Death and Disability from Warfarin-Associated Intracranial and Extracranial Hemorrhages

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks

Ischemic stroke (IS) and major bleeding, which are serious adverse events in patients with atrial fibrillation (AF), could have seasonal variations, but there are few reports. In the Shinken Database 2004-2016 (n=22,018), 3,581 AF patients (average age, 63.5 years; 2,656 men, 74.2%; 1,388 persistent AF, 38.8%) were identified. Median CHADS2and HAS-BLED scores were both 1 point. Oral anticoagulants were prescribed for 2,082 (58.1%) patients (warfarin, 1,214; direct oral anticoagulants [DOACs], 868). Incidence and observation period (maximum 3 years) of IS, extracranial hemorrhage (ECH), and intracranial hemorrhage (ICH) were counted separately for the northern hemisphere seasons. During the mean follow-up period of 2.4 years, there were totals of 90 IS, 73 ECH, and 33 ICH cases. The respective incidence rates per 1,000 patient-years in spring, summer, autumn, and winter were 8.5, 8.8, 7.5, and 16.8 for IS, 7.2, 9.7, 3.8, and 13.1 for ECH, and 2.7, 1.9, 3.8, and 7.0 for ICH. The number of patients with DOACs relatively increased among those with ECH in summer. Significant seasonal variations were observed for IS, ECH, and ICH events in AF patients, and were consistently the highest in winter. A small peak of ECH was observed in summer, which seemed, in part, to be related to increased DOAC use.

Dabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes. To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention. Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016. Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily. Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated. A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS2 score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke. Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.

The American Heart Association recommends extended cardiac monitoring for the diagnosis of subclinical atrial fibrillation (AF) among patients with acute ischemic stroke and no clear source of embolism. In this meta-analysis by Dr. Tsivgoulis and colleagues, investigators pooled high-quality observational cohort and randomized clinical trial data involving nearly 3,000 patients to evaluate the probability of identifying AF, initiation of anticoagulation, and stroke recurrence risk. Although all cardiac monitors increased the risk of AF detection and anticoagulation initiation, implantable loop recorders were associated with the highest probability of AF detection and anticoagulation initiation. Compared with patients who underwent conventional monitoring, those with prolonged monitoring were associated with a lower risk of recurrent stroke, although this risk was driven by patients monitored in observational (nontrial) cohort studies (relative risk [RR] 0.29, 95% CI 0.15–0.59 vs RR of stroke in randomized clinical trials 0.72, 95% CI 0.49–1.07). Dr. Meinel emphasizes that intracranial and systemic hemorrhages ought to be considered along with recurrent ischemic stroke in the decision to anticoagulate a patient with AF. The investigators acknowledge that intracranial hemorrhages are a highly fatal complication after anticoagulation, and although the risk of death due to major extracranial hemorrhage is also considerable, the mortality rate is far lower than what is seen among intracranial hemorrhages. Fortunately, most bleeding events and deaths due to such events are generally low (<5%). Owing to lack of available data on bleeding rates and mortality in many studies reported in this meta-analysis, the investigators cannot be certain of the low risks across all populations. That said, there were no significant differences in all-cause mortality with prolonged vs conventional cardiac monitoring in 2 of the included studies. Dr. Scharf also comments that the burden of subclinical AF and etiologies of recurrent stroke (e.g., small vessel or large vessel atherosclerosis) are also integral to evaluating the efficacy of anticoagulation in these patients. All authors eagerly await the results of randomized trials evaluating the potential benefit of anticoagulation after AF detection through prolonged cardiac monitoring. The American Heart Association recommends extended cardiac monitoring for the diagnosis of subclinical atrial fibrillation (AF) among patients with acute ischemic stroke and no clear source of embolism. In this meta-analysis by Dr. Tsivgoulis and colleagues, investigators pooled high-quality observational cohort and randomized clinical trial data involving nearly 3,000 patients to evaluate the probability of identifying AF, initiation of anticoagulation, and stroke recurrence risk. Although all cardiac monitors increased the risk of AF detection and anticoagulation initiation, implantable loop recorders were associated with the highest probability of AF detection and anticoagulation initiation. Compared with patients who underwent conventional monitoring, those with prolonged monitoring were associated with a lower risk of recurrent stroke, although this risk was driven by patients monitored in observational (nontrial) cohort studies (relative risk [RR] 0.29, 95% CI 0.15–0.59 vs RR of stroke in randomized clinical trials 0.72, 95% CI 0.49–1.07). Dr. Meinel emphasizes that intracranial and systemic hemorrhages ought to be considered along with recurrent ischemic stroke in the decision to anticoagulate a patient with AF. The investigators acknowledge that intracranial hemorrhages are a highly fatal complication after anticoagulation, and although the risk of death due to major extracranial hemorrhage is also considerable, the mortality rate is far lower than what is seen among intracranial hemorrhages. Fortunately, most bleeding events and deaths due to such events are generally low (<5%). Owing to lack of available data on bleeding rates and mortality in many studies reported in this meta-analysis, the investigators cannot be certain of the low risks across all populations. That said, there were no significant differences in all-cause mortality with prolonged vs conventional cardiac monitoring in 2 of the included studies. Dr. Scharf also comments that the burden of subclinical AF and etiologies of recurrent stroke (e.g., small vessel or large vessel atherosclerosis) are also integral to evaluating the efficacy of anticoagulation in these patients. All authors eagerly await the results of randomized trials evaluating the potential benefit of anticoagulation after AF detection through prolonged cardiac monitoring.

A study using Medicare data concluded that among patients aged 65 years or older, rivaroxaban had a less favorable benefit-harm profile compared with other non-vitamin K oral anticoagulants (NOACs); however, it is unclear whether this finding persists in younger users. To compare major extracranial bleeding (MEB), gastrointestinal bleeding (GIB), intracranial hemorrhage (ICH), and thromboembolic stroke in individuals aged younger than 65 years using non-vitamin K oral anticoagulants (NOAC users) for nonvalvular atrial fibrillation (NVAF). This cohort study using health care claims data between October 2010 and February 2022 in the FDA Sentinel System included standard dose NOAC (rivaroxaban, apixaban, and dabigatran) users with NVAF aged 21 to 64 years. Analyses conducted between December 2022 and August 2023. Hazard ratios (HRs) and 95% CIs were estimated for each outcome (MEB, GIB, ICH, and thromboembolic stroke) in inverse probability of treatment-weighted pairwise comparisons: rivaroxaban vs apixaban, rivaroxaban vs dabigatran, and dabigatran vs apixaban. A total of more than 173 000 patients (mean [SD] age, 56.6 [7.23] years; 27.5% female; 72.5% male) were included across the 3 exposure cohorts. The number of NOAC users for each pairwise comparison were rivaroxaban (57 932) vs apixaban (96 057), rivaroxaban (57 399) vs dabigatran (20 188), and dabigatran (20 163) vs apixaban (96 668). Rivaroxaban was associated with higher risks of MEB and GIB compared with apixaban (MEB: HR, 1.91; 95% CI, 1.56-2.34; GIB: HR, 1.92, 95% CI, 1.54-2.39), while differences in thromboembolic stroke prevention were not significant (HR, 1.05; 95% CI, 0.77-1.44). Dabigatran was associated with higher thromboembolic stroke risk (rivaroxaban vs dabigatran: HR, 0.61; 95% CI, 0.39-0.94; dabigatran vs apixaban: HR, 1.74; 95% CI, 1.13-2.68). These findings suggest that for patients aged younger than 65 years treated with NOACs for NVAF, apixaban was associated with the most favorable benefit-harm profile. While the results suggest that rivaroxaban may have provided greater stroke prevention than dabigatran, it was associated with higher bleeding risks than apixaban without additional stroke prevention. The higher thromboembolic stroke risks observed with dabigatran in younger patients suggest important age-related differences in effectiveness that warrant further investigation.

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

Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation

Background and PurposePatients with nonvalvular atrial fibrillation (NVAF) who survive an intracranial hemorrhage (ICH) have an increased risk of ischemic stroke and systemic embolism (IS/ SE). We investigated whether starting oral anticoagulants (OACs) among older NVAF patients after an ICH was associated with a lower risk of IS/SE and mortality but offset by an increase in major bleeding.MethodsWe assembled a patient cohort from the Quebec Régie de l’Assurance Maladie du Québec (RAMQ) and Med-Echo administrative databases. We identified older adults with NVAF from 1995 to 2015. All patients with incident ICH and discharged in community were included. Patients were categorized according to OAC exposure. Outcomes included IS/SE, all-cause mortality, recurrent ICH and major bleeding after a quarantine period of 6 weeks. Crude event rates were calculated at 1-year of follow-up, and Cox proportional hazard models with a time-dependent binary exposure were used to assess adjusted hazard ratios (AHRs).ResultsThe cohort of 683 NVAF patients with ICH aged 83 years on average. The rates (per 100 person-years) for IS/SE, death, ICH and major bleeding were 3.3, 40.6, 11.4, and 2.7 for the no OAC group; and 2.6, 16.3, 5.2, and 5.2 for OAC group, respectively. The AHR for IS/SE and death was 0.10 (95% confidence interval [CI], 0.05 to 0.21), 0.43 (95% CI, 0.19 to 0.97) for recurrent ICH and 1.73 (95% CI, 0.71 to 4.20) for major extracranial bleeding comparing OAC exposure to non-exposed.ConclusionsInitiating OAC after ICH in older individuals with NVAF is associated with a reduction of IS/SE and mortality and a trend in recurrent ICH supporting its use after ICH.

Atrial fibrillation is prevalent in dialysis patients. Both ischaemic and haemorrhagic stroke are common in patients on dialysis with atrial fibrillation. In the general population, warfarin is highly effective for prophylaxis of ischaemic stroke, and though warfarin use likely increases the risk of intracranial haemorrhage, the absolute increase in risk is small. In the general population, absolute and relative increases in major extracranial bleeding from warfarin use are also both modest. In patients on dialysis, the effectiveness of warfarin as a prophylaxis for ischaemic stroke and its effects on intracranial or extracranial bleeding have not been assessed in randomized trials. Cohort studies vary greatly in their estimates of the magnitude of the increased risk of bleeding from warfarin use. A single cohort study found rates of intracranial haemorrhage in patients on dialysis with atrial fibrillation to be in an order of magnitude that is greater than those in the general population with atrial fibrillation, and that intracranial haemorrhage more than doubled in association with warfarin use. Basic, translational and limited clinical observations also implicate warfarin in the pathogenesis of vascular calcification, which is likely on the causal pathway to patient-important vascular outcomes. Finally, the effect of warfarin on ischaemic stroke in three recent large observational studies has been in the direction of harm, no benefit, and modest, non-statistically significant benefit, respectively. We believe that no clear recommendation can be made between three alternative approaches. It is acceptable to withhold or discontinue warfarin in patients on dialysis, to offer anticoagulants to all dialysis patients without a contraindication whose congestive heart failure, hypertension, age, diabetes and previous stroke or transient ischaemic attack (CHADS(2)) score >1 or 2 and to discuss and individualize prophylaxis on a patient-by-patient basis. Randomized trials of new agents are needed in this area.

IntroductionBleeding and thrombotic events (BTE) are frequent during extracorporeal membrane oxygenation (ECMO). They occur at varying timepoints and may be affected by temporal changes in coagulation and fibrinolysis. We aimed to assess various coagulation and fibrinolytic markers over time and their relationship with BTE.MethodsA single-centre prospective study was performed in 17 patients with severe respiratory failure receiving veno-venous ECMO. Blood samples were collected before and during ECMO, and around circuit decannulation.ResultsPrior to ECMO, D-Dimer, Plasmin-Antiplasmin complexes (PAP), Plasminogen-Activator Inhibitor-1 (PAI-1) and fibrinogen were elevated. There was an increase in D-Dimer and Prothrombin Fragments 1+2 (PF1+2) (729 to 1305pmol/L, p = .034) by day 1 and PAP increased by day 2 from baseline levels (median 1022 to 1797µg/L, p = .023). There was a strong positive correlation in PAP, PF1+2 and thrombin-antithrombin complexes (TAT) to D-Dimer. BTE were frequent - 18% had major extracranial haemorrhage and 24% had intracranial haemorrhage. Over time, there was a progressive elevation PAP in patients developing subsequent extracranial haemorrhage, whereas D-Dimer, PAP and PF1+2 increased after intracranial haemorrhage.ConclusionsThere were early changes in coagulation activity during ECMO by PF1+2 followed by subsequent fibrinolysis by PAP. Changes in PAP, PF1+2 and TAT were associated with major haemorrhage.

BackgroundThe effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke.MethodsDUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5–7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure.DiscussionWhen dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke.Trial registrationNL7409 (November 26, 2018)/NCT04256473 (February 5, 2020)

Recurrent Intracranial Hemorrhage and Venous Thromboembolism Following Initial Intracranial Hemorrhage in Patients with Brain Tumors on Anticoagulation

Patients with non-valvular atrial fibrillation treated with rivaroxaban for stroke prevention were more likely to experience both intracranial haemorrhage and major extracranial bleeding than those treated with dabigatran, a head-to-head trial published in JAMA Internal Medicine has shown. Researchers analysed data on 118 891 patients with non-valvular atrial fibrillation, aged 65 or older, who had started treatment with dabigatran (150 mg, twice daily) or rivaroxaban (20 mg, once daily) between 4 November 2011 and 30 June 2014. A total of 52 240 patients treated with dabigatran and 66 651 patients treated with rivaroxaban contributed 15 524 and 20 199 person years of treatment, respectively.1 Primary outcomes were thromboembolic stroke, intracranial haemorrhage, major extracranial bleeding …

The management of coumarin-induced over-anticoagulation Annotation.

To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeAD(Stroke) ) affects outcome and major haemorrhage rates. We used a multicentre CeAD(Stroke) database to compare CeAD(Stroke) patients treated with and without thrombolysis. Main outcome measures were favourable 3-month outcome (modified Rankin Scale 0-2) and 'major haemorrhage' [any intracranial haemorrhage (ICH) and major extracranial haemorrhage]. Adjusted odds ratios [OR (95% confidence intervals)] were calculated on the whole database and on propensity-matched groups. Among 616 CeAD(Stroke) patients, 68 (11.0%) received thrombolysis; which was used in 55 (81%) intravenously. Thrombolyzed patients had more severe strokes (median NIHSS score 16 vs. 3; P < 0.001) and more often occlusion of the dissected artery (66.2% vs. 39.4%; P < 0.001). After adjustment for stroke severity and vessel occlusion, the likelihood for favourable outcome did not differ between the treatment groups [OR(adjusted) 0.95 (95% CI 0.45-2.00)]. The propensity matching score model showed that the odds to recover favourably were virtually identical for 64 thrombolyzed and 64 non-thrombolyzed-matched CeAD(Stroke) patients [OR 1.00 (0.49-2.00)]. Haemorrhages occurred in 4 (5.9%) thrombolyzed patients, all being asymptomatic ICHs. In the non-thrombolysis group, 3 (0.6%) patients had major haemorrhages [asymptomatic ICH (n = 2) and major extracranial haemorrhage (n = 1)]. As thrombolysis was neither independently associated with unfavourable outcome nor with an excess of symptomatic bleedings, our findings suggest thrombolysis should not be withheld in CeAD(Stroke) patients. However, the lack of any trend towards a benefit of thrombolysis may indicate the legitimacy to search for more efficient treatment options including mechanical revascularization strategies.