Statins: what is the evidence for their use?

Mel Stevens
DipPharmPract MRPharmS
Formerly Principal Pharmacist
Cardiothoracic Services
St George’s Hospital
London, UK

In the first part of this two-part series we examined the pharmacological action, relative potencies, potential for interactions and side-effects, cost, cost-effectiveness and appropriate dosing of the statins, noting the imminent expiry of patents. Safety and side-effects are hot topics with regards to rates of myositis, rhabdomyolysis and the recent withdrawal of cerivastatin.

In this second part we look at the established evidence and preliminary results from the Heart Protection Study, and outline current published treatment recommendations. Other proposed mechanisms of action include plaque stabilisation, and anti-inflammatory and antithrombotic properties. Further trial work is ongoing to define the role, scope and place in therapy for the statins as more questions are generated and answers sought.

Established evidence
The Scandinavian Simvastatin Survival Study (4S) was the first clinical trial to demonstrate conclusively that long-term therapy with statins substantially reduced the risk of death from all causes, as well as from cardiac events, in middle-aged patients with coronary heart disease (CHD) and raised cholesterol.(1) Subsequent trials have shown similar results (see Table 1); these included two large trials of pravastatin in patients who had already suffered a coronary event,(2,3) one trial of pravastatin as primary prevention,(4) and one of lovastatin as primary prevention.(5) A meta-analysis of over 30,000 patients in five comparable statin trials confirms that low-density lipoprotein (LDL)-cholesterol reduction associated with statin treatment decreases the risk of CHD and death in men and women, middle-aged and elderly.(7)

[[HPE05_table1_46]]

These trials established the efficacy of statin therapy for reducing mortality and coronary disease events in the circumstances studied, and the tolerability of long-term daily statin therapy, but doubts have remained about how widely statins should be prescribed. The Heart Protection Study will help address this question and provide substantially more safety information.

MRC/BHF Heart Protection Study(6)
This landmark trial was recently published. It was a large multicentre UK study, involving 20,536 patients who were followed up for a mean 5.5 years. It was designed to investigate the effects of cholesterol lowering with 40mg simvastatin and also to determine any benefit of antioxidant vitamin (A, C and E) supplementation. A wide range of disease categories were included to generate evidence for treatment of patients with known high risk, where benefits had not been clearly demonstrated.

Eligible patients were men and women aged between 40 and 75 years with CHD, diabetes (type 1 and type 2), noncardiac vascular disease or previous history of stroke. The results are shown in Table 2.

[[HPE05_table2_46]]

The benefits of statin therapy, found to be additive to existing treatments, were seen across all ages in both men and women. The reduction in event rate was described in all subcategories of patient studied, including those without diagnosed coronary disease who had cerebro­vascular disease, peripheral artery disease or diabetes, and regardless of presenting cholesterol level. Antioxidant vitamins were found not to prevent heart disease.

This large clinical trial provides robust evidence supporting the widespread use of statin therapy in many more patients. The message is that treatment should be defined by level of risk rather than a numerical cholesterol measurement. The public health and economic implications of this study are considerable. It may take time before guidelines (and budgets) are updated to reflect these developments.

Treatment recommendations
The National Service Framework for Coronary Heart Disease (NSF-CHD) in the UK emphasises the importance of appropriate management of patients with established CHD (secondary prevention) and those at high risk of suffering with it (primary prevention in high-risk populations).(8) This requires routine risk assessments to identify these patients and robust follow-up to ensure they are, and continue to be, treated according to current best knowledge and practice.

Goals of treatment are to reduce total cholesterol to less than 5.0mmol/l (or by 30%, whichever is greater) or to reduce LDL-cholesterol to less than 3.0mmol/l (or by 25%, whichever is greater). This carries a large economic burden if all eligible patients are to be treated.

Treatment guidelines with similar messages are available in the form of the UK(9) and European(10) recommendations on the prevention of CHD. However, as understanding of lipid science and risk is evolving, aims of treatment are not easily defined numerically and other questions are arising.

