Background: COVID-19 (coronavirus disease 2019) is associated with heightened risks of venous and arterial thrombosis and hospitalization due to respiratory failure. To assess whether prophylactic anticoagulation can safely reduce the frequency of venous and arterial thrombosis, hospitalization, and death in nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor, we conducted the PREVENT-HD double-blind, placebo-controlled randomized trial (A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic COVID-19] Infection). Methods: PREVENT-HD was conducted between August 2020 and April 2022 at 14 US integrated health care delivery networks. A virtual trial design used remote informed consent and clinical monitoring and facilitated data collection through electronic health record integration with a cloud-based research platform. Nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor were enrolled and randomly assigned to either 10 mg of oral rivaroxaban or placebo daily for 35 days. The primary efficacy outcome was time to first occurrence of a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic arterial embolism, hospitalization, or death through day 35. The principal safety end point was International Society on Thrombosis and Hemostasis critical-site or fatal bleeding. The last study visit was on day 49. Results: The study was terminated prematurely because of enrollment challenges and a lower-than-expected blinded pooled event rate. A total of 1284 patients underwent randomization with complete accrual of primary events through May 2022. No patients were lost to follow-up. The primary efficacy outcome occurred in 22 of 641 in the rivaroxaban group and 19 of 643 in the placebo group (3.4% versus 3.0%; hazard ratio, 1.16 [95% CI, 0.63–2.15]; P =0.63). No patient in either group experienced critical-site or fatal bleeding. One patient receiving rivaroxaban had a major bleed. Conclusions: The study was terminated prematurely after enrollment of 32% of planned accrual because of recruitment challenges and lower-than-expected event rate. Rivaroxaban prescribed for 35 days in nonhospitalized patients with symptomatic COVID-19 at risk for thrombosis did not appear to reduce a composite end point of venous and arterial thrombotic events, hospitalization, and death. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04508023.

Prior to 2012, the American Academy of Orthopaedic Surgeons (AAOS) and American College of Chest Physicians (ACCP) differed in their recommendations for postoperative pharmacologic venous thromboembolism prophylaxis (VTEP) after total joint arthroplasty. More specifically, aspirin (ASA) monotherapy was not endorsed by the ACCP as an acceptable prophylaxis. In 2012, the ACCP supported ASA monotherapy compared with no prophylaxis. Our aim was to investigate the impact of the convergence of ACCP and AAOS recommendations on surgeon prescribing patterns after knee arthroplasty (KA). This is a retrospective chart review. We collected data to assess preoperative VTE risk and examined VTEP prescriptions on postoperative day 1 (POD1) and at discharge (D/C) from 7/2008 to 12/2011 (pre-period) and 1/2012 to 7/2014 (post-period). Adult patients undergoing primary and revision KA were identified by ICD-9 procedure codes. Patients on preoperative full-dose anticoagulation and with hypercoagulability disorders were excluded. Of 368 records reviewed, 329 were included in the analysis. There were no differences between the two period groups for age, sex, BMI, estrogen therapy, malignancy, smoking status, prior VTE, bilateral procedures, or surgery within 3 months. On POD1, in the pre-period, 4.6 % were prescribed ASA monotherapy versus 44.4 % in the post-period (p < 0.001). On D/C, in the pre-period, 13.9 % were prescribed ASA versus 55.6 % in the post-period (p < 0.001). Our results indicate a statistically significant change in orthopedist prescribing patterns after guideline convergence. Furthermore, there was no apparent change in VTE risk between the two study groups when excluding patients necessitating full anticoagulation. Prior literature has shown that the divergence in guidelines influenced physicians away from ASA and toward more potent anticoagulants in order to avoid potential litigation. Once its role in VTEP was supported by the ACCP, it appears that ASA monotherapy was readily and rapidly incorporated into clinical practice. ASA may be favored over other VTEP agents for its lower bleeding risk profile and cost. This study highlights the profound impact clinical practice guidelines have on clinician prescribing patterns. Although prospective randomized trials are needed to compare the efficacy of ASA with other VTEP agents, ASA is now a predominant part of the VTEP armamentarium after KA.

Thromboprophylaxis of hospitalized patients at risk of venous thromboembolism (VTE) presents challenges owing to patient heterogeneity and lack of adoption of evidence-based methods. Intuitive practices for thromboprophylaxis have resulted in many patients being inappropriately prophylaxed. We conducted a narrative review summarizing system-wide thromboprophylaxis interventions in hospitalized patients. Multiple interventions for thromboprophylaxis have been tested, including multifaceted approaches such as national VTE prevention programs with audits, pre-printed order entry, passive alerts (either human or electronic), and more recently, the use of active clinical decision support (CDS) tools incorporated into electronic health records (EHRs). Multifaceted health-system and order entry interventions have shown mixed results in their ability to increase appropriate thromboprophylaxis and reduce VTE unless mandated through a national VTE prevention program, though the latter approach is potentially costly and effort- and time-dependent. Studies utilizing passive human or electronic alerts have also shown mixed results in increasing appropriate thromboprophylaxis and reducing VTE. Recently, a universal cloud-based and EHR-agnostic CDS VTE tool incorporating a validated VTE risk score revealed high adoption and effectiveness in increasing appropriate thromboprophylaxis and reducing major thromboembolism. Active CDS tools hold promise in improving appropriate thromboprophylaxis, especially with further refinement and widespread implementation within various EHRs and clinical workflows.

