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Aspirin, Apixaban, or Warfarin for Extended Treatment of Venous Thrombosis?

Three studies1-3 and two editorials4,5 provide a wealth of insight

Henry I. Bussey, Pharm.D.
January, 2013

The “top line” findings are summarized in the two following paragraphs and more detail is provided below the two paragraphs.

Background: The importance of preventing recurrent symptomatic venous thromboembolism (VTE) is supported by the observation that the recurrent VTE rate is approximately 10%/yr if anticoagulation is stopped. Recurrent VTE has a mortality rate of 5% to 10% and increases the risk of post-thrombotic syndrome by as much as six fold.2 Warfarin anticoagulation is highly effective at preventing VTE recurrence, but usually carries a significant bleeding risk and may be time-consuming and inconvenient to manage. Patient self testing and/or self dosing, however, may reduce these obstacles to warfarin use.6

Top Line Summaries

Aspirin (ASA): Two placebo controlled studies evaluated the benefit of giving 100 mg of aspirin daily to patients who were completing a “standard” course of anticoagulation for a first ever unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE). Combined analysis of the two studies showed that ASA reduced VTE recurrence and other major vascular events (stroke, myocardial infarction, etc.) by slightly more than 30%, with very little increase in bleeding. Because this level of efficacy is probably slightly less than one-half of the protection provided by warfarin anticoagulation, clinicians and patients should weigh the risks, costs, and convenience of ASA vs. warfarin when deciding what therapy to use. Furthermore, one should realize that these results may not apply to individuals with different levels of risks than those studied, or to those who have had more than one VTE episode. Neither study was based in the U.S. which also raises the question of how the U.S. lifestyle and associated obesity rates might alter the results.

Apixaban: Extended treatment with apixaban 2.5 mg or 5 mg twice a day, when compared to placebo in patients who had completed standard therapy for DVT or PE, produced an 81% reduction in VTE recurrence without an increase in major bleeding. Furthermore, the net clinical benefit (defined as the reduction in the composite event rate of recurrent VTE + death due to VTE + myocardial infarction + stroke + death due to cardiovascular disease + major bleed) improved by approximately 76%. That is, the composite event rate of 10.4% on placebo was reduced to 2.4% and 2.5% with 2.5 mg. and 5 mg. apixaban, respectively.

Additional Details

Aspirin: The Aspirin for the Prevention of Recurrent Venous Thrombosis trial (WARFASA for warfarin followed by aspirin or placebo)1 and the Aspirin to Prevent Venous Thromboembolism (ASPIRE)2 evaluated ASA vs. placebo in patients with a first ever episode of DVT or PE. Each was accompanied by informative editorials.4,5 The WARFASA trial was done in Italy and Austria while ASPIRE was a British-based study that included sites in 5 countries. Both studies used 100 mg ASA (ASPIRE used an enteric coated product while WARFASA did not specify). The two studies were designed similarly to facilitate a pooled analysis. The main results are summarized in Table 1. Taken separately, the studies appear to have conflicting results: (1) The 26% reduction in recurrent venous thrombosis (VTE) in ASPIRE was not statistically significant (p=0.09) but the 42% reduction in WARFASA was. (2) ASA did not reduce arterial events in WARFASA but did so in the ASPIRE. When the data were combined, however, patients on ASA had a 32% reduction in VTE recurrence (p=0.007) and a 34% reduction in other major vascular events (such as myocardial infarction and stroke) (p=0.002) without an increase in major or clinically significant bleeding. As discussed in the accompanying editorials, these results suggest that ASA may have intermediate efficacy between a higher recurrence rate if anticoagulation is stopped and a lower recurrence if anticoagulation is continued. The bleeding rate with ASA is comparable to that of well-managed warfarin but lower than that of warfarin that is sub-optimally managed; and, of course, ASA is inexpensive and does not require laboratory monitoring. It would appear that ASA may be a reasonable choice for those with low to moderate risk of bleeding and/or those with low to moderate risk of recurrence. The safety and efficacy of ASA for those at higher risks of bleeding and/or VTE recurrence, however, remains to be determined.

Table 1. Major Findings of ASA vs Placebo in WARFASA and ASPIRE
Measure WARFASA ASPIRE
Total “n" 402 first ever unprovoked VTE 822 first ever unprovoked VTE
Duration of std anticoag. 6 to 18 mo 90% completed 3 mo to 12 mo
Duration 2 yrs (median 24.6 mo) 4yrs (mean 37.2 mo)
VTE Recurrence (%/yr) 11Pl vs 5.9 ASA (HR=0.58)* 6.5 Pl vs 4.8 ASA (HR=0.74)#
Death (%/yr) 1.3% Pl vs 1.4% ASA#  
Arterial events (%/yr) 1.3% Pl vs 1.9% ASA#  
VTE+MI+Stroke+CV death (%/yr)   8.0 Pl vs 5.2 ASA (HR=0.66)*
VTE+MI+Stroke+ Maj Bld+ Death any cause (%/yr)   9.0 Pl vs 6.0 ASA (HR=0.67)*
Maj. or Clin. Sig. Bleed (%/yr)   1.1 Pl vs 0.6 ASA#
Maj. Bleed 1 in each group  
Discontinued med. (%/yr)   15.1 Pl vs 11.9 ASA (na)
Contrast and Combined Findings
Aspirin Reduced VTE recurrence? Yes, 42% reduction* No, 26% reduction#, but “on treatment” = 35% reduction
Arterial events reduced? No, 1.3 vs 1.9 %/yr with Pl vs ASA Yes (in composite event rates)
Combined data 32% Reduction in Recurrence Rate*
34% Reduction in Major Vascular Events*
* = statistically significant, # = not statistically significant, MI= myocardial infarction, CV= cardiovascular related, Maj Bld= major bleeding, Clin. Sig. Bleed = non-major but clinically significant bleeding

Apixaban: The Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First Line Therapy Extended Treatment (AMPLIFY-EXT) trial compared extended therapy with either apixaban 2.5 mg or 5 mg twice daily vs. placebo in 2,482 patients who had completed 6 to 12 months of anticoagulation. The main findings are presented in Table 2.

Table 2. Summary of Major Event Rates
Treatment VTE Maj. Bleed Clin. Rel. Bleed Death (any cause)
2.5 mg Apix., n=840 1.7%* 0.2% 3.0% 0.8%
5 mg Apix., n=813 1.7%* 0.1% 4.2% 0.5%
Placebo, n=829 8.8% 0.5% 2.3% 1.7%
Apix.= apixaban, VTE= venous thromboembolism, Clin. Rel. Bleed= clinically relevant non-major bleeding. *= statistically significant vs. placebo with p<0.001

Apixaban, therefore, appears to be comparable to what one would expect with well managed warfarin with an 80% reduction in recurrent VTE (8.8% vs 1.7%) with a low bleeding risk. Even so, the costs of therapy and the inability to monitor or reverse therapy may be viewed by some as limitations of apixaban. Interestingly, the study also reported a number of other findings. Because of regulatory agency approval, the primary event was not simply recurrent VTE but rather recurrent VTE and death from any cause. The rates for this primary event were 11.6% for placebo vs 3.8% and 4.2% for the 2.5 mg and 5 mg apixaban groups, respectively. These rates, however, are almost certainly over estimates because any patients who were lost to follow up were presumed to have had a primary end point event. The corresponding lost-to-follow-up rates were 2.3%, 1.5%, and 2.5% for placebo, 2.5 mg and 5 mg apixaban groups, respectively. If one presumes that the none of the patients lost to follow up had a primary event and subtract the lost-to-follow-up rates from the reported primary event rates, the “adjusted” event rates would be 9.3%, 2.3%, and 1.7% for placebo, 2.5 mg and 5 mg apixaban groups, respectively.

References

  1. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. New England Journal of Medicine 2012; 366:1959-67. (DOI: 10.1056/NEJMoa1114238)

  2. Brighton TA, Eikelboom J, Mann, K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. New England Journal of Medicine 2012; 367:1979-87. (DOI: 10.1056/NEJMoa1210384)

  3. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. New England Journal of Medicine 2012 (Dec. 8th online DOI: 10.1056/NEJMoa1207541)

  4. Becker RC. Aspirin and the prevention of venous thromboembolism. (ed) New England Journal of Medicine 2012; 366: 2028-30.

  5. Warkentin TE. Aspirin for dual prevention of venous and arterial thrombosis. (ed) New England Journal of Medicine 2012; 367:2039-41. (DOI: 10.1056/NEJM31211480

  6. Bussey HI and Bussey M. Warfarin management: International normalized ratio self-testing and warfarin self-dosing. Circulation 2012; 126:e52-e54. (DOI: 10.1161/CIRCULATIONAHA.112.095877)
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