Other proposed actions
The cardiovascular event reductions and mortality benefits seen with statins extend beyond those that would be expected from LDL-cholesterol reduction alone. Statins are thought to confer plaque stabilisation, anti-inflammatory and antithrombotic effects.(11)

One explanation is that the downstream consequences of blocking the mevalonate pathway will also suppress signalling proteins on plasma membrane. It is suggested that these biochemical changes affect smooth muscle proliferation, endothelial function, nitric oxide availability and angioneogenesis.

Statins have also shown benefit in the context of other related clinical situations. Some studies include coronary stenting where reduced restenosis rates were observed with pravastatin,(12) although two previous trials showed no effect with lovastatin or fluvastatin. Benefits have been described in heart transplant patients who are prone to accelerated coronary vasculopathy,(13) and in graft protection following coronary artery bypass surgery.(14)

There have also been several observational reports of reduced fracture risk associated with statin use from registry analyses.(15) A randomised controlled trial is needed to define whether this is a causal effect.

Conclusion
The statins are powerful modulators of serum cholesterol profiles. Although the available agents differ in their relative potency, it appears to be a class effect. Studies have shown that lowering cholesterol reduces the progression and/or induces regression of coronary atherosclerosis. Other effects such as plaque stabilisation and anti-­inflammatory action are being investigated.

The megatrials clearly demonstrate a significant reduction in a variety of clinical endpoints in a secondary prevention population. Evidence supports the use of simvastatin or pravastatin for secondary prevention, but it is felt to be a class effect.

The Heart Protection Study provides an extension of existing evidence to firm up the strategy for statin treatment in a wide range of high-risk patients. Primary prevention is also effective, but must be targeted at those who will receive most benefit to optimise scarce healthcare resources.

The most important consideration in the use of statins is the patients’ overall risk of CHD rather than the lipid profile in isolation. Cholesterol-lowering treatments should be targeted at:

• Patients with evidence of established ­athero­sclerotic disease:

i. Those who have had a myocardial infarction.
ii. Those who have CHD (angina).
iii. Those who have peripheral vascular disease.
iv. Those who have had a stroke.

• Patients at high risk of any of the above. Defined as >30% risk of having an event in next 10 years.

Cerivastatin was withdrawn due to unacceptable rates of myopathy, rhabdomyolysis and deaths linked particularly to use of higher doses or combined therapy with gemfibrozil. The other statin agents are very well-tolerated, and side-effect rates in trials are similar to placebo.

[[HPE05_box1_47]]

References

1. Scandinavian Simvastatin Survival Study (4S) group. Lancet 1994;344:1383-9.
2. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339(19):1349.
3. Sacks FM, et al, for the Cholesterol and Recurrent Events Trial Investigators (CARE). N Engl J Med 1996;335(14):1001-9.
4. Shepherd J, Cobbe SM, Ford I, et al. West of Scotland Coronary Prevention Study Group (WOSCOPS). N Engl J Med 1995;333:1301-7.
5. Downs JR, Clearfield M, Weis S, et al. JAMA 1998;279:1615-22.
6. Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
7. LaRosa JC, He J, Vupputuri S. JAMA 1999;282:2340-6.
8. Department of Health UK. National Service Framework for Coronary Heart Disease: Our Healthier Nation: Chapter 2 – Preventing coronary heart disease in high risk patients. London: Department of Health; 2000. Available from URL: http://www.doh.gov.uk/nsf/coronary.htm
9. Wood DA, Durrington P, Poulter N, et al, on behalf of the Societies. Heart 1998;80 Suppl 2:S1-29.
10. Wood DA, De Backer G, et al. Eur Heart J 1998:19:1434-503.
11. Rosenson RS, Tangey CC.  JAMA 1998;279:1643-50.
12. Mulder HJ, Bal ET, Jukema JW, et al. Am J Cardiol 2000;86:742.
13. Kobashigawa JA, Katznelson S, Laks H, et al. N Engl J Med 1995;333:621-7.
14. Knatterud GL, Rosenberg E, Campeau L, et al. Circulation 2000;102:157.
15. Meier CR, Schlienger RG, Kraenzlin ME, et al. JAMA 2000;283:3205-10.