Outpatient Management of Patients With Low-risk Pulmonary Embolism: Another Piece of Evidence

Olivier Sanchez; Marc Humbert

Disclosures

Eur Heart J. 2020;41(4):519-521. 

In this issue of the European Heart Journal, Barco and colleagues present the results of a prospective, multicentre, international, single-arm investigator-initiated and academically sponsored phase IV management trial (HoT-PE) including patients with acute low-risk pulmonary embolism (PE), and testing the efficacy and safety of early transition from hospital to ambulatory treatment using the oral factor Xa inhibitor rivaroxaban.[1] In this study, patients with low-risk PE were defined as having none of the HESTIA criteria present, and an absence of right ventricular (RV) enlargement or dysfunction [RV/left ventricular (LV) ratio ≥ 1.0], and of free-floating thrombi in the right atrium or ventricle on transthoracic echocardiography (TTE) or computed tomographic pulmonary angiography (CTPA). The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. The safety outcomes included major bleeding, clinically relevant non-major bleeding, and serious adverse outcomes. A planned interim analysis after the first 525 patients fulfilled pre-specified early termination criteria of the study (<6 symptomatic/fatal events). In fact, only three patients [0.6%; one-sided upper 99.6% confidence interval (CI) 2.1%] suffered symptomatic non-fatal VTE recurrence. Major bleeding occurred in 6 (1.2%; two-sided 95% CI 0.4–2.5%) of the 519 patients comprising the safety population and 31 patients (6.0%; 95% CI 4.1–8.4%) experienced a non-major clinically relevant bleeding event during the 3 month follow-up. Lastly, there were two cancer-related deaths (0.4%; 95% CI 0.1–1.4%). Thus, these results demonstrate that early discharge of carefully selected low-risk PE patients receiving rivaroxaban is safe and effective.

There is growing evidence that outpatient treatment using low-molecular weight heparin (LMWH) and vitamin K antagonists (VKAs) is an effective and safe treatment option in selected patients with low-risk PE. In a systematic review, among 1258 patients treated at home (<24 h of hospitalization), the 3 month rate of VTE recurrence was 1.47% (95% CI 0.47–3.0), the rate of major bleeding was 0.81% (95% CI 0.37–1.42), and the 3 month all-cause mortality rate was 1.58% (95% CI 0.71–2.80).[2,3] Based on these results, the 2014 European Society of Cardiology Guidelines suggest that patients with acute low-risk PE should be considered for early discharge and continuation of treatment at home, if proper outpatient care and anticoagulant treatment can be provided (class of recommendation IIa, level of evidence C).[4] In accordance with these recommendations, some centres have implemented or are considering implementing a care organization to increase the use of outpatient treatment of selected low-risk PE patients. However, there is no consensual definition of low-risk PE and selection criteria for outpatient care proposal are still a matter of debate. Several risk stratification models have been developed, but the Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are the most validated—albeit in post hoc analysis for sPESI—and their use is recommended by the 2014 ESC Guidelines.[4] An alternative pragmatic approach, mainly applied in Canada and the Netherlands, is to use a checklist of explicit exclusion criteria like those mentioned in the HESTIA rule.[5] These main criteria correspond to situations where in-hospital care is required. Two randomized controlled trials and one prospective cohort study, using either the PESI or the HESTIA rule to selecting low-risk patients with PE eligible for outpatient treatment, demonstrated similar efficacy and safety.[5–7] Recently, the results of a meta-analysis have suggested that the risk of early mortality and PE-related complications may be elevated, despite a low clinical severity score (sPESI=0), in patients with RV dysfunction as assessed on CTPA or TTE.[8] However, in the VESTA study, adding N-terminal-pro-brain natriuretic peptide (NT-proBNP) to the HESTIA rule did not improve the safety of outpatient treatment compared to applying the HESTIA rule alone.[7] In the present study, the authors combined the HESTIA rule to the assessment of RV dysfunction on CTPA or TTE, and included patients with none of the HESTIA criteria and an absence of RV dysfunction or intracardiac thrombi. Interestingly, 300 patients with none of the HESTIA criteria, but with RV dysfunction or intracardiac thrombi, were not included in the HoT-PE study. It would have been very interesting to have had information on 3 month VTE recurrence and major bleeding risk in this subgroup. Nevertheless, using these criteria, the authors of the HoT-PE trial included 525 patients among 2854 patients with objectively proven PE in the participating centres. When regarding the rate of events in studies applying strategies based on PESI or sPESI, or the HESTIA rule alone or in combination with the assessment of RV dysfunction, there is no evidence for significant differences in efficacy (VTE recurrence) and safety (major bleeding).[1,3,5–7] On the other hand, the proportion of patients managed as outpatients seems larger with the HESTIA rule alone (50%) than with PESI (21%), sPESI (14%), or the HESTIA rule combined with RV dysfunction (18%).[1,3,5–7] However, these data should be interpreted cautiously since the strategies were not compared directly against each other in the same population of patients with PE. An international randomized controlled study (HOME-PE, clinicaltrials.gov identifier: NCT02811237), is currently investigating whether strategies based on the HESTIA rule alone or on the simplified PESI score are equally safe, and which of the two is the most efficient for outpatient management decision-making. While waiting for the results of the HOME-PE trial, one of the important messages of the HoT-PE study for daily clinical practice is to carefully select low-risk patients with PE for early discharge by using one of these validated scores or rule.

Even if the selection of low-risk PE patients is a crucial step, in all of these studies, a specific follow-up protocol was performed for all patients treated at home.[1,3,5–7] Indeed, patients were seen, or at least contacted by phone, within the first days following discharge, at 7–14 days, and after 1 and 3 months. Therefore, centres wishing to support outpatient treatment are encouraged to implement this careful follow-up protocol in their daily practice in order to increase the safety of early discharge of low-risk patients (Take home figure). Lastly, most previous studies that have assessed outpatient treatment have used LMWH and VKA. The HoT-PE trial provides interesting data on the use of rivaroxaban in outpatient treatment. Taken together, the results of the HoT-PE trial add another piece of evidence for the careful treatment of selected low-risk patients with PE at home and will contribute to the decrease of the mean length of hospital stay.

Take home figure.

Selection and follow-up for outpatient treatment of low-risk patients with pulmonary embolism. CTPA, computed tomographic pulmonary angiography; PE, pulmonary embolism; PESI, Pulmonary Embolism Severity Index; RV, right ventricular; sPESI, simplified PESI; TTE, transthoracic echocardiography.

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