No Anticoagulation Option for VTE Prevention? Try Aspirin

August 26, 2014

DALLAS, TX — Daily aspirin can cut the adjusted recurrence risk by more than a third over three to four years after acute therapy for a first "unprovoked" venous thromboembolism (VTE), suggests a combined analysis of two trials comparing aspirin at 100 mg/day vs placebo in patients with recent deep vein thrombosis (DVT) or pulmonary embolism (PE)[1]. The net clinical benefit, which also considered MI, stroke, and associated bleeding, was about 37% improved with aspirin; both outcomes in adjusted analyses were strongly significant (p=0.003 and p<0.001, respectively).

That doesn't mean aspirin is better against recurrent VTE than continued treatment with vitamin-K antagonists such as warfarin or the new oral anticoagulants (NOACs). Treatment with those agents may lower the risk by at least twice as much, notes a report on the prospectively planned INSPIRE analysis of the combined ASPIRE and WARFASA trials, published August 25, 2014 in Circulation.

It means, rather, that aspirin can be effective for cutting VTE risk in patients "who are not or who are no longer taking anticoagulant therapy," commented first author Dr John Simes (University of Sydney, Australia) in an email to heartwire . He said the findings are conclusive enough to be included in practice now for such patients.

Included would be a limited group of patients in whom oral anticoagulants are contraindicated because of an untoward bleeding risk, he said, and "a larger group of patients that discontinue therapy for a variety of reasons, including inconvenience of monitoring therapy, bleeding episodes, and costs. It is estimated that the majority of patients with an unprovoked VTE are no longer on oral anticoagulants after 12 months."

Simes said, "The relative effects of aspirin therapy were similar across different patient subgroups, but larger absolute effects were observed among those at greater risk of further events—in particular men and older patients."

The new report is a much fuller version of the cursory, preliminary analysis of the combined trials included in the ASPIRE primary publication[2], covered by heartwire in November 2012. ASPIRE and WARFASA on their own "were not individually powered to detect moderate treatment effects for particular outcomes or subgroups," write Simes et al.

"Because this [current] combined patient-level analysis was defined before any unblinding of study outcomes of either individual trial, it has the same scientific rigor as a single larger randomized study," according to the report.

For the combined total of 1224 patients, the crude rate of recurrent VTE was 15.8% over a median follow-up of 30.4 months. Patients were on their assigned treatment for a median of 24.2 months in the modified intention-to-treat analysis (all patients who received at least one dose were randomized).

Adjusteda Hazard Ratio (95% CI) for Outcomes in ASPIRE/WARFASA Analysis, Aspirin vs Placebo

End points HR (95% CI) p
Venous thromboembolism 0.65 (0.49–0.86) 0.003
Net clinical benefitb 0.64 (0.50–0.83) <0.001
Major vascular eventsc 0.63 (0.48–0.83) <0.001
All-cause mortality 0.82 (0.45–1.52) 0.53
Major bleeding 1.31 (0.48–3.53) 0.60
a. Adjusted for age, sex, qualifying event (DVT only vs PE with or without DVT), body-mass index, and duration of anticoagulation
b. Defined as effect on recurrent VTE, MI, stroke, all-cause mortality, or major bleeding
c. Symptomatic VTE, MI, stroke, or cardiovascular death

In a similarly adjusted subgroup analysis, the risks of DVT and of PE on aspirin were reduced by 37% each (p=0.006 and p=0.06, respectively)

After further adjustment for patient adherence to treatment, the risk of VTE recurrence was reduced by 42% (p=0.005) for those who received aspirin.

The study didn't address whether adding aspirin to oral anticoagulation might further lower VTE risk, "but it would probably result in a slight increased risk of bleeding," Simes speculated for heartwire . "Due to the larger risk reduction in events with oral anticoagulants, we would not recommend using the combination, unless there were other clinical indications, such as coronary heart disease."

ASPIRE was funded by grants from the National Health and Medical Research Council, New Zealand Health Research Council, New South Wales Health, and Australian Society of Thrombosis and Haemostasis. WARFASA was funded partially by Bayer HealthCare. Aspirin and placebo for both studies were provided by Bayer HealthCare. Neither Simes nor his coauthors had disclosures.

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