Rates Of Major Bleeding Research Articles

Combining rivaroxaban with aspirin for peripheral artery disease: an in-depth systematic review and meta-analysis

Abstract Funding Acknowledgements None. Introduction Peripheral artery disease (PAD) poses a significant challenge in the realm of cardiovascular medicine, necessitating a multifaceted approach to mitigate its impact and enhance patient outcomes. One treatment approach involves the combined use of rivaroxaban, a direct oral anticoagulant, and aspirin, a commonly used antiplatelet agent in decreasing possible complications that can develop in patients with PAD. Methods An extensive search of randomized controlled trials (RCTs) comparing the efficacy of rivaroxaban in combination with aspirin versus aspirin monotherapy among individuals diagnosed with peripheral artery disease. The assessment of this treatment approach involved evaluating the following primary outcomes: a decrease in major adverse cardiovascular events (MACE) and the need for major amputation. Safety profile was also evaluated by examining the rate of major bleeding, utilizing the scoring tool from International Society of Thrombosis and Hemostasis (ISTH). The analyses were performed using a random effects analysis approach via Review Manager V5.4. Results This meta-analysis encompassed three studies involving a total of 9,352 participants. There was reduction of MACE in rivaroxaban with aspirin therapy (RR 0.83 [95% CI: 0.71-0.97] I2 = 29%, p = 0.02] but there was no significant difference in terms of major amputation rates (RR 0.96 [95% CI: 0.80-1.14] I2 = 0%, p = 0.62). However, there was increased risk of bleeding in rivaroxaban with aspirin therapy (RR 1.46 [95% CI: 1.17-1.82] I2=0, p = 0.0009) compared to aspirin alone. Conclusion Rivaroxaban combined with aspirin therapy demonstrated a 17% reduction in MACE compared with aspirin monotherapy but didn’t reduce major amputation rates. Also, doing this strategy poses a higher risk of bleeding. Therefore, a balance between the risks and benefits of this combined therapy necessitates a thorough assessment of individual patient profiles, considering factors such as overall cardiovascular risk, comorbidities, and bleeding tendencies. Further research and long-term studies are needed to establish comprehensive guidelines for the appropriate utilization of this combination therapy in various patient populations.

P2Y12 monotherapy versus standard dual antiplatelet therapy after percutaneous coronary intervention: a systematic review and meta-analysis

Abstract Funding Acknowledgements None. Introduction Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor after percutaneous coronary intervention (PCI) is the recommended therapy for lowering the ischemic risk among patients with acute coronary syndrome (ACS). However, the increased incidence of bleeding is a major concern. Monotherapy with a P2Y12 inhibitor after short-term DAPT to reduce adverse cardiovascular events and bleeding rates has not been fully established and remains uncertain. This meta-analysis aims to determine the effectiveness of P2Y12 inhibitor monotherapy after short-term DAPT in reducing cardiovascular and bleeding events. Methods A comprehensive search of randomized controlled trials (RCTs) examining the use of short-term DAPT followed by P2Y12 monotherapy in patients with ACS who underwent PCI was conducted. Outcome measures for all-cause mortality, myocardial infarction, and bleeding rates were analyzed using a random-effects model via Review Manager V5.4. Results A total of six randomized controlled trials (RCTs) with 36,724 subjects were analyzed. There were no significant differences in all-cause mortality (RR 0.89 [95% CI: 0.78-1.02], I² = 0%, p = 0.10) and myocardial infarction (RR 1.00 [95% CI: 0.88-1.14], I² = 0%, p = 0.72) between the P2Y12 inhibitor group and dual antiplatelet therapy (DAPT) group. There was a lower rate of major bleeding in the P2Y12 group compared to the DAPT group (RR 0.65 [95% CI: 0.49-0.88], I² = 76%, p = 0.002). The major sources of substantial heterogeneity are due to different intervals of de-escalation and baseline risk factors prior to PCI in each study. Conclusion P2Y12 monotherapy has similar rates of all-cause mortality and myocardial infarction. However, early de-escalation leads to a lower incidence of bleeding. P2Y12 monotherapy showed a 35% decreased risk of bleeding compared to the DAPT strategy. This suggests that P2Y12 monotherapy is a preferable antiplatelet strategy in patients undergoing PCI, especially in the high-risk bleeding population.

Comparison of Dual Antiplatelet Therapies for Minor, Nondisabling, Acute Ischemic Stroke: A Bayesian Network Meta-Analysis.

