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New Paradigms of Extended Thromboprophylaxis in Medically Ill Patients

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New Paradigms of Extended Thromboprophylaxis in Medically Ill Patients Journal of Clinical Medicine Review New Paradigms of Extended Thromboprophylaxis in Medically Ill Patients Kira MacDougall 1 and Alex C Spyropoulos 2,3,* 1 Department of Internal Medicine, Northwell Health at Staten Island University Hospital, Staten Island, NY 10305, USA; [email protected] 2 Center for Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA 3 Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, 130 E 77th St., New York, NY 10075, USA * Correspondence: [email protected]; Tel.: +01-(212)-434-6776; Fax: +01-(212)-434-6781; Cell: +01-(914)-319-5553 Received: 18 February 2020; Accepted: 24 March 2020; Published: 2 April 2020 Abstract: Extended thromboprophylaxis given to medically ill patients for up to 45 days following an acute hospitalization remains an emerging topic among many hospital-based health care providers. Recent advancements in the field of extended thromboprophylaxis using risk stratification and careful patient selection criteria have led to an improved safety profile of direct oral anticoagulants (DOACs) and established net clinical benefit when given to key patient subgroups at high risk of venous thromboembolism (VTE) and low risk of bleeding. The Food and Drug Administration (FDA) has now approved the DOACs betrixaban and rivaroxaban for both in-hospital and extended thromboprophylaxis in medically ill patients in these key subgroups, which represents more than one-quarter of hospitalized medically ill patients. This has potential to significantly reduce VTE-related morbidity and mortality for these patients. Emerging data also supports reductions in the risk of arterial thromboembolism in medically ill patients with extended thromboprophylaxis post-hospital discharge using DOACs. This article aims to review the most recent concepts of predicting and preventing VTE and to discuss emerging paradigms of extended thromboprophylaxis in hospitalized medically ill patients utilizing an individualized, risk-adapted approach. Keywords: venous thromboembolism; medically ill patients; direct oral anticoagulants; extended thromboprophylaxis 1. Introduction A significant proportion of the estimated 20 million hospitalized, acutely-ill medically-ill patients in the USA and EU are at risk of developing venous thromboembolism (VTE) [1,2]. Prophylactic treatments with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the pentassacharide fondaparinux have shown a 50%–60% reduction in total VTE given for 6–14 days [3–5]. However, hospital length-of-stay (LOS) in the USA now averages approximately 4.5 days and is decreasing in Canada and the European Union [6]. Despite consistent data that show more than 60% of all VTEs occur after the post-hospital discharge period and that the majority of VTE events (approximately 80%) occur within 6 weeks after discharge, post-hospital thromboprophylaxis is given to less than 4% of hospitalized medically-ill patients [7,8]. Until recently, the topic of extended thromboprophylaxis with direct oral anticoagulants (DOACs) for up to 45 days in hospitalized medically ill patients has been a controversial one. At least 25% of all medically ill patients are at sufficient VTE risk to benefit from extended thromboprophylaxis, J. Clin. Med. 2020, 9, 1002; doi:10.3390/jcm9041002 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 1002 2 of 10 but earlier placebo-controlled randomized trials with enoxaparin, and the DOACs rivaroxaban and apixaban, failed to establish a definitive net clinical benefit in overall populations due to an increase in bleeding [9–11]. Data from meta-analyses supported an approximate 40% decrease in symptomatic VTE and VTE-related death with extended thromboprophylaxis, but at a cost of a two-fold increase in major bleeding (MB) [12]. Antithrombotic guidelines for the overall population of medically ill patients have recommended against routine use of extended thromboprophylaxis with DOACs without reference to specific subgroups that may benefit from such a strategy, with the exception of one guideline (International Union of Angiology) that recommended an individualized approach for extended thromboprophylaxis [13–15]. There have been recent developments and new data in the field of extended thromboprophylaxis in medically ill patients that have led to an improved safety profile of DOACs and the establishment of net clinical benefit in key patient subgroups. These developments led to recent FDA approvals of both betrixaban and rivaroxaban for both in-hospital and extended thromboprophylaxis in key subgroups of medically ill patients [16,17]. These approvals have potential in preventing both VTE-related morbidity and mortality and associated risks of arterial thromboembolism in this population [18–20]. This article aims to review the most recent concepts of predicting and preventing VTE and to discuss emerging paradigms of extended thromboprophylaxis in key patient subgroups of hospitalized medically ill patients utilizing an individualized, risk-adapted approach. 2. Extended Thromboprophylaxis during the Post-Hospital Discharge Period While most VTE-prevention efforts in hospitalized medically-ill patients have been directed towards the period of acute hospitalization, studies now show that at least 60% of all VTE events occur in the post-hospital discharge period [8,21]. During the first 21-days following discharge, the rate of symptomatic VTE more than doubles and there is an associated 5-fold increase in fatal pulmonary embolism (PE) within 45 days [21]. Despite this being a high-risk period with significant health consequences, the benefits of extended duration thromboprophylaxis remained uncertain among hospital-based health care providers, as reflected in antithrombotic guidelines [13,15]. There have been five studies on extended thromboprophylaxis in medically ill patients four studies comparing extended prophylaxis with enoxaparin 40 mg daily, apixaban 2.5 mg twice daily, rivaroxaban 10 mg daily, and betrixaban 80 mg daily, to standard of care enoxaparin 40 mg daily given for 6 to 14 days that used screening ultrasonography of the lower limbs to assess deep venous thrombosis (DVT) [9–11,18,19], and one study comparing extended thromboprophylaxis with rivaroxaban post hospital discharge with placebo that used symptomatic VTE and VTE-related mortality as the primary efficacy endpoint [19]. The results of these studies were mixed. The Extended Prophylaxis for Venous Thromboembolism in Acutely Ill Medical Patients with Prolonged Immobilization trial (EXCLAIM trial) revealed a net clinical benefit with the use of extended-duration enoxaparin in patients with severe immobility, age older than 75 years, and female sex, but only after a major protocol amendment during the study which rendered the results difficult to interpret [9]. In the Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients trial (ADOPT trial), an overall low VTE risk population was identified, and apixaban failed to show efficacy and was associated with significantly more MB events [10]. The Rivaroxaban for Thromboprophylaxis in Acutely Ill Medical Patients trial (MAGELLAN trial) identified a higher VTE risk population and saw a significant reduction in VTE risk with extended-duration rivaroxaban compared to enoxaparin (Relative Risk (RR) 0.77; 95% CI 0.62–0.96) but was associated with an almost 3-fold increase in the risk of MB, including a numerically greater number of fatal bleeds [11]. The Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients trial (APEX trial) with the DOAC betrixaban also identified a high VTE risk population and narrowly failed to show efficacy in the primary efficacy outcome utilizing a defined patient subgroup, but a pre-specified exploratory analysis provided evidence suggesting a benefit for betrixaban in the total population (RR 0.76; 95% CI 0.63–0.97) [18]. Importantly there was no increase in the risk of MB (0.57% vs. 0.67%, p = 0.55), although there J. Clin. Med. 2020, 9, 1002 3 of 10 was an increase in major or clinically-relevant non-major bleeding (3.1% vs. 1.6%, p < 0.001) [18]. A bivariate analysis of this trial revealed a net clinical benefit of 0.51% (95% CI 0.89% to 0.1%) − − − over enoxaparin [22]. The Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness trial (MARINER trial) failed to meet its primary efficacy endpoint but revealed significant reductions in the pre-specified secondary outcomes of symptomatic non-fatal VTE (Hazards Ratio (HR) 0.44; 95% CI 0.22–0.89) and symptomatic VTE and all-cause mortality (HR 0.73, 95% CI 0.54–0.97, p = 0.033) [19]. The incidence of MB in both groups was very low (0.28% vs. 0.15, HR 1.88; 95% CI 0.84–4.23), although there was an increase in clinically relevant non-major bleeding (1.42% vs. 0.85%, HR 1.66; 95% CI 1.17–2.35) [19]. Furthermore, the primary efficacy endpoint was met in a sub-group of patients given a 3–6-day course of rivaroxaban (HR 0.55; 95% CI 0.31–0.97), which reflects current LOS in USA hospitals [6,19]. Importantly, a post-hoc analysis of the MAGELLAN trial that excluded approximately 20% of the study population by removing the five key bleeding risk factors used to identify a low bleed risk population in the MARINER trial (bronchiectasis/pulmonary cavitation, active cancer, active gastroduodenal ulcer/history of bleeding within 3 months, and dual antiplatelet
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