Authors' objectives

To estimate the reduced risk of coronary heart disease and total mortality associated with statin drug treatment, particularly in elderly individuals and women.

Searching

MEDLINE was searched from 1966 to December 1998 using the following MeSH: 'hydroxy-methyl-glutaryl-CoA reductase inhibitors', 'simvastin', 'lovastatin', 'pravastatin', 'coronary disease' and 'myocardial infarction'. In addition, the keywords 'statin' and 'coronary heart disease' were used. The search was restricted to those studies conducted in human participants, published in English language journals, and classified as clinical trials in the MEDLINE database. A manual search was also performed using the authors' reference files and reference lists from original communications and review articles.

Study selection

Assessment of study quality

The authors do not state that they assessed validity.

Data extraction

All data were abstracted in duplicate using a standardised protocol and reporting form. Any disagreements were resolved by consensus. The authors of the primary studies were not contacted for additional information.

The categories of data extracted from the study were: the name of the study, the year of publication, and the country of origin; the number of participants; the mean age, and the age and gender distributions of the participants; the presence of pre-existing myocardial infarction; the mean baseline levels of total-, LDL- and HDL- cholesterol, and triglycerides; the net changes in lipids during intervention; the type and dosage of statin; the duration of the intervention; and the results for major cardiovascular events.

Methods of synthesis

Results of the review

Five randomised, placebo-controlled, double-blind trials comprising a total of 30,817 participants were included.

The mean length of follow-up was 5.4 years. All the chi-squared tests for heterogeneity were non significant. Statin drug treatment was associated with a mean reduction (weighted by sample size) of 20% in the total cholesterol level, 28% in LDL-cholesterol levels, and 13% in triglyceride levels. However, it was also associated with a mean increase of 5% in HDL-cholesterol levels. Overall, statin drug treatment reduced the risk of major coronary events by 31% (95% confidence interval, CI: 26, 36, P<0.001) and fatal coronary disease by 29% (95% CI: 20, 36, P<0.001). Compared with the control groups, active treatment was associated with an absolute risk reduction in coronary disease of 36 events and 13 deaths per 1,000 patients. The NNT was 28 to prevent a major coronary event and 75 to prevent a death from coronary disease. Compared with the control groups, those receiving active treatment had a 21% reduction in all-cause mortality (95% CI: 14, 28, P<0.01) and a 27% reduction in the odds of cardiovascular mortality (95% CI: 19, 34, P<0.001). Active treatment was also associated with an absolute risk reduction of 16 and 14 deaths per 1,000 patients from all-causes and cardiovascular disease, respectively. The corresponding NNTs to prevent death were 61 (all-causes) and 69 (cardiovascular disease). Noncardiovascular mortality was similar in bot the active treatment and control groups, with an OR of 0.93 (95% CI: 0.81, 1.07, P=0.29).

Treatment effects in primary and secondary prevention trials.

Active treatment was associated with a 34% risk reduction (95% CI: 23, 43, P<0.001) in major coronary events in the 2 primary prevention trials, and a 30% risk reduction (95% CI: 24, 35, P<0.001) in the 3 secondary prevention trials. In addition, it was associated with a lower risk of coronary disease mortality (OR 0.73, 95% CI: 0.51, 1.05, P=0.09), cardiovascular mortality (OR 0.68, 95% CI: 0.50, 0.93, P=0.01), and all-cause mortality (OR 0.87, 95% CI: 0.71, 1.06, P=0.18) in the 2 primary prevention trials. Active treatment was also associated with a lower risk of coronary disease mortality (OR 0.71, 95% CI: 0.63, 0.80, P<0.001), cardiovascular mortality (OR 0.73, 95% CI: 0.66, 0.82, P<0.001), and all-cause mortality (OR 0.77, 95% CI: 0.70, 0.85, P<0.001) in the 3 secondary prevention trials.

Active treatment was not significantly associated with a change in noncardiovascular mortality in either the 2 primary prevention trials (OR 1.04, 95% CI: 0.80, 1.35, P=0.75) or the 3 secondary prevention trials (OR 0.89, 95% CI: 0.75, 1.04, P=0.15).

Treatment effects according to gender and age.

