Tag: Venous Thrombo Embolism

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life. Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The benefit of thromboprophylaxis in this patient population however is uncertain. This is because previously published randomized trials included cancer patients both at both low and high risk for VTE.

Khorana score is a validated risk tool which helps to identify patients at increased risk for VTE. Several studies have suggested benefit from thromboprophylaxis in patients with a score of 3 or higher, whereas the benefit of thromboprophylaxis in patients with a score of 2 is unclear, although there is a substantial risk of VTE in this group as well. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Edoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule.

The AVERT (Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients ) trial is a randomized, placebo-controlled, double-blind clinical trial which evaluated the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score 2 or more). Eligible patients (N=574) were randomized in a 1:1 ratio to receive apixaban or placebo and 563 patients were included in the modified intention-to-treat analysis. The first dose of apixaban or placebo was administered within 24 hours after the initiation of chemotherapy. The mean patient age was 61 years, and the common types of primary malignancies were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). Eligible patients included those who had a newly diagnosed cancer or progression of known cancer after complete or partial remission and who were initiating a new course of chemotherapy with a minimum treatment intent of 3 months. Inclusion required a Khorana score of 2 or higher. Exclusion criteria included hepatic disease associated with coagulopathy, platelet count of less than 50,000 per cubic millimeter, acute leukemia, myeloproliferative neoplasm, planned stem-cell transplantation and GFR of less than 30 ml/min. The Primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main Safety outcome was a major bleeding episode.

Venous thromboembolism occurred in 4.2% in the apixaban group and 10.2% in the placebo group (HR=0.41; P<0.001). This benefit and was predominantly driven by a lower rate of pulmonary embolism in the apixaban group than in the placebo group. The rate of major bleeding was significantly higher with apixaban than with placebo in the modified intention-to-treat analysis (3.5% versus 1.8%, respectively; HR=2.00), but the rate however was not significantly higher with apixaban than with placebo in the analysis of outcomes during the treatment period (2.1% versus 1.1%, respectively; HR=1.89). There was no significant difference in the Overall Survival between the treatment groups and the authors attributed this to trial design and the fact that most of the patients had advanced cancer, which was the most common cause of death.

It was concluded that thromboprophylaxis with apixaban at a dose of 2.5 mg twice daily resulted in a significantly lower risk of venous thromboembolism when compared to placebo, among ambulatory cancer patients who were initiating chemotherapy, and had an intermediate to high risk of venous thromboembolism. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. Carrier M, Abou-Nassar K, Mallick R, et al. for the AVERT Investigators. N Engl J Med 2019;380:711-719

SUMMARY: It is estimated that up to 30% of patients with nonvalvular atrial fibrillation may receive antiplatelet agents along with oral anticoagulants, due to comorbid cardiovascular conditions. The concomitant use of Vitamin K Antagonist (VKA) such as Warfarin along with antiplatelet agents, has in previously published studies, shown to increase the risk of bleeding, compared with VKAs alone.

Direct Oral AntiCoagulants (DOACs) are often prescribed for thromboembolic events. This class of anticoagulants, have a rapid onset and offset of action, short half-life, predictable anticoagulant effects, no laboratory monitoring and fixed dosing schedule. The half-life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and DOACs are ineffective in patients with mechanical heart valves. Direct Oral AntiCoagulants have a favorable efficacy and safety profile, compared with Vitamin K Antagonists (VKAs) and are increasingly being used for ischemic stroke prevention among patients with nonvalvular atrial fibrillation. In several clinical studies, DOACs have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to Vitamin K Antagonist (VKA) such as Warfarin. Meta-analysis of randomized controlled trials (RCTs) assessing the efficacy of DOACs along with AcetylSalicylic Acid (ASA), in nonvalvular atrial fibrillation has shown similar risk of major bleeding but a decreased risk of intracranial hemorrhage, when compared with VKAs plus ASA. Some of the studies included in this meta-analysis however had methodological limitations.

