Higher Risk Of Major Bleeding Research Articles

Efficacy and Safety of Oral Anticoagulants in Patients with Systolic Heart Failure in Sinus Rhythm: A Systematic Review and Meta-analysis of Randomized Controlled Trials and Cohort Studies.

Introduction There is conflicting evidence on the risk–benefit ratio of oral anticoagulants (OAC) in heart failure (HF) patients without atrial fibrillation. We aimed to evaluate the efficacy and safety of OAC in HF patients in sinus rhythm. Methods A systematic literature search was conducted using PubMed and Embase. We included randomized controlled trials (RCT) and cohort studies, comparing OAC with antiplatelet or no treatment/placebo in patients with HF. Outcomes evaluated were stroke, myocardial infarction (MI), all-cause mortality, and major bleeding. Results Five RCTs and three cohort studies were included. OAC was associated with a reduced risk of ischemic stroke when compared with no treatment/placebo (odds ratio [OR] = 0.67, 95% confidence interval [CI]: [0.47, 0.94]) and antiplatelet therapy (OR = 0.55, 95% CI: [0.37, 0.81]). No significant reduction was found in MI, when OAC was compared with no treatment/placebo (OR = 0.82, 95% CI: [0.63, 1.07]) or antiplatelet therapy (OR = 1.04, 95% CI: [0.60, 1.81]). The all-cause mortality analysis showed no significant reduction when comparing OAC with no treatment/placebo (OR = 0.99, 95% CI: [0.87, 1.12]) or antiplatelet therapy (OR = 1.00, 95% CI: [0.86, 1.16]). The nonsignificant effect of OAC on all-cause mortality was supported by a meta-analysis of the three cohort studies (OR = 1.02, 95% CI: [0.75, 1.38]). Patients treated with OAC had a significantly higher risk of major bleeding than patients receiving antiplatelet therapy (OR = 2.16, 95% CI: [1.55, 3.00]) and a numerically higher risk when compared with no treatment/placebo (OR = 2.38, 95% CI: [0.87, 6.49]). Conclusion The present study does not support the routine use of OAC in patients with HF in sinus rhythm.

Major bleeding risk with non-vitamin K antagonist oral anticoagulant vs. aspirin in heart failure: network meta-analysis.

AimsRelative bleeding risks of different antithrombotic agents in heart failure (HF) patients is an important consideration in treatment decision making, making detailed comparative analysis desirable. The aim of this study was to conduct a network meta‐analysis to investigate the major bleeding risk for individual novel oral anticoagulants (NOACs) vs. aspirin among patients with HF.Methods and resultsWe searched Pubmed, EMBASE, Cochrane Collaboration Central Register of Controlled Clinical Trials, and Clinicaltrials.gov from 1966 to November 2019 to identify relevant randomized clinical trials. Studies comparing individual NOACs vs. aspirin were analysed using direct study‐level meta‐analysis. Studies comparing aspirin to warfarin and NOACs to warfarin were then additionally added using network (direct and indirect) study‐level meta‐analysis. Primary endpoint was major bleeding. Final analysis included nine trials with 34 367 participants, including one direct comparison trial (apixaban vs. aspirin) and eight indirect comparison trials against the shared warfarin comparator (four aspirin trials and one trial each of apixaban, dabigatran, rivaroxaban, and edoxaban). For apixaban, network meta‐analysis combing direct and indirect comparison showed that major bleeding risk might not be different between apixaban and aspirin (odds ratio, 1.18 [95% confidence interval, 0.38 to 3.65]) in HF patients. In contrast, indirect‐comparison meta‐analysis showed dabigatran, rivaroxaban, and edoxaban compared with aspirin might be associated with a higher risk of major bleeding in HF patients.ConclusionsIn network meta‐analysis, apixaban might be associated with a comparable risk of major bleeding compared with aspirin in patients with HF, while other NOACs might be associated with a higher risk. However, such results were not strongly convincing because of lack of direct comparison in an original trial and small sample size of trials and participants. A clinical trial directly comparing apixaban vs. aspirin in patients with HF and sinus rhythm may be worth undertaking.

