Increase In Risk Of Major Bleeding Research Articles

ACOD frente a AVK en pacientes con fibrilación auricular y bioprótesis: revisión sistemática y metanálisis

Introduction and objectivesDirect oral anticoagulant (DOAC) therapy has been shown to be safe and effective in patients with atrial fibrillation (AF). However, outcomes in AF patients with bioprosthetic valves are unclear, as this population has been underrepresented in clinical trials. The aim of this study was to assess the safety and efficacy of DOACs in this population based on the existing published literature. MethodsA systematic search and review were conducted to identify randomized clinical trials and comparative observational studies published from 2017 to January 2022 that compared DOACs and vitamin K antagonists (VKAs) in AF patients with bioprosthetic valves. Hazard ratios (HR) were collected to compare the 2 treatments in terms of cardiovascular and all-cause mortality, stroke/systemic embolism, and major bleeding. A meta-analysis combining the results was performed. ResultsWe included 12 studies (30 283 patients). DOACs and VKAs were compared based on HRs at the 95% confidence interval. DOAC therapy was associated with a significant 9% reduction in all-cause mortality (HR, 0.91; 95%CI, 0.85-0.97; P=.0068; I2=8%), with no significant differences in the risk of stroke/systemic embolism (HR, 0.87; 95%CI, 0.67-1.14; P=.29; I2=45%) or major bleeding (HR, 0.82; 95%CI, 0.67-1.00; P=.054; I2=48.7%). ConclusionsDOAC therapy in AF patients with bioprosthetic valves may be associated with a significant reduction in all-cause mortality, with no reduction in the efficacy of stroke/systemic embolism prevention or increase in major bleeding risk.

DOAC versus VKA in patients with atrial fibrillation and bioprosthetic valves: a systematic review and meta-analysis

Introduction and objectivesDirect oral anticoagulant (DOAC) therapy has been shown to be safe and effective in patients with atrial fibrillation (AF). However, outcomes in AF patients with bioprosthetic valves are unclear, as this population has been underrepresented in clinical trials. The aim of this study was to assess the safety and efficacy of DOACs in this population based on the existing published literature. MethodsA systematic search and review were conducted to identify randomized clinical trials and comparative observational studies published from 2017 to January 2022 that compared DOACs and vitamin K antagonists (VKAs) in AF patients with bioprosthetic valves. Hazard ratios (HR) were collected to compare the 2 treatments in terms of cardiovascular and all-cause mortality, stroke/systemic embolism, and major bleeding. A meta-analysis combining the results was performed. ResultsWe included 12 studies (30 283 patients). DOACs and VKAs were compared based on HRs at the 95% confidence interval. DOAC therapy was associated with a significant 9% reduction in all-cause mortality (HR, 0.91; 95%CI, 0.85-0.97; P=.0068; I2=8%), with no significant differences in the risk of stroke/systemic embolism (HR, 0.87; 95%CI, 0.67-1.14; P=.29; I2=45%) or major bleeding (HR, 0.82; 95%CI, 0.67-1.00; P=.054; I2=48.7%). ConclusionsDOAC therapy in AF patients with bioprosthetic valves may be associated with a significant reduction in all-cause mortality, with no reduction in the efficacy of stroke/systemic embolism prevention or increase in major bleeding risk.

Impact of NOAC and VKA on outcome of patients with newly diagnosed atrial fibrillation and diabetes: a report from the GARFIELD-AF registry

