Cochrane review questions evidence for statins for primary prevention in low risk groups

A Cochrane review published on 18 January questions the evidence for prescribing statins for primary prevention in people at low cardiovascular risk, after finding selective reporting of outcomes, failure to report adverse events, and inclusion of people with cardiovascular disease in published studies.

The reviewers analysed randomised controlled trials of statins in adults with no requirements for participants to have particular LDL or HDL cholesterol concentrations and where no more than 10% of participants had a history of cardiovascular disease (Cochrane Database of Systematic Reviews 2011;(1):CD004816, doi:10.1002/14651858.CD004816.pub4). All studies included also had to have a minimum duration of one year and follow-up of six months.

“We wanted to examine benefits and harms from statins in primary prevention,” explained Shah Ebrahim, professor of public health at the London School of Hygiene and Tropical Medicine and a member of the review team. “Previous reviews have combined primary and secondary prevention which hides true effects in people without previous CVD [cardiovascular disease].”

The team found 14 randomised controlled trials, with a total of 34 272 participants. Eleven trials recruited patients with specific conditions, including raised lipid concentrations, diabetes, and hypertension.

The results showed that none of the eight trials reporting on total mortality showed strong evidence of a reduction in this end point, but pooling the data gave a 17% reduction in all cause mortality (relative risk 0.83 (95% confidence interval 0.73 to 0.95)).

Further analysis showed a 30% reduction in combined fatal and non-fatal cardiovascular events with statins (relative risk 0.7 (0.61 to 0.79)).

Professor Ebrahim said, “Estimates of benefit were in line with previous reviews, but as we included only low risk people, confidence intervals were wide. Absolute benefits were small, and evidence of selective reporting of outcomes makes the evidence less robust.”

Previous systematic reviews of statins in primary prevention have shown greater benefits, but some of these included trials in which more than 10% of patients had a previous history of cardiovascular disease, the Cochrane reviewers said. The baseline rates of all cause mortality events in two recent reviews were 1.4 and 1.7 per 100 person years at risk, which was higher than the 1 per 100 in the Cochrane review.

Despite efforts to minimise bias in terms of blinding and use of intention to treat analysis, the review found that more than a third of trials reported outcomes selectively. And some trials were stopped early after reaching end points.

“In primary prevention where worldwide the numbers of patients eligible for treatment are massive, there might be motivations to use composite outcomes and early stopping to get results that clearly support intervention,” suggested the Cochrane reviewers.

They also pointed out that all but one of the trials they included had drug company sponsorship. Published trials that are drug industry sponsored are more likely than trials without such sponsorship to report results that favour drug over placebo, they said.

In an accompanying editorial Carl Heneghan, director of the Centre for Evidence-Based Medicine at the University of Oxford, said, “The Cochrane Review guidance is helpful in highlighting that the current evidence does not support use of statins below a 1% annual all cause mortality risk or an annual CVD event rate of below 2%” (www.thecochranelibrary.com/details/editorial/983199/Considerable-uncertainty-remains-in-the-evidence-for-primary-prevention-of-cardi.html).

He added that this is in line with guidance from the National Institute for Health and Clinical Excellence, which suggests that statins should be used as part of the management strategy for the primary prevention of cardiovascular disease in adults who have a 20% or greater 10 year risk of developing it.

“Some patients may be taking statins with little chance of benefit because their CVD risk is low,” said Professor Ebrahim. “This is a waste of NHS money and exposes patients to potential—and inadequately assessed—harms.”