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Claxton L, Simmonds M, Beresford L, et al. Coenzyme Q10 to manage chronic heart failure with a reduced ejection fraction: a systematic review and economic evaluation. Southampton (UK): NIHR Journals Library; 2022 Jan. (Health Technology Assessment, No. 26.4.)

Cover of Coenzyme Q10 to manage chronic heart failure with a reduced ejection fraction: a systematic review and economic evaluation

Coenzyme Q10 to manage chronic heart failure with a reduced ejection fraction: a systematic review and economic evaluation.

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Chapter 1Background

Chronic heart failure

Chronic heart failure (CHF) is a significant and growing health-care challenge, as increasing numbers of people live longer and survive ischaemic heart disease. In high-income countries, 10–15% of individuals over the age of 75 years suffer from the disorder1,2 and, despite substantial improvement over the last two decades,3,4 overall prognosis remains poor. Disease morbidity and mortality are high, with a 5-year survival rate of 25% after hospitalisation for heart failure with a reduced ejection fraction (HFrEF).5 Those living with CHF may experience persistent shortness of breath, ankle swelling, tiredness, frequent stays in hospital and reduced quality of life (QoL), as well as a shorter life expectancy.

Chronic heart failure accounts for a large proportion of UK hospital admissions (2% of bed-days and 5% of emergency admissions)6 and an NHS annual spend of around £2.3B.7 The King’s Fund has identified heart failure as an ambulatory care-sensitive condition, where effective primary care interventions could avoid hospitalisation, have significant benefit on patients’ QoL and reduce service costs.8 There is, therefore, an unmet and increasing need for effective therapies both to improve health and well-being and to help keep patients out of hospital and reduce the economic burden on health-care systems. To achieve comprehensive coverage of the at-risk population and to maximise both clinical effectiveness and cost-effectiveness, new treatments should be easy to deliver in primary care settings and be acceptable and safe in a broad spectrum of patients, including the elderly and those with multiple comorbidities.

Heart failure and coenzyme Q10

Heart failure is characterised by cardiomyocyte energy depletion9 due to mitochondrial dysfunction10 and adenosine triphosphate depletion,11 leading to abnormal calcium handling and impaired contractile function.12 Coenzyme Q10 (co-Q10) is an endogenous, vitamin-like, fat-soluble quinone found in high concentrations in myocardium, liver and kidney mitochondria. It is an electron carrier crucial to mitochondrial adenosine triphosphate production13 and has antioxidant14,15 and anti-atherogenic properties.16 Natural production of co-Q10 peaks in a person’s twenties, thereafter declining with increasing age. Cardiomyocytes in patients with heart failure are deficient in co-Q10,17,18 and low myocardial and/or circulating levels are associated with worse symptoms1921 and poorer heart function,22 although there is inconsistency of effect of low circulating levels on prognosis.2224 A common but infrequently recognised feature of heart failure is micronutrient deficiency25 and the use of co-Q10 in practice may be as a single supplement or as part of a multi-micronutrient supplement.

It has been shown that oral co-Q10 supplementation (up to 300 mg/day) leads to increased serum and myocardial levels,21 but it is uncertain whether or not this increase in levels translates to clinical benefit. Co-Q10 is not available on prescription in the UK, but it can be bought over the counter.

Statins and coenzyme Q10

Statins block the production of both cholesterol and co-Q10, and there is some evidence that statin use reduces serum levels of co-Q10.26,27 Although younger and healthier statin users appear to tolerate this depletion, it has been suggested that when this happens in CHF patients, it worsens myocardial function. Should this be the case, patients using statins may face competing risks and benefits and have a greater capacity to benefit from co-Q10.

There is divided opinion on the clinical effectiveness and potential role of co-Q10 in treating CHF. At one extreme, it has been suggested that adjunctive co-Q10 is essential for those receiving statins and that this should be noted in US black-box labelling.28 By contrast, current National Institute for Health and Care Excellence (NICE) guidance actively lists this as a ‘do not do’ (i.e. do not offer co-Q10 or vitamin D to increase adherence to statin treatment).6 Existing research evidence is inconclusive.

Existing clinical trial and systematic review evidence

Early uncontrolled studies suggested beneficial effects on left ventricular ejection fraction (LVEF), exercise tolerance and symptoms, at a variety of doses.25,29,30 Most randomised trials of co-Q10 have been small, reported surrogate outcomes and had mixed results. Recent systematic reviews of single co-Q10 supplementation have been limited by the nature and incompatibility of the reported data.

A systematic review reported by Fotino et al.,31 which included 13 randomised controlled trials (RCTs) and 395 participants, reported a 3.7% mean net increase in LVEF [95% confidence interval (CI) 1.60% to 5.74%] and a –0.3 mean change in New York Heart Association (NYHA) class (95% CI –0.66 to 0.06). A Cochrane review published in 2014,32 which included seven RCTs and 914 participants, was able to analyse only LVEF and exercise capacity owing to incomplete reporting in trial publications. It found no clear effects, concluding that ‘there is no convincing evidence to support or refute the use of co-Q10 for heart failure’.32 Neither of these reviews included the more recently published Q-SYMBIO trial33 (420 participants), which reported a halving of all-cause risk of death [hazard ratio (HR) 0.51, 95% CI 0.30 to 0.89]. A more recent systematic review, published in July 2017,34 of 14 trials and 2149 participants, did include the Q-SYMBIO trial. This systematic review34 reported a significant reduction in mortality [relative risk (RR) 0.69, 95% CI 0.50 to 0.95] and an improvement in exercise capacity, but also stated that, owing to limitations, further trials were needed.34 Another systematic review,35 of 16 trials and 1662 participants, also reported a significant reduction in mortality (pooled HR 0.62, 95% CI 0.40 to 0.95), as well as reduced hospitalisation (HR 0.39, 95% CI 0.29 to 0.53).35 A more recent review36 of nutraceuticals (which did not include a meta-analysis) concluded that there was insufficient evidence to demonstrate the efficacy of co-Q10.36 None of these systematic reviews was able to explore potential effect modifiers, such as the use of statins.

Rationale

Despite a long history, and therapeutic promise, there is considerable uncertainty about the effectiveness of co-Q10 in CHF. Most trials have been small, and systematic reviews have been limited by incomplete reporting and data limitations. As co-Q10 is classed as a nutritional supplement and is not subject to the same regulatory processes as pharmaceuticals, some trials have not undergone the same independent scrutiny as for licensed medicines. Publication bias may be substantial.

The planned individual participant data (IPD) meta-analysis would have provided an opportunity to collect unreported outcomes and data from participants excluded from published analyses,37 support time-to-event analyses38 and model covariate treatment interactions, as well as enable robust independent scrutiny of the existing trial evidence. However, despite considerable effort, insufficient IPD were available from trial investigators to support an IPD meta-analysis.

Therefore, we undertook the meta-analysis using aggregate data. Although previous systematic reviews exist, we improved on these by bringing them up to date, incorporating additional aggregate data derived from the IPD that were obtained and completing additional analyses, including comparing estimates of effectiveness in people taking statins with those in people not taking statins.

To the best of our knowledge, there was no existing economic evaluation of co-Q10 in CHF and so there was a need to explore whether or not prescription of co-Q10 could be cost-effective.

Copyright © 2022 Claxton et al. This work was produced by Claxton et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.
Bookshelf ID: NBK577336

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