Risk benefit analysis of statin trials favours lower doses

Introduction: Optimal dosing is a balance between drug efficacy and adverse side effects. Adverse drug reactions account for around 5% of hospital admissions and significant mortality. Side effects degrade quality of life and reduce compliance.

It is presently assumed that the lower the cholesterol, the greater the reduction in coronary risk. This appears to be why physicians increasingly prescribe statins at many multiples of their ED50, However efficacy does not increase significantly near or on the plateau of the dose response curve, whereas adverse effects are likely to multiply.

Methods: We examined the main published randomised placebo controlled trials of long term statin therapy and evaluated the statin dose used in each trial as a multiple of its ED50.

Results: The newer statins are often prescribed at much higher multiples of their ED50. For example, the ED50 of atorvastatin is 3 mg. However, 40-80 mg is commonly prescribed in coronary care units, despite the absence of robust evidence to support such high doses. In contrast, reductions in myocardial infarction and stroke of up to 33% have been comprehensively documented with only 20-40 mg of simvastatin, a much lower multiple of the simvastatin ED50 of 12 mg.

Increasing the dose of atorvastatin from 10 to 80 mg in TNT reduced cardiovascular events only a further 22% (< 15% when referenced to placebo) but non-cardiovascular mortality increased 25% (p=0.06). A 4 to 16-fold increase in statin dose in SEARCH, TNT, IDEAL and PROVE-IT TIMI was not associated with any significant reduction in total mortality, which usefully summarises efficacy and safety.

Total mortality was not lower on statins compared to placebo in most large published trials. The exceptions were when high risk patients were treated - coronary disease in LIPID and 4S (p<0.001 and 0.003, respectively), and in HPS (p=0.003) which also included patients with diabetes or peripheral artery disease. These secondary prevention benefits on mortality were seen with only 20-40 mg doses of pravastatin or simvastatin, just above their respective ED50s.

Myalgiahas been reported in up to 29% of patients and increased 7-fold when simvastatin dose was increased from 20 to 80 mg in SEARCH. Statin hepatitis, seen in up to 4% of patients, increased 3to21-fold when the dose was increased 4to16-fold in TNT, IDEAL, PROVE-IT TIMI and SAGE.

Conclusion: Successive doubling of statin dose is associated with progressively smaller decrements in serum cholesterol but close to doubling of adverse events. Total mortality is reduced by statins in coronary patients but only with low doses. The benefit risk balance is less clear in primary prevention in patients seen before their first coronary or stroke event.Rather than striving for ever lower cholesterol with increasing statin dose, combined attention to reduction of smoking, blood pressure, glucose and weight is likely to reduce coronary risk more efficiently and safely.