Statins for the primary prevention of cardiovascular disease

Background
Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past 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 people 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 people 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
Randomised 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 (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% 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 non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), change in blood total cholesterol concentration, revascularisation, 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) were calculated.

Main results
Fourteen randomised control trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR 0.83, 95% CI 0.73 to 0.95) as was combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79). Benefits were also seen in the reduction of revascularisation rates (RR 0.66, 95% CI 0.53 to 0.83). Total cholesterol and LDL cholesterol 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 endpoints and revascularisations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. 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 among people at low cardiovascular risk.

Plain language summary
Statins for the primary prevention of cardiovascular disease. Cardiovascular disease (CVD) is ranked as the number one cause of mortality and is a major cause of morbidity world wide. Reducing high blood cholesterol which is a risk factor for CVD events is an important goal of medical treatment. Statins are the first-choice agents. Since the early statin trials were reported, several reviews of the effects of statins have been published highlighting their benefits particularly in people with a past history of CVD. However for people without a past history of CVD (primary prevention), the evidence is less clear. The aim of this systematic review is to assess the effects, both in terms of benefits and harms of statins for the primary prevention of CVD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE until 2007. We found 14 randomised control trials with 16 trial arms (34,272 patients) dating from 1994 to 2006. All were randomised control trials comparing statins with usual care or placebo. Duration of treatment was minimum one year and with follow up of a minimum of six months. All cause mortality. coronary heart disease and stroke events were reduced with the use of statins as was the need for revascularisations. Statin treatment reduced blood cholesterol. Taking statins did not increase the risk of adverse effects such as cancer. and few trials reported on costs or quality of life. This current systematic review highlights the shortcomings in the published trials and we recommend that caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.

From press release:

Statins: Benefits Questionable in Low-Risk Patients
There is not enough evidence to recommend the widespread use of statins in people with no previous history of heart disease, according to a new Cochrane Systematic Review. Researchers say statins should be prescribed with caution in those at low risk of cardiovascular disease (CVD).

CVD is the most common cause of death, accounting for nearly a third of all deaths worldwide. Cholesterol-lowering statins are first line treatments for heart patients and the benefits are well established. However, there is less evidence that statins are beneficial for preventing heart problems in those who have no history of CVD. Given that low cholesterol has been shown to increase the risk of death from other causes, statins may do more harm than good in some patients.

The researchers reviewed data from 14 trials involving 34,272 patients. Outcomes in patients given statins were compared to outcomes in patients given placebos or usual care. Combined data from eight trials involving 28,161 patients that provided data on deaths from all causes showed that statins reduced the risk of dying from 9 to 8 deaths for every 1000 people treated with statins each year. Statins reduced fatal and non-fatal events, including heart attack, stroke and revascularization surgery, as well as blood cholesterol levels.

However, the researchers say that the conclusions of their review are limited by unclear, selective and potentially biased reporting and that careful consideration should be given to patients’ individual risk profiles before prescribing statins.

“It is not as simple as just extrapolating the effects from studies in people who have a history of heart disease,” said lead researcher Fiona Taylor, from the Cochrane Heart Group at the London School of Hygiene and Tropical Medicine in London, UK. “This review highlights important shortcomings in our knowledge about the effects of statins in people who have no previous history of CVD. The decision to prescribe statins in this group should not be taken lightly.”

The researchers point out that all but one of the trials they reviewed were industry-sponsored. “We know that industry-sponsored trials are more likely to report favourable results for drugs versus placebos, so we have to be cautious about interpreting these results,” said Taylor. “The numbers eligible for treatment with statins are potentially great so there might be motivations, for instance, to stop trials earlier if interim results support their use.”

A separate Cochrane Systematic Review, conducted by some of the same authors, considered the effects of combined approaches to reducing the risk of heart disease, including using education and counselling to encourage people to change their diets and stop smoking. The authors concluded that combined interventions had little or no impact on deaths or disease caused by CVD. In an editorial accompanying the reviews, Carl Heneghan, University of Oxford, concluded that, “Although various multiple prevention strategies exist, the most effective and cost-effective intervention for primary prevention in adults at low risk currently remains unclear.”