Dual antiplatelet therapy (DAPT) appears to be an effective treatment option for minor (nondisabling) acute ischemic stroke. This conclusion is based on trials that include both transient ischemic attack (TIA) and minor stroke; however, these 2 conditions may differ. To compare DAPT regimens specifically for minor stroke. PubMed was searched for randomized clinical trials published up to November 4, 2023. Search terms strategy included TIA, transient ischemic attack, minor stroke, or moderate stroke, with the filter randomized controlled trial. Unpublished data on minor stroke were sourced from authors and/or institutions. Trials testing DAPT within the first 24 hours of a minor stroke (defined as a National Institutes of Health Stroke Scale score ≤5) were included by consensus. Of 1508 studies screened, 6 (0.3%) initially met inclusion criteria and were reviewed. The study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by multiple observers. Bayesian fixed-effect network meta-analysis was conducted. Secondary analysis performed for high-risk TIA alone. Treatments were ranked using a probability measure called surface under the cumulative rank curve (SUCRA). The primary outcome was subsequent ischemic stroke at 90 days. Secondary outcomes included major hemorrhage, mortality, and hemorrhagic stroke. The number needed to treat (NNT) and number needed to harm (NNH) were obtained. Five trials were included that described 28 148 patients, of whom 22 203 (78.9%) had a minor stroke. Of these, 13 995 (63.0%) were in DAPT groups and 8208 (37.0%) in aspirin (acetylsalicylic acid) groups. Aspirin and ticagrelor had a 94% probability of being the superior treatment for minor stroke (SUCRA, 0.94) for the primary outcome. Both aspirin and ticagrelor (NNT, 40; 95% CI, 31-64) and aspirin and clopidogrel (NNT, 58; 95% CI, 39-136) were superior to aspirin alone in the prevention of recurrent ischemic stroke at 90 days. Both treatments had higher rates of major hemorrhage than aspirin alone (NNH for aspirin and ticagrelor, 284; 95% CI, 108-1715 vs NNH for aspirin and clopidogrel, 330; 95% CI, 118-3430), but neither had increased risk of hemorrhagic stroke or death. For high-risk TIA, ticagrelor and aspirin had a 60% probability (SUCRA, 0.60) and clopidogrel and aspirin had a 40% probability (SUCRA 0.40) of being a superior treatment; neither was optimum, but both were superior to aspirin alone for the primary outcome. These findings suggest that DAPT with aspirin and ticagrelor has higher probability of being the superior treatment among patients with minor stroke when presence of CYP2C19 loss-of-function alleles has not been excluded. For patients with TIA, the superiority of aspirin and ticagrelor vs aspirin and clopidogrel was not demonstrated.

Long-term effectiveness and safety of edoxaban in patients with atrial fibrillation: 4-year data from the ETNA-AF-Europe study

BackgroundTo assess long-term effectiveness and safety of edoxaban in Europe. Methods and resultsETNA-AF-Europe, a prospective, multinational, multi-centre, post-authorisation, observational study was conducted in agreement with the European Medicines Agency. The primary and secondary objectives assessed real-world safety (including bleeding and deaths) and effectiveness (including stroke, systemic embolic events and clinical edoxaban use), respectively.Median (interquartile range) age of the 13,164 patients was 75.0 (68.0–80.0) years; CHA2DS2-VASc and HAS-BLED scores were 3.0 (2.0–4.0) and 2.0 (1.0–2.0), respectively. Follow-up duration was 3.98 (3.21–4.05) years. Patients on edoxaban 30 mg (n = 3042) at baseline were older (80.0 vs 73.0 years), more likely assessed as frail by investigators (27.0% vs 6.6%) and had more comorbidities than those on edoxaban 60 mg (n = 9617; missing dosing information for n = 505). Annualised event rates of all-cause and cardiovascular death in the overall population, edoxaban 60 mg and edoxaban 30 mg groups were 4.1%, 2.8% and 8.4%, and 1.0%, 0.7% and 2.0%, respectively. Annualised rates of stroke were relatively constant throughout the follow-up, transient ischaemic attack and systemic embolism were < 1% in the overall population. Rates of any major and major gastrointestinal bleeding were low, with slightly higher rates for edoxaban 30 vs 60 mg group. Intracranial haemorrhage was uncommon (0.2%). ConclusionsIn European patients with AF, long-term therapy with edoxaban is associated with low and relatively constant annualised rates of stroke and major bleeding. Differences in outcomes between the two approved doses are attributable to differences in clinical characteristics.

Prognostic impact of heart failure admission in survivors of acute myocardial infarction.

The incidence and prognosis of symptomatic heart failure following acute myocardial infarction (AMI) in the primary percutaneous coronary intervention era have rarely been reported in the literature. This study aimed to (i) determine the incidence of heart failure admission among AMI survivors, (ii) compare 1year outcomes between patients with heart failure admission and those without, and (iii) identify the independent risk factors associated with heart failure admission. The Japan Acute Myocardial Infarction Registry is a prospective multicentre registry from which data on consecutively enrolled patients with AMI from 50 institutions between 2015 and 2017 were obtained. Among the 3411 patients enrolled, 3226 who survived until discharge were included in this study. The primary endpoint was all-cause mortality. The secondary endpoints were major adverse cardiovascular events (defined as cardiovascular mortality, non-fatal myocardial infarction, or non-fatal cerebral infarction) and major bleeding events corresponding to Bleeding Academic Research Consortium Type 3 or 5. Clinical outcomes were compared between the patients who were and were not admitted for heart failure. Over a median follow-up of 12months, 124 patients (3.8%) were admitted due to heart failure. Independent risk factors for heart failure admission included older age, female sex, Killip class ≥2 on admission, left ventricular ejection fraction <40%, estimated glomerular filtration rate ≤30mL/min/1.73m2, a history of malignancy, and non-use of angiotensin-converting enzyme inhibitors at discharge. The cumulative incidence of all-cause mortality was significantly higher in the heart failure admission group than in the no heart failure admission group (11.3% vs. 2.5%, P<0.001). The rates of major adverse cardiovascular events (16.9% vs. 2.7%, P<0.001) and major bleeding (6.5% vs. 1.6%, P<0.001) were significantly higher in the heart failure admission group. Heart failure admission was associated with a higher risk of all-cause mortality, even after adjusting for potential confounders (adjusted hazard ratio: 2.41, 95% confidence interval: 1.33-4.39, P=0.004). Utilizing real-world data of the contemporary percutaneous coronary intervention era from the Japan Acute Myocardial Infarction Registry database, this study demonstrates that the heart failure admission of AMI survivors was significantly associated with higher all-cause mortality rates.

Evaluation of Apixaban Use in Patients With Advanced Kidney Disease.

Background: Current guidelines and literature suggest apixaban may be used in patients with severe kidney disease and atrial fibrillation (AF) for stroke and systemic embolism risk reduction (SSE) or patients with acute venous thromboembolism (VTE). Limited data is available for long-term safety and efficacy outcomes in this patient population. Objective: Evaluate the use of apixaban for AF or VTE in patients with advanced kidney disease. Methods: This single-center, retrospective, Investigational Review Board approved study evaluated patients ≥18 years of age with severe kidney disease on apixaban therapy for VTE or AF from March 1, 2018, to December 31, 2020. The primary outcome was major bleeding from apixaban initiation/continuation until 12 months after discharge. The secondary outcomes included a composite bleed (major bleeding, clinically relevant non-major bleeding, and minor bleeding), the occurrence of VTE or SSE, and death during hospitalization from any cause other than bleeding. Results: Overall, 156 patients met inclusion criteria. Six patients experienced major bleeding (3.8%). Composite bleeding occurred in 16 patients (10.3%); no patients had SSE or VTE, and 4 patients died from causes other than bleeding (2.6%). Limitations included the small sample size and retrospective nature of the study. Conclusion: This study demonstrated that patients with advanced chronic kidney disease on apixaban for AF or VTE had low major bleeding and similar overall bleeding rates compared with previously published literature. When considering the use of apixaban in this population, risks and benefits should be weighed in addition to the consideration of FDA-label dosing guidance.

Impact of restrictive platelet transfusion strategies on transfusion rates: A cohort study in very preterm infants.

Evidence supports a restrictive platelet transfusion threshold in preterm neonates. We aimed to describe the effect of implementing this threshold on transfusion rates. This retrospective observational cohort study included all very preterm infants (born <32 weeks' gestation) admitted to a neonatal intensive care unit between 2004 and 2022, divided into three epochs. Platelet transfusion thresholds changed from 30 × 109/L for stable neonates and 50 × 109/L for unstable neonates (January 2004 to December 2009) to 20 × 109/L for stable neonates and 50 × 109/L for unstable neonates (January 2010 to June 2019) to 25 × 109/L for non-bleeding neonates and 50 × 109/L for neonates with major bleeding (July 2019 to July 2022). The primary outcome was the percentage of transfused neonates in each epoch. Secondary outcomes included the median number of transfusions per neonate, the percentage of transfusions given above 25 or 50 × 109/L, and major bleeding and mortality rates. The percentage of neonates transfused was 12.2% (115/939), 5.8% (96/1660), and 4.8% (25/525) in Epoch I, II, and III, respectively (p < .001), a relative reduction of 61%. The median number of transfusions per transfused neonate was 2.0 (interquartile range [IQR]: 1.0-3.0) in Epoch I, and 1.0 (IQR: 1.0-2.0) in subsequent Epochs (p = .04). The percentage of infants receiving at least one transfusion above 50 × 109/L in Epoch I, II, and III was 51.3% (59/115), 17.7% (17/96), and 20.0% (5/25; p < .001). Mortality and bleeding rates did not significantly differ between epochs. Implementation of restrictive platelet guidelines led to reduction of the rate and number of platelet transfusions.

Impact of perioperative low-molecular-weight heparin therapy on clinical events of elderly patients with prior coronary stents implanted > 12 months undergoing non-cardiac surgery: a randomized, placebo-controlled trial

BackgroundLittle is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. This randomized trial was designed to compare the clinical benefits and risks of antiplatelet drug discontinuation via LMWH bridging therapy.MethodsPatients were randomized 1:1 to receive subcutaneous injections of either dalteparin sodium or placebo. The primary efficacy endpoint was cardiac or cerebrovascular events. The primary safety endpoint was major bleeding.ResultsAmong 2476 randomized patients, the variables (sex, age, body mass index, comorbidities, medications, and procedural characteristics) and percutaneous coronary intervention information were not significantly different between the bridging and non-bridging groups. During the follow-up period, the rate of the combined endpoint in the bridging group was significantly lower than in the non-bridging group (5.79% vs. 8.42%, p = 0.012). The incidence of myocardial injury in the bridging group was significantly lower than in the non-bridging group (3.14% vs. 5.19%, p = 0.011). Deep vein thrombosis occurred more frequently in the non-bridging group (1.21% vs. 0.4%, p = 0.024), and there was a trend toward a higher rate of pulmonary embolism (0.32% vs. 0.08%, p = 0.177). There was no significant difference between the groups in the rates of acute myocardial infarction (0.81% vs. 1.38%), cardiac death (0.24% vs. 0.41%), stroke (0.16% vs. 0.24%), or major bleeding (1.22% vs. 1.45%). Multivariable analysis showed that LMWH bridging, creatinine clearance < 30 mL/min, preoperative hemoglobin < 10 g/dL, and diabetes mellitus were independent predictors of ischemic events. LMWH bridging and a preoperative platelet count of < 70 × 109/L were independent predictors of minor bleeding events.ConclusionsThis study showed the safety and efficacy of perioperative LMWH bridging therapy in elderly patients with coronary stents implanted > 12 months undergoing non-cardiac surgery. An alternative approach might be the use of bridging therapy with half-dose LMWH.Trial registrationISRCTN65203415.

On-X aortic valve replacement patients treated with low-dose warfarin and low-dose aspirin.

To assess if warfarin targeted to international normalized ratio (INR) 1.8 (range 1.5-2.0) is safe for all patients with an On-X aortic mechanical valve. This prospective, observational registry follows patients receiving warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus daily aspirin (75-100 mg) after On-X aortic valve replacement. The primary end point is a composite of thromboembolism, valve thrombosis and major bleeding. Secondary end points include the individual rates of thromboembolism, valve thrombosis and major bleeding, as well as the composite in subgroups of home or clinic-monitored INR and risk categorization for thromboembolism. The control was the patient group randomized to standard-dose warfarin (INR 2.0-3.0) plus daily aspirin 81 mg from the PROACT trial. A total of 510 patients were enroled at 23 centres in the UK, USA and Canada. Currently, the median follow-up duration is 3.4 years, and median achieved INR is 1.9. The primary composite end point rate in the low INR patients is 2.31% vs 5.39% (95% confidence interval 4.12-6.93%) per patient-year in the PROACT control group, constituting a 57% reduction. Results are consistent in subgroups of home or clinic-monitored, and high-risk patients, with reductions of 56%, 57% and 57%, respectively. Major and total bleeding are decreased by 85% and 73%, respectively, with similar rates of thromboembolic events. No valve thrombosis occurred. Interim results suggest that warfarin targeted at an INR of 1.8 (range 1.5-2.0) plus aspirin is safe and effective in patients with an On-X aortic mechanical valve with or without home INR monitoring.

Characterization of the Benefits and Risks of Therapeutic Anticoagulation in Patients Admitted with Severe COVID-19 (CRITAC).

Severe COVID-19 is associated with increased rates of thrombotic complications. Recent provincial recommendations in British Columbia have suggested providing thromboprophylaxis with therapeutic anticoagulation for hospital inpatients with severe COVID-19 who do not have a high risk of bleeding. To characterize the rates of major bleeding, thrombotic events, complications from COVID-19, and adverse effects among patients with severe COVID-19 treated with therapeutic anticoagulation. This retrospective chart review involved patients with laboratory-confirmed COVID-19 who were admitted to 3 sites within a local health authority between April 1 and December 31, 2021, and received therapeutic anticoagulation for thromboprophylaxis. After screening of 1036 patients, 72 patients were included in the study. The mean age of participants was 54 years, 63% (n = 45) were male, and 92% (n = 66) were receiving supplemental oxygen by nasal prongs on admission. The primary outcome, major bleeding, was experienced by 1 patient (1%). Increasing oxygen requirements resulting in progression to high-flow nasal cannula occurred in 11 patients (15%), and 5 patients (7%) required admission to the intensive care unit. One patient (1%) experienced a thrombotic event, and 1 patient (1%) had a minor bleed. The mean duration of hospitalization was 10 (standard deviation 10.8) days. One death occurred during the study period, and no cases of heparin-induced thrombocytopenia were observed. In this study of hospital inpatients with severe COVID-19 who were deemed to be at low risk of bleeding and who received therapeutic anticoagulation, there were low rates of both major bleeding and thrombotic events.

Effectiveness and safety of rivaroxaban for anticoagulation therapy in COVID-19: A meta-analysis of randomized controlled trials.

To evaluate the effectiveness and safety of rivaroxaban anticoagulation in COVID-19 patients. PubMed, Embase, Cochrane Library electronic databases, and ClinicalTrials.gov were searched to identify all relevant randomized controlled trial studies from December 2019 to July 2023. A total of 6 randomized controlled trials, which included a total of 3323 patients, were considered for evaluation. Overall, short-term all-cause mortality and hospitalization rates were not significantly different between the rivaroxaban and control groups. Thrombotic events were significantly reduced in the rivaroxaban prophylaxis group compared to the placebo control group. However, the reduction in thrombotic events was not significantly different between rivaroxaban therapy and heparin or low-molecular-weight heparin (LMWH). Rivaroxaban prophylaxis and the therapeutic dose may be associated with a higher rate of overall bleeding rate, but major bleeding rates did not differ substantially. Rivaroxaban may reduce thrombotic events in COVID-19 patients, but it does not appear to have an advantage over heparin or LMWH, and it may increase the risk of bleeding.INPLASY Reg. No.: INPLASY 202370097.

Low-dose warfarin with a novel mechanical aortic valve: Interim registry results at 5-year follow-up

ObjectivesTo evaluate whether warfarin targeted at an international normalized ratio of 1.8 (range, 1.5-2.0) after On-X mechanical aortic valve implant is safe for all patients. MethodsThis prospective, observational clinical registry assessed adverse event rates in adult patients receiving low-dose warfarin (target international normalized ratio, 1.8; range, 1.5-2.0) plus daily aspirin (75-100 mg) during a 5-year period after On-X aortic valve implant. The primary end point is the combined rate of major bleeding, valve thrombosis, and thromboembolism overall and in 4 subgroups. The comparator is the Prospective Randomized On-X Anticoagulation Trial control group patients on standard-dose warfarin (international normalized ratio, 2.0-3.0) plus aspirin 81 milligrams daily. ResultsA total of 510 patients were recruited at 23 centers in the United States, United Kingdom, and Canada between November 2015 and January 2022. This interim analysis includes 229 patients scheduled to complete 5-year follow-up by August 16, 2023. The linearized occurrence rate (in percent per patient-year) of the primary composite end point of major bleeding, valve thrombosis, and thromboembolism is 1.83% compared with 5.39% (95% confidence interval, 4.12%-6.93%) in the comparator group. Results are consistent in clinic-monitored and home-monitored patients and in those at high risk for thromboembolism. Major bleeding and total bleeding were reduced by 87% and 71%, respectively, versus the comparator group, without an increase in thromboembolic events. ConclusionsInterim results support the continued safety of the On-X aortic mechanical valve with a target international normalized ratio of 1.8 plus low-dose aspirin through 5 years after implant, with or without home monitoring.

Periprocedural Anticoagulation Management of Patients Undergoing Colonoscopy with Polypectomy.

Introduction/Objective Colonoscopy with polypectomy is an integral component of colorectal cancer screening. There are limited data and consensus on periprocedural anticoagulation management, especially regarding bleeding risk with uninterrupted anticoagulation and thromboembolic risk with interruption. Our aim was to determine the incidence of bleeding and thromboembolic complications among colon screening participants undergoing colonoscopy following implementation of a novel patient care pathway for standardized periprocedural anticoagulation management. Methods We conducted a retrospective study including all participants (age 50-74) on an oral anticoagulant (e.g., vitamin K antagonists, direct oral anticoagulants) referred to the British Columbia Colon Screening Program for colonoscopy following abnormal fecal immunochemical test in a 6-month period (March-August 2022). Data relating to their specific periprocedural anticoagulant management and colonoscopy results including method of polypectomy were obtained. Primary outcomes were major bleeding and arterial or venous thromboembolic events from time of oral anticoagulant interruption until 14 days of postcolonoscopy. Secondary outcomes included nonmajor and minor bleeding, acute coronary syndrome, emergency room visit, hospital admission, and death due to any cause. Results Over the 6-month period, 162 participants completed standardized periprocedural anticoagulation management, colonoscopy ± polypectomy, and 14-day follow-up. One (0.6%) had a major bleeding event and one (0.6%) had an arterial thromboembolic event. Conclusions A novel patient care pathway for standardized periprocedural anticoagulation management with a multidisciplinary team is associated with low rates of major bleeding and thrombotic complications after colonoscopy with polypectomy.

Use of apixaban in adults with congenital heart disease and atrial arrhythmias: The PROTECT-AR study

BackgroundAdults with congenital heart disease (ACHD) and atrial arrhythmias (AA) face an increased risk of thromboembolic events. Limited data exist on the use of non-vitamin K oral anticoagulants for thromboprophylaxis in ACHD. We aimed to assess the effectiveness and safety of apixaban in ACHD patients with AA. MethodsPROTECT-AR (NCT03854149) was a prospective, multicenter, observational study conducted from 2019 to 2023. ACHD patients with atrial fibrillation, atrial flutter, or intra-atrial re-entrant tachycardia on routine apixaban treatment were included. The historical control group consisted of patients previously on vitamin K antagonist (VKA), who were analyzed prior to their transition to apixaban. The primary effectiveness endpoint was the composite of stroke or thromboembolism. The primary safety endpoint was major bleeding. ResultsThe study enrolled 218 ACHD patients with AA on apixaban, of which 73 were previous VKA users. The analysis covered 527 patient-years of prospective exposure to apixaban and 169 patient-years of retrospective exposure to VKA. The annualized rate of stroke or thromboembolism was 0.6% in the apixaban group and 1.8% in the VKA group (absolute difference − 1.2%; upper limit of one-sided 95% confidence interval [CI] 0.9%, lower than the predefined non-inferiority margin of +1.8%, Pnon-inferiority < 0.001). The annualized rate of major bleeding was 1.5% in the apixaban group and 2.4% in the VKA group (hazard ratio 0.64; 95% CI 0.19–2.10, P = 0.48). ConclusionIn ACHD patients with AA, routine apixaban use exhibited a non-inferior rate of stroke or thromboembolism compared to historical VKA use, alongside a similar rate of major bleeding.

Acute pulmonary embolism in cancer patients admitted to intensive care unit: Impact of anticoagulant treatment on 90-day mortality and risk factors, results of a multicentre retrospective study

BackgroundAcute pulmonary embolism (PE) is a life-threatening situation in cancer patients. In this situation, anticoagulant therapy is complex to administer due to the risk of bleeding. Only few studies have been conducted when these patients are admitted to the intensive care unit (ICU). The aim of this study was to assess the association between anticoagulation strategies as well as other factors with 90-day mortality in patients with cancer and PE admitted to ICU. Major bleeding was also evaluated according to the type of anticoagulation. MethodsRetrospective study carried out in 4 ICUs in France over a 12-year period (2009–2021). All patients with cancer and PE were included. An overlap propensity score weighting analysis was performed in the subgroup of patients treated with either unfractionated heparins (UFH) alone or low-molecular-weight heparins (LMWH) alone on 90-day mortality and major bleeding. ResultsA total of 218 consecutive cancer patients admitted to ICU and presenting PE were included. The 90-day mortality rate was 42 % for the global cohort. After propensity score analysis in the subgroup of patients treated with either “UFH alone” (n = 80) or “LMWH alone” (n = 71), the 90-day mortality was similar in patients treated with UFH alone (42.6 %) vs LMWH alone (39.9 %): OR = 1.124, CI 95 % [0.571–2.214], p = 0.750. There was a significant increased toward major bleeding rates in the “UFH alone” group (25.5 %) as compared to “LMWH alone” group (11.5 %), p = 0.04. ConclusionIn 218 patients admitted to ICU and presenting PE, the 90-day mortality rate was 42 %. Treatment with UFH alone was associated with a mortality comparable to treatment with LMWH alone but it appeared to be more prone to major bleeding.

A Phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis

Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access bleeding, major atherothrombotic events (composite of fatal or non-fatal myocardial infarction, ischemic stroke, acute limb ischemia/major amputation, systemic embolism, symptomatic venous thromboembolism), AV-access thrombosis, and clotting of the hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), versus 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P= 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB bleeding and post-dialysis AV-access bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P= 0.002) and AV-access thrombosis (P= 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114.

Effectiveness and Safety of Edoxaban Compared With Apixaban in Elderly Patients With Nonvalvular Atrial Fibrillation: A Real-World Population-Based Cohort Study.

The very elderly (≥80 years) are at high risk of nonvalvular atrial fibrillation and thromboembolism. Given its recent approval, the comparative effectiveness and safety of edoxaban in this population, relative to the commonly used apixaban, remain unknown. Using the United Kingdom Clinical Practice Research Datalink, we identified a cohort of patients aged ≥80 with incident nonvalvular atrial fibrillation and newly treated with edoxaban or apixaban between 2015 and 2021. Cohort entry was defined as the first prescription for one of the 2 drugs. We used propensity score fine stratification and weighting for confounding adjustment. A weighted Cox proportional hazards model was used to estimate the hazard ratios (HR) with 95% CI of ischemic stroke/transient ischemic attack/systemic embolism (primary effectiveness outcome) and of major bleeding (primary safety outcome) associated with edoxaban compared with apixaban. We also assessed the risk of all-cause mortality and a composite outcome of ischemic stroke/transient ischemic attack, systemic embolism, gastrointestinal bleeding, and intracranial hemorrhage as secondary outcomes. The cohort included 7251 new-users of edoxaban and 39 991 of apixaban. Edoxaban and apixaban had similar incidence rates of thromboembolism (adjusted rates, 20.38 versus 19.22 per 1000 person-years; adjusted HR, 1.06 [95% CI, 0.89-1.26]), although the rates of major bleeding were higher with edoxaban (adjusted rates, 45.57 versus 31.21 per 1000 person-years; adjusted HR, 1.42 [95% CI, 1.26-1.61]). The risk of the composite outcome was 21% higher with edoxaban (adjusted HR, 1.21 [95% CI, 1.07-1.38]). All-cause mortality was similar between edoxaban and apixaban (adjusted HR, 1.04 [95% CI, 0.96-1.12]). In very elderly patients with nonvalvular atrial fibrillation, edoxaban resulted in similar thromboembolism prevention as apixaban, although it was associated with a higher risk of major bleeding. These findings may improve the management of nonvalvular atrial fibrillation by informing physicians on the choice of anticoagulant for this vulnerable population.

Outcomes of venous thromboembolism in patients with inherited thrombophilia treated with direct oral anticoagulants: insights from the RIETE registry.

While direct oral anticoagulants (DOACs) are frequently used to treat venous thromboembolism (VTE), the outcomes of patients with inherited thrombophilia (IT) receiving DOACs for VTE remain understudied. We used data from the international RIETE registry to compare the rates of VTE recurrences, major bleeding, and mortality during anticoagulant treatment in VTE patients with and without IT, grouped by the use of DOACs or standard anticoagulant therapy. Among 103,818 enrolled patients, 21,089 (20.3%) were tested for IT, of whom 8422 (39.9%) tested positive: Protein C deficiency 294, Protein S deficiency 726, Antithrombin deficiency 240, Factor V Leiden 2248, Prothrombin gene mutation 1434, combined IT 3480. Overall, 14,189 RIETE patients (6.2% with IT) received DOACs, and 89,629 standard anticoagulation (8.4% with IT), mostly with heparins followed by vitamin K antagonists. Proportions of patients receiving DOACs did not differ between IT-positive and IT-negative patients. Rates of VTE recurrence on anticoagulant treatment were highest in patients with AT deficiency (P < 0.01). Rates of on-treatment major bleeding and all-cause mortality were lowest among patients with Factor V Leiden (FVL) or PT G20210A mutations, compared with patients who tested negative. Patients with IT who received DOACs had lower rates of major bleeding than those receiving standard anticoagulation. Excluding FVL and Protein S deficiency, patients with IT had lower rates of VTE recurrence with DOACs than with standard anticoagulation. DOACs are equally safe and effective in VTE patients with IT, with lower bleeding rates than those on standard anticoagulation.

Clinical Characteristics and Incidence of Hemorrhagic Complications in Patients Taking Factor Xa Inhibitors in Spain: A Long-Term Observational Study.

Objective. To analyze the clinical characteristics of patients taking Factor Xa inhibitors (FXai), either direct FXai or enoxaparin (only in active cancer patients), and to estimate the incidence of and risk factors for major bleeding during FXai use. Methods. A retrospective cohort study, which included secondary data from computerized health records of primary care centers and hospitals in seven Spanish Autonomous Communities. Results. 9374 patients were analyzed, with 8972 taking direct FXai and 402 enoxaparin. At baseline, the mean age (SD) was 71.8 (9.4) years, 56.0% were women, 76.3% had hypertension, 33.6% had type 2 diabetes, and 25.5% had heart failure. The most common indication for FXai use was atrial fibrillation (72.3%), followed by venous thromboembolism (22.2%) and non-mechanical cardiac-valve replacement (5.6%). At the end of the follow-up period, the incidence rates of major bleeding overall, gastrointestinal, and intracranial were 10.2, 9.0, and 0.8 per 100 person-years, respectively. The total incidence of fatal major bleeding was 0.5 per 100 person-years. Incidence rates of all bleedings progressively decreased over time, with 62.5% of the first events occurring in the initial three months and reaching 76.8% within six months following initiation of treatment. Only 4.8% of the 1st major bleedings led to death, 2.3% in the case of major gastrointestinal bleeding, and 30.8% after an intracranial bleeding. 65.9% of patients discontinued anticoagulation after experiencing major bleeding. Conclusions. In Spain, patients taking FXai were old and had many comorbidities. Despite incidence rates of major bleeding were high, incidence rates of intracranial and fatal bleedings were low, but more efforts are required due to their relevant clinical impact.

Incidence and Predictors of Worsening Renal Function in Edoxaban-Treated Atrial Fibrillation Patients Within ETNA-AF-Europe Registry

BackgroundManaging patients with atrial fibrillation (AF) and worsening renal function (WRF) remains a clinical challenge due to the need of dose adjustment of non-vitamin K antagonist oral anticoagulants. ObjectivesTo determine the incidence of WRF in patients with AF treated with edoxaban, the association of WRF with clinical outcomes, and predictors of WRF and clinical outcomes in these patients. MethodsThis is a subanalysis of the Edoxaban Treatment in routiNe clinical prActice for patients with non-valvular Atrial Fibrillation in Europe study (NCT02944019), an observational study of edoxaban-treated patients with AF. WRF was defined as a ≥25% reduction in creatinine clearance between baseline and 2 years. ResultsOf the 9,054 patients included (69% of the total 13,133 enrolled), most did not experience WRF (90.3%) during the first 2 years of follow-up. WRF occurred in 9.7% of patients. Patients with WRF had significantly higher rates of all-cause death (3.88%/y vs 1.88%/y; P < 0.0001), cardiovascular death (2.09%/y vs 0.92%/y; P < 0.0001), and major bleeding (1.51%/y vs 0.98%/y; P = 0.0463) compared with those without WRF. Rates of intracranial hemorrhage (0.18%/y vs 0.18%/y) and of any stroke/systemic embolic events were low (0.90%/y vs 0.69%/y; P = 0.3161) in both subgroups. The strongest predictors of WRF were a high CHA2DS2-VASc score, high baseline creatinine clearance, low body weight, and older age. Most predictors of WRF were also predictors of clinical outcomes. ConclusionsWRF occurred in approximately 10% of edoxaban-treated AF patients. Rates of death and major bleeding were significantly higher in patients with WRF than without. Stroke events were low in both subgroups.