Re-initiation of anticoagulation after central nervous system hemorrhage during treatment with direct oral anticoagulants: a single hospital cohort study.

Direct Oral Anticoagulants for Prevention of Recurrent Thrombosis in Myeloproliferative Neoplasms

BackgroundThe benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) has not been well established yet. This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF.MethodsPubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF. The primary endpoint was thromboembolic events. The relative risks and standard errors were pooled by random-effect models using the generic inverse variance method.ResultsSeven observational studies involving 9395 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a similar risk of thromboembolic events [RR (95%CI): 0.93 (0.73–1.20), p = 0.59] and ischemic stroke [RR (95%CI): 0.65 (0.33–1.28), p = 0.22]. The incidence of major bleeding was comparable between the two groups [RR (95%CI): 0.75 (0.49–1.15), p = 0.19]. Meanwhile, DOAC therapy was superior to VKA therapy in reducing the incidences of all-cause death [RR (95%CI): 0.44 (0.35–0.55), p < 0.001], cardiovascular death [RR (95%CI): 0.41 (0.22–0.75), p = 0.004], and intracranial hemorrhage [RR (95%CI): 0.42 (0.24–0.74), p = 0.003].ConclusionIn patients with HCM and AF, DOAC therapy was similar to VKA therapy in reducing the risk of thromboembolic events, without increasing bleeding risk. In addition, the DOAC group displayed significant advantages in reducing mortality and intracranial hemorrhage compared with the VKA group. Further randomized controlled trials are needed to provide more evidence for DOAC therapy in this population.

For patients with atrial fibrillation, clinicians often prescribe antiplatelet therapy rather than oral anticoagulation, which may be related to a concern that direct oral anticoagulants (DOACs) are associated with a higher risk of intracranial bleeding, despite being less effective for stroke prevention. To determine whether DOAC therapy, compared with single-agent antiplatelet therapy, was associated with an increased risk of intracranial and major hemorrhage. A systematic search of PubMed and Embase databases from inception to February 7, 2024, was performed. Randomized clinical trials that compared DOAC therapy with single-agent antiplatelet therapies were included. Trials with active follow-up of less than 30 days or a sample size less than 200 were excluded. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Data were extracted independently by 2 researchers. A random-effects meta-analysis model was used to report pooled treatment effects and 95% CIs. The primary outcome was occurrence of intracranial hemorrhage. A total of 9 randomized clinical trials were included (45 494 participants). DOAC therapy was not associated with significantly higher odds of intracranial hemorrhage compared with antiplatelet therapy (0.55% vs 0.48% over a mean trial follow-up of 17.1 months; odds ratio [OR], 1.15; 95% CI, 0.71-1.88), but there was heterogeneity among trials (I2 = 53.7%). In an analysis by DOAC agent, the respective estimates for intracranial hemorrhage risk were as follows: rivaroxaban, OR, 2.09 (95% CI, 1.20-3.64); dabigatran, OR, 1.00 (95% CI, 0.61-1.64); and apixaban, OR, 0.72 (95% CI, 0.44-1.17). Overall, DOAC therapy was associated with higher odds of major hemorrhage compared with antiplatelet therapy (2.41% vs 1.76% over a mean trial follow-up of 15.5 months; OR, 1.39; 95% CI, 1.07-1.80), with the following estimates by agent: rivaroxaban, OR, 1.91 (95% CI, 1.22-3.00); dabigatran; OR, 1.21 (95% CI, 0.86-1.69); and apixaban, OR, 1.09 (95% CI, 0.73-1.63). In this systematic review and meta-analysis, DOAC therapy was not associated with a significantly higher risk of intracranial hemorrhage compared with antiplatelet therapy, but was associated with a higher risk of major hemorrhage. These findings support the safety of DOAC compared with antiplatelet therapy with respect to risk of ICH and reinforce adherence with current atrial fibrillation guidelines.

