Interpreting The JUPITER Trial: Statins can prevent VTE, but more study is needed
ABSTRACTAnalysis of a secondary end point of the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) found that a statin reduced the risk of venous thromboembolism (VTE) in apparently healthy people with high levels of C-reactive protein and normal levels of low-density lipoprotein cholesterol (N Engl J Med 2009; 360:1851– 1861). Still, pending more study, statins should not be substituted for proven prophylaxis and anticoagulation, especially for patients with recurrent deep venous thrombosis, hospitalized patients, postoperative patients, and other patients prone to VTE.
KEY POINTS
- Risk factors for VTE overlap with those for arterial thrombosis, although the data are mixed.
- The statin drugs have a number of effects on factors other than lipid levels, notably on markers of inflammation and on clotting factors.
- In the JUPITER trial, the incidence of VTE in people taking rosuvastatin (Crestor) 20 mg/day was about half that in people taking placebo. This was a relatively healthy population, and the incidence in both groups was low.
- Further study is needed in patients at risk of VTE.
Rosuvastatin prevents heart attack, stroke
On the recommendation of the trial’s independent data and safety monitoring board, JUPITER was stopped early because the trial drug showed evidence of efficacy in preventing the combined primary end point of a first major cardiovascular event—ie, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from a cardiovascular cause.22 (The cardiovascular outcomes of the JUPITER study were reviewed by Shishehbor and Hazen23 in the January 2009 issue of the Cleveland Clinic Journal of Medicine; see doi:10.3949/ccjm.75a.08105).
Formal follow-up for the trial's primary and secondary efficacy end points ended then, but data on VTE continued to be collected until each patient’s closeout visit as part of a safety monitoring protocol. The last closeout visit occurred on August 20, 2008. The primary analysis focused on events occurring up to March 30, 2008, the date the study was stopped.
Secondary end point results: Rosuvastatin prevents VTE
At a median follow-up of 1.9 years, an episode of VTE had occurred in 94 (0.53%) of the 17,802 patients—34 in the rosuvastatin group and 60 in the placebo group.1 This translates to 0.18 and 0.32 events per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for the rosuvastatin group 0.57, 95% confidence interval [CI] 0.37–0.86, P = .007).
Forty-four cases of VTE were classified as provoked and 50 cases were categorized as unprovoked. The risk reduction was statistically significant for provoked cases (hazard ratio 0.52, 95% CI 0.28–0.96, P = .03), but not for unprovoked events (hazard ratio 0.61, 95% CI 0.35–1.09, P = .09).
Subgroup analysis revealed no significant association between patient characteristics and the impact of rosuvastatin on the risk of a VTE event, but, as expected, more benefit was associated with higher baseline lipid levels.
STILL TOO SOON TO ADVISE ROUTINE STATIN USE TO PREVENT VTE
While the JUPITER trial data show an apparent benefit of statin use on the rate of VTE events, advising routine use of statins to prevent VTE is premature, for three main reasons.
Many must be treated to prevent one case of VTE. The number needed to treat (NNT) with rosuvastatin for 5 years to prevent either a case of VTE or a cardiovascular event was 21, and the NNT to prevent one cardiovascular event was 25. In a review of the two most recent case-control studies investigating the effects of statins on VTE,18,19 Cushman24 calculated that the NNT to prevent one VTE event each year was 333 for those age 75 and older. Though the Jupiter data did not provide the specific incidence of VTE at 1 year, except graphically, we can estimate that the NNT to prevent one VTE event at 1 year in the study is also very high.
Practically speaking, the perceived benefits of VTE prevention require large numbers to be treated, and the net clinical gain is still largely in preventing arterial events such as heart attack and stroke rather than VTE.
Statins, though safe, can still have adverse effects. The JUPITER study found a trend (albeit nonsignificant) toward more muscle complaints and elevations on liver function testing in apparently healthy persons taking a statin.22 Although severe complications of statin therapy such as rhabdomyolysis and elevations of creatine phosphokinase are rare, patients taking a statin have a 39% higher risk of an adverse event, most commonly myalgias or abnormalities on liver function testing.25 Were statins to be given routinely to even more people than they are now, more adverse outcomes would be likely.
More study is needed. The JUPITER study did not address a high risk of VTE. In fact, the investigators provided no information as to the VTE history of those enrolled.
Clearly, statins should not be substituted for proven prophylaxis and anticoagulation without further investigation, especially for patients with recurrent deep venous thrombosis, hospitalized patients, postoperative patients, and other patients prone to VTE.
OUR VIEW
The JUPITER study is an important leap forward in adding to our knowledge of how to prevent VTE. For people with another indication for taking a statin (eg, a previous cardiovascular event, hyperlipidemia), it is helpful to know that their risk of VTE may be reduced without exposure to the risks of other kinds of conventional thromboprophylaxis.
We look forward to additional studies to elaborate on the benefits of statins in both the prevention and treatment of VTE for averagerisk and VTE-prone populations.
