|Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis
|Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B, Klarenbach S, McAlister FA, Wiebe N, Manns B, Alberta Kidney Disease Network
The review concluded that both low- and high-potency statins were efficacious in preventing death and cardiovascular-related morbidity in people at low risk of cardiovascular events, although the number needed to treat to prevent one adverse outcome was relatively high for any statin. The authors' conclusions reflect the evidence available and appear likely to be reliable.
To assess the efficacy and harms of statins in people at low cardiovascular risk.
MEDLINE and EMBASE were searched to January 2011 without language restrictions. Search terms were reported and a modified search strategy from a previous systematic review was used. Health technology assessment and clinical trial registries were searched. Reference lists of relevant reviews were checked. Manufacturers were contacted for further studies and unpublished reports.
Eligible studies were parallel group randomised controlled trials (RCTs) that compared a statin against no statin treatment in patients (≥16 years) at low cardiovascular risk (definition provided) who were followed up for at least six months. Eligible statins were atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin. Studies had to report at least one of all-cause mortality, unstable angina, acute myocardial infarction (fatal or nonfatal), stroke or transient ischaemic attack (fatal or nonfatal), surgical or percutaneous revascularisation, length of stay, quality of life, persistence on statin therapy and adverse events. Trials with fewer than 30 participants per study arm were excluded.
Participants had a median age of 58 years (range 51 to 76). Zero to 100% (median 62%) of participants were male. Around half of the participants had hypertension. Mean 10-year risk of cardiovascular-related death or nonfatal myocardial infarction was 6% (range zero to 18%). The median baseline level of low-density lipoprotein cholesterol was 4.0mmol/L (range 2.8 to 5.2mmol/L). All six types of statin were studied. Around one third of the trials used pravastatin. Comparator treatments varied; most studies used placebo.
Two reviewers independently selected studies for inclusion. Disagreements were resolved by a third reviewer through consensus.
Assessment of study quality
Twelve criteria were assessed for areas such as randomisation, blinding, attrition, statistical analysis and presentation of results.
Two reviewers independently assessed study quality (risk of bias). Disagreements resolved by a third reviewer through consensus.
Intention-to-treat data (where reported) were extracted to calculate relative risks (RR) with 95% confidence intervals (CI). Investigators were contacted when numbers of cardiovascular-related deaths or nonfatal myocardial infarction were unclear.
One reviewer extracted data which were checked by a second reviewer.
Methods of synthesis
Meta-analyses were performed to calculate pooled relative risks and 95% CIs using a random-effects model. Heterogeneity was assessed using the I2 statistic. The number needed to treat (NNT) and absolute risk reduction were calculated for outcomes with statistically significant risk ratios. Publication bias was assessed using a weighted regression test. Indirect comparisons were performed.
Univariable and bivariable meta-regression analyses were used to examine factors that may have influenced the association between statins and all-cause mortality: duration of study, year of study, baseline cholesterol levels, observed annual cardiovascular risk in the control group, absolute and percentage change in low-density lipoprotein cholesterol from baseline in the statin group, the point at which low-density lipoprotein cholesterol was measured, daily initial dose of statin, potency of statin, mean age of participants, proportion of male participants, proportion who had diabetes, proportion who had hypertension and risk of bias items. Subgroup analyses explored the effect of statin potency. In sensitivity analyses the estimated 10-year risk of cardiovascular-related death or nonfatal myocardial infarction for the average participant in each trial was calculated.
Results of the review
Twenty-nine RCTs (80,711 participants, range 74 to 17,802) were included. Median duration of follow up was two years. The authors stated that the trials generally exhibited a moderate risk of bias. Most studies had unclear reporting of allocation concealment methods. There was no evidence of publication bias.
All-cause mortality (RR 0.90, 95% CI 0.84 to 0.97, I2=2%, NNT=239; 19 RCTs), incidence of any type of stroke (RR 0.83, 95% CI 0.74 to 0.93, I2=0%, NNT=291; 14 RCTs), incidence of any type of myocardial infarction (RR 0.63, 95% CI 0.50 to 0.79, I2=13%, NNT=216; 13 RCTs) and coronary revascularisations (RR 0.66, 95% CI 0.57 to 0.77, I2=7%, NNT=131; eight RCTs) were all significantly lower following statin treatment compared to control treatment. There was no significant difference for fatal myocardial infarctions (eight RCTs), fatal strokes (five RCTs) and serious adverse events (17 RCTs). Results of sensitivity analyses were broadly similar to the results of the main analyses.
Indirect comparisons showed no significant differences between high- and low-potency statins in terms of all-cause mortality, fatal or non-fatal myocardial infarction and stroke. Results for other outcomes were reported.
Both low- and high-potency statins were efficacious in preventing death and cardiovascular-related morbidity in people at low risk of cardiovascular events, although the number needed to treat to prevent one adverse outcome was relatively high for any statin.
The review addressed a clear question and was supported by appropriate inclusion criteria. Attempts to identify relevant studies in any language were undertaken by searching two electronic databases and checking references. Suitable methods (such as independent duplicate processes) were employed throughout the review to reduce risks of reviewer error and bias. Study quality was assessed with the results used in a sensitivity analysis. It was unclear exactly how the overall assessment of risk of bias was produced. Sufficient study details were provided except for control treatment details in individual studies. Appropriate methods were used to pool data and assess and investigate heterogeneity.
The authors' conclusions reflect the evidence available and appear likely to be reliable.
Implications of the review for practice and research
Practice: The authors stated that the as-yet unproven potential for high-potency statins to prevent cardiovascular outcomes more effectively must be balanced against their higher costs compared with low-potency statins.
Research: The authors stated that an individual patient data analysis in low risk patients (including published and unpublished data) would be a useful addition to the literature.
Canadian Agency for Drugs and Technology in Health; Alberta Heritage Foundation for Medical Research Interdisciplinary Team Grants Program.
Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B, Klarenbach S, McAlister FA, Wiebe N, Manns B, Alberta Kidney Disease Network. Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ: Canadian Medical Association Journal 2011; 183(16): E1189-E1202
Subject indexing assigned by NLM
Angina, Unstable /epidemiology; Cardiovascular Diseases /prevention & Diabetes Mellitus /epidemiology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors /therapeutic use; Myocardial Infarction /epidemiology; Myocardial Revascularization /statistics & Neoplasms /epidemiology; Primary Prevention; Randomized Controlled Trials as Topic; Rhabdomyolysis /epidemiology; Risk Assessment; Stroke /epidemiology; control; numerical data
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