The advent of direct-acting oral anticoagulants (DOACs) has transformed the care of patients requiring prevention and treatment for thrombotic disease. Many randomized clinical trials have demonstrated the efficacy and safety of these agents and their comparative advantages over conventional anticoagulants such as vitamin K antagonists (VKAs). While historically clinicians and patients raised questions about the reversal of DOAC-associated bleeding, federal approval in recent years of targeted DOAC reversal agents, along with adjunctive modalities, has given clinicians reliable pharmacologic options. Yet, optimal reversal strategies for bleeding at specific anatomic locations and in specific clinical scenarios remains uncertain. We present here a narrative review of the literature on the reversal of DOAC-associated bleeding or for urgent procedures. The totality of the reversal literature synthesized here yields several clear conclusions: (1) targeted DOAC reversal with specific agents demonstrates superior efficacy for both bleeding and urgent surgical indications when compared to the use of non-specific agents, such as prothrombin complex concentrates (PCCs); (2) at the same time, high-quality data suggest potentially increased thrombotic risks, particularly for ischemic stroke, when using the specific targeted agent andexanet; (3) in all cases of life-threatening bleeding, timely reversal is of the essence; (4) in particular, there is growing consensus that DOAC-associated intracranial hemorrhage (ICH) should be reversed promptly, with a goal door-to-reversal time of 60 min; (5) future research will focus on optimizing clinical pathways for reversal to address “calls to action” from professional groups on this critical topic.

Background Andexanet is U.S. Food and Drug Administration (FDA) approved for the reversal of critical bleeding from factor Xa inhibitors and off-label for surgical reversal. Data are lacking on andexanet administration processes. Methods We retrospectively studied patients at a 23-hospital system who received andexanet from November 2019 to March 2023. Abstractors coded demographics, comorbidities, anticoagulant use, andexanet indication, and process times. The primary outcome was presentation-to-andexanet time; diagnosis, ordering, and administration times were calculated. Secondary outcomes included in-hospital postandexanet major thromboembolism/bleeding and mortality. Results In total, 141 patients were analyzed. Andexanet indications were predominantly neurologic bleeding (85.8%). Twenty-four patients (17.0%) were transferred from nontertiary/academic centers to tertiary/academic centers. The median presentation-to-administration time was 192.5 minutes (interquartile range [IQR]: 108.0–337.0 minutes). Components were as follows: 72.5 minutes (IQR: 39.0–137.5 minutes) for bleeding diagnosis; 35.5 minutes (IQR: 0–96.5 minutes) for andexanet ordering; and 53.0 minutes (IQR: 38.5–78.5 minutes) for administration, which was longer at tertiary/academic hospitals (ratio 1.5, 95% confidence interval [CI]: 1.2–2.0, p = 0.002). Gastrointestinal or other critical bleeding (ratio 2.59, 95% CI: 1.67–4.02, p < 0.001), and tertiary/academic center treatment (ratio 1.58, 95% CI: 1.15–2.18, p = 0.005), were associated with increased time. Major thromboembolism, bleeding, and mortality occurred in 10.6, 12.0, and 22.9% of patients, respectively. Conclusions In our cohort, the median presentation-to-administration time was over 3 hours. Cumulative times were longer at tertiary/academic hospitals and for gastrointestinal/other bleeding. Postandexanet major thromboembolism/bleeding occurred more at tertiary/academic hospitals, possibly related to transfers. Prospective studies may elucidate clinical decision-making bottlenecks.

Background: Coronavirus disease 2019 (COVID-19) is associated with elevated rates of major and fatal thrombotic events, postulated to be the result of a hypercoagulable state mediated through inflammatory and immunomodulatory mechanisms. Early observational studies showed that disease severity and elevated serum D-dimer levels can predict thrombotic risk in patients hospitalized with COVID-19 and reported an alarming phenomenon of breakthrough thrombosis despite standard-of-care prophylaxis, suggesting the need for enhanced thromboprophylactic strategies. Areas of Uncertainty: Data on anticoagulant agent selection, dosing, and duration for COVID-19 inpatients are now poised to inform updated professional society guidance. However, there remains limited high-quality data regarding postdischarge and especially ambulatory patients with COVID-19. Data Sources: This review includes published, peer-reviewed, observational, and randomized controlled trial data and major professional society guidance informing thrombosis prevention and treatment in patients with COVID-19. Therapeutic Advances: There remains great variability in the approach to anticoagulation in COVID-19. This article will review pathogenesis of COVID-related thrombosis and the evidence guiding thromboprophylaxis particularly in inpatients, with attention to the INSPIRATION, ACTION, RAPID, HEP-COVID, and multiplatform trials. Emerging thromboprophylaxis data from the postdischarge setting (particularly the recently published MICHELLE trial), and the outpatient setting, will be examined. Finally, thrombosis treatment considerations will briefly be reviewed. Conclusions: Substantial high-quality data support practice changes to COVID-19 thromboprophylaxis. Risk stratification by setting, disease severity, and biomarkers such as D-dimer is critical in considering choice, dose, and duration of anticoagulants.