Pulmonary embolism (PE) is a common disease, with an estimated annual incidence of 70 cases per 100 000.1,2 This condition can be life-threatening if not treated rapidly and appropriately and often leads to chronic disease and disability.3 Mortality from PE, 15% at three months, exceeds that for acute myocardial infarction.4 Risk stratification helps to optimize the selection of patients who will benefit from more aggressive therapy, such as thrombolysis or embolectomy, in addition to anticoagulation.4 High-risk patients are also most susceptible to the dreaded complication of chronic thromboembolic pulmonary hypertension.4 In order to predict early (in-hospital or 30-day) outcomes, both PE-related risk and the patient's clinical status and comorbidities should be taken into consideration, and can be measured using risk scores such as the pulmonary embolism severity index (PESI).5 Intermediate-high risk patients have positive cardiac laboratory biomarkers, signs of right ventricular (RV) dysfunction on an imaging test and PESI class III-V or simplified PESI (sPESI) ≥1.

The conventional PE treatment approach consists of a parenteral anticoagulant such as enoxaparin for at least five days, followed by a vitamin K antagonist (VKA) such as warfarin, and continued for at least three months.6 Although effective, this regimen is challenging, as enoxaparin requires daily subcutaneous injections and VKAs require close monitoring and dose adjustment.7 The recently developed direct oral anticoagulants (DOACs), which inhibit factor Xa or thrombin, can overcome these limitations.8 DOACs have been tested against conventional therapy in large phase III studies for the treatment of PE: EINSTEIN-PE for rivaroxaban, RE-COVER and RE-COVER II for dabigatran, AMPLIFY for apixaban and Hokusai-VTE for edoxaban.1,9–11 Rivaroxaban and apixaban allow for a single drug regimen, eliminating the need for initial parenteral anticoagulation, while dabigatran and edoxaban are initiated after a course of parenteral therapy.1 In all these studies, DOACs were shown to be at least as effective as VKAs for preventing recurrent VTE and VTE-related death, and demonstrated a similar or reduced incidence of major and/or major plus non-major clinically relevant bleeding (the principal safety outcome events), compared with conventional treatment.12 All DOACs have been approved for the treatment of PE and are recommended as alternatives to standard therapy in international guidelines.5,13 Although these recommendations are based on randomized clinical trials (RCTs),1,9–11 the real-world use of DOACs compared with warfarin is less clear. Phase III trials have selective inclusion criteria, and the reproducibility of their findings needs to be assessed in broader patient populations like those seen in routine clinical practice.14 Safety outcomes in clinical practice may diverge from trials for several reasons, including selective inclusion criteria and the limited duration of follow-up in the latter.15 Also, intermediate-high risk PE patients represent a particular subset of PE patients with a poorer prognosis,16 but are under-represented in RCTs and are not reported as an independent group in any of the PE RCTs. In this study we aimed to report the efficacy and safety of a DOAC-based regimen compared with a conventional treatment approach in patients admitted to a cardiac care unit with intermediate-high risk PE.

We conducted a single-center, retrospective cohort study of patients with confirmed PE treated with the standard anticoagulation regimen (CONV) or with DOACs. The study was approved by the local ethics committee and was in accordance with the 2008 Declaration of Helsinki.

Study population

Between January 2010 and August 2015, 116 consecutive patients admitted with intermediate-high risk PE were included. Patients with intermediate-high risk PE were defined as those with positive myocardial lesion markers (troponin I), right ventricular dysfunction (assessed by echocardiography), and PESI class III-V or sPESI ≥1. After the introduction of DOACs in our hospital's pharmacy (in August 2013), all PE patients with indication and without contraindication were started on DOACs for treatment of acute PE. We retrospectively selected a historical cohort of PE patients with similar clinical characteristics treated with a CONV approach between February 2010 and September 2014. A total of 57 patients initially treated by thrombolysis were excluded from the analysis (Figure 1).

Figure 1.

Study population flowchart. CONV: conventional anticoagulation; DOAC: direct oral anticoagulant; PE: pulmonary embolism.

(0.1MB).

The choice of DOAC was left to the discretion of the attending physician. The treatment regimens were as recommended by the manufacturer.1 Discharge reports were used to obtain information on demographics, personal history and laboratory workup. All patients were followed for up to three months after discharge.

The clinical characteristics of the study population are shown in Table 1. Of the 59 patients included, 35 (59%) were managed with a CONV approach and 24 (40%) with a DOAC approach. The mean patient age was 62±19 years (median 58, range 29-87) and 61±17 years (median 57, range 24-78) for the CONV and DOAC groups, respectively (p=0.770). No differences were found between the CONV and DOAC groups in gender or laboratory tests. Creatinine clearance was similar (p=0.881). Regarding cardiac biomarkers, no significant differences were found between the two groups, although B-type natriuretic peptide (BNP) levels were numerically higher in the CONV group (Table 1).

In the DOAC group, three cases of PE were provoked (cancer, surgery and prolonged immobilization), while 11 in the CONV group were provoked (childbirth, chronic pulmonary embolism, cancer, surgery and immobilization). None of the patients in the DOAC group had a prior history of PE or known thrombophilia, while in the CONV group, two patients had a prior PE (these patients had a history of cancer); none had known thrombophilia.