Anticoagulant Use and the Risk of Thromboembolism and Bleeding in Postoperative Atrial Fibrillation After Noncardiac Surgery

BackgroundAn effective and safe oral anticoagulation (OAC) strategy for patients with new postoperative AF (POAF) after noncardiac surgery remains unclear. We aimed to determine the association between OAC use and 1) thromboembolic events and 2) major bleeding in patients with POAF after noncardiac surgery. MethodsA retrospective cohort (1999-2015) was used to identify patients with new POAF after inpatient noncardiac surgery. Initiation of OAC was defined as prescription of an OAC within 30 days following hospital discharge. Times to first hospital admission or emergency department visit for a thromboembolic or major bleeding event were compared using Cox proportional hazards models. ResultsWe identified 22,007 patients with new POAF after inpatient noncardiac surgery. The majority of patients had intermediate (CHA2DS2-VASc 2-3: 45%) to high (CHA2DS2-VASc ≥ 4: 42%) thromboembolic risk. During a mean follow-up of 4 years, a total of 1099 (5%) thromboembolic and 3250 (15%) bleeding events occurred. Compared with patients not on anticoagulation, anticoagulation did not reduce the risk for thromboembolic events (adjusted hazard ratio [aHR] 0.89, 95% CI 0.73-1.07). In patients initiated on anticoagulation, there was an association with a higher risk for major bleeding (aHR 1.14, 95% CI 1.04-1.25). ConclusionsIn patients with new POAF after noncardiac surgery, anticoagulation was not associated with a reduction in long-term thromboembolic events; however, this was accompanied by an overall increased risk for major bleeding. Future prospective clinical studies are needed to better address the role for anticoagulation therapy in the setting of POAF after noncardiac surgery to understand the efficacy and safety of treatment.

Dual Antiplatelet Therapy After Percutaneous Coronary Intervention and Drug-Eluting Stents: A Systematic Review and Network Meta-Analysis.

The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with drug-eluting stents remains uncertain. We compared short-term (<6-month) DAPT followed by aspirin or P2Y12 inhibitor monotherapy; midterm (6-month) DAPT; 12-month DAPT; and extended-term (>12-month) DAPT after percutaneous coronary intervention with drug-eluting stents. Twenty-four randomized, controlled trials were selected using Medline, Embase, Cochrane library, and online databases through September 2019. The coprimary end points were myocardial infarction and major bleeding, which constituted the net clinical benefit. A frequentist network meta-analysis was conducted with a random-effects model. In 79 073 patients, at a median follow-up of 18 months, extended-term DAPT was associated with a reduced risk of myocardial infarction in comparison with 12-month DAPT (absolute risk difference, -3.8 incident cases per 1000 person-years; relative risk, 0.68 [95% CI, 0.54-0.87]), midterm DAPT (absolute risk difference, -4.6 incident cases per 1000 person-years; relative risk, 0.61 [0.45-0.83]), and short-term DAPT followed by aspirin monotherapy (absolute risk difference, -6.1 incident cases per 1000 person-years; relative risk, 0.55 [0.37-0.83]), or P2Y12 inhibitor monotherapy (absolute risk difference, -3.7 incident cases per 1000 person-years; relative risk, 0.69 [0.51-0.95]). Conversely, extended-term DAPT was associated with a higher risk of major bleeding than all other DAPT groups. In comparison with 12-month DAPT, no significant differences in the risks of ischemic end points or major bleeding were observed with midterm or short-term DAPT followed by aspirin monotherapy, with the exception that short-term DAPT followed by P2Y12 inhibitor monotherapy was associated with a reduced risk of major bleeding. There were no significant differences with respect to mortality between the different DAPT strategies. In acute coronary syndrome, extended-term in comparison with 12-month DAPT was associated with a reduced risk of myocardial infarction without a significant increase in the risk of major bleeding. The present network meta-analysis suggests that, in comparison with 12-month DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy reduces major bleeding after percutaneous coronary intervention with drug-eluting stents, whereas extended-term DAPT reduces myocardial infarction at the expense of more bleeding events.

Safety and efficacy of anticoagulant monotherapy in atrial fibrillation and stable coronary artery disease: A systematic review and meta-analysis

BackgroundAdjunctive use of oral anticoagulant (OAC) and antiplatelet therapy (APT) in patients with stable coronary artery disease (CAD) and nonvalvular atrial fibrillation (AF) is a challenge of daily practice. MethodsA comprehensive literature search of databases was performed to identify studies comparing the safety and efficacy of OAC monotherapy and combined therapy (OAC plus single (S) APT). Events including major adverse cardiovascular events (MACE), all-cause mortality, stroke and major bleeding were analyzed. ResultsSeven articles comprising 11,070 subjects were identified. Combined therapy was associated with a significantly higher risk of major bleeding (pooled hazard ratio (HR) of 1.62, 95% CI 1.40–1.86, p=<0.0001) compared to the OAC monotherapy. There was no significant difference between the two comparison arms in terms of MACE (HR 1.14; 95% CI 0.97–1.34, p = 0.11), stroke (HR 1.05; 95% CI 0.77–1.43, p = 0.78) and all-cause mortality (HR 1.15; 95% CI 0.94–1.40, p = 0.16). Stratified analysis by inclusion of only patients with coronary stents attenuated the safety effect of monotherapy. Subgroup analysis based on the study design, type of OAC, major bleeding criteria and APT revealed findings consistent with the pooled HR. The combined therapy group had a 19% and 38% higher risk of MACE in studies with a history of MI (p = 0.03) and with the use of rivaroxaban (p = 0.02), respectively. ConclusionOAC monotherapy might have a lower incidence of major bleeding events with no higher overall risk of MACE, ischemic stroke and all-cause mortality compared to the combined therapy group.

Off-label dosing of non–vitamin K antagonist oral anticoagulants and clinical outcomes in Asian patients with atrial fibrillation

Off-label dosing non-vitamin K antagonist oral anticoagulants (NOACs) are commonly prescribed for Asian patients with atrial fibrillation (AF). The purpose of this study was to investigate the associations between inappropriate dosing of NOACs and clinical outcomes. We used medical data from a multicenter health care system in Taiwan, which included 2068, 5135, 2589, 1483, and 2342 AF patients taking dabigatran, rivaroxaban, apixaban, edoxaban, and warfarin, respectively. The risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding in patients treated with underdosing or overdosing NOACs were compared to those of on-label dosing NOACs and warfarin. About 27% and 5% of AF patients were treated with underdosing and overdosing NOACs, respectively. Compared to on-label dosing, underdosing NOACs were associated with a significantly higher risk of IS/SE (adjusted hazard ratio [aHR] 1.59; 95% confidence interval [CI] 1.25-2.02; P <.001), whereas overdosing NOACs were associated with a significantly higher risk of major bleeding (aHR 2.01; 95% CI 1.13-3.56; P = .017). Compared to warfarin, the 4 on-label dosing NOACs were associated with a comparable risk of IS/SE and a significantly lower risk of major bleeding, whereas underdosing NOACs were associated with a higher risk of IS/SE (aHR 1.46; P = .012). About 3 in 10 Asian AF patients were treated with off-label dosing NOACs in daily practice. Compared to on-label dosing, underdosing was associated with a higher risk of IS/SE, whereas overdosing was associated with a higher risk of major bleeding. Thus, even for Asian AF patients at higher risk for bleeding, NOACs still should be prescribed at the dosing based on clinical trial criteria and guideline recommendations.

Correction to: Aprotinin in adults at high risk of major blood loss during isolated CABG with cardiopulmonary bypass: a profile of its use in the EU

Prophylactic treatment with aprotinin, a haemostatic antifibrinolytic agent, is indicated to reduce blood loss and blood transfusion in adults with a high risk of major bleeding undergoing primary or repeat isolated coronary artery bypass graft (CABG) with cardiopulmonary bypass. Overall, aprotinin was consistently more effective than tranexamic acid, e-aminocaproic acid, desmopressin and placebo in reducing massive blood loss, the need for transfusions of blood products, and the need for reoperation due to diffuse bleeding in trials in this patient population, and was generally well-tolerated. The approval of aprotinin in the EU was reinstated by the European Medicines Agency (EMA) in 2012, following subsequent analysis of the clinical data that led to its suspension in 2007. The EMA analysis concluded that the reduction in massive bleeding provided by aprotinin in patients undergoing isolated CABG is clinically relevant, as it reduces complications, the need for blood product transfusions and the length of hospital stay, without increasing mortality. The relaunch of aprotinin was accompanied by a risk management to assess the pattern of use and safety of aprotinin in clinical practice. Data from centres enrolled in the Nordic Aprotinin Patient Registry are being collected and will be assessed in the final report.

Safety and efficacy of drug eluting stents vs bare metal stents in patients with atrial fibrillation: A systematic review and meta-analysis

ObjectiveA systematic review and meta-analysis was performed to evaluate the safety and efficacy of drug-eluting stents (DES) vs bare-metal stents (BMS) in atrial fibrillation (AF) patients. MethodsWe systematically searched 5 engines until May 2019 for cohort studies and randomized controlled trials (RCTs). Primary outcomes were major bleeding and major adverse cardiac events (MACE) including cardiac death, myocardial infarction, target vessel revascularization (TVR) or stent thrombosis. Effects of inverse variance random meta-analyses were described with relative risks (RR) and their 95% confidence intervals (CI). We also stratified analyses by type (triple [TAT] vs dual [DAT]) and duration (short-vs long-term) of antithrombotic therapy. ResultsTen studies (3 RCTs; 7 cohorts) including 10,353 patients (DES: 59.6%) were identified. DES did not show higher risk of major bleeding than BMS (5.6% vs 6.9%, RR 1.07; 95%CI, 0.89–1.28, p = 0.47; I2 = 0%) or MACE (12% vs 13.6%; RR 0.96; 95%CI 0.81–1.13, p = 0.60; I2 = 44%). Although, DES almost decreased TVR risk (6.4% vs 8.4%, RR 0.78; 95%CI, 0.61–1.01, p = 0.06; I2 = 15%). Stratified analyses by type and duration of antithrombotic therapy showed no differences in major bleeding or MACE between both types of stents. In DES, long-term TAT showed higher major bleeding risk than long-term DAT (7.7% vs 4.7%, RR 1.48, 95%CI 1.08–2.03, p = 0.01; I2 = 12%). For both types of stents, MACE risk was similar between TAT and DAT. ConclusionsIn patients with AF undergoing PCI, DES had similar rate of major bleeding and MACE than BMS. DAT seems to be a safer antithrombotic therapy compared with TAT.

Severe renal impairment and risk of bleeding during anticoagulation for venous thromboembolism

BackgroundDetection of severe renal impairment in patients with venous thromboembolism (VTE) is mandatory both for selecting anticoagulant therapy and for evaluating major bleeding risk, increased by severe renal impairment. ObjectivesTo determine whether the Cockcroft and Gault (CG) and Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formulas identify severe renal impairment in the same VTE patients presenting the same risk of major bleeding. Patients/MethodsWe compared clinical characteristics and outcomes during the first 3 months of anticoagulation between VTE patients in the RIETE registry with severe renal impairment according to the CG and/or CKD‐EPI formula (estimated glomerular filtration rate <30 mL/min and <30 mL/min/1.73 m2, respectively). The primary outcome was major bleeding. ResultsUp to October 2017, 41 796 patients were included in RIETE. Among the 4676 patients with severe renal impairment according to at least one of the formulas, this was not confirmed by the other formula in 1904 (40.7%). Major bleeding risk was increased in every patient subgroup with severe renal impairment vs patients without this condition (CG or CKD‐EPI < 30: odds ratio [OR] = 2.26, 95% confidence interval [CI 2.01‐2.53], only CG < 30: OR = 1.72, 95% CI [1.37‐2.13], only CKD‐EPI < 30: OR = 2.34, 95% CI [1.77‐3.05], CG+CKD‐EPI < 30: OR = 2.47, 95% CI [2.16‐2.83], all vs CG+CKD‐EPI > 30). ConclusionThe CG and CKD‐EPI formulas identify different subgroups of patients with severe renal impairment, leading to discordant results in 40.7% of these patients. Irrespective of the formula used for their identification, patients with severe renal impairment have a higher risk of major bleeding under anticoagulant therapy.

Impact of concomitant antiplatelet therapy on the efficacy and safety of direct oral anticoagulants for acute venous thromboembolism: Systematic review and meta‐analysis

BackgroundDirect oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE). Concomitant antiplatelet therapy may potentiate the antithrombotic effects of DOACs. ObjectivesWe evaluated the impact of concomitant antiplatelet therapy on the efficacy and safety of DOACs. Patients/MethodsMEDLINE, EMBASE, and Clinicaltrial.gov were searched for randomized controlled trials of DOACs for the treatment of acute VTE. The efficacy outcome was symptomatic recurrent VTE and VTE‐related death; the primary safety outcome was major bleeding. ResultsSix randomized controlled trials included 26 924 patients of whom 3550 (13.2%) received concomitant antiplatelet therapy, mainly aspirin (67.7%). Concomitant antiplatelet therapy did not reduce the incidence of recurrent VTE and VTE‐related death with any oral anticoagulant (odds ratio [OR] 1.17; 95% confidence interval [CI], 0.92‐1.48), with DOACs (OR 1.21; 95% CI, 0.86‐1.71), or VKAs alone (OR 1.16; 95% CI, 0.77‐1.73). Compared with no antiplatelet therapy, concomitant antiplatelet therapy was associated with a higher risk of major bleeding in patients with any oral anticoagulant (OR 1.79; 95% CI, 1.22‐2.63), DOACs (OR 1.89; 95% CI, 1.04‐3.44), or VKAs (OR 1.73; 95% CI, 1.16‐2.59). In patients receiving concomitant antiplatelet therapy, there were no statistically significant differences in efficacy or safety outcomes with DOACs or VKAs (OR 0.99; 95% CI, 0.64‐1.51, and OR 0.68; 95% CI, 0.32‐1.45, respectively). ConclusionsConcomitant use of antiplatelet therapy with oral anticoagulants does not appear to affect the risk of recurrent VTE and increases the risk of major bleeding.

Treatment of venous thromboembolism in patients with cancer: from clinical trials to real life

Approximately one-fifth of all cases of venous thromboembolism (VTE) are related to cancer. VTE complications may have a substantial impact on prognosis, quality of life and care in patients with cancer. Patients with cancer-related VTE are at increased risk of developing recurrent VTE compared to patients without cancer, but also have a higher risk of major bleeding. In the last years, direct oral anticoagulants (DOACs) have been evaluated in a head-to-head comparison with low molecular weight heparin (LMWH) in two randomized trials for the long-term treatment of VTE in patients with advanced cancer. The results of these trials show that DOACs have a similar efficacy profile, but probably higher risk of bleeding, compared to LMWH dalteparin. Because DOACs offer a simple oral treatment regimen without the need for anticoagulation monitoring, they could be attractive alternatives to LMWHs in these setting. The American Society of Clinical Oncology guidelines, published in August 2019, recommend LMWH, edoxaban and rivaroxaban as first-choice therapies for long-term anticoagulation in cancer patients with VTE. However, several practical issues should be considered concerning the long-term use of DOAC treatment in patients with cancer. Major concerns have been highlighted about the gastrointestinal bleeding risk in patients with gastrointestinal cancers and the potential drug-drug interactions in combination for some specific anticancer therapies. Several studies comparing DOACs with LMWH are currently ongoing to refine our knowledge concerning treatment with DOACs in patients with cancer-associated VTE.

Platelet count and risk of major bleeding in venous thromboembolism

The relationship between platelet count and risk of major bleeding in patients with venous thromboembolism (VTE) during anticoagulation remains unclear. We therefore investigated the association between platelet count, measured at VTE diagnosis and before the thrombotic event, and risk of major bleeding. Participants comprised 744 patients with incident VTE derived from the Tromsø Study. Major bleedings were recorded during the first year after VTE. Cox-regression was used to calculate hazard ratios (HRs) for major bleeding across platelet count quartiles. There were 55 major bleedings (incidence rate 9.1/100 person-years, 95% confidence interval [CI] 7.0–11.8). The major bleeding risk increased across quartiles of platelet count measured at VTE diagnosis (P for trend<0.02). In the age- and sex-adjusted model, subjects with platelet count in the highest quartile (≥300x109/L) had a 4.3-fold (95% CI 1.7–10.9) higher risk of major bleeding compared to those with platelet count in the lowest quartile (≤192x109/L), and exclusion of patients with cancer yielded similar results. When platelet count was measured on average 7 years before a VTE, the corresponding HR was 2.5 (95% CI 0.9–6.7). Our results suggest that increasing platelet count, assessed several years before and at VTE diagnosis, is associated with a higher risk of major bleeding, and could be a stable individual marker of major bleeding risk in VTE-patients.

P0643PROGNOSTIC IMPACT OF THROMBOCYTOPENIA IN THE RISK OF INTRAHOSPITAL BLEEDING IN ACUTE KIDNEY INJURY (AKI) PATIENTS

Abstract Background and Aims Low platelet count is a marker of adverse events in acute kidney injury (AKI) patients. Thrombocytopenia has often been reported as an indicator of underlying disease severity and worse patient outcomes; however, it’s role in the prediction of the risk of bleeding is not well defined. Our study aimed to assess the prognostic impact of admission thrombocytopenia in the risk of major bleeding in non-septic, non-post surgery AKI patients. Method This retrospective study enrolled patients with AKI hospitalized at tertiary care hospital during the three years. Admission thrombocytopenia was defined as a platelet count &amp;lt; 150x103/mL. The primary endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis. Results Of 178 included patients (age 61.7±11.1 years; 68.3% males), 26 (14.6%) had thrombocytopenia. These patients had more comorbidities: cancer (19.4 vs 9.6%; p=0.05); previous ulcer disease (17.6 vs. 8.8; p=0.04) and bleeding history (7.4% vs. 2.0%;p=0.04). While in a hospital, there was a trend for the use of more blood transfusions (7.4% vs. 2.7%; p=0.03) and more concomitant medications (12.7 vs. 5.1; p&amp;lt;0.05) in patients with thrombocytopenia. During a hospital stay (IQR: 7-29 days), 19 patients (10.7%) died), 22 (12.35%) had major bleeding, and 5 (2.8%) intracranial bleeding. After adjusting for age, presence of cancer, and use of oral anticoagulant medications, patients with thrombocytopenia had a higher risk of major bleeding (HR 3.34 95%CI: 1.57-7.26; p &amp;lt; 0.001). Conclusion Thrombocytopenia is a predictor of major intrahospital bleeding in the non-septic, non-post surgery AKI patients. It should be regarded in bleeding risk estimation and therapeutic strategy decisions.

Role of Aspirin for Primary Prevention in Persons with Diabetes Mellitus and in the Elderly.

To review the clinical evidence of the effect of aspirin as primary prevention for patients with diabetes mellitus and in healthy elderly. Two trials were performed to study these two patient populations: ASCEND showed that the use of low-dose aspirin in persons with diabetes, who did not have prior cardiovascular disease, led to a lower risk of cardiovascular events than placebo (8.5% vs 9.6%, rate ratio 0.88, 95% CI 0.79-0.97; p = 0.01). However, it showed a similar magnitude of increased risk of major bleeding among the aspirin group compared with placebo (4.1% vs 3.2%, rate ratio 1.29, 95% CI 1.09-1.52; p = 0.003). ASPREE showed that the use of low-dose aspirin in healthy elderly did not prolong disability-free survival (21.5% vs 21.2%, HR 1.01, 95% CI 0.92-1.11; p = 0.79); however, the rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs 2.8%, HR 1.38, 95% CI 1.18-1.62; p < 0.001). Additionally, further analyses of secondary end points of death, cardiovascular disease, and major hemorrhage were also studied. Higher all-cause mortality was seen among healthy elderly who received aspirin compared with placebo (12.7% vs 11.1%, HR 1.14, 95% CI 1.01-1.29) and was primarily attributed to cancer-related deaths. Similar risk of cardiovascular disease was seen among elderly who received aspirin compared with placebo (10.7% vs 11.3%, HR 0.95, 95% CI 0.83-1.08) and resulted in a significantly higher risk of major hemorrhage (8.6% vs 6.8%, HR 1.38, 95% CI 1.18-1.62; p < 0.001). These studies show that the use of low-dose aspirin as primary prevention in patients with diabetes and in the elderly does not have overall beneficial effect compared with its use in secondary prevention. In patients with diabetes without prior cardiovascular disease, the benefits of aspirin use were counterbalanced by the bleeding risk. Additionally, in healthy elderly, the use of aspirin did not prolong disability-free survival and instead led to a higher rate of major hemorrhage.

Aspirin or anticoagulation after cryptogenic stroke with patent foramen ovale: systematic review and meta-analysis of randomized controlled trials.

Since closure has restrictive eligibility criteria, the vast majority of patients with cryptogenic stroke and patent foramen ovale (PFO) receive medical treatment. However, the optimal antithrombotic strategy is still unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to define risk/benefit profile of anticoagulation compared with antiplatelet treatment in PFO-related stroke. Systematic review protocol was registered in PROSPERO (CRD42019117559). Following PRISMA guidelines, we searched MEDLINE, EMBASE, and Cochrane CENTRAL database (2000-2019) for RCTs randomly allocating patients with cryptogenic stroke and PFO to medical treatment. Risk of bias was assessed with Cochrane RoB tool. Main outcomes were stroke recurrence and major bleeding. RoPE score-dependent analysis was implemented to define a possible role for patient selection. Five RCTs met inclusion criteria (3 high-, 1 fair-, 1 poor-quality RCTs). Overall, meta-analysis included 1565 patients (mean age 55.5years), 753 (48.1%) receiving anticoagulation. Compared with antiplatelet treatment, anticoagulation conveyed no net benefit in prevention of recurrent stroke (OR = 0.66, 95% CI 0.41-1.07, pheterogeneity= 0.46), and associated with a non-significant higher risk of major bleeding (OR = 1.64, 95% CI 0.79-3.43, pheterogeneity= 0.57). In patients with high RoPE score, anticoagulation significantly reduced the risk of recurrent stroke (OR = 0.22, 95% CI 0.06-0.8, pheterogeneity= 0.88). Our meta-analysis shows that anticoagulation confers no net benefit in recurrent stroke prevention over antiplatelets in patients with PFO-related stroke. RoPE score might help in selecting patients benefiting from anticoagulation, but further trials are needed to delineate risk/benefit profile of anticoagulation.

Psychotropic Drugs and Outcome in Patients Receiving Anticoagulant Therapy for Venous Thromboembolism.

The influence (if any) of the use of psychotropic drugs on outcome in patients receiving anticoagulant therapy for venous thromboembolism (VTE) has not been consistently evaluated. We used data from the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the risk for VTE recurrences, major bleeding, or death during the course of anticoagulant therapy, according to the use of psychotropics at baseline. Among 49,007 patients with VTE enrolled from February 2009 to September 2019, total 5,230 (11%) were using psychotropics at baseline: antidepressants 3,273 (6.7%), antipsychotics 1,588 (3.2%), and anticholinesterases 369 (0.7%). During the course of anticoagulation, 1,259 patients developed VTE recurrences, 1,231 bled, and 3,988 died (fatal pulmonary embolism 269 and fatal bleeding 187). On multivariable analysis, patients using psychotropics at baseline had a similar risk for VTE recurrences (adjusted hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.58-1.12), a nonsignificantly higher risk for major bleeding (adjusted HR: 1.15; 95% CI: 0.97-1.35), and a higher risk for intracranial bleeding (adjusted HR: 1.83; 95% CI: 1.32-2.53) or death (adjusted HR: 1.44; 95% CI: 1.32-1.57) compared with those not using psychotropics. When separately analyzed, the highest risk for intracranial bleeding was found in patients using antidepressants (adjusted HR: 1.60; 95% CI: 1.08-2.37) or antipsychotics (adjusted HR: 2.02; 95% CI: 1.17-3.49) but not in those on anticholinesterases (adjusted HR: 1.69; 95% CI: 0.62-4.60). During the course anticoagulation for VTE, patients using psychotropics at baseline were at increased risk for intracranial bleeding.

Aortic valve stenosis provides complementary information to bleeding risk scores in non-valvular atrial fibrillation patients initiating anticoagulation.

BackgroundThe identification of modifiable bleeding risk factors may be of relevance. The aim is to evaluate if aortic stenosis (AS) provides additional information to bleeding risk scores for predicting major bleeding (MB) in non-valvular atrial fibrillation (AF).MethodsWe designed a retrospective multi-center study including 2880 consecutive non-valvular AF patients initiating oral anticoagulation between January 2013 and December 2016. AS was defined as moderate or severe according to European echocardiography guidelines criteria. HASBLED, ATRIA and ORBIT scores were used to evaluate the bleeding risk. MB was defined according to the International Society on Thrombosis and Haemostasia criteria and registered at 18 months of follow-up.Results168 (5.8%) patients had AS. Patients with AS had higher risk for MB compared to those without AS (HR = 2.13, 95% CI: 1.40–3.23, P < 0.001). Patients without AS and low-intermediate bleeding risk (0 points) showed the lowest MB rate, whereas the MB rate observed among patients with AS and high bleeding risk (2 points) was the highest one. Discrimination and reclassification analyses showed that AS provided additional information to bleeding risk scores for predicting MB at 18 months of follow-up.ConclusionsIn this population, AS was associated with an increased risk for MB at midterm follow-up. The three scoring systems showed a moderate discriminatory ability for MB. Moreover, the addition of AS was associated with a significant improvement in their predictive accuracy. We suggest that the presence of this valvulopathy should be taken into account for bleeding risk assessment.

What are the Characteristics of Patients Experiencing Adverse Drug Reactions to Oral Anticogulants and How Can Such Reactions be Prevented?

Oral anticoagulants, including vitamin K inhibitors (VKAs) and direct anticoagulants (DOACs) are important for preventing and treating thromboembolic diseases. However, they are not recommended for use in all patients due to negative side effects and adverse drug reactions (ADRs). Currently, there is a paucity of information about their use in real life. Therefore, the aim of this pilot study is to report on the rate of serious ADRs in oral anticoagulant users, determine patient characteristics associated with increased risk of ADRs, and identify possible management strategies for reducing risk of ADRs within a hospital setting. Patients admitted to the Internal Medicine Department of the Vimercate Hospital were recruited between November 1, 2015 and October 31, 2016. All patients reporting an ADR associated with anticoagulant use were selected. Demographic, clinical, and observational data were extracted from electronic hospital records, in particular, by the hospital discharge letters and other clinical records. The main outcome of the study was to evaluate the incidence of anticoagulants serious adverse drug reactions conditioning hospital admission, the percentage of preventable reactions, and the determinants of those. Of the 2,064 admissions, 102 (4.9%) eligible patients were identified. Age ranged from 60-95 years (mean = 81.9, standard deviation = 6,59) and 47.1% (n=48) were female. Of the 102 cases, 68 used VKAs and 34 used DOACs. The most common admission diagnosis was heart failure following anemia or hemorrhage (56 cases), followed by acute hemorrhage (with or without anemia; 29 cases), and anemia not associated with evident hemorrhage (17cases). The majority of VKA users (n=65, 95.6%) had a high risk of major bleeding. ADRs were found to be preventable in 96% of VKA users and 68% of DOACs users. This study highlights the large percentage of ADRs from oral anticoagulants that can be avoided with more careful patient management. Periodic check-up of cardiac and renal function, as well as blood count, may be useful for reducing the risk of ADRs, especially in older DOACs users. Further research is needed to get new data to improve the patients monitoring system.

Optimal duration of Vitamin K antagonists anticoagulant therapy after venous thromboembolism: a systematic review and network meta-analysis of randomized controlled trials

BackgroundThe optimal duration of oral anticoagulant therapy for patients with venous thromboembolism (VTE) remains highly uncertain in clinical practice. It is essential to accurately assess the effect of anticoagulant therapy in reducing recurrent VTE against the risk of inducing major bleeding.MethodsRandomized controlled trials were identified by searching PubMed, Web of Science, Embase, and the Cochrane library, reporting rates of recurrent VTE and major bleeding in patients taking Vitamin K Antagonists (VKA) with VTE and comparing different durations.ResultsEleven RCTs with 3109 participants utilizing varied durations were included in the meta-analysis. Longer VKA therapy was associated with significantly lower rates of VTE recurrence compared with shorter duration of VKA therapy (OR 0.75, 95%CI 0.57–0.99), with significant difference noted in major bleeding risk (OR 2.31, 95%CI 1.17–4.56). During anticoagulation duration, patients treated by 6-month VKA had higher risk of major bleeding compared with 3-month VKA regimen (OR 33.45, 95%CI 2.00–559.67).ConclusionsRegimen longer than 6 months did not show statistical elevation of major bleeding risk. VKA treatment strongly reduces the risk of recurrent VTE during anticoagulation therapy. The absolute risk of recurrent VTE declines over time while the risk for major bleeding after 6 months’ treatment did not demonstrate a continuous significant increase with extended duration of VKA therapy.

Ischemic Stroke and Bleeding: Clinical Benefit of Anticoagulation in Atrial Fibrillation After Intracerebral Hemorrhage.

Background and Purpose- Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHA2DS2-VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult. Methods- We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)-a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHA2DS2-VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs. Results- Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs. Conclusions- Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00930280.