A randomized trial of rosuvastatin in the prevention of venous thromboembolism

Abstract

Background: Controversy persists regarding the extent of shared pathways between arterial and venous thrombosis and whether treatments of known efficacy for one disease process have consistent benefits for the other. Observational studies have yielded variable estimates of the effect of statin therapy on the risk of venous thromboembolism, and evidence from randomized trials is lacking.

Methods: We randomly assigned 17,802 apparently healthy men and women with both low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to receive rosuvastatin, 20 mg per day, or placebo. We followed participants for the first occurrence of pulmonary embolism or deep-vein thrombosis and performed analyses of the data on an intention-to-treat basis.

Results: During a median follow-up period of 1.9 years (maximum, 5.0), symptomatic venous thromboembolism occurred in 94 participants: 34 in the rosuvastatin group and 60 in the placebo group. The rates of venous thromboembolism were 0.18 and 0.32 event per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio with rosuvastatin, 0.57; 95% confidence interval [CI], 0.37 to 0.86; P=0.007); the corresponding rates for unprovoked venous thromboembolism (i.e., occurring in the absence of a known malignant condition, trauma, hospitalization, or surgery) were 0.10 and 0.17 (hazard ratio, 0.61; 95% CI, 0.35 to 1.09; P=0.09) and for provoked venous thromboembolism (i.e., occurring in patients with cancer or during or shortly after trauma, hospitalization, or surgery), 0.08 and 0.16 (hazard ratio, 0.52; 95% CI, 0.28 to 0.96; P=0.03). The rates of pulmonary embolism were 0.09 in the rosuvastatin group and 0.12 in the placebo group (hazard ratio, 0.77; 95% CI, 0.41 to 1.45; P=0.42), whereas the rates of deep-vein thrombosis only were 0.09 and 0.20, respectively (hazard ratio, 0.45; 95% CI, 0.25 to 0.79; P=0.004). Consistent effects were observed in all the subgroups examined. No significant differences were seen between treatment groups in the rates of bleeding episodes.

Conclusions: In this trial of apparently healthy persons, rosuvastatin significantly reduced the occurrence of symptomatic venous thromboembolism. (ClinicalTrials.gov number, NCT00239681.)

Figure 1

Panel A. Cumulative incidence of venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model. Panel B. Cumulative incidence of unprovoked venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model. Panel C. Cumulative incidence of provoked venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model.

Figure 1

Panel A. Cumulative incidence of venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model. Panel B. Cumulative incidence of unprovoked venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model. Panel C. Cumulative incidence of provoked venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model.

Figure 1

Panel A. Cumulative incidence of venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model. Panel B. Cumulative incidence of unprovoked venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model. Panel C. Cumulative incidence of provoked venous thromboembolism by treatment group in JUPITER. The P-value is based on a likelihood ratio test of the effect of rosuvastatin in a proportional hazards model.

Figure 2

Effects of rosuvastatin on the occurrence of venous thromboembolism according to baseline characteristics. The relative hazards for rosuvastatin as compared with placebo are shown, with the size of each black square proportionate to the number of participants who developed venous thromboembolism in the subgroup; the horizontal lines indicate 95% confidence intervals. The dashed vertical line indicates the overall relative hazard for the complete trial cohort. The incidence rate in the placebo group is the number of events per 100 person-years of follow-up. Not shown are P-values for tests of interaction between rosuvastatin and indicators of subgroup categories, each of which was non-significant (P>0.10). Data were missing for some participants in some subgroups. The metabolic syndrome was defined according to consensus criteria of the American Heart Association and the National Heart, Lung, and Blood Institute.