By Michael Crawford, MD
Professor of Medicine, Associate Chief for Education, Division of Cardiology, University of California, San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: Low-risk pulmonary embolus patients discharged in < 48 hours on rivaroxaban recorded a nominal three-month rate of recurrent emboli or major bleeding, suggesting such patients do not need to be hospitalized for treatment of pulmonary emboli.
SOURCE: Barco S, Schmidtmann I, Ageno W, et al. Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: An international multicenter single-arm clinical trial. Eur Heart J 2020;41:509-518.
Prior studies of using vitamin K antagonists to treat low-risk pulmonary embolism (PE) patients at home have been controversial due to study design limitations, including the definition of low risk. Recently, direct oral anticoagulants (DOACs) have been used successfully to treat acute PE patients.
Barco et al conducted a multicenter, single-arm study of early discharge and ambulatory treatment with rivaroxaban in low-risk PE patients to determine its efficacy and safety (HOT-PE trial). The identification of low-risk PE patients employed the European Society of Cardiology clinical criteria, plus the presence of normal right ventricular (RV) size and function and the absence of mobile thrombi in the right heart on echocardiograms. Treatment with heparin or an oral anticoagulant was allowed before enrollment. Researchers cut off prior treatment, and started subjects on rivaroxaban less than two hours later. The doses of rivaroxaban followed the manufacturer’s recommendations. Patients were discharged within 48 hours of the diagnosis of PE, and treatment continued for three months. The primary efficacy outcome was recurrent PE or PE-related death. The safety outcomes were major bleeding, clinically relevant nonmajor bleeding, and serious adverse events.
An interim analysis was conducted after 525 patients had completed their three-month visit to determine if premature study discontinuation was warranted for clear efficacy or harm. In 49 centers in seven countries, 2,854 patients with PE were screened and 525 were enrolled (2,329 were excluded). The enrolled patients’ average age was 57 years, and 46% were women. The median length of initial hospitalization was 37 hours. Only three of the 525 enrolled patients experienced the primary outcome of recurrent nonfatal PE, so the study ended prematurely based on prespecified statistical criteria. The primary safety outcome of major bleeding occurred in six patients, clinically significant bleeding in 31, and serious adverse events in 58. Two patients died of cancer. The authors concluded that selected low-risk PE patients can be treated effectively and safely with early discharge on rivaroxaban therapy.
Since the efficacy and safety of DOAC vs. warfarin in outpatients with deep vein thrombosis (DVT) has been demonstrated, the investigators in HOT-PE believed it was unnecessary to include a conventionally treated control group. Exclusion criteria were straightforward: serious comorbidities, another condition requiring hospitalization, and a social environment not conducive to ambulatory anticoagulation management. In fact, 21% of patients recorded a simplified pulmonary embolism severity index (sPESI) score of ≥ 1 (a score of 0 is low risk), but the authors excluded patients with right heart dysfunction and thrombi, which clinical indices such as sPESI do not consider. Also, in their multivariate analysis, neither age nor a history of cancer (both in sPESI) affected the results.
The study ended early at 50% of the planned enrollment because the primary endpoint of recurrent PE was 0.6%, so the null hypothesis was rejected early. The authors of similar studies with warfarin observed PE recurrence rates of 0.6-2.0%. The safety outcome of major bleeding was 1.2% in the Barco et al study and 0.7-1.8% in prior trials with warfarin. In previous trials of rivaroxaban in DVT, the major bleeding rates were 0.5-2.0%. Thus, efficacy and safety are similar to PE trials with warfarin and DVT studies with DOACs.
The decision to discharge a patient early after PE is important because PE can be fatal. In this study, three patients experienced recurrent PE, and there were no PE-related deaths over the three months of the study. These results are compelling for triaging more patients to ambulatory care, but how many are going to meet the inclusion criteria for early discharge? In this trial, it was 20% — significant enough to reduce costs and make some patients happy. Of course, it does require initial hospitalization and treatment with heparin, enoxaparin, or other anticoagulants, along with an echocardiogram to cull the highest-risk patients with right ventricular dysfunction or mobile thrombi. However, this would be standard protocol for most other hospitalized patients. The next step is identifying low-risk patients at the point of first encounter with immediate triage of low-risk patients to ambulatory care. The key to this step is the availability of echocardiography.