Reinitiation of Anticoagulation After Warfarin-Associated Intracranial Hemorrhage and Mortality Risk: The Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) Study

doi:10.1016/j.cjca.2011.10.002

Canadian Journal of Cardiology

Volume 28, Issue 1, January–February 2012, Pages 33-39

https://doi.org/10.1016/j.cjca.2011.10.002 Get rights and content

Abstract

Background

While warfarin-related intracranial hemorrhage (ICH) occurs in 0.25%-1.1% patients per year, little is known about the practice and outcomes of anticoagulant reinitiation.

Methods

We studied a cohort of consecutive patients with warfarin-related ICH (intracerebral or subarachnoid) admitted to 13 stroke centres in the Registry of the Canadian Stroke Network between July 2003 and March 2008. We examined patterns of warfarin reinitiation and variables associated with 30-day and 1-year outcomes.

Results

Among the 284 patients studied (mean age 74 ± 12 years), warfarin was restarted in-hospital in 91 patients (32%). Factors associated with restarting warfarin were lower stroke severity (adjusted odds ratio [aOR] 2.07, 95% confidence interval [CI]; 1.20-3.57, P = 0.009) or presence of valve prosthesis (aOR 3.07, 95% CI; 1.29-7.27, P = 0.011). Mortality rates were not higher in those who restarted warfarin in-hospital: 31.9% vs 54.4% (30-day, P < 0.001) and 48% vs 61% (1-year, P = 0.04), and bleeding was not increased. Multivariable predictors of mortality included initial international normalized ratio > 3.0 (aOR, 3.28 [30-day, P < 0.001] and 3.32 [1-year, P = 0.003]), greater stroke severity (aOR, 6.04 [30-day] and 4.22 [1-year]; both P < 0.001), and intraventricular hemorrhage (aOR, 2.19 [30-day; P = 0.03] and 2.04 [1-year; P = 0.04]). In selected patients who reinitiated warfarin, there was no increase in 30-day (aOR, 0.49; P = 0.03) or 1-year mortality (aOR, 0.79; P = 0.43).

Conclusions

In selected patients at high thrombosis risk, reinitiation of warfarin after ICH did not confer increased mortality or bleeding events.

Résumé

Introduction

Tandis que l'hémorragie intracrânienne liée à la warfarine se produit chez 0,25 % à 1,1 % des patients chaque année, on en connaît peu sur la pratique et les résultats de la reprise d'anticoagulant.

Méthodes

Nous avons étudié une cohorte de patients consécutifs ayant eu une hémorragie intracrânienne (intracérébrale ou sous-arachnoïdienne) liée à la warfarine qui avaient été admis dans 13 centres d'accident vasculaire cérébral (AVC) inscrits au Registre du Réseau canadien contre les accidents cérébrovasculaires entre juillet 2003 et mars 2008. Nous avons examiné les profils de la reprise de warfarine et les variables associées aux résultats à 30 jours et à 1 an.

Résultats

Parmi les 284 patients étudiés (âge moyen de 74 ± 12 ans), la warfarine a été réintroduite à l'hôpital chez 91 patients (32 %). Les facteurs associés à la réintroduction de la warfarine ont été la diminution de la sévérité de l'AVC (ratio d'incidence approché ajusté [RIAa] à 2,07, intervalle de confiance [IC] de 95 %; 1,20-3,57, P = 0,009) ou la présence d'une prothèse valvulaire (RIAa à 3,07, IC de 95%; 1,29-7,27, P = 0,011). Les taux de mortalité n'ont pas été plus élevés chez ceux qui ont réintroduit la warfarine à l'hôpital : 31,9 % vs 54,4 % (30 jours, P < 0,001) et 48 % vs 61 % (1 an, P = 0,04), et le risque d'hémorragie n'a pas augmenté. Les prédicteurs multivariables de mortalité ont inclus le rapport international normalisé initial > 3,0 (RIAa, 3,28 [30 jours, P < 0,001] et 3,32 [1 an, P = 0,003]), la plus grande sévérité d'AVC (RIAa, 6,04 [30 jours] et 4,22 [1 an]; P < 0,001 dans les deux cas) et l'hémorragie intraventriculaire (RIAa à 2,19 [30 jours; P = 0,03] et à 2,04 [1 an; P = 0,04]). Chez les patients sélectionnés qui ont repris la warfarine, il n'y a eu aucune augmentation de la mortalité à 30 jours (RIAa, 0,49; P = 0,03) ou à 1 an (RIAa, 0,79; P = 0,43).

