Expert Review: Acute Coronary Syndrome, Lipid / Metabolic

Lowering LDL-C with statins in patients at low risk of vascular disease: a meta-analysis


Both clinical trials and very large meta-analyses have shown that statins reduce LDL- cholesterol (LDL-C) and prevent cardiovascular disease (CVD) events. This meta-analysis explored the lipid-lowering effects of statin therapy in patients at very low risk of CVD.

Knowledge Gap
There has been some controversy over the role of statins in primary prevention, especially whether this therapy benefits people who are at low risk of CVD. This meta-analysis compared the efficacy of statins in people at varying degrees of CVD risk to see if the benefits persisted at low risk levels.

This study was conducted as a meta-analysis using individual participant data from 22
trials of statin therapy compared with placebo (n=134537; mean LDL-C difference 1·08 mmol/L; median follow-up 4·8 years), and five trials of high-dose compared with lower-dose statin therapy (n=39 612; difference 0·51 mmol/L; 5·1 years).

The endpoint was major CVD events defined as major coronary events, strokes, or coronary revascularisations. The analysis was performed using baseline five-year major cardiovascular event rates on control therapy (no statin or low-intensity statin) ranging from<5%, to ≥30%. The CVD event rate reduction ratio (RR) per 1.0 mmol/L LDL-C was calculated.

Statin therapy reduced the risk of CVD events by 21% (RR 0·79[0·77–0·81], per 1·0 mmol/L reduction) irrespective of age, gender, baseline LDL-C or presence of previous CVD.

The proportional reduction in CVD events was similar in the lower-risk as in the higher-risk categories (range 0·62[0·47–0·81] to 0·79[0·74–0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57[0·36–0·89], and 0·61[0·50–0·74], p<0·001) and in coronary revascularisations (RR 0·52[0·35–0·75], and 0·63[0·51–0·79]; p<0·001). For stroke, the reduction in risk in participants CVD even rates <10% (0·76[0·61–0·95], p=0·001) was similar to that in higher risk categories (p=0·3).

In participants without a history of CVD statins reduced events by 15% (0·85 [0·77–0·95]) and all-cause mortality by 9% (0·91[0·85–0·97]). The proportional reductions were similar by baseline CVD event risk. There was no evidence that statins increased cancer incidence (RR 1·00[0·96–1·04]), cancer mortality (RR 0·99[0·93–1·06]), or other non-cardiovascular mortality.

This meta-analysis of patients enrolled in clinical trials showed that in individuals with a five-year event rate of major cardiovascular events less than 10%, each 1 mmol/L reduction in LDL-C produced an absolute reduction in major CVD events of 11 per 1000 over five years. This benefit exceeded any known hazards of statin therapy.

Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The report suggests that these guidelines may need to be reconsidered in light of these findings.

Perspective – Clinical Impact

This latest meta-analysis of the randomised trials of statin therapy shows that relative rates of event reduction were similar per 1 mmol LDL-C reduction irrespective of the baseline event rate category.

Large benefits were seen in rates of coronary heart disease events and coronary interventions in the low-risk group. However trial participants are not a randomly selected group, and many of these trials in the meta-analysis included patients who had previously recieved statin therapy. Furthermore, although the database did examine fatal endpoints, it did not investigate harms resulting in morbidity outcomes. Thus the increased rate of diabetes that occurs with statin exposure and is related to the dose of statin did not form part of the analysis, though it would likely significantly impact on any health economic analysis of the data.

Additionally, as statin therapy is extended to lower-risk groups who are asymptomatic for any manifestation of atherosclerosis, adherence becomes a key issue as does the rate of side-effects affecting morbidity. Statins are not side-effect free and the best estimates suggest 2-5% of individuals may be statin intolerant. Despite their known benefits many patients discontinue statins even in secondary prevention within two years of initiation.

In primary prevention the rates of discontinuation are far higher (except in genetic hyperlipidaemias) and can approach 50% at two years.

Recommending statins for lower-risk groups may seem to be a good idea, but unless mechanisms can be devised to ensure compliance and patients are willing to take lifelong medication for overtly absent disease then this will not be an effective intervention or recommendation.

Corresponding author from original paper

Cholesterol Treatment Trialists’ group:

Citation: The Lancet, Early Online Publication, 17 May 2012doi:10.1016/S0140-6736(12)60367-5

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