Abstract Introduction Diabetes mellitus (DM) is one of the most common comorbidities observed in patients with atrial fibrillation (AF). It is associated with increased risks of stroke/SE and death. Purpose To assess the impact of NOAC and VKA on outcomes of newly diagnosed AF in patients with DM and 2-year follow-up. Methods The study population comprised 52,010 patients with newly diagnosed AF, 11,542 DM and 40,468 non-DM, who were enrolled in GARFIELD-AF, the largest multinational prospective AF registry. Adjusted hazard ratios (HRs) were obtained through Cox proportional-hazard models to quantify the effects of diabetes on death, stroke/SE and major bleeding. Comparative effectiveness analyses were restricted to 18,373 patients eligible for oral anticoagulation (OAC) enrolled between 2013- 2016 after NOACs became available in most countries. Safety and effectiveness of NOAC and VKA in DM and non-DM patients were assessed with propensity scores using an overlap weighting scheme. Weights were applied to Cox proportional-hazards models to estimate the effects of NOAC vs VKA use for each endpoint. Results Compared to non-DM patients, DM patients (44.5% with oral antidiabetic drug, 13.4% with insulin) had higher BMI (28.7 vs 26.4), more frequent history of heart failure (24.8% vs 21.9%), acute coronary syndromes (15.9% vs 9.2%), vascular disease (32.6% vs 22.6%), stroke/TIA/SE (12.8% vs 10.9%), hypertension (85.7% vs 73.7%), hypercholesterolemia (55.3% vs 37.7%), moderate to severe CKD (14.4% vs 9.6%). They had higher rates of OAC use (70.5% vs 65.8%), were more often treated with VKA (44.0% vs 38.0%), or AP in combination with OAC or as monotherapy (40.6% vs 33.8%), were at higher risk of stroke/SE according to CHA2DS2-VASc score [4.0 (3.0; 5.0) vs (3.0 (2.0; 4.0)], had at 2-year follow-up significantly higher rates of all-cause death, stroke/SE, and major bleeding (Figure 1). Overall, OAC vs no OAC led in both non-DM and DM populations to similar risk reduction for death [HR 0.75 (0.69–0.83) vs 0.74 (0.64–0.86)], stroke/SE [0.69 (0.58–0.83) vs 0.70 (0.53–0.93)], and similar increase in major bleeding risk [HR 1.40 (1.14–1.71) vs 1.37 (0.99–1.89)]. NOAC use trended toward lower all-cause death (significant for non-DM but not for DM) and major bleeding rates than VKA in both non-DM and DM patients. A non-significant increase in stroke/SE rates was observed in DM patients (Figure 2). Conclusion At baseline, DM patients had higher rates of OAC prescription. They had higher rates of all cause, cardiovascular and non-cardiovascular death, stroke/SE, and major bleeding than non-DM patients. Lower rates of all-cause death and of major bleeding were observed with NOACs compared with VKAs in both DM and non-DM patients and of stroke/SE in non-DM patients. These results tend to show that in DM AF patients, NOACs should be favoured over VKA, though higher rates of CKD in DM patients may limit the uptake of such drugs. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The GARFIELD-AF registry was funded by an unrestricted research grant from Bayer AG. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Investigation of the arcane inhibition of human organic anion transporter 3 by benzofuran antiarrhythmic agents

The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. However, inhibitory activity of amiodarone and dronedarone against OAT3 remains arcane. Here, we conducted in vitro transporter inhibition assays in OAT3-transfected HEK293 cells which revealed amiodarone, dronedarone and their respective major pharmacologically-active metabolites N-desethylamiodarone and N-desbutyldronedarone possess inhibitory activity against OAT3, with corrected Ki values of 0.042, 0.019, 0.028 and 0.0046 μM respectively. Protein binding effects and probe substrate dependency were accounted for in our assays. Static modelling predicted 1.29-, 1.01-, 1.29- and 1.16-fold increase in rivaroxaban exposure, culminating in a predicted 1.29-, 1.01-, 1.28- and 1.15-fold increase in major bleeding risk respectively, suggesting potential OAT3-mediated DDI between amiodarone and rivaroxaban. Future work involving physiologically-based pharmacokinetic modelling is crucial in holistically predicting the complex DDIs between the benzofuran antiarrhythmic agents and rivaroxaban.

COMPASS criteria applied to a contemporary cohort of unselected patients with stable coronary artery diseases: insights from the START registry.

Recently, the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial demonstrated that dual therapy reduced cardiovascular outcomes compared with aspirin alone in patients with stable atherosclerotic disease. We sought to assess the proportion of patients eligible for the COMPASS trial and to compare the epidemiology and outcome of these patients with those without COMPASS inclusion or with any exclusion criteria in a contemporary, nationwide cohort of patients with stable coronary artery disease. Among the 4068 patients with detailed information allowing evaluation of eligibility, 1416 (34.8%) did not fulfil the inclusion criteria (COMPASS-Not-Included), 841 (20.7%) had exclusion criteria (COMPASS-Excluded), and the remaining 1811 (44.5%) were classified as COMPASS-Like. At 1 year, the incidence of major adverse cardiovascular event (MACE), a composite of cardiovascular death, myocardial infarction, and stroke, was 0.9% in the COMPASS-Not-Included and 2.0% in the COMPASS-Like (P = 0.01), and 5.0% in the COMPASS-Excluded group (P < 0.0001 for all comparisons). Among the COMPASS-Like population, patients with multiple COMPASS enrichment criteria presented a significant increase in the risk of MACE (from 1.0% to 3.3% in those with 1 and ≥3 criteria, respectively; P = 0.012), and a modest absolute increase in major bleeding risk (from 0.2% to 0.4%, respectively; P = 0.46). In a contemporary real-world cohort registry of stable coronary artery disease, most patients resulted as eligible for the COMPASS. These patients presented a considerable annual risk of MACE that consistently increases in the presence of multiple risk factors.

