ASPIRE Trial – Aspirin for VTE Prophylaxis

The ASPIRE trial, recently published in the NEJM, examined the role of aspirin after patients with VTE’s had completed at least 6 weeks of full anticoagulation (although most completed 6+ months).  This is the sister trial to the WARFASA trial, which required 6-18 months of warfarin therapy.

Important Inclusion/Exclusion Criteria

• Included patients with a first-ever, unprovoked VTE after completion of 6 weeks to 24 months of full anticoagulation therapy
• “Provoked” VTE’s included confinement to bed, major surgery, pregnancy, and oral contraceptives/hormone replacement therapy

Study Design

• Multicenter, randomized, double-blind study
• Randomized to aspirin 100 mg daily or placebo for 2-4 years
• Primary efficacy endpoint: symptomatic recurrent VTE (DVT or PE)
• Primary safety endpoint: major or clinically relevant non-major bleeding

An Underpowered Study

• Originally, the trial was designed and powered for 3,000 patients; however, this number was reduced to a goal of 1,500 patients due to slow recruitment
• With the smaller enrollment goal, the trial was powered for a secondary endpoint of major vascular events (composite of VTE, MI, CVA, cardiovascular death)
• It was prospectively determined that the trial results would be combined with its sister trial, WARFASA, to be powered for the recurrent VTE
• In the end, the trial completed enrollment of only 822 patients, which severely limited its power

Results

• Included 822 patients with most (73%) completing at least 6 months of full anticoagulation prior to enrollment.  Patients completed a median of about 27 months of study treatment.
• There was no difference in the primary endpoint (recurrent VTE) between aspirin and placebo (14% vs. 18%, HR 0.52 to 1.05, p=0.09)
  • Recall that the study was severely underpowered to detect a difference
  • The WARFASA trial had a 2-year recurrence rate of 6.6% (aspirin) and 11.2% (placebo)
• The “main” secondary endpoint (major vascular events) was improved with aspirin (5.2% per year vs. 8% per year, p=0.01, NNT 35)
• Bleeding events were rare and no different between treatment groups

“In this context, aspirin, although substantially less effective than warfarin, provides an attractive alternative because it is simple and inexpensive and its safety profile is well documented.”

– ASPIRE author conclusion

Pooled Data with WARFASA

The ASPIRE and WARFASA trials were designed a priori to be combined in a single analysis.  The authors report the results of the pooled analysis within the ASPIRE manuscript:

• Recurrent VTE was improved with aspirin (HR 0.68, 95% CI 0.51 to 0.90)
• Major vascular events were improved with aspirin (HR 0.66, 95% CI 0.51 to 0.86)
• Clinically relevant bleeding was no different between aspirin and placebo (HR 1.47, 95% CI 0.70 to 3.08)

Discussion and Conclusion

• Although ASPIRE was dramatically underpowered, it generally supports the same data (particularly in a pooled analysis) as WARFASA
• Pharmacologically, 81 mg should have the same antiplatelet effect as the higher aspirin dose used in both ASPIRE and WARFASA (100 mg)
• Given the extremely favorable side safety profile, aspirin therapy should be considered in patients with unprovoked VTE’s after completing an appropriate duration of full anticoagulation