ACC 2009: JUPITER: Rosuvastatin Reduces Risk of VTE in Healthy Subjects

March 29, 2009

UPDATED March 29, 2009 (Orlando, Florida) —The use of rosuvastatin (Crestor, AstraZeneca) in healthy individuals reduced the risk of symptomatic venous thromboembolism (VTE), and the treatment effect was similar to and independent of the previously reported reduction in cardiovascular events [1].

The findings, from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), presented during a late-breaking clinical-trials session at the American College of Cardiology 2009 Scientific Sessions and published online today in the New England Journal of Medicine, suggest a widening use of statins in different patient populations.

Presenting the results during an afternoon press conference, lead investigator Dr Robert Glynn (Brigham and Women's Hospital, Boston, MA) said that VTE is a "big, common, terrible event" that is less understood than other arterial conditions and that JUPITER is not the first study to show VTE to be as prevalent as and in some studies more prevalent than MI and stroke.

Yet when middle-aged adults see their physician "and are fortunate not to have a vascular event, and they talk about ways to keep that up for the next year, VTE is not part of the conversation," said Glynn. "And yet it's really common. The doctor has nothing to do for it, so that's why it's not part of the conversation. There are no primary-prevention strategies."

Are There Shared Venous and Arterial Pathways?

Although venous and arterial thrombosis can often occur together and share some risk factors, the JUPITER researchers note that there is still controversy regarding the "nature and extent of their shared pathways" and whether treatments for one condition can have consistent benefits in the other. The existing data are mixed in terms of benefits with the use of statins in VTE.

The JUPITER trial included 17 802 healthy men and women assigned to rosuvastatin 20 mg or placebo and was designed to assess whether statin therapy should be given to apparently healthy individuals with normal LDL cholesterols but elevated C-reactive-protein (CRP) levels (>2.0 mg/L). The occurrence of VTE was a protocol-specific secondary end point of the trial, and patients were followed for the first occurrence of pulmonary embolism or deep-vein thrombosis (DVT).

During a median follow-up of 1.9 years--the JUPITER trial was stopped early based on evidence of a reduction in cardiovascular morbidity and mortality among patients treated with rosuvastatin--there was an observed 43% reduction in the risk of VTE among those treated with statin therapy. Overall, there was a significant reduction in the risk of DVT, but only a statistically nonsignificant trend toward reducing pulmonary-embolism events. None of the baseline characteristics modified the relationship of rosuvastatin to the risk of VTE, report the researchers.

Occurrence of Venous Thromboembolism

End point Patients with event, rosuvastatin (n=8901) Events/100 person-years, rosuvastatin, n Patients with event, placebo (n=8901), n Events/100 person-years, placebo, n Hazard ratio (95% CI)
Total VTE 34 0.18 60 0.32 0.57 (0.37–0.86)
Unprovoked* 19 0.10 31 0.17 0.61 (0.35–1.09)
Provoked* 15 0.08 29 0.16 0.52 (0.28–0.96)
Pulmonary embolism 17 0.09 22 0.12 0.77 (0.41–1.45)
DVT only 17 0.09 38 0.20 0.45 (0.25–0.79)

*Unprovoked VTE is defined as VTE occurring in the absence of a known malignant condition, trauma, hospitalization, or surgery, whereas a provoked VTE occurs in patients with cancer, during or shortly after trauma, hospitalization, or surgery.

Additional analyses were performed to identify the independent effects of rosuvastatin on VTE beyond the benefits in arterial events observed in the JUPITER trial. Among those who had VTE as the first event, there was a significant 43% reduction in risk. This reduction in the risk of VTE as a first event is similar to the 44% reduction in risk associated with rosuvastatin for the prevention of a primary cardiovascular event.

Occurrence of Venous Thromboembolism and Cardiovascular Events

End point Patients with event, rosuvastatin (n=8901), n Events/100 person-years, rosuvastatin, n Patients with event, placebo (n=8901), n Events/100 person-years, placebo, n Hazard ratio (95% CI)
VTE with no prior cardiovascular event 32 0.17 56 0.30 0.57 (0.37–0.88)
Cardiovascular event with no prior VTE 141 0.76 249 1.35 0.56 (0.46–0.69)
VTE after cardiovascular event 2 0.61 4 0.65 0.98 (0.18–5.34)
First cardiovascular event or VTE 173 0.93 305 1.66 0.56 (0.47–0.68)

The group notes the rates of VTE were not different in placebo patients who had LDL-cholesterol or triglyceride levels that exceeded specified cut points or those who had HDL cholesterol levels below specified cut points. These findings, they write, are consistent with other studies showing no association between triglycerides, LDL and HDL cholesterol, and the risk of VTE.

Speaking with the media, Glynn said that the benefit of statins in VTE is not likely through their effect on lipids. Statins, on the other hand, do have pronounced anticoagulant effects, as well as effects on inflammation, and this has been hypothesized as the mechanism of benefit. Despite the possible anticoagulant effect, investigators did not observe a bleeding risk in statin-treated patients, although future studies are needed to understand why statins work in the VTE setting.

Glynn said that the reduced risk of VTE in statin-treated primary-prevention patients must be included in the net benefit of statin therapy and should be considered as part of the wider treatment goal. The risk reduction of VTE is consistent with the overall trial, but the number needed to treat to prevent one primary end point, which was 25 over five years in JUPITER, is further reduced to 21 when VTE is included.

"There is no suggestion here that one initiates statin therapy focused directly on venous thromboembolism," said Glynn. "The suggestion is that it be considered with the coronary events. Some years ago, the focus on statins was only on coronary events, and now it's widely and appropriately used in stroke. We're suggesting a wider treatment target indicates a greater benefit."

To heartwire , Dr James Stein (University of Wisconsin, Madison), who was not part of the JUPITER study, said the absolute rates of DVT and pulmonary embolism were low, but similar, as Glynn noted, to the rates of stroke and MI.

"So if you think the benefit of statins on MIs and strokes in this study were important, you have to think the benefit on VTE is important, too," he said. "DVT reduction added to the net benefit of being on a statin and was not just in CV patients who happened to be hospitalized."

AstraZeneca funded the JUPITER trial. Glynn reports receiving research support from AstraZeneca.

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