In order to address this clinically important safety issue, the authors conducted this population-based study to compare the incidence of intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding between concomitant DOAC/antiplatelet use and concomitant VKA/antiplatelet use, in patients with nonvalvular atrial fibrillation. This study was conducted among a cohort of patients with newly diagnosed nonvalvular atrial fibrillation, between January 2011 and March 2014, using computerized health care databases from Quebec. Of the 14, 407 patients included in this study, 5301 patients initiated concomitant DOAC/antiplatelet use, while 9106 patients initiated concomitant VKA/antiplatelet use. DOACs included PRADAXA® (Dabigatran), XARELTO® (Rivaroxaban), or ELIQUIS® (Apixaban) and antiplatelet agents included ASA (Aspirin), Dipyridamole, PLAVIX® (Clopidogrel), EFFIENT® (Prasugrel), or BRILINTA® (Ticagrelor). Three separate analyses were conducted for intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding. The median follow up was 1.6 months which was primarily driven by discontinuation of antiplatelet therapy.

It was noted that concomitant DOAC/antiplatelet therapy was associated with a similar risk of gastrointestinal bleeding (HR 1.08) but with a decreased risk of intracranial hemorrhage (HR 0.46) and other major bleeding (HR 0.68), compared with concomitant VKA/antiplatelet therapy.

The authors concluded that based on the results of this population-based study, compared with concomitant Vitamin K Antagonist /antiplatelet use, concomitant Direct Oral AntiCoagulants/antiplatelet use was associated with a similar risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage and other major bleeding. These findings could provide guidance to physicians and help in decision making, for patients requiring concomitant treatment with oral anticoagulants and antiplatelets. Concomitant Use of Direct Oral Anticoagulants with Antiplatelet Agents and the Risk of Major Bleeding in Patients with Nonvalvular Atrial Fibrillation. Douros A, Renoux C, Yin H, et al. The American Journal of Medicine 2019; 132:191-199

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.

Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. However, the efficacy and safety of DOACs for the treatment of cancer-associated VTE have not been established. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. In the EINSTEIN trial which compared XARELTO® with LMWH followed by COUMADIN® in patients with acute symptomatic DVT or PE, only 5.5% of patients had active cancer at baseline.

This study was conducted to assess VTE recurrence rates in patients with active cancer, treated with either XARELTO® or FRAGMIN® (Dalteparin) and whether XARELTO® would offer an alternative treatment for cancer patients with VTE. SELECT-D (Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism) is a randomized, open-label, multicenter pilot trial in which patients with active cancer, who had symptomatic Pulmonary Embolism (PE), incidental PE, or symptomatic lower-extremity proximal Deep Vein Thrombosis (DVT) were enrolled to receive either XARELTO® or FRAGMIN®. Active cancer was defined as a diagnosis of cancer (other than Basal-cell or Squamous-cell skin carcinoma) in the previous 6 months, any treatment for cancer within the previous 6 months, recurrent or metastatic cancer, or cancer not in Complete Remission (hematologic malignancy). In this study, 58% of the patients had metastatic disease, approximately 25% of patients had Colorectal cancer and 83% were receiving chemotherapy at the time of their VTE. A total of 406 patients were randomly assigned in a 1:1 ratio to receive either FRAGMIN® 200 IU/kg SC once daily for the first 30 days and then 150 IU/kg SC daily for an additional 5 months or XARELTO® 15 mg orally twice daily for 3 weeks, then 20 mg once daily for a total of 6 months. Patients were assessed at 3-month intervals until month 12 and then at 6-month intervals until month 24. The primary outcome was VTE recurrence over 6 months, using compression ultrasound (CUS). Secondary outcomes were major bleeding and Clinically Relevant NonMajor Bleeding (CRNMB).

The cumulative VTE recurrence rate at 6 months was 11% for patients receiving FRAGMIN® and 4% for patients receiving XARELTO® (HR=0.43). The 6-month cumulative rate of major bleeding was 4% for FRAGMIN® and 6% for XARELTO® (HR= 1.83). Corresponding cumulative rate of CRNMB at 6 months was 4% and 13% respectively. Most major bleeding events were GI, and there were no CNS bleeds. Patients with esophageal or gastroesophageal cancer experienced more major bleeds with XARELTO® than with FRAGMIN® (36% versus 11%). Overall Survival at 6 months was 70% with FRAGMIN® and 75% with XARELTO®.

