25) | 54 (25) |
| Diabetes treatment | 44 (22) | 51 (24) |
| Medical devices | ||
| Cardiac resynchronization therapy device | 2 | 5 |
| Implantable cardioverter-defibrillator | 3 | 4 |
Values are presented as mean (SD), mean ± SD (range), or n (%), unless otherwise indicated.
ACE inhibitor – angiotensin-converting enzyme inhibitor; ARB – angiotensin receptor blocker; BMI – body mass index; CoQ10 – coenzyme Q10; EDD – end-diastolic diameter; EF – ejection fraction; ESD – end-systolic diameter; HF – heart failure; 6MWT – 6-minute walk test; NT-proBNP – N-terminal pro-B-type natriuretic peptide; NYHA – New York Heart Association.
Patients who met the inclusion criteria were additionally assessed for eligibility for a 2-week run-in period, during which they received placebo capsules three times daily. Patients were evaluated at the beginning and end of this period according to NYHA functional class, VAS, the 6-minute walk test, and echocardiography. Serum samples were collected to determine CoQ10 and NT-proBNP levels. Patients receiving stable standard HF treatment were randomly assigned to parallel groups receiving either CoQ10 or identically appearing placebo capsules. The randomization sequence was generated using a random-number generator, which assigned all participants in blocks of six, with their names kept in sealed envelopes. Sequentially numbered coded medication packages were distributed to participants, and their use was supervised by the principal pharmacist at each local center, who was instructed to assign each new patient the next available randomization number.
The overview of events, with outcomes recorded for up to 106 weeks, is presented chronologically in Table 2. All patients continuously received their assigned treatment for the planned duration of the study. Once the first primary endpoint (MACE) occurred, patient outcomes were reviewed, and only the first event was included in this analysis. Following a MACE event (hospitalization for HF), patients were offered continued blinded treatment with their randomly assigned study medication for up to 2 years.
Table 2. Major Cardiovascular Events
| Endpoint | CoQ10 (N=202), n (%) | Placebo (N=218), n (%) | Total (N=420) |
|---|---|---|---|
| Death due to MI | 2 | 3 | 5 |
| Death due to HF | 1 | 10 | 11 |
| Sudden cardiac death | 9 | 13 | 22 |
| Hospitalization due to worsening HF | 12 | 24 | 36 |
| Hospitalization due to acute HF | 3 | 5 | 8 |
| Hospitalization due to acute HF and IABP | 2 | 2 | 4 |
| LVAD | 0 | 1 | 1 |
| Total | 30* | 57 | 87 |
*Values are n or n (%); p=0.005.
IABP – intra-aortic balloon pump; LVAD – left ventricular assist device; MI – myocardial infarction; HF – heart failure.
Hospitalization due to worsening HF was defined as the development of worsening symptoms requiring intravenous diuretic therapy. The need for inotropic support and an intra-aortic balloon pump was also recorded.
In the Q-SYMBIO trial, hospitalizations occurring within 30 days after randomization were not considered primary endpoints in either group. Previous observational studies had shown improvement in HF symptoms after approximately 4 weeks (up to 12 weeks) of adjunctive CoQ10 supplementation (14). It was established that increased serum levels may result in increased mitochondrial CoQ10 levels after at least 2 weeks (17). Based on this assessment, a 30-day observation period was considered appropriate. Other studies investigating HF have also included an early quarantine period (16). All potential adverse events were monitored from the beginning of the study.
Measurement of Serum Coenzyme Q10 and NT-proBNP
To measure serum CoQ10 and NT-proBNP levels, a 25 ml venous blood sample was collected while patients were at rest and before breakfast and medication administration. Serum was separated from the blood samples by centrifugation at 3,000 g and subsequently stored at –20 °C or –80 °C for storage periods exceeding 6 months. Serum samples were analyzed to determine CoQ10 levels using high-performance liquid chromatography with ultraviolet detection (18) and NT-proBNP using the Elecsys 2010 immunoassay (Roche Diagnostics Mannheim, Germany) (19).
Statistical Analysis
The results of the calculation protocols are presented in Table 3. All prespecified response analyses and endpoints were assessed according to the intention-to-treat principle. Descriptive analyses of baseline data were reported as frequencies. Categorical data were reported as percentages, while continuous data were reported as mean and standard deviation for normally distributed data and as median with lower and upper quartiles for non-normally distributed data.
All responses from the health status questionnaires and blood sample results obtained at 16 and 106 weeks were analyzed as individual changes from baseline. The significance of treatment effects on continuous responses was analyzed using a linear model in which each study center was treated as a random variable. Treatment effects were also analyzed and adjusted for predefined confounders, including age, sex, NYHA functional class, diagnosis at inclusion (HF due to ischemic heart disease or dilated cardiomyopathy), and center.
To assess treatment effects on categorical responses, the chi-square test of independence with exact p values was used. Cumulative incidence curves assessing the risk of hospitalization due to HF, cardiovascular mortality, and all-cause mortality were constructed using the Kaplan-Meier method and analyzed using a Cox proportional hazards regression model stratified by center.
Following the intention-to-treat analysis, an additional sensitivity analysis was performed. For the primary endpoint, a worst-case scenario was used, assuming that patients assigned to the intervention group whose data were censored experienced a MACE because they were no longer followed, whereas patients receiving placebo did not experience such events. The hazard ratio (HR) was adjusted in MACE subanalyses. These analyses were stratified according to risk factors present at baseline, and treatment-by-factor interaction tests were performed. Adverse event rates between treatment groups were compared using the chi-square test of independence with exact p values.
For the primary efficacy variables in the short-term phase, the study was considered to have achieved its prespecified objective if the between-group difference was p≤0.05 for all three endpoints. For the primary endpoint in the long-term phase, the study was considered to have achieved its prespecified objective if the between-group difference was p<0.05. For secondary endpoints, statistical significance was defined as p<0.05. All data were analyzed using Stata/SE 11-2 statistical software for Windows (StataCorp LP, College Station, Texas).
Results
A total of 420 patients were randomly assigned to active treatment with CoQ10 (N=202) or placebo (N=218). Thirty-six patients withdrew from the study (22 patients from the CoQ10 group and 14 patients from the placebo group). Analysis of the reasons for withdrawal revealed no significant difference between the groups (p=0.118). By the end of the study, outcome status was known for all patients except four in each treatment group, whose data were classified as lost to follow-up.
Baseline Characteristics of the Study Population
The baseline characteristics of both groups, determined after the 2-week run-in period, were similar (Table 1). The mean duration of HF in both groups was approximately 3 years, while the mean baseline left ventricular ejection fraction of 31% and the distances covered during the 6-minute walk test were similar in both groups. Standard HF treatment in the study groups was established at the beginning of treatment. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were prescribed to 90% of these patients, while 75% of patients received evidence-based doses of beta-blockers. Doses were rarely changed throughout the study, making it unlikely that minor changes could have influenced differences in the parameters.
Within 30 days after randomization, 2 of 4 patients experienced unplanned hospitalizations due to HF. No deaths were recorded in either group during this period.
Effect on Prespecified Endpoints at Week 16
At week 16, improvements in NYHA functional class, VAS scores, and 6-minute walk test results were observed in both treatment groups, with no statistically significant difference between the groups. There were no significant differences in heart rate, blood pressure, or echocardiographic measurements.
At week 16, serum CoQ10 levels increased significantly in the CoQ10-treated group and were approximately three times higher than at baseline. Significant changes from baseline in serum NT-proBNP levels were observed between the groups at week 16. In the CoQ10 group, there was a trend toward a mean NT-proBNP reduction of 384 pg/ml (20%), whereas in the placebo group there was a proportional increase in NT-proBNP of 199 pg/ml (12%).
Effect on Prespecified Endpoints at Week 106
Compared with the placebo group, fewer MACE events were recorded in the CoQ10 group at week 106 (57 [26%] vs. 30 [15%], respectively). This represents a relative reduction of 43% in such events (p=0.005, Fisher’s exact test) (Table 2). According to Cox regression analysis, compared with the placebo group, the rate of HF events in the CoQ10 group was 0.50 (95% confidence interval [CI]: 0.32–0.80; p=0.003).
Effect on Prespecified Secondary Endpoints at Week 106
Compared with the placebo group, at week 106 the CoQ10 group had a greater number of patients with an improved NYHA functional class (N=68, 45% and N=86, 58%, respectively; p=0.028). Thus, functional class improved by at least one NYHA level. No major differences in echocardiographic measurements were observed between the groups.
Compared with baseline values, which did not differ substantially between the groups, serum NT-proBNP levels decreased by a mean of 1,137 pg/ml (60%) in the CoQ10 group and by a mean of 881 pg/ml (52%) in the placebo group.
Discussion
Results from studies investigating CoQ10 therapy in HF have been accumulating since the late 1980s. However, these studies were not sufficiently robust to allow assessment of major endpoints.
Q-SYMBIO was the first sufficiently comprehensive study in which an appropriate dose of CoQ10 was administered and adequate follow-up was conducted to assess the efficacy of CoQ10 in HF and HF-related mortality.
Despite substantial advances in the medical treatment of HF, CoQ10 supplementation in our study markedly reduced the incidence of MACE and cardiovascular death by 43%, while all-cause mortality was reduced by 42%. In addition, after 2 years, CoQ10 supplementation improved patients’ symptoms according to NYHA functional classification.
The dose and formulation of CoQ10 selected for the Q-SYMBIO study produced therapeutic CoQ10 levels in serum and tissues (17), which were necessary to achieve a beneficial effect on MACE. In addition to the higher CoQ10 dose, the Bio-Quinone Q10 supplement manufactured by the Danish company and used in controlled trials demonstrated good bioavailability (20, 21).
Over 16 weeks, we observed a small decrease in NT-proBNP levels in the CoQ10 group. After 106 weeks, compared with baseline, NT-proBNP concentrations increased by more than half in both groups; this finding may indicate that patients with the most severe symptoms had the highest NT-proBNP levels. Monitoring NT-proBNP may be an important tool for ensuring the clinical stability of outpatients with HF (15).
Meta-analyses of studies investigating CoQ10 therapy have demonstrated a small but significant improvement in left ventricular ejection fraction (9–11). Changes in other parameters, such as improved exercise capacity, observed in studies of CoQ10 therapy were modest, as demonstrated in a Scandinavian crossover study comparing 100 mg CoQ10 with placebo (25). Nevertheless, the increase in exercise capacity observed with CoQ10 treatment was of a similar magnitude to that reported in earlier trials of angiotensin-converting enzyme inhibitors (26).
In the largest 1-year Italian study conducted in 1993, the CoQ10 dose was 50 mg two to three times daily, depending on the patient’s weight. Compared with the placebo group, fewer patients in the CoQ10 group were readmitted because of progressive HF, and fewer patients in the CoQ10 group died (N=21 and N=16, respectively), although the difference was not statistically significant (27).
In HF, CoQ10 treatment may interrupt the adverse metabolic cycle (30) by favorably modifying redox processes. In addition, CoQ10 treatment may improve stabilization of mitochondrial permeability and protect myocardial cells from loss through apoptosis (28). CoQ10 has also been shown to improve endothelial function (31), which may protect the myocardium from ischemia (17). High levels of reactive oxygen species resulting from oxidative stress in HF increase the need for antioxidants (32). This may compromise the role of CoQ10 in the respiratory chain and ultimately explain the low levels of this substance in the myocardial tissue of patients with HF (6).
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) block the mevalonate pathway and thereby inhibit both cholesterol and CoQ10 synthesis (33, 34). Additional CoQ10 supplementation in patients with HF who are taking statins, as well as pre-existing CoQ10 deficiency, may therefore be an important consideration and, at least theoretically, may contribute to the neutral results of randomized controlled trials of statin therapy in HF (6).
Endogenous CoQ10 synthesis declines with age, and elderly patients may therefore benefit from supplementation with this substance (35). A 5-year randomized, double-blind, placebo-controlled trial involving healthy elderly individuals investigated supplementation with CoQ10 and selenium, which was associated with reduced cardiovascular mortality (36).
Many patients with HF are debilitated by defects in substrate utilization and the energy supply chain (37, 38). Because current medications used to treat HF cannot replace essential micronutrients, possible deficiencies of these substances may contribute to symptoms and poorer survival in HF (29). Several abnormalities may be present, and additional studies may therefore be required to comprehensively investigate the molecular causes of HF.
Summary
Our results demonstrate that, in patients with moderate to severe HF, CoQ10 therapy added to standard treatment is safe, well tolerated, and associated with symptom improvement and a reduction in MACE.
Source: Internistas, No. 10
