Patients hospitalized for an acute medical illness are at an increased risk for developing venous thromboembolism (VTE) in the six weeks after discharge, but treatment with rivaroxaban after discharge did not reduce VTE or VTE-related mortality risk, according to results from a placebo-controlled study published in The New England Journal of Medicine.
“The role of extended thromboprophylaxis in this population is unclear, as it has shown either excess bleeding or beneficial effects mainly from reducing asymptomatic deep vein thrombosis (DVT),” lead author Alex C. Spyropoulos, MD, of Northwell Health in Chicago, told ASH Clinical News. Although rivaroxaban did not appear to increase bleeding risk in this study, the authors noted, “the usefulness of extended thromboprophylaxis remains uncertain.”
In the MARINER (Medically Ill Patient Assessment of Rivaroxaban versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trial, researchers enrolled 12,019 patients (median age = 69.7 years; range not provided) who had been hospitalized for three to 10 consecutive days with heart failure, respiratory insufficiency, stroke, or infectious or inflammatory disease.
All participants were required to have risk factors for VTE (defined as a score of ≥4 on the 10-point modified IMPROVE model) and to have previously received low-molecular-weight heparin or unfractionated heparin during their hospital stay.
On the day of hospital discharge, investigators randomized patients to receive either once-daily rivaroxaban 10 mg (n=6,007) or placebo (n=6,012) for a total of 45 days. Patients with renal insufficiency received a lower dose of rivaroxaban (7.5 mg).
During the 45-day follow-up, the authors observed fewer instances of symptomatic VTE with rivaroxaban than with placebo, but there was no significant difference in the rates of the composite endpoint of symptomatic VTE (including DVT and nonfatal pulmonary embolism) or VTE-related mortality: 0.83 percent for rivaroxaban and 1.10 percent for placebo (hazard ratio [HR] = 0.76; 95% CI 0.52-1.09; p=0.14).
Rates of VTE-related mortality (secondary endpoint) were also similar between the two treatment groups: 0.72 percent for rivaroxaban and 0.77 percent for placebo (HR=0.93; 95% CI 0.62-1.42; p value not provided).
Rates of other efficacy outcomes are presented in TABLE.
In addition, there were no significant differences between the rivaroxaban and placebo groups in the safety analyses (p values were not reported):
- major bleeding: 0.28% for rivaroxaban vs. 0.15% for placebo (HR=1.88; 95% CI 0.84-4.23)
- nonmajor clinically relevant bleeding: 1.42% vs. 0.85% (HR=1.66; 95% CI 1.17-2.35)
- other bleeding: 0.90% vs. 0.57% (HR=1.59; 95% CI 1.03-12.44)
“The observation that there appeared to be no effect with rivaroxaban on VTE-related death raises the question of whether the definition used in the trial (which included sudden and unexplained death) was specific enough to capture true thrombotic-related causes of death,” Dr. Spyropoulos noted. “These differences in risk suggest that the number needed to treat to prevent one symptomatic VTE is 430 while the number needed to harm to cause one major bleed is 856, suggesting a [net] populational health benefit of rivaroxaban in approximately 25 to 30 percent of medically ill patients that fit the criteria for this study.”
The authors listed the difficulty of defining VTE-related mortality as a potential limitation of the study, as well as the possible underdosing of patients with moderate renal impairment who received rivaroxaban at 7.5 mg once-daily.
According to Dr. Spyropoulos, additional research should work toward more accurately identifying mortality “caused by thrombotic mechanisms and should focus on the patients who are at highest risk of thrombosis that may benefit from anticoagulant prophylaxis,” he added.
The corresponding authors report financial relationships with Janssen, which also supported the study.
Spyropoulos AC, Ageno W, Albers GW, et al. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018;379:1118-27.