Predicting Major Bleeding in Ischemic Stroke Patients With Atrial Fibrillation.

Performance of risk scores for major bleeding in patients with atrial fibrillation and a previous transient ischemic attack or ischemic stroke is not well established. We aimed to validate risk scores for major bleeding in patients with atrial fibrillation treated with oral anticoagulants after cerebral ischemia and explore the net benefit of oral anticoagulants among bleeding risk categories. We analyzed 3623 patients with a history of transient ischemic attack or stroke included in the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). We assessed performance of HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count or function, hypertension [uncontrolled], anemia, genetic factors, excessive fall risk, and stroke), Shireman, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and ORBIT scores (older age, reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) with C statistics and calibration plots. Net benefit of oral anticoagulants was explored by comparing risk reduction in ischemic stroke with risk increase in major bleedings on warfarin. During 6922 person-years of follow-up, 266 patients experienced a major bleed (3.8 per 100 person-years). C statistics ranged from 0.62 (Shireman) to 0.67 (ATRIA). Calibration was poor for ATRIA and moderate for other models. The reduction in recurrent ischemic strokes on warfarin was larger than the increase in major bleeding risk, irrespective of bleeding risk category. Performance of prediction models for major bleeding in patients with cerebral ischemia and atrial fibrillation is modest but comparable with performance in patients with only atrial fibrillation. Bleeding risk scores cannot guide treatment decisions for oral anticoagulants but may still be useful to identify modifiable risk factors for bleeding. Clinical usefulness may be best for ORBIT, which is based on a limited number of easily obtainable variables and showed reasonable performance.

Duration of dual antiplatelet therapy after drug-eluting stent implantation: Meta-analysis of large randomised controlled trials.

Patients receive dual antiplatelet therapy (DAPT) for 6–12 months after drug-eluting stents (DES) implantation. The efficacy and safety of prolonged DAPT has been questioned. Therefore, we performed a meta-analysis on randomised trials comparing different DAPT durations. Literature was searched on trials comparing different DAPT durations. For inclusion, reports must report frequency of cardiovascular and bleeding events. Ten trials were included. Compared to 12 months, DAPT beyond 12 months was associated with fewer myocardial infarctions (OR 0.58 95%CI: 0.40–0.84) and stent thrombosis (OR 0.35 95%CI: 0.20–0.62), but more major bleeds (OR 1.60 95%CI: 1.22–2.11) and all-cause (OR 1.30 95%CI: 1.02–1.66) mortality. There was no significant alteration in risk of stroke (OR 0.93 95%CI: 0.66–1.31) or cardiac (OR 1.12 95%CI: 0.73–1.71) mortality. Compared to less than 12 months DAPT, 12 months DAPT did not reduce risk of myocardial infarction, stent thrombosis, strokes, cardiac or all-cause mortality, but increased the risk of major bleeds (OR 1.60 95%CI: 1.22–2.11). DAPT beyond 12 months reduce risk of myocardial infarction and stent thrombosis, but there is substantial increase in major bleeding risk and all-cause mortality which need to be addressed. DAPT beyond 12 months does not appear to alter the risk of stroke.

Bivalirudin for the treatment of patients with confirmed or suspected heparin‐induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an adverse immune-mediated response to unfractionated heparin and, less commonly, low molecular weight heparin. It is associated with a high thrombotic risk and the potential for limb and life-threatening complications. Argatroban is the only approved and currently available anticoagulant for HIT treatment in the USA. To report safety and efficacy outcomes with bivalirudin for HIT treatment. We retrospectively examined records from our registry of patients with a suspected, confirmed or previous history of HIT and who had received bivalirudin for anticoagulation in a single tertiary-care center over a 9-year period. We identified 461 patients who received bivalirudin: 220 (47.7%) were surgical patients, and 241 (52.3%) were medical patients. Of this population, 107 (23.2%) were critically ill, and 109 (23.6%) were dialysis-dependent. Suspected, confirmed and previous history of HIT were reported in 262, 124 and 75 patients, respectively. Of 386 patients with suspected or confirmed HIT, 223 patients (57.8%) had thrombosis at HIT diagnosis. New thrombosis was identified in 21 patients (4.6%) while they were on treatment with therapeutic doses of bivalirudin. No patient required HIT-related amputation. Major bleeding occurred in 35 patients (7.6%). We found a significant increase in major bleeding risk in the critically ill population (13.1%; odds ratio 2.4, 95% confidence interval 1.2-4.9, P=0.014). The 30-day all-cause mortality rate was 14.5% (67 patients), and eight of 67 (1.7%) deaths were HIT-related. Bivalirudin may be an effective and safe alternative option for the treatment of both suspected and confirmed HIT, and appears to reduce the rate of HIT-related amputation.

Genetic Risk Factors for Major Bleeding in Patients Treated With Warfarin in a Community Setting

The influence of warfarin pharmacogenomics on major bleeding risk has been little studied in long-term users and non-specialist care settings. We conducted a case-control study to evaluate associations between CYP2C9*2/*3, VKORC1(1173), and CYP4F2*3 variants and major bleeding among patients treated with warfarin in a community setting. We calculated major bleeding odds ratios, adjusting for race, duration of warfarin use, age, gender, and body mass index. In 265 cases and 305 controls with 3.4 and 3.7 mean years of warfarin use, respectively, CYP4F2*3 was associated with decreased major bleeding risk (odds ratio: 0.62; 95% confidence interval: 0.43-0.91). CYP2C9*2/*3 and VKORC1(1173) had null associations overall, but there was a nonsignificant increase in major bleeding risk in patients with duration <6 months (odds ratio: 1.30; 95% confidence interval: 0.60-2.83; odds ratio: 1.23; 95% confidence interval: 0.57-2.64, respectively). In summary, in the largest study of warfarin pharmacogenomics and major bleeding to date, we found a 38% lower risk in patients with CYP4F2*3, potentially reflecting interaction with warfarin and dietary vitamin K intake and warranting additional evaluation.

Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta‐analysis

Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease. To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence-based guidelines. Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0-3.5, and ASA, 50-650 mg daily, with at least 3 months of follow-up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model. Four thousand four hundred and forty-two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83-1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71-3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61-1.75). Minor bleeding, from a 1748-patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13-2.00). This meta-analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0-3.5, and ASA, 50-650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.

Warfarin Exposure and the Risk of Thromboembolic and Major Bleeding Events Among Medicaid Patients with Atrial Fibrillation

Outcomes of anticoagulation have been assessed in commercially insured populations, but similar data do not exist for Medicaid populations. To assess the association between warfarin exposure and rates of thromboembolic and bleeding events among patients with nonvalvular atrial fibrillation (NVAF) enrolled in California Medicaid. Using a retrospective cohort design based on administrative claims data, we selected Medicaid enrollees aged 50 years and older based on their first claim with a diagnosis of AF between January 1, 1998, and March 31, 2002. Patients were excluded if they had selected contraindications to warfarin, claims for valve replacement procedures, or evidence that AF resulted from transient or reversible causes. Pharmacy claims and prothrombin time tests were used to define subsequent periods of warfarin use (exposure) and nonuse (nonexposure) by all patients. The relative rates of hospitalization for thromboembolic and bleeding events associated with periods of warfarin exposure versus nonexposure were estimated. The 4355 study patients had a mean age of 74 years, and 65% were female. Fifty-nine percent filled any prescriptions for warfarin following AF diagnosis. Across all patients, warfarin exposure occurred during 37% of days after diagnosis. Thromboembolic events were 27% less frequent during periods of warfarin exposure relative to periods of non-exposure (p < 0.01). Major bleeding events were not significantly more common during periods of warfarin exposure (p = 0.55). In this Medicaid population with NVAF, warfarin use was low and was associated with a relatively modest reduction in thromboembolic events, with no increase in major bleeding risk.