There were four in-hospital death in the CONV group, whereas no deaths occurred in the DOAC group. No recurrent PE was recorded in any of the groups during admission or during the three-month follow-up. Regarding the safety outcome, no major bleeding events were observed in either group. There was a statistically significant difference (p=0.002) between the CONV (4.7±2.4) and the DOAC (3.0±1.5) groups in length of stay. No differences were found regarding echocardiographic parameters at discharge, including PASP (p=0.471) and right ventricular systolic function (p=0.684) (Table 2).

The demand for real-world data in addition to clinical trial data is increasing.17 Non-interventional studies are crucial for obtaining a different perspective on the safety and effectiveness of drugs when used in routine clinical practice. Studies performed with real-world populations complement the outcomes of pivotal trials through the use of unselected real-world populations and conditions. Here, we report a real-world observational study analyzing the use of DOACs in the treatment of intermediate-high risk PE. We show that the efficacy and safety of such a strategy is comparable to the conventional, VKA-based approach and that length of stay may be reduced with a DOAC-based regimen, a critical finding in the intensive care unit setting.

DOACs have been tested against conventional therapy for the treatment of PE in large phase III trials: EINSTEIN-PE for rivaroxaban, RE-COVER and RE-COVER II for dabigatran, AMPLIFY for apixaban and Hokusai-VTE for edoxaban. In all these these trials, DOACs were shown to be at least as effective as VKAs for preventing recurrent VTE and VTE-related death, and demonstrated a similar or reduced incidence of major and/or major plus non-major clinically relevant bleeding (principal safety outcome events), compared with conventional treatment. A meta-analysis of the phase III VTE trials concluded that DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups, and concluded that treatment with a DOAC significantly reduces the risks of major bleeding.18 However, intermediate-high risk PE defines a population at higher risk of both thrombotic and bleeding complications that is not well represented in most trials of DOACs in VTE, as most do not include information on cardiac necrosis markers or right ventricular function. Therefore, real-world treatment data on this specific stratum of PE patients are paramount.

Our study shows similar rates of death and recurrent PE during hospital stay and follow-up in both groups. Additionally, no major bleeding events were observed within three months of beginning treatment. These results highlight the safety of anticoagulation in this population and are consistent with those of RCTs on DOACs, in which the incidence of major bleeding was around 1% for all studies. In other studies in the real-world setting, the risk of bleeding related to DOACs was similar to that for warfarin.19 Reassuringly, the findings of our study are in line with those in the literature for patients treated in routine clinical practice.20

Another important point relates to the efficacy of DOACs for thrombus disintegration in intermediate-high risk PE patients, who may have a higher thrombotic burden in the lung vasculature. It is suggested that DOACs may be even more effective than warfarin in patients with markers of RV dysfunction, as shown in the Hokusai-VTE trial. However, in this trial RV dysfunction was analyzed only by elevation of BNP, a criterion that does not reflect usual clinical practice, which is to integrate laboratory, imaging and clinical risk score data.11

In line with the evidence from RCTs,11 we found no differences between the groups in two surrogate markers of right ventricular afterload, echocardiographically-estimated PASP and right ventricular function. It is therefore plausible that thrombus resolution rate and extent would be similar in both treatment regimens.

We found a significant difference between the two groups in length of stay, which was more than one day shorter in the DOAC group. This finding is probably due to the fact that the maximum anticoagulant effect of warfarin is only achieved 3-5 days after the first dose, and dosage needs to be adjusted according to the international normalized ratio (INR) before the patient is discharged. With the DOAC treatment strategy, after the patient is stabilized in terms of heart failure, oxygen saturation and pain (which frequently occurs before the target INR is achieved), there is no need to prolong hospitalization.

Among study limitations, we highlight the study's retrospective design and the use of a historical cohort of patients treated with VKAs, the small number of patients enrolled, related to the early experience using DOACS in treating PE, and the absence of thrombotic or bleeding events, a fact that reflects the very good prognosis of correctly treated PE, even those of intermediate-high risk.

The adoption of a DOAC treatment strategy in intermediate-high risk PE patients in this typical real-world cohort was associated with comparable efficacy and safety to the conventional treatment regimen of parenteral anticoagulant plus warfarin. Importantly, length of stay was significantly reduced. No differences were found regarding right ventricular function markers at discharge. Further studies in larger cohorts will help to clarify the use of DOACs in this challenging PE population.

R.B. has received speaker fees from BMS/Pfizer, Bayer and Daiichi-Sankyo, investigator fees from Bayer and personal fees (advisory board) from BMS/Pfizer and Bayer.

S.M. has received speaker fees from BMS/Pfizer and Bayer, investigator fees from Bayer and personal fees (advisory board) from Bayer.

P.M. has received speaker fees from BMS/Pfizer, Bayer, Daiichi-Sankyo and Boheringer-Ingelheim, investigator fees from Bayer, Boheringer-Ingelheim and Daiichi-Sankyo and personal fees (advisory board) from BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo.