Author + information
- Simon B. Dimmitt, MBBS, BMedSc(Hons)∗ (, )
- Hans G. Stampfer, MBBS,
- Alicia Moran, BSc,
- Marianne Scartozzi and
- John B. Warren, MD
- ↵∗School of Medicine and Pharmacology, University of Western Australia, Suite 304, 25 McCourt Street, Subiaco, Western Australia 6008, Australia
The review by Smith and Grundy (1) of the American College of Cardiology/American Heart Association Cholesterol Treatment Guideline is helpful, but recommendations for statin dosing are not supported by robust evidence. Simvastatin is routinely available in a 16-fold range of strengths (5 to 80 mg) but the relationship between statin dose and outcomes remains controversial. When allowance is made for the efficacies of the different statins (2), an audit of Western Australian pharmacies disclosed a 64-fold range in statin dose prescribed. Statin dose has important consequences for individual patient outcomes: avoidable cardiovascular events with insufficient dose, unnecessary side effects with excessive dose.
Compared with the reduction in low-density lipoprotein (LDL) cholesterol with the maximum dose of atorvastatin, 80 mg daily, the effective dose that lowers LDL by 50%, the ED50, is about 3 mg (2). A dose of 20 mg daily is near the top of the dose response curve and likely to be sufficient for most patients. The relationship with coronary events weakens with lower levels of cholesterol (3). The reduction in mortality seen with only 20 to 40 mg of simvastatin in the Heart Protection Study was independent of the fall in serum cholesterol. Clinicians should probably avoid unnecessarily high statin doses that increase side effects without meaningful additional clinical benefit.
Higher dosing is partly driven by small acute coronary studies, which by 3 months demonstrate only a marginal benefit. The benefit of statin therapy in meta-analysis even after 1 year is only one third of that seen by 5 years (2). Atorvastatin 10 mg daily, compared with placebo, reduces serum LDL cholesterol by around 40% (1.8 mmol/l) and after 3 years reduces coronary events upward of 40% (2). The effects of different doses of a statin on outcome were best addressed in the TNT (Treating to New Targets) study, in which increasing the dose of atorvastatin 8-fold, from 10 to 80 mg daily, had no impact on mortality and reduced coronary events only a modest 21% but increased abnormal liver function 6-fold (4). Extrapolating from the 40% reduction in coronary events with 10 mg daily of atorvastatin in meta-analysis and the TNT findings, 80 mg would be predicted to reduce coronary events by 47% compared with placebo, a small additional benefit, at a price of increased side effects. The additional coronary risk reduction seen with higher dose atorvastatin in the TNT study is arguably redundant given that a similar additional benefit is seen with any single antihypertensive drug, or aspirin, which patients are usually also prescribed.
The risks of statins are underestimated in recent studies, where statin-intolerant patients were excluded. Independent audits (5) and earlier randomized clinical trials showed that adverse effects are relatively common and include fatigue, myopathy, liver dysfunction (3), cerebral hemorrhage, subtle cognitive impairment, neuropathy, renal failure (5), diabetes mellitus, and cataracts (5). Adverse effects are dose related (5), usually appear before cardiovascular benefits are obtained and impact negatively on quality of life, important given the lifelong nature of statin therapy.
Statins are clearly indicated in secondary prevention but have not been shown to increase life expectancy in primary prevention. Serum cholesterol can be elevated in patients without coronary disease; atheroma can be difficult to predict and imaging with computed tomography may guide statin therapy. Titrating the dose against the individual’s cholesterol response may not be reliable given inherent variability of measurement and the confounding effects of posture and intercurrent illness. Excessive statin dose increases risks of side effects and may confer little additional benefit. Closer attention to weight reduction, smoking, blood pressure, and glucose probably reduces coronary risk more effectively and safely.
- American College of Cardiology Foundation
- Smith S.C.,
- Grundy S.M.
- Law M.R.,
- Wald N.J.,
- Rudnicka A.R.
- Hippisley-Cox J.,
- Coupland C.