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By Bradley St. Pierre, PharmD; Michelle Crisher, PharmD; Domenico Grande, Pharm D; Vitaliy Perets, PharmD, pharmacy residents, St. John Hospital and Medical Center, Detroit

The increased risk of venous thromboembolism (VTE) in patients hospitalized for an acute medical illness has been well documented in the literature.1 Uncertainty exists as to whether this risk extends beyond hospitalization, as some literature suggests that the risk of VTE may persist for 30 or more days after discharge.2  Extended duration prophylaxis in medically ill patients has been studied with enoxaparin, apixaban and rivaroxaban. Although overall incidence of VTE is decreased, this benefit is offset by the increase in major bleeding events and cost. As such, clinical practice guidelines recommend against VTE prophylaxis extending beyond that of the acute hospital stay.1

Betrixaban is a new direct oral anticoagulant that is FDA-approved for extended duration VTE prophylaxis in adult patients hospitalized for an acute medical illness who are at high risk for thromboembolic complications. In the APEX (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban) trial, patients with acute medical illness were randomized to receive either betrixaban 80 mg once daily for 35 to 42 days, or enoxaparin 40 mg subcutaneously for six to 14 days.4 Included patients were divided into three cohorts: patients with elevated d-dimer levels, patients with elevated d-dimer levels and age greater than 75 years, and all enrolled patients. Sequential, pre-specified cohort analyses were performed assessing a composite primary efficacy endpoint of asymptomatic proximal deep vein thrombosis and symptomatic venous thromboembolism. Given the first analysis in cohort one (patients with elevated d-dimer levels) showed no significant difference between groups, subsequent analyses were deemed exploratory. In these analyses, including one assessing the overall population, betrixaban had a statistically significant decrease in the composite endpoint. For safety, there was no difference in major bleeding between groups at any point during therapy until seven days after discontinuation of study medications. Given these results, should extended-duration anticoagulation be standard practice?

Studies looking at VTE risk following hospitalization

Several studies have investigated the risk of thromboembolic events following hospital discharge, evaluating the need for extended duration thromboprophylaxis. One retrospective study of administrative claims data (n=11,139) noted 366 symptomatic VTE events within a 180 day period, 56.6 percent of which occurred post discharge. Amin and colleagues concluded that the risk for VTE is highest during the first 19 days after hospital admission extending into the period after discharge. The major limitations of this study are that fewer than half of patients (46.7 percent) received thromboprophylaxis during hospitalization and that ~80 percent of VTE events during days zero to 19 occurred during hospitalization.2

Another study by Fanikos and colleagues looked at the incidence of post-discharge VTE in high risk discharge patients based on a validated risk scoring tool incorporating major and minor risk factors for VTE.5 This was a case-control study of patients ordered to continue VTE prophylaxis with heparin or enoxaparin after hospital discharge (n=461) compared to no prophylaxis (n=922). There was no difference in the incidence of VTE events in patients receiving extended pharmacologic prophylaxis versus no prophylaxis (5 percent vs. 4.3 percent; P = 0.58). However, fewer patients were alive at 90 days in the group receiving extended prophylaxis and major bleeding occurred more frequently. To note, close to 50 percent of patients had cancer, since this was considered a high risk factor for VTE, whereas little emphasis was placed on immobilization in the validated risk scoring tool. Therefore, immobilized patients may have been underrepresented compared to the study populations, which showed a benefit of extended duration prophylaxis.

Based on the available evidence, the risk of VTE extending beyond hospitalization and benefit of thromboprophylaxis is unclear. Further studies are needed to evaluate the risk of VTE after discharge, to define the patient population that may benefit from extended duration prophylaxis, and to conduct a cost analysis of extended VTE prophylaxis beyond the acute hospital stay.

References

  1. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;41(2):e195S-e226S.
  2. Amin AN, Varker H, Princic N, et al. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. 2012;7(3):231-238.
  3. Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-23.
  4. Cohen AT, Harrington RA, Goldhaber SZ et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375(6):534-544
  5. Fanikos J, Rao A, Seger AC et al et al. Venous thromboembolism prophylaxis for medical service—mostly cancer—patients at hospital discharge. Am J Med. 2011;124(12):1143-50

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