Extended low-dose apixaban (Eliquis) after venous thromboembolism (VTE) provoked by events like trauma or surgery in patients with obesity or other enduring risk factors dramatically reduced recurrences without much risk of major bleeding, the HI-PRO trial showed.
Twice daily 2.5-mg doses of the direct oral anticoagulant (DOAC) for 12 months slashed the rate of symptomatic recurrent VTE over that period by a relative 87%, on par with the effect of extended-duration secondary prevention in unprovoked VTE, reported Gregory Piazza, MD, of Brigham and Women's Hospital in Boston, at the European Society of Cardiology meeting.
The rate dropped to just 1.3% compared with 10.0% among patients given placebo (P<0.001), according to the findings simultaneously published in the New England Journal of Medicine.
Major bleeding occurred in one patient out of 300 in the apixaban group and none in the placebo group. Clinically relevant nonmajor bleeding rates were 4.8% and 1.7%, respectively (HR 2.68, 95% CI 0.96-7.43, P=0.06).
"The most striking finding of this trial is the unexpectedly high risk of recurrence in the placebo group at 1 year, which more closely resembled findings for unprovoked VTE than for truly provoked events," wrote Neil A. Zakai, MD, of the University of Vermont in Burlington, in an accompanying editorial.
"For decades, the guidance was simple: treat a provoked VTE -- one caused by a transient factor such as surgery, trauma, or immobility -- for 3 to 6 months, stop, and move on. Safer anticoagulants and emerging evidence now challenge this long-held approach," he noted, with experts arguing for distinctions such as major versus minor and transient as compared with persistent.
The new findings "invite us to reconsider whether the 'provoked' label is a license to discontinue anticoagulation or the beginning of a more nuanced conversation with our patients," Zakai wrote.
He pointed out that the findings probably reflected the definition of "provoked," relying on clinician judgment rather than standardized definitions for provoking factors unlike in previous epidemiologic studies. The most common provoking factors for the index VTE were surgery (33.5%), immobility (31.3%), trauma (19.2%), and acute medical illness (18.3%). But minor triggers were not uncommon, such as long-haul travel (16.7%). Only 9.3% of the patients had been hospitalized in the 3 months preceding the index VTE event.
The trial was done at a single-center, with more than half of the patients enrolled by a single clinician. While this raises the possibility of a definition of provoked VTE reflecting local practice patterns, it reflects everyday clinical practice, Zakai wrote.
The researchers agreed that the dichotomy of provoked versus unprovoked is "insufficient to determine the duration of anticoagulation." Enduring risk factors -- obesity for about half of the study population, chronic inflammatory or autoimmune disorder for about half, atherosclerotic cardiovascular disease for about 30%, and chronic lung disease for around 20% -- appeared to select a group that approximated recurrence risk of high-risk patients (>8%), they argued.
Post hoc subgroup analysis found consistent impact on the primary endpoint in patients with both major and minor transient provoking factors.
The 600 adults in the trial had VTE after a transient provoking factor and had at least one enduring risk factor. After completing at least 3 months of anticoagulation, they were randomly assigned to double-blind treatment with oral apixaban (2.5 mg twice daily) or placebo for 12 months. VTE with active cancer was excluded, as was anyone with active or recent bleeding events.
The participants' mean age was 59.5; 57.0% were female; and 19.2% had non-white race.
A secondary composite outcome of cardiovascular death, nonfatal myocardial infarction, stroke or transient ischemic attack, systemic embolism, major adverse limb event, or coronary or peripheral ischemia leading to revascularization occurred at a similarly low rate with apixaban and with placebo (0.7% and 1.0%, HR 0.67, 95% CI 0.11-3.98).
The only major bleeding event in the apixaban group was a 3-mm parafalcine subdural hematoma after a fall from a horse that didn't lead to hospitalization or drug discontinuation after neurosurgical consultation.
Among the additional safety findings, one patient in the apixaban group and three in the placebo group died, but no deaths were attributed to cardiovascular or hemorrhagic causes.
"Extended anticoagulation can offer substantial benefit to selected patients with provoked VTE but only if we are able to identify them accurately," Zakai wrote. "Future prevention strategies should blend scientific evidence, clinician judgment, and patient values. The goal is not simply to decide whether to extend therapy but to know for whom the benefits outweigh the risks -- and how patients and treating clinicians weigh those benefits and risks. The 'provoked' label should not end the conversation regarding the duration of anticoagulation; it should be the opening to an individualized patient-centered conversation."
Disclosures
HI-PRO was supported by a research grant from the Bristol-Myers Squibb (BMS)-Pfizer Alliance.
Piazza disclosed relationships with Alexion Pharmaceuticals, Amgen, Bayer, Boston Scientific, BMS, Esperion Therapeutics, Janssen Global Services, NAMSA, Penumbra, Pfizer, Regeneron Pharmaceuticals, and Thrombolex.
Zakai disclosed no relationships with industry.
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