ESC 2018 - Munich

Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness

Presented at the ESC congress 2018 by: AC Spyropoulos

Introduction and methods

Anticoagulant prophylactic therapy decreases the risk of venous thromboembolism (VTE) in acute medical illness such as heart failure, respiratory insufficiency, stroke, and infectious or inflammatory diseases. High VTE risk patients can be identified using risk scores, like for example the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score. This randomized trial evaluated the efficacy and safety of rivaroxaban compared with placebo when given at discharge for 45 days to medically ill patients who were at risk for VTE.

The Medically Ill Patient Assessment of Rivaroxaban versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER) trial, a randomized, double-blind, placebo-controlled study, enrolled patients aged ≥40 years, with an IMPROVE risk score ≥4, or an IMPROVE risk score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range, who had been hospitalized for at least 3 and not more than 10 consecutive days with one of the following conditions: heart failure with a left ventricular ejection fraction of 45% or less, acute respiratory insufficiency or exacerbation of chronic obstructive pulmonary disease, acute ischemic stroke, or acute infectious or inflammatory disease, including rheumatic diseases.

All patients were on low-molecular-weight heparin or unfractionated heparin during the index hospitalization, and were randomly assigned in a 1:1 ratio to receive either rivaroxaban or placebo from discharge for 45 days. The rivaroxaban dose was 10 mg/day for patients with creatinine clearance (CrCl) ≥ 50 ml/min, and 7.5 mg/day for patients with a CrCl ≥30 and < 50 ml/min.

The primary efficacy outcome was the composite of any symptomatic VTE, including deep-vein thrombosis (DVT) and pulmonary embolism (PE), or death related to VTE. The principal safety outcome was major bleeding, defined as overt bleeding associated with a decrease in the hemoglobin level of ≥2 g/dl, bleeding that led to transfusion of ≥2 units of packed red cells or whole blood, bleeding that occurred in a critical site (i.e., intracranial, intra-spinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding.

Main results

• A total of 12,024 patients, with similar baseline characteristics, were randomized.
• The primary efficacy outcome occurred in 50 (0.83%) of 6,007 patients in the rivaroxaban group and in 66 (1.10%) of 6,012 patients in the placebo group (HR: 0.76; 95%CI: 0.52-1.09; P=0.14).
• Symptomatic non-fatal DVT and non-fatal PE occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (HR: 0.44; 95%CI: 0.22-0.89; P=0.023).
• When stratifying data according to dose stratum/baseline renal function, those treated with 10mg rivaroxaban QD showed a primary event rate of 0.65% and the respective placebo group 0.98% (P=0.075), while those in the stratum treated with 7.5 mg rivaroxaban QD showed 1.64%, as did the respective placebo group (P=0.994).
• Major bleeding occurred in 17 (0.28%) of 5,982 patients in the rivaroxaban group and in 9 (0.15%) of 5,980 patients in the placebo group (HR: 1.88; 95%CI: 0.84-4.23; P=0.124), and non-major clinically relevant bleeding was also increased with rivaroxaban treatment (1.42% vs. 0.85%, HR: 1.66, 95%CI: 1.17-2.35, P=0.004).

Conclusion

Compared with placebo, rivaroxaban given to medically ill patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic VTE and death due to VTE. No effect on VTE-related death was apparent. The lower dose of rivaroxaban given to patients with moderate renal impairment may have been insufficient to afford protection from VTE.

Discussion

During the press conference, the question was raised whether the study was long enough to see a separation of the curves. At 20 days post-randomization, separation was actually seen, which was more prominent in the data of symptomatic VTE. The curves did not seem to separate further if the study would have been longer.

Moreover, it was discussed that these data may affect clinical practice, not in the sense that they will change guidelines, but they can aid in clinical decision making regarding anticoagulant prophylaxis in patients at risk for VTE after hospital discharge. Use of the validated IMPROVE risk score can help identify patients that may benefit from treatment, rather than the more intuitive estimate and basing it on risk factors as was done before. This study can move the needle as to how to assess patients at the bedside.

• Our reporting is based on the information provided at the ESC congress -