IntroductionPostmarketing pharmacovigilance reports have raised concerns about non-bleeding adverse events associated with direct oral anticoagulants (DOACs), but only limited results are available from large claims databases.ObjectiveThe aim of this study was to assess the potential association between DOAC initiation and the onset of four types of non-bleeding adverse events by sequence symmetry analysis (SSA).MethodsSSA was performed using nationwide data from the French National Healthcare databases (Régime Général, 50 million beneficiaries) to assess a cohort of 386,081 DOAC new users for the first occurrence of four types of non-bleeding outcomes: renal, hepatic, skin outcomes identified by using hospitalization discharge diagnoses, and gastrointestinal outcomes by using medication reimbursement. Asymmetry in the distribution of each investigated outcome occurring before and after initiation of DOAC therapy was used to test the association between DOAC therapy and these outcomes. SSA inherently controls for time-constant confounders, and adjusted sequence ratios were computed after correcting for temporal trends. Negative (glaucoma) and positive (bleeding, depressive disorders) control outcomes were used and analyses were replicated on a cohort of 310,195 patients initiating a vitamin K antagonist (VKA).ResultsThis study demonstrated the expected positive association between either DOAC or VKA therapy and hospitalised bleeding and initiation of antidepressant therapy, while no association was observed between either DOAC or VKA therapy and initiation of antiglaucoma medications. For DOAC therapy, signals were the associations with hepatic outcomes, including acute liver injury [for the 3-month time window, aSR3 = 2.71, 95% confidence interval (CI) 1.79–4.52]; gastrointestinal outcomes, including initiation of drugs for constipation and antiemetic drugs (aSR3 = 1.31, 95% CI 1.27–1.36; and 1.17, 95% CI 1.12–1.22, respectively); and kidney diseases (aSR3 = 1.33, 95% CI 1.29–1.37).ConclusionResults of this nationwide study suggest that DOACs are associated with rare but severe liver injury and more frequent gastrointestinal disorders. A low risk of kidney injury with DOAC therapy can also not be excluded.Electronic supplementary materialThe online version of this article (10.1007/s40264-018-0668-9) contains supplementary material, which is available to authorized users.

Background Among patients with atrial fibrillation, clinicians often prescribe anti-platelet therapy rather than oral anticoagulation which may relate to a concern that direct oral anticoagulants (DOAC) are associated with a higher risk of bleeding. We completed a meta-analysis to determine whether DOAC therapy, compared to single anti-platelet, was associated with an increased risk of major haemorrhage, with a primary focus on intracranial haemorrhage (ICH). Methods We searched PubMed and Embase databases up to 7/2/2024. Randomised controlled trials (RCT) that compared DOAC therapy to single anti-platelet agents were included. Trials with follow-up less than 30 days, or sample size less than 200 were excluded. A random-effects meta-analysis model was used to report pooled treatment effects and 95% confidence intervals (CIs). The primary outcome was occurrence of ICH. Results A total of 9 RCTs were included (n=45,493). Overall, DOAC therapy was not associated with significantly higher odds of ICH compared to anti-platelet therapy (Odds ratio (OR) 1.14; 95% CI, 0.71-1.82), but there was heterogeneity among trials (I2 = 49.3). In an analysis by DOAC agent, the respective estimates for ICH risk were; Rivaroxaban (OR 2.05; 95% CI, 1.09-3.83); Dabigatran (OR 1.00; 95% CI, 0.61-1.64) and Apixaban OR 0.72; 95% CI, 0.44-1.17). DOAC therapy was associated with higher odds of major haemorrhage compared to aspirin (OR 1.39; 95% CI,1.07-1.80), with the following estimates by agent; Rivaroxaban (OR 1.91; 95% CI 1.22-3.00); Dabigatran (OR 1.21; 95% CI 0.86-1.69); Apixaban OR 1.09; 95% CI 0.73, 1.63). DOAC therapy was associated with higher odds of GI haemorrhage then control (OR 1.39; 95% CI,1.11, 1.73). Conclusion DOAC therapy was not associated with a significantly higher risk of ICH compared to anti-platelet therapy, but risks may differ among DOAC agents. DOAC therapy was associated with a higher risk of major haemorrhage, mostly related to GI haemorrhage.

Localization, Management, Resource Consumption and Outcome of Major Gastrointestinal Bleeding in Patients with Direct Oral Anticoagulants, Vka and Antiplatelet Therapy

The efficacy and bleeding complications of direct oral anticoagulant (DOAC) therapy for cancer-associated venous thromboembolism (VTE) in routine clinical practice remain unclear. Moreover, data on long-term outcomes in patients with cancer-associated VTE who received DOAC therapy are limited.Methods and Results:This retrospective study enrolled 1,096 consecutive patients with acute VTE who received warfarin or DOAC therapy between April 2014 and May 2017. The mean follow-up period was 665±490 days. The number of cancer-associated VTE patients who received DOAC therapy was 334. Patients who could not be followed up and those prescribed off-label under-dose DOAC were excluded. Finally, 303 patients with cancer-associated VTE were evaluated. The number of cases of major bleeding and VTE recurrence was 54 (17.8%) and 26 (8.6%), respectively. In the multivariate analysis, the factors correlated with major bleeding were high cancer stage, high performance status, liver dysfunction, diabetes mellitus, and stomach cancer; those correlated with recurrent VTE were initial diagnosis of pulmonary embolism, uterine cancer, and previous cerebral infarction. Major bleeding was an independent risk factor of all-cause death. In the Kaplan-Meier analysis, those who received prolonged DOAC therapy had lower composite major bleeding and recurrent VTE risks than those who did not. In DOAC therapy for cancer-associated VTE, major bleeding prevention is important because it is an independent risk factor of death.

Safety and Efficacy of Direct Oral Anticoagulants in Comparison to Low Molecular Weight Heparin in Hematological Malignancies

Background and purpose: The incidence of non-traumatic intracranial hemorrhage (ICH) during treatment with direct oral anticoagulants (DOACs) is lower than that during warfarin treatment. The characteristics of intracranial hemorrhage during DOAC therapy, however, remain unclear. Therefore, we performed a nationwide survey in Japan to examine the clinical characteristics and outcomes of DOAC-associated ICH using data obtained from the Japanese Diagnosis Procedure Combination (DPC)-based Payment System. Methods: We analyzed the data of 1,567 patients with ICH (DOAC-associated ICH, 88; warfarin-associated ICH, 1,479) who were urgently hospitalized at 575 institutions across Japan from April 2010 to March 2013 for whom prescription data before admission were available. Results: The annual number of patients with all anticoagulant (DOAC or warfarin)- associated ICH in each year from 2010 to 2013 was 226, 252, 426, and 663, representing 15.7%, 15.4%, 16.1%, and 16.1% of all ICH cases in the same period, respectively. There was an increase in the proportion of patients who presented with DOAC-associated ICH in all anticoagulant-associated ICH in each year from 2010 to 2013 (0%→0.4%→3.8%→10.7%). The proportion of patients with impaired consciousness (three-digit score on Japan Coma Scale) at admission (DOAC, 19.3%; Warfarin, 25.4%; P=0.20), in-hospital mortality within 7 days (DOAC, 11.4%; Warfarin, 19.5%; P=0.06), and mRS score of 5-6 at discharge (DOAC, 27.3%; Warfarin, 37.4%; P=0.06) were lower in the patients with DOAC-associated ICH. The rates of surgery for hematoma removal were significantly lower in the patients with DOAC-associated ICH (NOAC, 2.3%; Warfarin, 9.7%; P=0.019). Conclusions: This is the largest nationwide study of DOAC-associated ICH in a real-world situation in Japan, revealing that the patients with DOAC-associated ICH had better clinical outcomes compared with warfarin-associated ICH, probably due to milder hemorrhage at admission.

DIRECT ORAL ANTICOAGULANTS IN PORTAL VEIN THROMBOSIS IN CIRRHOTIC PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Efficacy and Safety of Direct Oral Anticoagulants: A Systematic Review of Population Based Studies

Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAA) is advantageous over previous treatment options due to high efficacy, short treatment duration, and relatively few drug interactions. Similarly, direct oral anticoagulants (DOAC) are generally preferred over warfarin for the management of thrombosis and atrial fibrillation due to a favourable safety profile. Direct-acting antivirals inhibit DOAC transport through P-glycoprotein inhibition leading to a theoretical increase in bleeding risk. We evaluated the incidence of bleeding in patients who received concurrent DAA and DOAC therapy and stratified the analysis based on the patient's cirrhosis status. We conducted a multicenter, retrospective cohort study to evaluate bleeding in patients with HCV and cirrhosis compared to patients with HCV without cirrhosis. Patients receiving at least 1 month of overlapping DAA and DOAC therapy between May 2017 and August 2020 at 11 medical centers in the United Kingdom and three medical centers in the United States were included. Charts were manually reviewed to identify baseline characteristics as well as thromboembolic or bleeding events. Bleeding events were categorized as major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). Of 204 total patients, 36 patients (18%) had cirrhosis and 168 patients (82%) did not have cirrhosis. The majority of patients were male (79%) and Caucasian (75%). Sofosbuvir/velpatasvir (32%) and rivaroxaban (57%) were the most commonly prescribed DAA and DOAC, respectively. Leading indications for anticoagulation included thrombosis (75%) and atrial fibrillation (21%). There were three MB events (1.5%) all of which occurred in patients with additional risk factors (age over 65 and on antiplatelet therapy) and no CRNMB occurred while on DOAC and DAA therapy. Of the three MB, one occurred in a patient with cirrhosis and two in patients without cirrhosis, RR 1.23 (0.56-2.76). In conclusion, in this multicenter cohort study of concurrent DAA and DOAC use, MB was uncommon and there was no CRNMB. There was no significant difference in bleeding events among patients with cirrhosis compared to those without cirrhosis. These findings support the use of DAA among patients requiring DOAC.

ABSTRACTObjectives: To investigate whether direct oral anticoagulant (DOAC) therapy at acute hospitals is continued after transfer to subacute or chronic hospitals and geriatric health services facilities in Japan.Methods: Acute hospitals routinely transfer patients to nearby subacute or chronic hospitals and geriatric health services facilities after acute stroke treatment. To elucidate the status of antithrombotic therapy, particularly DOAC therapy, we conducted a questionnaire survey of chief physicians at 33 subacute or chronic hospitals and geriatric health services facilities in the vicinity of Kawasaki City.Results: Responses were received from 23 hospitals and geriatric health services facilities (5 convalescent and rehabilitation hospitals, 5 chronic hospitals, 13 geriatric health services facilities). The number of convalescent hospitals responding, ‘no problem with DOAC administration’ before transfer to subacute or chronic hospitals and geriatric health services facilities increased from 4 (80%) at the introduction of DOACs to 5 (100%) presently. The number of chronic hospitals and geriatric health services facilities also increased from 1 (20%) to 3 (60%) and 4 (30.8%) to 5 (38.5%), respectively, albeit not significantly. The number of convalescent hospitals, chronic hospitals, and geriatric health services facilities requesting pre-transfer change of oral anticoagulants decreased from 20% to 0%, 60% to 40%, and 69.2% to 61.5%, respectively. All convalescent hospitals continued DOAC therapy after transfer. However, only 40.0% of chronic hospitals and 46.2% of geriatric health services facilities used DOACs in the present period. Warfarin was used instead at 3 (60%) chronic hospitals and 7 (53.8%) geriatric health services facilities and antiplatelet drugs were used at 1 hospital/facility each (20% and 7.7%, respectively). Nine (39.1%) hospitals and facilities cited high DOAC costs for the switch.Conclusions: Convalescent hospitals have incorporated DOAC use and readily accept patients receiving DOACs at transferring hospitals. Conversely, many chronic hospitals and geriatric health services facilities eventually switch from DOACs to warfarin or antiplatelet drugs due to cost. Efforts to resolve these barriers to continued administration of DOACs between acute hospitals and subacute or chronic hospitals and geriatric health services facilities in Japan are needed as soon as possible.

Background The benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) have not been well established yet. Purpose This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF. Methods PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF. Results Five studies involving 8103 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a significant lower risk of all-cause death [RR (95%CI): 0.44 (0.35-0.55)]. Meanwhile, DOAC therapy group was similar to VKA therapy in reducing ischemic stroke [RR (95%CI): 0.65 (0.33-1.28)] and thromboembolic events [RR (95%CI): 0.95 (0.74-1.22)]. The incidence of major bleeding [RR (95%CI): 0.69 (0.44-1.07)] were comparable between the two groups. Conclusion In patients with HCM and AF, DOAC therapy were superior or non-inferior to VKA therapy in reducing the risk of all-cause death and thromboembolic events, without increasing bleeding risk. Further RCTs are needed to provide more evidence for DOAC therapy in this population.Efficacy and safety endpoints in DOAC th

Background The All Nippon AF In the Elderly (ANAFIE) Registry showed that taking any DOACs was associated with reduced stroke/systemic embolisms and was not associated with increased major bleeding in very elderly (≥80 years) patients with nonvalvular atrial fibrillation (NVAF) at high bleeding risk (1). However, the relationship between very elderly (≥80 years) cardioembolic stroke (CES) patients with NVAF at high bleeding risk and direct oral anticoagulant (DOAC) therapy before stroke onset remains unknown. Methods During a 10-year period from April 2011 to March 2021, 364 CES patients (≥80 years) with NVAF admitted to our hospital within 48 hours after stroke onset and with a modified Rankin Scale (mRS) score of 0 or 1 before onset were studied. High bleeding risk was defined as having any following factors; a bleeding history, renal dysfunction (creatinine clearance &amp;lt;30 ml/min), low body weight (≤45 kg), use of antiplatelet or nonsteroidal anti-inflammatory drugs. They were divided into two groups: high bleeding risk group (H group) (n=214; median 85 years [82-88]; 144 women [67%]) and non-high bleeding risk group (Non-H group) (n=150; median 84 years [82-87]; 69 women [46%]). We compared stroke severity between the two groups and evaluated effect of DOAC treatment on stroke severity and functional outcome. Results CHADS₂ score was significantly higher in the H group than in the Non-H group (median 4 [3-4] versus 3 [2-4], p=0.002). NIHSS (National Institutes of Health Stroke Scale) score on admission and proportion of mortality (mRS:6) were relatively higher in H group than in Non-H group, but there were no significant differences among the two groups. However, mRS score at discharge was worse in the H group than in the Non-H group (median 4 [2-5] versus 3 [1-4], p=0.002). The patients in the H group were further divided into three groups based on the treatment with OAC before stroke onset: DOAC therapy (n=20), no-OAC (n=148) and warfarin therapy (n=46). The number of patients with NIHSS (≥8) on admission and mRS (≥5) at discharge were 8 (40%), 104 (70%), and 30 (65%) (p=0.03) and 3 (15%), 60 (41%) and 23 (50%) (p=0.03), respectively. Multivariate analysis confirmed that DOAC therapy had a lower odds ratio (OR) for severe stroke (NIHSS ≥8) on admission (OR to no-OAC=0.22; 95% confidence interval [CI]=0.08-0.62; p=0.005) and poor functional outcome (mRS ≥5) at discharge (OR=0.20; 95% CI=0.05-0.80; p=0.02), when no-OAC was used as a reference after adjusting for confounders. Conclusion Very elderly (≥80 years) CES patients with NVAF at high bleeding risk have severe CES than those at non-high bleeding risk. However, DOAC therapy before stroke onset may be associated with reduced stroke severity on admission and poor functional outcome at discharge in very elderly (≥80 years) CES patients with NVAF at high bleeding risk.