It was concluded that XARELTO® was associated with relatively low VTE recurrencein patients with cancer but with higher Clinically Relevant NonMajor Bleeding, compared with LMWH, FRAGMIN®. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). Young AM, Marshall A, Thirlwall J, et al. Journal of Clinical Oncology 2018;36:2017-2023

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Currently, VTE prophylaxis is recommended only for hospitalized patients and this intervention prevents only about 50% of the VTE burden in the general community. Therefore, identifying non-hospitalized individuals at risk for VTE is important to further reduce the incidence of VTE and improve survival.

Infections, which are common, have been associated with VTE. These episodes however have been labeled idiopathic, as these patients are not pregnant or postpartum, have not been on hormone therapy or hormonal contraception, do not have active malignancy and have not had recent nursing home confinement, trauma, fracture, immobilization or leg paresis. Infection promotes thrombosis from endothelial damage and tissue factor-induced activation of the procoagulant pathway, as well as downregulation of the endogenous anticoagulant pathway, and inhibition of fibrinolysis. Venous thrombosis has also been linked to neutrophil activation and promotion of platelet aggregation through the P-selectin mediated pathway.

In order to address the independent association of recent infection with VTE, the authors performed a population-based, case-control study within their local community, nested within the population of Olmsted County, Minnesota, to estimate the magnitude of risk of VTE due to active infection, taking advantage of Rochester Epidemiology Project (REP) resources, to identify all Olmsted County residents with incident VTE and matched controls drawn from the same population. The authors identified 1303 cases of objectively diagnosed incident Deep Vein Thrombosis or Pulmonary Embolism over the 13-year period from 1988 to 2000 along with 1494 matched controls without VTE. They then looked for an association of infection and site of infection with VTE, after adjusting for all other known VTE risk factors.

It was noted that infection and site of infection were risk factors for VTE, compared with no infection. Any infection increased the odds of VTE by 4.5 fold (P<0.0001) compared with no infection, when unadjusted for other VTE risk factors. The odds of VTE due to any infection was 2.4 fold higher compared with no infection, after adjusting for all established VTE risk factors (P<0.0001). An Odds Ratio (OR) is a measure of association between an exposure and an outcome. The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure. Intra-abdominal infection imparted the highest magnitude of risk (OR, 18), followed by oral infection (OR, 12), systemic bloodstream infection (OR, 11), lower respiratory infection such as pneumonia (OR, 3.6), and symptomatic urinary tract infection (OR, 2.2). Oral infection was a significant independent risk factor for VTE compared with no infection, after adjusting for other risk factors and for other infections (OR, 11.6). Oral candidiasis comprised 75% of oral infections among VTE patients. It is conceivable that oral candidiasis is a potential marker for patient debility that may be a VTE risk factor, not captured by the other covariates.

It was concluded that infection is an independent risk factor for VTE and VTE risk can be further stratified by site of infection. Is Infection an Independent Risk Factor for Venous Thromboembolism? A Population-Based, Case-Control Study. Cohoon KP, Ashrani AA, Crusan DJ, et al. The American Journal of Medicine 2018;131:307-316

SUMMARY: The FDA on May 3, 2018 approved AndexXa® (Andexanet Alfa), a recombinant coagulation Factor Xa, inactivated-zhzo), for patients treated with XARELTO® (Rivaroxaban) and ELIQUIS® (Apixaban), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. It is estimated that 4 million individuals are presently on Factor Xa inhibitors, and in the US there were approximately 117,000 hospital admissions attributable to Factor Xa inhibitor-related bleeding and nearly 2000 bleeding related deaths per month. There are presently five New Oral Anticoagulants approved in the US for the treatment of Venous ThromboEmbolism (VTE). They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half-life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and direct oral anticoagulants are ineffective in patients with mechanical heart valves. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, until now, there were no specific agents available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention. The FDA in 2015, granted accelerated approval to PRAXBIND® (Idarucizumab), for the treatment of patients treated with PRADAXA®, a direct thrombin inhibitor, when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. However, the Factor Xa inhibitors approved in the US for the treatment of VTE did not have an antidote until this new approval. As such, some Health Care Providers discouraged their patients from taking these direct oral anticoagulants until an antidote became available, should their patients need urgent surgical intervention.

AndexXa® (Andexanet alfa) is a recombinant, modified human Factor Xa decoy protein without intrinsic catalytic activity, that binds Factor Xa inhibitors. The approval of AndexXa® was based on data from two Phase III ANNEXA studies (ANNEXA-A and ANNEXA-R) as well as interim data from the ongoing ANNEXA-4 study. ANNEXA-A and ANNEXA-R are randomized, double-blind, placebo-controlled, Phase III studies which evaluated the safety and efficacy of AndexXa® in reversing the anticoagulant effect of ELIQUIS® and XARELTO® respectively, in healthy volunteers aged 50-68 years. A two-part randomized placebo-controlled study was conducted for each Factor Xa inhibitor, to evaluate AndexXa® administered as a bolus or as a bolus plus a 2-hour infusion. The Primary endpoint was reduction in anti-Factor Xa activity levels, a measure of Factor Xa inhibition by the anticoagulant. Secondary endpoints included reduction in plasma levels of free unbound XARELTO® or ELIQUIS® and restoration of the endogenous thrombin potential (ETP), a measure of thrombin generation.

ANNEXA-A Study: In Part 1, 33 healthy participants were given ELIQUIS® 5 mg twice daily for 3.5 days and then randomized in a 3:1 ratio to receive either AndexXa® administered as a 400 mg IV bolus or placebo. Within 2-5 minutes of completion of the bolus dose, AndexXa® rapidly reduced the anticoagulant activity of ELIQUIS® by 94% compared with placebo (P<0.001), as measured by anti-Factor Xa activity. The reversal of anti-factor Xa activity persisted for 2 hours. Further, AndexXa® significantly reduced the level of free (unbound) ELIQUIS® in the plasma compared with placebo (P<0.001) and fully restored thrombin generation in 100 percent of subjects (P<0.001 vs. placebo). In Part 2, 31 healthy participants received ELIQUIS® 5 mg twice daily for four days and then randomized in a 3:1 ratio to receive either AndexXa® administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes or placebo. AndexXa® significantly reduced anti-Factor Xa activity by 92% compared with placebo (P<0.001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound ELIQUIS® was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound ELIQUIS® compared with placebo (P<0.001). AndexXa® also restored thrombin generation to normal in all participants who received the compound (p<0.001 vs. placebo).

ANNEXA-R Study: In Part 1, 41 healthy volunteer participants were given XARELTO® 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either AndexXa® administered as an 800 mg IV bolus or placebo. Within 2-5 five minutes of completion of the bolus dose, AndexXa® significantly reversed the anticoagulant activity of XARELTO® by 92% compared with placebo (P<0.001), as measured by anti-Factor Xa activity. Further, AndexXa® significantly reduced the level of free (unbound) XARELTO® in the plasma compared with placebo (P<0.001) and fully restored thrombin generation in 96% of participants (P<0.001 versus placebo). In Part 2, 39 healthy volunteers were given XARELTO® 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either AndexXa® administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or placebo. AndexXa® significantly reduced anti-Factor Xa activity by 97% compared with placebo (P<0.001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound XARELTO® was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound XARELTO® compared with placebo (P<0.001). AndexXa® also restored thrombin generation to normal in all participants who received this agent (P<0.001 versus placebo).

ANNEXA-4 Study: This is an ongoing, multicenter, prospective, open-label, single-group study designed to evaluate the use of AndexXa® in patients with acute potentially life-threatening major bleeding, within 18 hours after the administration of one of four Factor Xa inhibitors – ELIQUIS®, XARELTO®, SAVAYSA®, or LOVENOX® (Enoxaparin). . All patients received a bolus dose of AndexXa® within 3-6 hours following presentation to the ER followed by a 2-hour infusion of the drug. The two co-primary outcomes were the percent change in the anti-Factor Xa activity and the rate of excellent or good hemostatic efficacy, 12 hours after the AndexXa® infusion. Anti-Factor Xa activity was measured by means of a validated chromogenic assay of Factor Xa enzymatic activity. Among the 185 evaluable high-risk patients in this open-label study, hemostatic efficacy was adjudicated as excellent or good by the independent committee, 12 hours after the AndexXa® infusion in 83% of patients. It was noted that following the bolus dose of AndexXa®, the median anti-Factor Xa activity decreased by 90% from baseline, among patients receiving XARELTO® and by 93% among patients receiving ELIQUIS® and these levels remained the same during the 2-hour infusion.

In conclusion, AndexXa® is the first and only antidote indicated for patients treated with XARELTO® and ELIQUIS® when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. The availability of this antidote assures both patients and health care providers to consider Factor Xa inhibitors with greater confidence. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. Siegal DM, Curnutte JT, Connolly SJ, et al. N Engl J Med 2015; 373:2413-242. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. Connolly SJ, Milling TJ, Eikelboom JW, et al. N Engl J Med 2016; 375:1131-1141

Perioperative Interruption of Direct Oral Anticoagulants in Patients with Venous Thromboembolic Disease

SUMMARY: Direct Oral AntiCoagulants (DOACs) are often prescribed for thromboembolic events. This class of anticoagulants, have a rapid onset and offset of action, short half-life and predictable anticoagulant effects, without the need for routine monitoring. Further, several studies have demonstrated non-inferiority or superiority of this class of drugs compared with Vitamin K Aantagonists (VKAs), with regards to prevention and treatment of thromboembolic events. It is estimated that each year 10-15% of patients on DOACs will undergo an invasive procedure or surgery and will require temporary interruption of anticoagulation prior to standard-risk procedures and procedures with increased risk for bleeding. Several studies have evaluated the perioperative interruption of DOACs based on half-life of the anticoagulant and the underlying procedural bleeding risk in patient with Atrial Fibrillation. Whether these findings can be extrapolated to patients with VTE, has remained unclear.

The authors in this study evaluated the thrombotic and bleeding outcomes following the perioperative interruption of Direct Oral AntiCoagulants, in patients with prior VTE (Venous ThromboEmbolism). This retrospective study included 190 patients who were on Direct Oral AntiCoagulants, such as PRADAXA® (Dabigatran), XARELTO® (Rivaroxaban), SAVAYSA® (Edoxaban) or ELIQUIS® (Apixaban), for previous VTE, and were scheduled to undergo an invasive procedure or surgery. They required temporary interruption of anticoagulation prior to standard-risk procedures and procedures with increased risk for bleeding. About 80% of the patients had unprovoked VTE, as the most recent thrombotic event, and 25% of the patients had recurrent VTE. The mean age was 59 years.

The timing to interrupt and reinitiate Direct Oral Anticoagulant therapy was at the discretion of the treating physician, and typically DOACs were held for three half-lives prior to and restarted 2 days following standard-bleeding risk procedures, and for five half-lives prior to and restarted 4 days following high-bleeding risk procedures. The mean time from last dose of DOAC to surgery was 56.9 hours for standard-bleeding risk procedures and 69.9 hours for high-bleeding risk procedures. The mean time to therapeutic dosing of DOACs was 47 hours in the standard-bleeding risk group and 80.2 hours in the high-bleeding risk group. Approximately 41% of patients also received prophylactic doses of Low Molecular Weight Heparin or DOACs in the immediate postoperative period before re-initiation of therapeutic anticoagulation. Also taken into consideration was the elimination half-life of DOACs which can be increased by decreased renal function (PRADAXA® > SAVAYSA® > XARELTO® and ELIQUIS®), severe hepatic insufficiency (XARELTO® and ELIQUIS® > SAVAYSA® > PRADAXA®) and drug interactions. The Primary efficacy outcome was the 30-day symptomatic VTE rate, and the Primary safety outcome was the 30-day major bleeding rate. Secondary outcomes included overall mortality and the rate of clinically relevant non-major bleeding.

The 30-day VTE rate was 1.05% and the 30-day major bleeding rate was 0.53%. There were no deaths during the 30-day follow-up period. The rate of clinically relevant non-major bleeding was 3.16%.

It was concluded that perioperative interruption of Direct Oral AntiCoagulants, using a strategy that considered the half-life of the DOAC and the underlying procedural bleeding risk, appeared to be both safe and effective among patients with prior Venous ThromboEmbolism. Thrombotic and bleeding outcomes following perioperative interruption of direct oral anticoagulants in patients with venous thromboembolic disease. Shaw J, de Wit C, Le Gal G, et al. J Thromb Haemost. 2017;doi:10.1111/jth.13670