SUMMARY: Recent evidence on use of statins — implications for when to offer a statin and which one to offer

By Chris Corfield
Chris Corfield chief pharmacist, NHS Hammersmith and Fulham

This article is based on two papers: “The effectiveness of statins for primary prevention in people without established cardiovascular disease” (Paper 1) and “If a patient wants to take a statin, and offering it is in line with national guidance, which one should be recommended?” (Paper 2).

Paper 1. Primary prevention

Three recent meta-analyses quantified the benefits of statins used for primary prevention in people without established cardiovascular disease. The first, which included trials with mean follow-up of 4.1 years, found absolute risk reductions for all cause mortality, major coronary events and major cerebrovascular events of 0.6, 1.3 and 0.4 per cent, giving numbers needed to treat (NNT) to avoid an event of 167, 77 and 245, respectively.

Unfortunately about 6 per cent of patients in the analysis had a previous cardiovascular event; treatment of these was secondary rather than primary prevention.

The second was “cleaner”, based on data from only individuals without clinically manifest cardiovascular disease. It found that use of statins was not associated with a statistically significant reduction in the risk of all-cause mortality (risk ratio 0.91; 95 per cent confidence interval 0.83–1.01; absolute risk reduction 0.3 per cent not significant).

The third found that statins reduced all-cause mortality (relative risk 0.83, 95 per cent confidence intervals 0.73–0.95) and combined fatal and non-fatal cardiovascular disease endpoints (RR 0.70, 95 per cent CI 0.61–0.79) but the authors found evidence of selective reporting of outcomes and inclusion of people with cardiovascular disease. See below for the relevance of the latter.

The JUPITER trial of rosuvastatin merits comment. A reappraisal concluded that it was flawed, finding, for example, that cardiovascular mortality in the trial was surprisingly low compared with total mortality and that of those people who suffered a myocardial infarction, far fewer died than would have been expected.

Average risk reduction

A fourth meta-analysis found that each 1.0mmol/L reduction in LDL cholesterol at one year after randomisation reduced the annual rate of major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2–3mmol/L would reduce risk by about 40–50 per cent.

The size of the absolute risk reduction achieved with a statin depends on the patient’s baseline absolute risk as well as the LDL cholesterol reduction achieved.

People who have clinically manifest cardiovascular disease are at high risk of a cardiovascular event. As an indication, in the 4S trial, in which patients with angina pectoris or previous myocardial infarction were randomised to simvastatin or placebo with a median follow-up period of 5.4 years, 28 per cent of patients in the placebo group had a major coronary event. So the patients in 4S were at higher baseline risk than the conventional threshold risk for offering statin for primary prevention (20 per cent or greater 10-year risk of developing cardiovascular disease).

The relative risk reduction per 1.0mmol/L LDL cholesterol reduction is similar irrespective of baseline absolute risk of a CV event, so patients with the highest baseline risk obtain the largest reduction in absolute risk. In 4S the NNT to avoid one death was 30 and the NNT to avoid one major coronary event was 15.

Adverse reactions

In 2009 the Medicines and Healthcare products Regulatory Agency reported the outcome of a Europe-wide review on statins. It concluded that statins are generally well tolerated by most people who use them, but that prescribers and patients should be aware of the potential for adverse reactions the review identified: depression, sleep disturbances, memory loss, sexual dysfunction and, very rarely, interstitial lung disease.

A large meta-analysis found no significant effects of statins on deaths from cancer or other non-vascular causes or on cancer incidence.
In 2010 the MHRA warned about great er risk of myopathy in those receiving the highest licensed dose of simvastatin, 80mg daily.

A retrospective cohort study quantified a number of adverse effects (acute renal failure, moderate or severe myopathy or liver dysfunction, cataract) that have been found to be associated with statin use. The numbers needed to harm over five years are presented in Paper 1. The possibility of residual bias or confounding cannot be discounted.

Estimating risk of a cardiovascular event

The QRISK2 risk estimation tool is arguably better than the modified Framingham risk equation that NICE used to recommend. QRISK2 is better at differentiating between those who go on to have a cardiovascular event and those who do not and more accurately estimates an individual’s risk. Against this, it identifies fewer men who go on to have an event than does the modified Framingham equation.

Paper 2. Which statin to use

NICE’s guidelines recommend a specific statin for some indications but not for others. ‘Which statin?’ choices are important, not least because of the large difference in the price of different statins.

Paper 2 highlights three relevant questions, suggests responses to them and then suggests first- or second-line statin choices informed by the responses. Factors considered include:

• The MHRA’s recent warning about increased risk of myopathy associated with 80mg simvastatin and a meta-analysis finding that all of the observed excess of rhabdomyolysis with more intensive statin therapy occurred in trials of simvastatin 80mg versus 20mg daily
• The finding that each 1.0mmol/L reduction in LDL cholesterol reduces the annual rate of major vascular events by just over a fifth
• The mean percentage reductions in LDL cholesterol achieved by the various doses of simvastatin, atorvastatin and rosuvastatin
• The November 2011 expiry of the UK Supplementary Protection Certificate for atorvastatin; cheaper generics should then appear
• Current prices
• The Drug and Therapeutics Bulletin’s recent questioning of whether adding ezetimibe to statin treatment is a cost-effective or outcome-based intervention — there are no published trials to show it reduces mortality or morbidity; the DTB said: “Since it is proving increasingly expensive for the NHS, prescribers should ask why they are using [ezetimibe].”

Millions of prescriptions for statins are generated; in 2009 the net ingredient cost of those dispensed in England was 5.4 per cent of the total for prescription items.

The two papers summarised here aim to provide an accessible overview of important recent publications on statins and to help pharmacists discuss statin choices with prescribers.