Title: Evaluation of Coenzyme Q10 (c0-Q10) in Chronic Heart Failure (CHF): An international collaborative systematic review and individual participant data meta-analysis (IPD-MA) with linked economic evaluation and value of information (VOI) analysis
Funder: Department of Health and Social Care

Abstract: DESIGN Systematic review (SR) and individual participant data meta-analysis (IPD-MA), decision model and value of information (VOI) analysis. HEALTH TECHNOLOGIES BEING ASSESSED Coenzyme Q10 (Co-Q10) singly and combined in multi micronutrient preparations. TARGET POPULATION Adult patients diagnosed with chronic heart failure (CHF). BACKGROUND Chronic heart failure (CHF) currently affects around a million individuals in the UK and has significant impact on NHS budget costing c. £2.3 billion annually. Myocardial co-enzyme Q10 (Co-Q10 ) depletion is a potential mechanism in the development and progression of CHF. Statins block the bio production of both cholesterol and Co-Q10 and there is some evidence that statin use reduces serum levels of Co-Q10. There is divided opinion about whether Co-Q10 should be given routinely to statin users. There is some research evidence that Co-Q10 supplementation improves functional outcomes in patients with CHF but limited evidence of impact on major cardiovascular events or mortality. Existing systematic reviews of aggregate data have been inconclusive and unable to explore potential effect modification by factors such as comorbidity or statin use. IPD-MA SR elements will follow CRD guidance and the IPD-MA will adopt robust methods and be reported in accordance with PRISMA-IPD. The protocol will be written in accordance with PRISMA-P and registered on PROSPERO. Trial investigators will be invited to join a collaborative group on whose behalf the IPD-MA will be published. An advisory group including clinical and patient experts will be established. Individual level data will be requested for all RCTs that meet pre-defined eligibility criteria and for all randomised participants (no names will be collected). Received data will be checked thoroughly and analyses carried out in accordance with the IPD-MA protocol and analysis plan. Outcomes will be patient focussed and include major cardiovascular events, mortality, hospitalisation, quality of life and side effects. Potential effect modifiers including co-morbidity, mainstream treatment including use of statins, and severity of condition will be investigated. We will conduct two-stage analyses as first steps in assessing effectiveness followed by one-stage statistical analysis. ECONOMIC EVALUATION AND VOI ANALYSES Results of the IPD-MA will inform development of an economic model that will evaluate the cost per quality adjusted life year (QALY) of Co-Q10 in CHF, and will quantify the main uncertainties facing decision makers. This will include a VOI analysis to quantify the value of undertaking a new trial. DISSEMINATION A full HTA report will be produced as well as separate journal articles for the IPD-MA and the economic analyses. Findings will be presented at national or international clinical meetings and a short video, aimed primarily for a patient and public audience, produced. A project website will be developed. Plain language summaries will be disseminated through a range of channels. TIMETABLE IPD-MA typically take around 2 years to establish relationships, negotiate release of and, code, clean and analyse data. Given the need to inform commissioning and design of a new trial, we will share pre-publication results with NIHR commissioners.

Lay abstract: CHRONIC HEART FAILURE (CHF) CHF affects around a million people in the UK, set to rise as the population ages and more people survive strokes and heart attacks. In CHF the heart is weakened which can cause shortness of breath, ankle swelling and tiredness. It is associated with shorter life, frequent stays in hospital and reduced quality of life. CHF costs the NHS around £2.3 billion per year. Co-enzyme Q10 (Co-Q10) is a vitamin-like substance that is vital for cell energy production. Low levels in heart muscle cells may be associated with developing and worsening of heart failure. It is possible that taking Co-Q10 supplements might improve outcomes and that this might be particularly relevant to people taking statins (as statins are thought to block bio production of Co-Q10 as well as cholesterol) Co-Q10 is not available on prescription in the UK but can be bought ‘over the counter’. EXISTING EVIDENCE Existing research is inconclusive. Clinical trials have mainly been small and focused on surrogate outcomes such as heart pumping function. Few have reported important outcomes such as hospital admissions or death. Previous systematic reviews have been limited by incomplete and inconsistent reporting and have not been able to investigate differences between different types of patient. METHODS To get round these problems we aim to obtain ‘raw’ data from Co-Q10 trials. We will seek data that trials collected but didn’t report, check data thoroughly, and perform analyses not previously considered in individual trials. This is called individual participant data meta-analysis (IPD-MA). IPD-MA enables thorough and flexible analysis including exploring risks and benefits in different types of patient, for example whether effects are similar in people with and without diabetes or in those taking and those not taking statins. We will search thoroughly for randomised trials that have compared Co-Q10 with placebo, given alongside routine treatments, such as statins. We will look for unpublished trials and collect anonymised data from each patient entered in each relevant trial, including information about them, their condition, treatments received and outcomes including cardiovascular events, functional tests, hospital admissions and quality of life as collected in the trial. A main challenge in IPD-MA is obtaining data. We have found that inviting trial investigators to join a collaborative group and publishing results by the group works well. We will also set up an advisory group that includes clinical and patient experts. We will follow best practice register the protocol in PROSPERO, use appropriate analytic methods and publish findings using an agreed reporting guideline. Alongside the IPD-MA, we will develop an economic model that will use IPD results to examine the benefits and costs of giving Co-Q10 alongside routine medicines in a UK setting. We will carry out a ‘value of information’ analysis that will consider the value of undertaking a new trial. TEAM AND TIMELINE We are experienced in IPD-MA have a multidisciplinary team including a consultant cardiologist who has previously completed a trial of Co-Q10. As it takes time to establish collaboration and secure supply of data, IPD-MA takes longer than standard systematic review and will take 24 months to complete. As findings will inform a new trial we will share results with NIHR commissioners before publication

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR