Two important questions regarding statin therapy are:

• What is the overall health impact when statins are prescribed for primary prevention?

• Should the dose of statin be titrated to achieve target lipid levels?

Three new randomized controlled trials (1-3) help answer the first question.

Estimating the overall health impact of statins in primary prevention requires balancing possible benefits and possible harms. The benefit is estimated by combining two cardiovascular serious adverse events known to be reduced by statins in secondary prevention trials: total myocardial infarction (fatal and non-fatal) (5) and total stroke (fatal and non-fatal) (6). The balance between benefit and harm (overall health impact) is estimated by total mortality and total serious adverse events. Serious adverse events include any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of hospitalization, or results in persistent or significant disability.

PROSPER

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) (1) studied the effect of pravastatin compared to placebo in two older populations of patients: 56% primary prevention (no past or symptomatic cardiovascular disease) and 44% secondary prevention (past or symptomatic cardiovascular disease) (Table 1). Pravastatin did not reduce total myocardial infarction or total stroke in the primary prevention population, RR 0.94 [0.78 - 1.14], but did so in the secondary prevention population, RR 0.80 [0.68 - 0.94], ARR 4.3%, NNT 23 for 3.2 years. Measures of overall health impact in the combined populations, total mortality and total serious adverse events, were unchanged by pravastatin as compared to placebo, RR 0.98 [0.84 - 1.14] and 1.01 [0.96 - 1.06], respectively.

ALLHAT-LLT

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) (2) was designed to determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolaemic, hypertensive patients with at least one additional coronary heart disease risk factor. The published data is for the whole population, 86% of which was primary prevention. Pravastatin did not reduce total myocardial infarction and total stroke, RR 0.91 [0.82 - 1.01]. Pravastatin also did not reduce total mortality, RR 0.99 [0.89 - 1.09]. Total serious adverse events were not reported.

ASCOT-LLA

The Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA) was designed to assess the benefits of atorvastatin versus placebo in hypertensive patients with average or lower-than-average cholesterol concentrations and at least three other cardiovascular risk factors. The published data is for the whole population, 82% of which was primary prevention. The trial was originally planned for 5 years, but was stopped after a median follow-up of 3.3 years because of a significant reduction in cardiac events. Atorvastatin reduced total myocardial infarction and total stroke, RR 0.82 [0.70 - 0.96], ARR 1.2%, NNT 83. Total mortality was not significantly reduced, RR 0.87 [0.71 - 1.05]. The trial report stated that total serious adverse events did not differ between patients assigned atorvastatin or placebo, but the actual numbers of serious adverse events were not given.

Overall health impact when statins are prescribed for primary prevention

To answer this question we combined the data from the 5 mostly primary prevention trials, the 3 above plus 2 published earlier (Tables 1 and 2). These calculations reflect a population that is 84% primary prevention and 16% secondary prevention. In the pooled data the statins reduced the cardiovascular measures, total myocardial infarction and total stroke by 1.4% as compared to control. This value indicates that 71 mostly primary prevention patients would have to be treated for 3 to 5 years to prevent one such event. This can be compared with the same pooled outcome in 4 large secondary prevention statin trials, ARR 4.8%, NNT 21 for 5 years (4).

In the 2 trials where serious adverse events are reported, the 1.8% absolute reduction in myocardial infarction and stroke should be reflected by a similar absolute reduction in total serious adverse events; myocardial infarction and stroke are, by definition, serious adverse events. However, this is not the case; serious adverse events are similar in the statin group, 44.2%, and the control group, 43.9% (Table 2). This is consistent with the possibility that unrecognized serious adverse events are increased by statin therapy and that the magnitude of the increase is similar to the magnitude of the reduction in cardiovascular serious adverse events in these populations. This hypothesis needs to be tested by analysis of total serious adverse event data in both past and future statin trials. Serious adverse event data is available to trial authors, drug companies and drug regulators. The other measure of overall impact, total mortality, is available in all 5 trials and is not reduced by statin therapy

Conclusions

• If cardiovascular serious adverse events are viewed in isolation, 71 primary prevention patients with cardiovascular risk factors have to be treated with a statin for 3 to 5 years to prevent one myocardial infarction or stroke.

• This cardiovascular benefit is not reflected in 2 measures of overall health impact, total mortality and total serious adverse events. Therefore, statins have not been shown to provide an overall health benefit in primary prevention trials.

Extracted from Therapeutics Letter, Number 48, http://www.ti.bc.ca

Comments from Management of Noncommunicable Diseases (NMC), World Health Organization

The ASCOT-LLA was ended early after an interim analysis showed an outcome in favour of statin treatment. However, the additional benefit to effective lowering of blood pressure by statin therapy is not impressive in absolute terms. The study population was mostly men/white, mean age 63, average of 3.7 risk factors in addition to hypertension. In other words, patients at rather high cardiovascular risk. Further statin treatment lowered total cholesterol by 1.3 mmol and blood pressure was well controlled; both factors contributing to the outcome.

On the other hand, the ALLHAT LLT trial patients had hypertension with at least one cardiovascular risk factor. The difference in total cholesterol between groups during the trial was only around 0.5 mmol/L and the trial failed to show any benefit in all-cause mortality (primary outcome) or in non fatal myocardial infarction and non-fatal coronary heart disease (secondary outcome).

The above findings, and the results of the other studies reiterate:

1. That the safety of statins have to be proven in people with low coronary heart disease risk. However, extremely large trials are required to demonstrate the safety of statins in terms of overall mortality in such subjects.

2. That treatment strategies in primary prevention of cardiovascular disease should depend on global cardiovascular risk assessment rather than on numerical values of individual risk factors.

References

1. Shepherd, J., Blauw, G.J., Murphy, M.B. et al. PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet, 360: 1623-1630 (2002).

2. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolaemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Journal of the American Medical Association, 288: 2998-3007 (2002).

3. Sever, P.S., Dhalof, B., Poulter, N.R. et al. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet, 361: 1149-1158 (2003).

4. Heart Protection Study Collaborative Group. MRC/ BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet, 360: 7-22 (2002).

5. Maron, D.J., Fazio, S., Linton, M.F. Current perspectives on statins. Circulation, 101: 207-213 (2000).

6. Crouse, J.R., Byington, R.P., Furberg, C.D. HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data. [erratum appears in Atherosclerosis 140: 193-194 1998]. Atherosclerosis, 138: 11-24 (1998).

7. Downs, J.R., Clearfield, M., Weis, S., et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Journal of the American Medical Association, 279: 1615-1622 (1998).

8. Shepherd, J., Cobbe, S.M., Ford, I. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. New England Journal of Medicine, 333: 1301-1307 (1995).