The risk reduction in major coronary events was similar for women (29%, 95% CI: 13, 42, P<0.001) and for men (31%, 95% CI: 26, 35, P<0.001). The absolute risk reduction was also similar in women (33 deaths per 1,000 patients, 95% CI: 13, 52) and men (37 deaths per 1,000 patients, 95% CI: 29, 44).

The overall, proportional risk reduction was similar for persons aged at least 65 years (32%, 95% CI: 23, 39, P<0.001) and those aged younger than 65 years (31%, 95%: 24, 36, P<0.001). The absolute risk reduction was slightly higher in persons aged at least 65 years (44 deaths per 1,000 patients, 95% CI: 30, 58), compared with persons younger than 65 years (32 deaths per 1,000 patients, 95% CI: 24, 40).

Sensitivity analysis: after including the 12 small non-outcome trials, the estimates for risk reduction were virtually unchanged. The risk reduction was 31% (95% CI: 26, 35, P<0.001) for major coronary events, 28% (95% CI: 19, 35, P<0.001) for fatal coronary disease, 27% (95% CI: 19, 34, P<0.001) for cardiovascular disease mortality, and 22% (95% CI: 15, 28, P<0.001) for all-cause mortality. The mortality from noncardiovascular disease was not significantly different between the placebo and treatment groups (OR 0.91, 95% CI: 0.80, 1.04, P=0.18).

Safety: the OR was 0.99 (95% CI: 0.90, 1.08, P=0.76) for cancer cases and 1.25 (95% CI: 0.83, 1.89, P=0.29) for asymptomatic episodes of elevated creatine kinase concentrations (greater than 10 times the upper reference limit). The OR for increased aspartate or alanine aminotransferase levels (greater than 3 times the upper reference limit) was 1.13 (95% CI: 0.95, 1.33, P=0.17).

Authors' conclusions

Our meta-analysis indicated that the reduction in LDL-cholesterol associated with statin drug treatment resulted in a decreased risk of coronary heart disease and all-cause mortality. The risk reduction was similar for men and women, and for elderly and middle-aged people.

CRD commentary

The review question and the inclusion criteria were stated clearly. Details of the primary studies were tabulated, although the adverse effects and number of withdrawals or drop-outs were not reported. The chi-squared tests for heterogeneity were conducted before the data were combined.

The search strategy was limited in that only one database was searched and only English language publications were included. In addition, there was no attempt to identify unpublished literature, and consequently a publication bias cannot be ruled out. However, it is unlikely that a large study will have been missed.

The validity of the included studies was not assessed, but only double-blind randomised controlled trials were included. Furthermore, all the included studies had sample sizes of at least 4,000 and follow-up periods of at least 5 years. The approach used to synthesise the results of the individual studies was appropriate, and heterogeneity was investigated. A sensitivity analysis was performed, which demonstrated the robustness of the review's findings.

The authors' conclusions were supported by the results.

Implications of the review for practice and research

Practice: The authors state that the benefits, in terms of morbidity, of lowering LDL-cholesterol have been under appreciated, particularly in older age groups. Prevention of morbid events results in a lower prevalence of congestive heart failure, angina, significant arrhythmia and debilitating strokes. Such interventions are likely to have a beneficial effect on both the quality of life for the individual patients, and the cost of caring for older patients imposed on families and societies. By placing undue attention on mortality alone as a measure of the success or failure of an intervention, clinicians fail to account for the importance of avoiding such disabilities.

Research: The authors did not state any implications for further research.

Bibliographic details

LaRosa J C, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282(24): 2340-2346. [PubMed: 10612322]

Original Paper URL

http://jama.ama-assn.org/

Other publications of related interest

Fleiss JL. Measures of effect size for categorical data. In: Cooper H, Hedges LV, editors. The handbook of research synthesis. New York (NY): Russell Sage Foundation; 1994. p. 246-60.

This additional published commentary may also be of interest. Statins and risk of coronary heart disease [letters]. JAMA 2000;283:2935-6.

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Anticholesteremic Agents /therapeutic use; Cholesterol, LDL /blood; Coronary Disease /epidemiology /prevention & control; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors /therapeutic use; Lipoproteins /blood; Male; Middle Aged; Mortality; Randomized Controlled Trials as Topic; Risk

AccessionNumber

12000008000

Database entry date

30/04/2002

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.