ASPIRE: Aspirin Good Option for Extended Treatment of VTE

November 04, 2012

LOS ANGELES — People who have suffered a first episode of unprovoked venous thromboembolism (VTE) need to have initial therapy with heparin followed by warfarin or one of the newer anticoagulants for a few months, but thereafter there is debate as to what they should do. Results of a new study--together with findings from an almost identical trial reported last year, WARFASA--now suggest that 100 mg per day of aspirin is a good option for ongoing treatment in these patients [1].

Dr Timothy Brighton (Prince of Wales Hospital, Sydney, Australia) reported the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study at the late-breaking clinical-trials sessions here at the American Heart Association 2012 Scientific Sessions today. Although aspirin as compared with placebo did not significantly reduce the rate of recurrence of VTE in ASPIRE, due to lack of power, it did significantly reduce the rate of major vascular events, with improved net clinical benefit.

And when the ASPIRE data are combined with the WARFASA results--something that was prospectively planned--"a clear effect is evident," say Brighton and colleagues, who published the ASPIRE study simultaneously in the New England Journal of Medicine. "ASPIRE has results that overall are consistent with WARFASA," senior author Dr John Simes (University of Sydney, Australia) told heartwire . "The pooled results show clear evidence that aspirin does reduce VTE events by about one-third, and it also significantly reduces the composite of VTE/stroke/MI and cardiovascular death," he noted.

In patients who are going to stop treatment anyway, aspirin provides a moderately effective treatment compared with not having anything.

"We are not advocating that patients should decide to stop anticoagulant therapy early as a result of these findings," Simes stresses. "But in patients who are going to stop anyway, aspirin provides a moderately effective treatment compared with not having anything. We believe this is a cheap and relatively safe therapy that should be considered to prevent further venous thromboembolic events, and not only is it of benefit in clinical terms, but it is cost saving," he adds.

In an accompanying editorial, Dr Theodore E Warkentin (McMaster University, Hamilton, ON) agrees that aspirin is a good option for many of these patients [2]. "Aspirin is inexpensive, does not require monitoring (in contrast to warfarin), and does not accumulate in patients with renal insufficiency (in contrast to dabigatran and rivaroxaban); in addition, if major bleeding occurs or the patient requires urgent surgery, the antiplatelet effects of aspirin can be reversed with transfusion of platelets."

Debate About Duration and Agent for Extended Therapy of Idiopathic VTE

Patients who have had an unprovoked VTE will receive initial "active" treatment, which can consist of heparin followed by low-molecular weight heparins, warfarin, or now, the option of newer anticoagulants, for around three to 12 months. Thereafter, there is debate as to how they should be treated, with the most widely followed guidelines on extended treatment, from the American College of Chest Physicians (ACCP), recommending that therapy continue indefinitely, especially for patients deemed at high risk.

But in practice, most patients do not get treatment for longer than three to six months, because many doctors feel uncomfortable giving indefinite anticoagulation that is associated with a moderately high risk of bleeding. Patients, too, say they do not want to take warfarin continuously, because of the monitoring required, and while newer oral anticoagulant agents are more convenient to use than warfarin, with reduced bleeding, they are expensive and have some other drawbacks.

But Brighton and colleagues explain that for patients who discontinue anticoagulation, the risk of a late recurrence of VTE after a first unprovoked event remains high: approximately 10% in the first year and 30% after 10 years. And recurrent VTE is associated with a case fatality rate of 5% to 10%, they observe.

Combined Analysis of ASPIRE, WARFASA; Aspirin Cuts Events by 33%

In their study, Brighton and colleagues randomized 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked VTE to receive aspirin 100 mg per day or placebo for up to four years. The primary outcome was the recurrence of VTE.

Simes explained to heartwire that they had originally planned to recruit 3000 patients to ASPIRE, but due to financial constraints they had to revise this figure to 2000. But then when WARFASA was published-- showing a significant 42% reduction in the rate of recurrence of VTE with 100 mg of aspirin per day as compared with placebo (p=0.02) in just over 400 patients--they decided to close ASPIRE early, because a prospective combined analysis of the two studies had been planned in advance of knowing the results of either trial.

Median follow-up in ASPIRE was 37.2 months, and in this time, VTE recurred in 73 of 411 patients taking placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs 4.8% per year; hazard ratio [HR] with aspirin 0.74; p=0.09). Simes said they would have needed to have had about a 40% reduction in recurrent VTE events in ASPIRE for the primary outcome to have been significant with this number of patients. He believes the 42% reduction seen in WARFASA was probably a little higher than the "real" effect.

Together, these two studies indicate that aspirin reduces by one-third the rate of recurrence of VTE as well as the rate of major vascular events, a composite outcome of VTE, stroke, MI, or cardiovascular death.

In ASPIRE, aspirin did significantly reduce the rate of the two prespecified secondary composite outcomes: the rate of VTE, MI, stroke, or cardiovascular death was reduced by 34% (HR 0.66; p=0.01); and the rate of VTE, MI, stroke, major bleeding, or death from any cause was reduced by 33% (HR 0.67; p=0.01).

There were no significant between-group differences in the rates of major or clinically relevant nonmajor bleeding episodes or in any other serious adverse events. "We showed clear evidence of net benefit," Simes said.

And when the results are combined with those from WARFASA, the picture becomes even clearer, he adds: a highly significant reduction of 32% in the rate of recurrence of VTE (p=0.007) and a reduction of 34% in the rate of major vascular events (p=0.002), with no excess risk of bleeding.

Warkentin agrees: "Together, these two studies indicate that aspirin reduces by one-third the rate of recurrence of VTE as well as the rate of major vascular events, a composite outcome of VTE, stroke, MI, or cardiovascular death." And moreover, these benefits "were achieved with a low risk of bleeding," he observes.

Aspirin Prevents Arterial Events, Too, and Will Be Cost Saving

Both Warkentin and the ASPIRE authors also point out the "added appeal" of aspirin in terms of its concomitant reduction of arterial thrombotic events. "People who've had a prior VTE that was unprovoked are at risk for further venous events, but they are also at increased risk for arterial events as well, even when they don't have underlying risk factors for that," Simes explains. "We have clearly demonstrated that aspirin is effective in reducing thrombotic events, both venous and arterial--we know from lots of earlier studies that it reduces arterial events."

If we are thinking globally, we are talking about saving millions of dollars.

And Simes stresses that major cost savings could be made by using aspirin in this way for extended treatment of VTE in economies across the world.

In Australia, for example, each deep vein thrombosis (DVT) or pulmonary embolism (PE) costs "roughly A$10 000 per case to treat," he notes. "If you give aspirin to 1000 patients with prior VTE, you will prevent about 20 to 30 recurrent episodes, with possibly an extra three bleeding episodes, and that would save over A$200 000. If we are thinking globally, we are talking about saving millions of dollars."

Brighton reports receiving consulting fees from Bayer Healthcare, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer, Amgen Australia, and GlaxoSmithKline. Simes has no conflicts of interest. Disclosures for the coauthors are listed in the paper. Warkentin reports consulting for GlaxoSmithKline, receiving grants from Bayer, payment for lectures including speaker's fees from Pfizer, and royalties from Informa.