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Effects of Statins on Nonlipid Serum Markers Associated with Cardiovascular Disease: A Systematic Review

Ethan M. Balk, MD, MPH; Joseph Lau, MD; Leonidas C. Goudas, MD, PhD; Harmon S. Jordan, ScD; Bruce Kupelnick, BA; Linda U. Kim, BA; and Richard H. Karas, MD, PhD
[+] Article and Author Information

From Tufts University School of Medicine and Tufts-New England Medical Center, Boston, Massachusetts.


Grant Support: By RxIntelligence (http://www.rxintelligence.com), a nonprofit organization dedicated to providing independent, objective information comparing the costs and effectiveness of pharmaceuticals.

Potential Financial Conflicts of Interest:Consultancies: R.H. Karas (Merck & Co., Pfizer); Honoraria: R.H. Karas (Merck & Co., Pfizer); Stock ownership or options (other than mutual funds): J. Lau (Merck & Co., Pfizer); Grants received: R.H. Karas (Merck & Co.).

Corresponding Author: Joseph Lau, MD, Tufts-New England Medical Center, Box 63, 750 Washington Street, Boston, MA 02111.

Current Author Addresses: Drs. Lau and Balk, Mr. Jordan, and Mr. Kupelnick: Tufts-New England Medical Center, Box 63, 750 Washington Street, Boston, MA 02111.

Dr. Karas: Tufts-New England Medical Center, Box 80, 750 Washington Street, Boston, MA 02111.

Dr. Goudas: Tufts-New England Medical Center, Box 298, 750 Washington Street, Boston, MA 02111.

Ms. Kim: Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.


Ann Intern Med. 2003;139(8):670-682. doi:10.7326/0003-4819-139-8-200310210-00011
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Background: Statins reduce cardiovascular events to a greater extent than can be explained by their effect on lipids. Several studies have attempted to elucidate mechanisms by which statins reduce cardiovascular risk.

Purpose: To summarize the effects of statins on nonlipid serum markers and to correlate statins' effect on serum markers with lipid levels and cardiovascular outcomes.

Data Sources: MEDLINE (1980 to 2003) search limited to English-language articles.

Study Selection: Studies reporting original data in at least 10 participants on the effect of statins on outcomes of interest, excluding studies of cerivastatin, drug combinations, and patients with organ transplants.

Data Extraction: Study design, sample size, treatment, and outcome data extracted on the basis of preestablished criteria. When appropriate, meta-analysis was performed by using a random-effects model.

Data Synthesis: All statins are effective at lowering C-reactive protein levels, and the effect is not dose-dependent. Studies do not demonstrate a correlation between statins' effects on C-reactive protein levels and on lipids or cardiovascular outcomes. Statins do not affect fibrinogen levels, and limited data suggest little effect on lipid oxidation, tissue plasminogen activator, or plasminogen activator inhibitor. Platelet aggregation data are inconclusive.

Conclusions: Among nonlipid serum markers examined, only C-reactive protein levels are statistically significantly affected by statins. These findings suggest that statin-mediated anti-inflammatory effects may contribute to the ability of statins to reduce risk for cardiovascular disease. Overall, however, available data are insufficient to support recommendations for using nonlipid serum markers in decisions regarding statin therapy for individual patients.

Figures

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Figure 1.
Changes in C-reactive protein (CRP) level: individual studies and summary estimates.(24)

Studies of statin versus placebo by statin. Studies used 2 different metrics to present results: absolute change and percentage change from baseline. Because median values are commonly reported for CRP, the 2 metrics are not convertible. No placebo-controlled trial evaluated fluvastatin. Circles and bars indicate mean and 95% CIs. Squares indicate median values (estimated by subtracting median effect of placebo from median effect of statin). Bays and colleagues reported 2 trials, “Study 133” and “Study 145,” in 1 article. *Statistically significant difference from baseline; †Median, 1.8 (CI, −1.5 to 5.1). ND = no data on statistical significance (remaining results nonsignificant).

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Figure 2.
Direct comparisons of statins' effect on C-reactive protein (CRP) level: individual studies.

Studies that compared the effect of 2 or more statins on CRP levels. No study was placebo-controlled. Average change from baseline shown. Squares indicate median changes; others are mean changes. Solid lines are 95% CIs, which were calculated as described in Methods section. Significance is reported as statistical significance of difference of effect among statins. A = atorvastatin; P = pravastatin; S = simvastatin.

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Figure 3.
Changes in fibrinogen level: individual studies and summary estimates.MIP(45)(50)

Studies of statin versus placebo with summary estimates, by statin, and relative change in fibrinogen level (µmol/L) are shown. Studies of individual cohorts with summary estimates, by statin, and change in fibrinogen level from baseline (µmol/L) are also presented. Circles and bars represent the mean change and 95% CIs for each study. Black circles represent placebo-controlled trials. White circles represent non–placebo-controlled trials. Black squares and bars represent the meta-analysis summary estimate for the given statin. White squares represent subanalyses, as noted, of pravastatin studies (from top to bottom: studies with mean fibrinogen levels greater than 11.75 µmol/L [400 mg/dL]; studies of patients with recent myocardial infarction [ ]; and other studies). Those studies without variance data, indicated as circles without accompanying bars, are not included in meta-analyses. The bottom-most pravastatin study reported a change from baseline of −1.2 µmol/L ( < 0.01); however, reported SD data suggested a nonsignificant change, as shown in graph . Cohort data from top-most simvastatin study not included because measurement tool for fibrinogen changed mid-study .

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Figure 4.
Direct comparisons of statins' effect on fibrinogen level: individual studies.solid line

These studies compared the effect of 2 or more statins on fibrinogen levels. No study was placebo-controlled. Mean changes from baseline and 95% CIs ( ), which were calculated as described in Methods section. Significance is reported as statistical significance of difference of effect among statins. A = atorvastatin; F = fluvastatin; L = lovastatin; ND = not defined; P = pravastatin; S = simvastatin.

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Appendix Figure.
Search and selection of studies for review.
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