Large Metaanalysis Finds Statins Effective in Low Risk Patients Reply

A very large metaanalysis provides strong evidence that the relative reduction in risk of statins is at least as great in low-risk patients as in high-risk patients. The finding, write the authors, provides evidence that expansion of guidelines to lower risk populations should be considered.

In their paper in the Lancet, the  the Cholesterol Treatment Trialists’ (CTT) Collaborators analyzed data from 134,537 patients in trials comparing statins to control therapy and 39,612 patients in trials comparing low and high dose statins. They examined the impact of statin therapy according to the baseline 5-year risk of a major vascular event on control therapy.  Statin therapy caused a consistent reduction in the relative risk of major vascular events and all-cause mortality independent of other factors, including age, sex, baseline LDL cholesterol, or established CV disease.

Here is the rate ratio for major vascular events across five levels of risk at baseline (note that 1 mmol of LDL cholesterol is equivalent to about 39 mg/dl of LDL):

        5 Year Risk         Rate ratio per 1.0 mmol/L of LDL reduction

  • <5%                          0·62 [99% CI 0·47–0·81]
  • ≥5% to <10%          0·69 [99% CI 0·60–0·79]
  • ≥10% to <20%       0·79 [99% CI 0·74–0·85]
  • ≥20% to <30%       0·81 [99% CI 0·77–0·86]
  •  ≥30%                       0·79 [99% CI 0·74–0·84]

The metaanalysis found no evidence for harm associated with statin therapy, including cancer or other non-vascular mortality.

The authors noted that people in the lowest two categories of risk in the study, who are expected to have a 5 year event rate lower than 10%, are not recommended for statin therapy in current guidelines. As generic statins are highly cost-effective, the result “suggests that these guidelines might need to be reconsidered.”

In an accompanying comment, Shah Ebrahim and Juan Casas ask whether everyone over the age of 50 should take statins. They calculate that, in the UK, adoption of a threshold of 10% would result in 83% of men over 50 years of age and 56% of women over the age of 60 as needing statins.

Here is the press release from the Lancet:

Meta-analysis confirms benefit of statins in those with no previous history of vascular disease and calls for guidelines to be reviewed (The Lancet)

Statin therapy safely reduces the risk of major vascular events (non-fatal heart attacks, strokes, and revascularisation surgery) by about a fifth in a wide range of individuals, including those with no previous history of vascular disease, both men and women, and the old and young, according to results of a new meta-analysis published Online First in The Lancet. These findings confirm the effectiveness of statins for primary prevention (preventing the development of vascular disease) and demonstrate that the benefits of widespread statin use greatly outweigh any known side effects, suggesting that current national and international treatment guidelines might need to be reviewed.

Cholesterol-lowering with statins is one of the most widely used treatments for patients with cardiovascular disease (CVD) and the benefits are well established. However, it is less clear if statins benefit those without CVD. Furthermore, although individuals without previous vascular disease are at low risk, at least half of all vascular events will occur among this group. At present, guidelines in the USA, Europe, and the UK restrict statins to people whose 10-year risk of a major vascular event is at least 20%.

In this study, the Cholesterol Treatment Trialists’ (CTT) Collaborators did a meta-analysis of 175 000 individuals in 27 randomised trials to explore the effects of lowering LDL cholesterol with statin therapy. Participants were grouped into one of five baseline categories of 5-year major vascular event risk. Outcomes were studied in trials comparing statin with no statin treatment and of more versus less intensive statin regimens.

The researchers found that statins reduced the risk of serious vascular events by 21% for each 1mmol/L reduction in LDL cholesterol in each of the 5 baseline risk groups, including those people with the lowest risk of vascular disease.

In individuals with a 5-year risk lower than 10% (comprising the two groups of lowest risk in these analyses), the already small risk was significantly lowered even in those without a history of vascular disease, mainly due to the reduction in major coronary events and revascularisation surgery. Indeed, the proportional reduction in major vascular events in the two lowest risk categories was at least as big as in the higher risk categories.

The authors say: “In individuals with 5-year risk of major vascular events lower than 10%, each 1mmol/L reduction in LDL cholesterol produces 11 fewer major vascular events per 1000 treated over 5 years, a benefit that greatly exceeds any known hazards of statin therapy.”

They note that there was no evidence that statin therapy increased cancer incidence or deaths from cancer or other non-vascular causes, adding that: “Statins may produce small increased risks of haemorrhagic strokes and in diagnoses of diabetes, but the definite benefits of statins greatly outweigh these potential hazards.”*

They conclude: “The present report shows that statins are indeed both effective and safe for people with a 5-year risk of major vascular events lower than 10% who would typically not be judged suitable for statin treatment…and, therefore, suggests that treatment guidelines might need to be reconsidered.

In an accompanying Comment, Shah Ebrahim from the London School of Hygiene and Tropical Medicine and Juan P Casas from University College and the London School Hygiene and Tropical Medicine, London point out: “Translation of the CTT findings into practice will require more affordable ways to identify individuals for treatment and keep them on optimal regimens. Because most people older than 50 years are likely to be at greater than 10% 10-year risk of CVD it would be more pragmatic to use age as the only indicator for statin prescription as originally proposed for the polypill. This approach would avoid the costs, ranging from £7 to more than £700 per patient screened, of vascular screening checks recently implemented in the UK.”

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