A 54-year-old man presents for a health maintenance visit. He has no significant medical history, has never smoked, and takes no medications. Other than a body mass index of 26 kg per m2, his examination is unremarkable. He has no family history of cardiovascular disease (CVD). A recent lipid panel revealed a total cholesterol level of 256 mg per dL (6.63 mmol per L), a high-density lipoprotein level of 51 mg per dL (1.32 mmol per L), and a low-density lipoprotein level of 162 mg per dL (4.20 mmol per L). You consider starting him on a statin to lower his cholesterol level and wonder if it is likely to reduce his risk of a cardiovascular event.
Do statins reduce cardiovascular events in persons without known coronary artery disease?
Trials to date have found that statins reduce all-cause mortality, composite cardiovascular outcomes, and revascularization. However, most trials included large numbers of persons with known CVD. Clear evidence of the effectiveness of statins to prevent a first cardiovascular event is lacking. (Strength of Recommendation: B, based on inconsistent or limited-quality patient-oriented evidence.)
Background: Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in persons with and without a history of coronary heart disease (CHD), is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in persons with coronary artery disease. The case for primary prevention, however, is less clear.
Objectives: To assess the effects, both harms and benefits, of statins in persons with no history of CVD.
Search Strategy: To avoid duplication of effort, we checked reference lists of previous systematic reviews. We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2007), Medline (2001 to March 2007), and EMBASE (2003 to March 2007). There were no language restrictions.
Selection Criteria: Randomized controlled trials of statins with minimum duration of one year and follow-up of six months, in adults with no restrictions on their total low-density lipoprotein or high-density lipoprotein cholesterol levels, and where 10 percent or less had a history of CVD, were included.
Data Collection and Analysis: Two authors independently selected studies for inclusion and extracted data. Outcomes included all-cause mortality, fatal and nonfatal CHD, CVD and stroke events, combined end points (fatal and nonfatal CHD, CVD, and stroke events), change in blood total cholesterol concentration, revascularization, adverse events, quality of life, and costs. Relative risk (RR) was calculated for dichotomous data, and for continuous data pooled weighted mean differences (with 95% confidence intervals [CIs]) were calculated.
Main Results: Fourteen randomized controlled trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes mellitus, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR = 0.83; 95% CI, 0.73 to 0.95), as were combined fatal and nonfatal CVD end points (RR = 0.70; 95% CI, 0.61 to 0.79). Benefits were also seen in the reduction of revascularization rates (RR = 0.66; 95% CI, 0.53 to 0.83). Total cholesterol and low-density lipoprotein cholesterol levels were reduced in all trials but there was evidence of heterogeneity of effects. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life.
Authors' Conclusions: Although reductions in all-cause mortality, composite end points, and revascularizations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events, and inclusion of persons with CVD. Only limited evidence showed that primary prevention with statins may be cost-effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention in persons at low cardiovascular risk.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
Statins are potent reducers of serum cholesterol levels. Their ability to reduce morbidity and mortality in patients with known CVD is well established. However, some authors have started to question the effectiveness of statins for the primary prevention of cardiovascular outcomes.1 To examine this specific body of evidence, the authors of this Cochrane review chose studies in which no more than 10 percent of participants had a history of CVD. This criterion eliminated several large trials that showed reductions in cardiovascular outcomes.2
A total of 16 arms from 14 clinical trials were included in the analysis. Trials typically reported on composite end points because of an overall small number of events. A few trials were stopped early, which can overestimate treatment effects. Other weaknesses included poor reporting of randomization techniques in several studies, and evidence of incomplete or selective outcome reporting. Trial participants were mostly middle-aged white men, calling into question the generalizability of the findings. All but one of the trials were at least partially industry supported.
Eight trials including more than 28,000 participants reported mortality data. Pooled analysis favored statin use with a relative risk (RR) of 0.83 (95% confidence interval [CI], 0.73 to 0.95). Pooled analysis of nine trials showed a reduction in coronary heart disease events with statin use (RR = 0.72; 95% CI, 0.65 to 0.79). Pooled analysis of six trials showed a reduction in fatal and nonfatal CVD events with statin use (RR = 0.74; 95% CI, 0.66 to 0.85). Pooled analysis of seven trials showed that statin use reduced combined fatal and nonfatal stroke events (RR = 0.78; 95% CI, 0.65 to 0.94).
Three trials with a combined 17,452 participants reported composite fatal and nonfatal coronary heart disease, CVD, and stroke events. All three trials showed statistically significant reductions; pooled analysis revealed an RR of 0.70 (95% CI, 0.61 to 0.79). Of more than 18,000 participants in the five trials reporting on revascularization, 1.7 per cent underwent percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. Pooled analysis showed a statistically significant reduction in the statin groups (RR = 0.66; 95% CI, 0.53 to 0.83).
A population-based cohort study with more than 2 million participants found statin use to be statistically associated with moderate to severe liver dysfunction, moderate to serious myopathy, acute renal failure, and cataracts.3 However, adverse event reporting was irregular in the trials included in this analysis. Eight trials did not report on adverse events at all. Pooled data showed no difference between intervention and control groups for myalgia, rhabdomyolysis, or any types of cancer.
Published guidelines include near-term risk, calculated with validated scoring systems, as a factor to determine when to start lipid-lowering therapy. The National Cholesterol Education Program, Adult Treatment Panel III, guidelines and the American Heart Association Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women use calculated risk as one factor to consider when starting lipid-lowering therapy.4,5 There is evidence that many patients who do not meet these criteria are being prescribed statins. One British study found that only 14 percent of patients being treated for primary prevention would be considered at high risk of CVD using an established risk score.6
Although this review does not prove that statins are ineffective for primary prevention of cardiovascular events, it highlights notable gaps in the literature concerning statin use in patients without a history of CVD. When determining whether to prescribe a statin to prevent a first cardiovascular event, a patient's overall cardiovascular risk should be estimated using a validated score, such as the Framingham risk score (calculator available at http://hp2010.nhlbihin.net/atpiii/calculator.asp). For those at highest risk, statins are likely to be beneficial. Because it is less certain whether patients at moderate or low risk will benefit from statin use, physicians should inform these patients of the gaps in the evidence, and assist them in weighing the potential cardiovascular benefits with the inconvenience, expense, and adverse effects of statins.