Objective

The aim of this research was to evaluate the cost-effectiveness of high-dose statins (atorvastatin 80 mg/day, rosuvastatin 40 mg/day and simvastatin 80 mg/day) versus simvastatin 40 mg/day in individuals with acute coronary syndrome (ACS) who have experienced a recent ACS event.

Methods

Eleven bibliographic databases covering the biomedical, scientific and grey literature were searched from inception to 2008 (supplemented by contact with experts in the field). Data relating to study design, baseline patient characteristics, clinical or surrogate outcome, and adverse events were abstracted and methodological quality was assessed. In addition, results of eligible randomised controlled trials (RCTs) were statistically synthesised (meta-analysed) where appropriate.

Meta-analyses of RCTs have shown that early, intensive statin therapy is of benefit in reducing death and cardiovascular events when prescribed immediately after an ACS compared with standard statin therapy. In the UK, most, if not all, initial prescribing is undertaken at the hospital and the decision to continue specialist prescribing outside the hospital is governed by the NHS primary care trusts (PCTs). However, there is great variation between PCTs in the management (including prescribing practices) of patients with ACS.

An existing Markov model was modified to explore the costs and benefits associated with a lifetime of the differing treatment regimens. Baseline transitions for the no treatment arm were derived from UK registries or UK-based RCTs. Costs and benefits were discounted at 3.5% in accordance with National Institute for Health and Clinical Excellence (NICE) guidelines for economic evaluations. A systematic review was used to identify RCTs of the different statin treatments. As there were no existing clinical data reporting outcomes in terms of hard clinical end points (e.g. numbers of myocardial infarctions or fatal events avoided) for rosuvastatin, benefits of statins were quantified in terms of a proxy measure, changes in low-density lipoprotein cholesterol (LDL-c). A Bayesian mixed treatment meta-analysis was used to combine the data from 28 clinical trials and a published relationship linking changes in LDL-c and relative risk of vascular events was utilised to estimate the benefit of treatment.

Results

A total of 3345 titles and abstracts were screened for inclusion in the review of clinical effectiveness. Of the titles and abstracts screened, 125 full papers were retrieved and assessed in detail. Of these, 30 papers met the inclusion criteria for the review, describing 28 trials. The Bayesian mixed treatment meta-analysis demonstrated a clear dose–response relationship in terms of reductions in LDL-c, with rosuvastatin 40 mg/day achieving the greatest percentage reduction (56%) from baseline, followed by atorvastatin 80 mg/day (52%), simvastatin 80 mg/day (45%) and simvastatin 40 mg/day (37%). Although the literature suggests that serious adverse events with statins are rare, their incidence is likely to be greater with higher doses. Adherence rates in general clinical practice are reported to be lower than those observed in clinical trials. However, there is some evidence that adherence could be higher in individuals with a history of cardiovascular disease, and in those who receive regular monitoring. Several clinical scenarios were used to explore the effect of adherence on the cost-effectiveness of the treatment regimens.

Using a threshold of £20,000 per quality-adjusted life-year (QALY), if it is assumed that the benefits and adherence rates observed in the clinical trials are generalisable to a clinical setting, or if it is assumed that individuals who do not tolerate the higher-dose statins are prescribed simvastatin 40 mg/day, then simvastatin 80 mg/day, atorvastatin 80 mg/day and rosuvastatin 40 mg/day would be considered cost-effective compared with simvastatin 40 mg/day in individuals with ACS. However, simvastatin 80 mg/day is not well tolerated because of the high incidence rates of less severe adverse events such as myopathy, which are likely to affect adherence levels in clinical practice. Recently published results show that the incidence of myopathy in individuals receiving simvastatin 80 mg/day was 26 times higher than the incidence rate in those receiving simvastatin 20 mg/day. With rates of defined premyositis also increased, simvastatin 80 mg/day cannot be recommended.

The reference case shows that rosuvastatin is the optimal treatment for individuals with a recent history of ACS when using a threshold of £20,000 per QALY. However, this is based on the assumption that the additional incremental reductions in LDL-c observed in patients treated with rosuvastatin 40 mg/day compared with atorvastatin will transfer into corresponding changes in relative risks of cardiovascular events. If the cost of atorvastatin decreases in line with that observed for simvastatin when the patent ends in 2011, atorvastatin 80 mg/day will be the most cost-effective treatment for all thresholds; if the cost reduces to 25% of the current value, atorvastatin 80 mg/day will be the most cost-effective treatment for thresholds between £5000 and £30,000 per QALY.

Conclusion

The Bayesian mixed treatment meta-analysis demonstrated a clear dose–response relationship in terms of reductions in LDL-c, with rosuvastatin 40 mg/day achieving the greatest percentage reduction (56%), followed by atorvastatin 80 mg/day (52%), simvastatin 80 mg/day (45%) and simvastatin 40mg/day (37%). Although the literature suggests that serious adverse events are rare for all statins, incidence rates are likely to be higher for individuals receiving the more potent doses. Adherence rates in general clinical practice are lower than those reported in clinical trials, may be correlated with less severe adverse event rates such as for myalgia, and are likely to vary by statin type and dose.

Using a threshold of £20,000 per QALY, if it is assumed that the benefits and adherence rates observed in the clinical trials are generalisable to a clinical setting, or if it is assumed that individuals who do not tolerate the higher-dose statins are prescribed simvastatin 40 mg/day, then simvastatin 80 mg/day, atorvastatin 80 mg/day and rosuvastatin 40 mg/day would all be considered cost-effective compared with simvastatin 40 mg/day in individuals with ACS. However, because of high incidence rates of myopathy/myalgia in individuals receiving simvastatin 80 mg/day, adherence is likely to be poor.

With current treatment costs and existing evidence our results show that rosuvastatin 40 mg/day is potentially the most cost-effective treatment. However, these results are based on the assumption that the larger benefits in LDL-c measurements will produce an equivalent reduction in cardiovascular event rates. Although data on event rates supporting this assumption are beginning to emerge, the evidence base for atorvastatin 80 mg/day is more robust. If the cost of atorvastatin decreases when the patent ends in 2011, atorvastatin 80 mg/day will be the most cost-effective treatment.

Recommendations for further research

Large long-term RCTs reporting effects in terms of clinical events are required to determine the optimum statin use for subgroups. These include head-to-head studies comparing higher-dose statins with lower-dose statins, studies of rosuvastatin and studies comparing high-dose statin monotherapy with combination therapies such as low-dose statins combined with alternative lipid modifications. Studies recruiting high-risk groups typically excluded from RCTs, such as individuals with recent ACS events or heart failure, diabetics and Asian people, should be considered. Long-term registry data are required to determine adherence rates and adverse event profiles for individual statins and doses when used in general clinical practice. Studies exploring the effects of interventions designed to increase adherence to statin therapy in general clinical practice and in subgroups are also required.

Publication

• Ara R, Pandor A, Stevens J, Rees A, Rafia R. Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation. Health Technol Assess 2009;13(34). [PubMed: 19604457]

NIHR Health Technology Assessment programme

The Health Technology Assessment (HTA) programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.

The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the 'National Knowledge Service'.

The HTA programme is needs led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects.

First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA programme then commissions the research by competitive tender.

Second, the HTA programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour.

Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies.

Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem.

The final reports from HTA projects are peer reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment.

Criteria for inclusion in the HTA journal series

Reports are published in the HTA journal series if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.

Reviews in Health Technology Assessment are termed 'systematic' when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 07/03/01. The protocol was agreed in January 2008. The assessment report began editorial review in December 2008 and was accepted for publication in January 2009. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Editor-in-Chief: Professor Tom Walley CBE

Series Editors: Dr Aileen Clarke, Dr Chris Hyde, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein