The Dilemma of Resuming Anticoagulation After Intracranial Hemorrhage

Stroke represents the most devastating complication of atrial fibrillation (AF). Our understanding of the pathophysiology of thromboembolism in patients with AF remains incomplete, and as such, our assessment and management of this risk is imperfect. Current guidelines regard the risk of thromboembolism as independent of the frequency or duration of AF.1 Paradoxically, standard practice in the pericardioversion period considers thromboembolic risk to accrue after 48 hours of AF.1 This recommendation, however, is based on limited data, including an observational study of 357 patients which demonstrated that the risk of thromboembolic events was <1% in patients with AF lasting <48 hours who cardioverted without prolonged anticoagulation therapy or a transesophageal echocardiogram.2 No strong randomized control trial data exist to specifically support a 48-hour safety cut-off, and recent data suggest that the duration of AF associated with a significantly increased risk of stroke may in fact be less.3–8 The emergence of technology to allow absolute quantification of the frequency and duration, or burden, of AF offers the opportunity to refine our assessment and management of thromboembolic risk associated with AF. It has been 200 years since William Wood described a ball thrombus in the left atrium of a patient with mitral stenosis9 and 170 years since Virchow identified the critical components required for thrombus formation.10 It took until 1930 for Harvey and Levine to first declare that “auricular fibrillation definitely increases the incidence of auricular thrombosis” in an autopsy series of patients with mural thrombi.11 Uncertainty as to whether nonrheumatic AF resulted in stroke continued for the next 40 plus years until Wolfe and colleagues, in their landmark analysis using the Framingham population data, identified a 5.6-fold increased risk of stroke in patients with chronic nonvalvular AF.12 With time it would become …

Outcome on Reinstitution of Anticoagulation Following Intracranial Hemorrhage: A Single Institutional Analysis

Background and ObjectivesIn patients with mechanical heart valves (MHVs), anticoagulation (AC) interruption after intracranial hemorrhage (ICH) poses a clinical dilemma because of competing risks of ischemic complications and hemorrhagic recurrence. To date, the optimal timing for resuming vitamin K antagonists (VKAs) remains unclear. The aim of this meta-analysis was to quantify the risks of ischemic stroke and recurrent ICH associated with VKA resumption in this population and explore the temporal risk dynamics.MethodsWe systematically searched PubMed, Embase, and Cochrane Library from inception to December 2023 for studies reporting ischemic or hemorrhagic outcomes in adults with MHVs who experienced ICH and were considered for VKA resumption. Primary outcomes were ischemic stroke before AC resumption and recurrent ICH after AC resumption. Random-effects meta-analyses were performed. Meta-regressions assessed whether timing of resumption influenced risk. Risk trajectories were estimated using a model-based approach.ResultsNine studies were included, comprising 435 patients with MHVs with confirmed ICH included in the pooled analysis. The mean age ranged from 54.1 to 75 years; 31.3% were female. The pooled incidence of recurrent ICH after AC reinitiation was 11.4% (95% CI 8.2–15.6; I2 = 0%), the incidence of ischemic stroke during AC suspension was 6.1% (95% CI 4.1–8.9; I2 = 0%), valve thrombosis occurred in 3.3% (95% CI 1.9–5.6; I2 = 0%), and mortality occurred in 4.9% (95% CI 2.0–11.5; I2 = 37%). Meta-regression demonstrated a significant inverse association between time to AC resumption and risk of recurrent ICH (regression coefficient −0.039; 95% CI −0.093 to 0.015; p = 0.13), corresponding to an approximate 50% relative reduction in risk at 11 days after ICH. No significant time-dependent association was observed for ischemic stroke (coefficient −0.013; 95% CI −0.065 to 0.039; p = 0.61).DiscussionIn patients with MHVs who experienced an ICH, this meta-analysis found that resumption of AC was associated with a recurrent ICH rate of 11.4% and an ischemic stroke rate of 6.1% during AC suspension. Meta-regression suggested a lower risk of recurrent ICH with later AC resumption, with a potential risk reduction at approximately 11 days after ICH. No time-dependent increase in ischemic stroke was observed. Limitations include the retrospective design of most studies and heterogeneous AC timing across cohorts.

The safety and efficacy of restarting anticoagulation therapy after intracranial hemorrhage (ICH) remain unclear. We performed a systematic review and meta-analysis to summarize the associations of anticoagulation resumption with the subsequent risk of ICH recurrence and thromboembolism. We searched published medical literature to identify cohort studies involving adults with anticoagulation-associated ICH. Our predictor variable was resumption of anticoagulation. Outcome measures were thromboembolic events (stroke and myocardial infarction) and recurrence of ICH. After assessing study heterogeneity and publication bias, we performed a meta-analysis using random-effects models to assess the strength of association between anticoagulation resumption and our outcomes. Eight studies were eligible for inclusion in the meta-analysis, with 5306 ICH patients. Almost all studies evaluated anticoagulation with vitamin K antagonists. Reinitiation of anticoagulation was associated with a significantly lower risk of thromboembolic complications (pooled relative risk, 0.34; 95% confidence interval, 0.25-0.45; Q=5.12, P for heterogeneity=0.28). There was no evidence of increased risk of recurrent ICH after reinstatement of anticoagulation therapy, although there was significant heterogeneity among included studies (pooled relative risk, 1.01; 95% confidence interval, 0.58-1.77; Q=24.68, P for heterogeneity <0.001). No significant publication bias was detected in our analyses. In observational studies, reinstitution of anticoagulation after ICH was associated with a lower risk of thromboembolic complications and a similar risk of ICH recurrence. Randomized clinical trials are needed to determine the true risk-benefit profile of anticoagulation resumption after ICH.

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Purpose Resumption of anticoagulation therapy (OAC) in patients with non-valvular atrial fibrillation (NVAF) suffering from intracranial haemorrhage (ICH) is challenging in clinical practice. The aim of this study was to evaluate impact of resumption of OAC on clinical outcomes in NVAF patients with history of ICH. Methods Consecutive patients with NVAF with or without OAC who survived from an index ICH between January 2018 and July 2022 in 16 public hospitals in Hong Kong were identified and analyzed retrospectively. Resumption of OAC was substantiated by new prescription obtained from electronic medical records. Patients were divided into 5 groups: (i) OAC naïve (as reference group); (ii) resume direct oral anticoagulant (DOAC); (iii) resume Vitamin K antagonist (VKA); (iv) discontinue DOAC; (v) discontinue VKA. Risks of ischemic stroke, recurrent ICH and all-cause mortality were estimated for all groups and compared with individuals without OAC, using adjusted sub-distribution hazard ratios (aSHR) derived from Fine and Gray regression models, accounting for death as competing risk, adjusting for components of CHA2DS2VASC and HASBLED scores. Sub-analysis was conducted to compare outcomes between different DOAC agents (i.e, apixaban, dabigatran, edoxaban, rivaroxaban), using VKA as reference among patients who resumed DOAC or VKA. Results Of 982 patients who met inclusion criteria (mean age 77.7±10.9, female 40.9%), 39.1% (n=384) were OAC naive, 32.2% (n=316) resumed DOAC, 12.6% (n=124) resumed VKA, 9.0% (n=88) discontinued DOAC and 7.1% (n=70) discontinued VKA. During a median follow-up period of 2.0 (IQR: 0.7-3.5) years, no statistically significant difference in risk of ischemic stroke was observed among 5 groups. Discontinuation of DOAC was associated with markedly higher risk of ischemic stroke (aSHR=8.32 (1.8-39.3)) only among AF patients with CHA2DS2VASC score ≥ 4, Risk of recurrent ICH was higher in patients who resumed VKA (aSHR=1.6(1.0-2.5)). Sub-analysis demonstrated resumption of apixaban was associated with lowest risk of recurrent ICH (aSHR=0.6(0.4-0.9)). Compared to OAC naïve patients, those who resumed DOAC (aSHR=0.5(0.4-0.7)) had lowest risk of all-cause mortality, whereas discontinuation DOAC (aSHR=1.9(0.4-2.5) and VKA (aSHR=1.6(0.2-2.2)) were both associated with increased mortality. Conclusion Our real-world data revealed among NVAF patients with prior ICH long term discontinuation of OAC was associated with increased risk of ischemic stroke. Recurrent ICH was highest among patients who resumed VKA and lowest with apixaban.

The risk of recurrent ischemic stroke, intracranial hemorrhage, and mortality in people with atrial fibrillation detected after stroke (AFDAS) is still unclear compared with people with known atrial fibrillation (KAF). We systematically reviewed the literature to provide updated estimates for the risk of recurrent stroke, intracerebral hemorrhage, and mortality in AFDAS compared with KAF. Our protocol was registered in PROSPERO (CRD42024583064). Presentation followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. We searched MEDLINE, EMBASE, Cochrane CENTRAL, and MedRxiv up to August 28, 2024, for studies comparing AFDAS and KAF for the following outcomes of interest: recurrent ischemic stroke (primary), intracerebral hemorrhage, mortality, and any stroke recurrence. We included cohort, observational studies (either prospective or retrospective) and randomized controlled trials and excluded studies with less than 15 patients per group. Eligible studies were assessed for bias using the Risk of Bias in Non-Randomized Studies tool. We pooled study-level results through random-effect meta-analysis of risk ratios (RRs). We also performed prespecified sensitivity analysis for study quality, timing of search for AF, propensity score matching, and study data source (administrative vs local data), and we planned meta-regression analysis to test for the interaction of sex, comorbid cardiovascular risk factors, and anticoagulation status on the difference between AFDAS and KAF. Seventeen studies were retrieved (n = 113,365; nKAF = 80,339; nAFDAS = 33,026; female in KAF, 49.0%; female in AFDAS, 45.1%), eight of which had low risk of bias. Ischemic stroke recurrence was significantly lower in AFDAS compared with the KAF group (RR = 0.79, 95% CI = 0.66-0.95, I2 = 70%; nstudies = 10). Meta-regression analysis revealed no interaction of anticoagulation, CHA2DS2-VASc score, or sex on the difference in risk of recurrent ischemic stroke between groups. Mortality was lower in the AFDAS group compared with KAF (RR = 0.84, 95% CI = 0.74-0.95, I2 = 74%; nstudies = 14). The rates of any intracerebral bleeding (RR = 0.97, 95% CI = 0.68-1.39, I2 = 58%; nstudies = 5) and any stroke recurrence (RR = 0.99, 95% CI = 0.75-1.30; I2 = 60; nstudies = 3) were similar in AFDAS and KAF. AFDAS may carry a lower risk of ischemic stroke recurrence and mortality compared with KAF, with similar risk of intracerebral hemorrhage. Stratification through implementation of AF burden measures may support more personalized management for people with AFDAS.

Scientific and Standardization Committee Communication: Guidance document on the periprocedural management of patients on chronic oral anticoagulant therapy: Recommendations for standardized reporting of procedural/surgical bleed risk and patient‐specific thromboembolic risk

(1) Background: Whether anticoagulation can be resumed in atrial fibrillation (AF) combined with intracranial hemorrhage (ICH), and which anticoagulation modality is used with better efficacy and safety, is unknown. (2) Method: Randomized controlled trials (RCTs) and observational studies on relevant topics were included by searching five databases: PubMed, EMBASE, EBSCO, Cochrane Central Register of Controlled Trial and ClinicalTrials. Bayesian network meta-analysis was performed to analyze the effect of oral anticoagulant (OAC), new oral anticoagulant (NOAC), warfarin, antiplatelet, left atrial appendage occlusion (LAAO) and no therapy in patients with AF after intracranial hemorrhage. (3) Results: We included 16 studies involving 25,483 patients. Compared with no antithrombotic therapy, the risk of thromboembolism and all-cause mortality were both reduced with OAC (OR: 0.38, 95% CI: 0.21-0.67; OR: 0.45, 95% CI: 0.25-0.8) and LAAO (OR: 0.11, 95% CI: 0.01-0.76; OR: 0.11, 95% CI: 0.01-0.88), and there was no increased risk of recurrent intracranial hemorrhage. Regarding thromboembolism, OAC (OR: 0.28, 95% CI: 0.11-0.69) was superior to antiplatelet therapy, and antiplatelet therapy (OR: 12.59, 95% CI: 1.57-133.50) was associated with a higher risk of thromboembolism than LAAO. There were no significant differences in recurrent intracranial hemorrhage between the interventions. LAAO appeared to be the best option for reducing thromboembolism (SUCRA: 0.96), recurrent intracranial hemorrhage (SUCRA: 0.75) and all-cause mortality (SUCRA: 0.94). (4) Conclusions: Based on this network meta-analysis, we hypothesize that LAAO has the highest likelihood of reducing the risk of thromboembolism and recurrent intracranial hemorrhage, as well as all-cause mortality in patients with AF after intracranial hemorrhage, followed by OAC.

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

SummaryBackgroundCerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location.MethodsWe undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM.Findings139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0–5·7 vs 29·5%, 4·1–55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1–15·4 vs 42·4%, 26·8–58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1–33·4) in year 1 to 5·0% (0·0–14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17).InterpretationThe risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men.FundingUK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

To evaluate the risk of recurrent intracranial hemorrhage (ICH) in patients on vitamin K antagonists (VKAs) after a first episode of ICH. The Cerebral Haemorrhage in patients Restarting Oral Anticoagulant Therapy (CHIRONE) Study collected data of patients eligible for the study from the database of 27 centers affiliated with the Italian Federation of Anticoagulation Clinics. We enrolled 267 patients (163 male, median age 73.9 years) who had received VKA anticoagulation after an ICH event. During the total period of follow-up (778 patient-years), ICH recurred in 20 patients (7.5%; rate 2.56 × 100 patient-years) at a median time of 16.5 months, and was fatal in 5 patients (25%; rate 0.4 × 100 patient-years). Male sex, hypertension, prosthetic valves, previous ischemic stroke, renal failure, cancer, and spontaneous events were associated with the risk of recurrence, though none of them in isolation reached statistical significance. More than one-third of spontaneous recurrences occurred in patients with a posttraumatic index event. Our results show that patients with a history of ICH carry a significant risk of recurrent ICH when treated with VKA anticoagulation. The risk is also present, though to a lower degree, in patients with previous posttraumatic events. All patients with a history of ICH require a careful evaluation of their thromboembolic risk to estimate the net clinical benefit of (re)starting anticoagulation with VKAs.

Cerebral microbleeds and prediction of intracranial haemorrhage

Dual-antiplatelet regimens for prevention of recurrent stroke promote antithrombotic effects but may increase the risk for hemorrhage. To qualitatively and quantitatively examine the risk for recurrent stroke and intracranial hemorrhage (ICH) linked to long-term dual- and single-antiplatelet therapy among patients with ischemic stroke and transient ischemic attack. PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials through March 2013 without language restrictions. The search identified 7 randomized, controlled trials that involved a total of 39,574 participants and reported recurrent stroke and ICH as outcome measures. All data from eligible studies were independently abstracted by 2 investigators according to a standard protocol. Recurrent stroke risk did not differ between patients receiving dual-antiplatelet therapy and those receiving aspirin monotherapy (relative risk [RR], 0.89 [95% CI, 0.78 to 1.01]) or clopidogrel monotherapy (RR, 1.01 [CI, 0.93 to 1.08]). Risk for ICH did not differ between patients receiving dual-antiplatelet therapy and those receiving aspirin monotherapy (RR, 0.99 [CI, 0.70 to 1.42]) but was greater among patients receiving dual-antiplatelet therapy than among those receiving clopidogrel monotherapy (RR, 1.46 [CI, 1.17 to 1.82]). Agents used in dual- and single-antiplatelet therapies varied across trials, and the relatively modest number of trials limited subgroup analysis. Compared with monotherapy, dual-antiplatelet therapy lasting more than 1 year after an index ischemic stroke or transient ischemic attack is not associated with a greater reduction in overall recurrent stroke risk. However, long-term dual-antiplatelet therapy is linked to higher risk for ICH than clopidogrel monotherapy in this patient population. Chang Gung Memorial Hospital.

Stroke prevention with oral anticoagulants (OACs) is the cornerstone for the management of atrial fibrillation (AF). However, data about the use of OACs among patients ≥90 years of age are limited. We aimed to investigate the risk of ischemic stroke and intracranial hemorrhage (ICH) and the net clinical benefit of OAC treatment for very elderly patients with AF (≥90 years of age). This study used the National Health Insurance Research Database in Taiwan. Risks of ischemic stroke and ICH were compared between 11 064 and 14 658 patients with and without AF ≥90 years of age without antithrombotic therapy from 1996 to 2011. Patients with AF (n=15 756) were divided into 3 groups (no treatment, antiplatelet agents, and warfarin), and the risks of stroke and ICH were analyzed. The risks of ischemic stroke and ICH were further compared between patients treated with warfarin and nonvitamin K antagonist OACs (NOACs) from 2012 to 2015 when NOACs were available in Taiwan. Compared with patients without AF, patients with AF had an increased risk of ischemic stroke (event number/patient number, incidence = 742/11 064, 5.75%/y versus 1399/14 658, 3.00%/y; hazard ratio, 1.93; 95% confidence interval, 1.74-2.14) and similar risk of ICH (131/11 064, 0.97%/y versus 206/14 658, 0.54%/y; hazard ratio, 0.85; 95% confidence interval, 0.66-1.09) in competing risk analysis for mortality. Among patients with AF, warfarin use was associated with a lower stroke risk (39/617, 3.83%/y versus 742/11 064, 5.75%/y; hazard ratio, 0.69; 95% confidence interval, 0.49-0.96 in a competing risk model), with no difference in ICH risk compared with nontreatment. When compared with no antithrombotic therapy or antiplatelet drugs, warfarin was associated with a positive net clinical benefit. These findings persisted in propensity-matched analyses. Compared with warfarin, NOACs were associated with a lower risk of ICH (4/978, 0.42%/y versus 19/768, 1.63%/y; hazard ratio, 0.32; 95% confidence interval, 0.10-0.97 in a competing risk model), with no difference in risk of ischemic stroke. Among patients with AF ≥90 years of age, warfarin was associated with a lower risk of ischemic stroke and positive net clinical benefit. Compared with warfarin, NOACs were associated with a lower risk of ICH. Thus, OACs may still be considered as thromboprophylaxis for elderly patients, with NOACs being the more favorable choice.