Conclusions

Chez les patients sélectionnés à risque élevé de thrombose, la reprise de la warfarine après l'hémorragie intracrânienne n'a pas contribué à une augmentation de la mortalité ou des événements hémorragiques.

Section snippets

Data sources

Phase 3 of the Registry of the Canadian Stroke Network (RCSN) includes audit information prospectively collected on all consecutive patients with acute stroke or transient ischemic attack (TIA) evaluated in the emergency department and admitted to hospital at acute institutions (7 academic and 6 community hospitals) across the province of Ontario, Canada.9, 10 These institutions each treat 500-1000 stroke cases annually (approximately 20% of all stroke/TIA cases in the province), and all are

Study cohort

Among 33,119 patients in the RCSN database, 4819 were acute hemorrhagic strokes and 399 of these occurred while the patients were receiving warfarin. Of these, patients were excluded because they were palliative (n = 39), transferred to a nonregistry hospital on presentation (n = 54), presented with recurrent hemorrhage (n = 13), or an ICH related to trauma or recent neurosurgical procedure (n = 9).

A cohort of 284 patients (mean age, 73.5 ± 12.3 years) met inclusion criteria, in whom warfarin

Discussion

ICH is one of the most serious complications of oral anticoagulant therapy, and is associated with significant mortality and morbidity. The selection of patients eligible for reinitiation of anticoagulation after ICH is contingent on weighing the risks of thrombosis against the risks of bleeding and, aside from expert opinion, there is little evidence available to guide this decision.16, 17 In this comparatively large cohort of patients presenting with warfarin-related intracerebral and

Funding Sources

The Registry of the Canadian Stroke Network is funded by the Canadian Stroke Network and the Ontario Ministry of Health and Long-Term Care. The Institute for Clinical Evaluative Sciences is supported in part by a grant from the Ontario Ministry of Health and Long-Term Care. This work was funded by an operating grant from the Canadian Stroke Network, and a clinician-scientist award (D.S.L.), and a New Investigator Award (M.K.K.) from the Canadian Institutes of Health Research.

Disclosures

The authors have no conflicts of interest to disclose.

Acknowledgements

The opinions, results, and conclusions are those of the authors and no endorsement by the Ontario Ministry of Health and Long Term Care or by the Institute for Clinical Evaluative Sciences or the Canadian Stroke Network is intended or should be inferred.

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Cited by (83)

Challenging anticoagulation cases: A case of pulmonary embolism shortly after spontaneous brain bleeding
2021, Thrombosis Research
Venous thromboembolism (VTE) is a common complication after intracranial hemorrhage (ICH); the incidence has been reported to vary between 18% to 50% for deep vein thrombosis and between 0.5% to 5% for pulmonary embolism (PE). According to current clinical practice guidelines, patients with acute VTE should receive anticoagulant treatment for at least 3 months in the absence of contraindications. Anticoagulant treatment reduces mortality, prevents early recurrences and improves long-term outcome in patients with acute VTE. However, recent ICH is an absolute contraindication for anticoagulant treatment due to the potential increased risk of hematoma expansion or recurrent ICH. Hematoma expansion occurs in approximately a third of patients within 24 h following the diagnosis of a spontaneous ICH. The risk for recurrent ICH depends on patients' features as well as on the feature of index ICH. Limited evidence is available on the risks of therapeutic anticoagulation started shortly after ICH. Expert consensus around the introduction of therapeutic anticoagulation suggests delaying therapeutic anticoagulation for at least 2 weeks after spontaneous ICH, until the risk re-bleeding becomes acceptable. Vena cava filters should be inserted to reduce the risk for (non) fatal PE until therapeutic anticoagulation can be started; antithrombotic prophylaxis should be started as soon as possible to avoid recurrent VTE after vena cava filter insertion. For patients presenting PE with hemodynamic compromise, percutaneous embolectomy should be considered. Most patients will be able to receive anticoagulant treatment within 4 weeks following spontaneous ICH; direct oral anticoagulants are probably the treatment of choice for those ICH patients tolerating anticoagulant treatment.
2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee
2020, Journal of the American College of Cardiology
Risk Factors for Hemorrhagic and Cardioembolic Complications of Intracerebral Hemorrhage Associated with Anticoagulants
2019, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Consequently, the number of patients presenting with intracerebral hemorrhage (ICH) who are taking anticoagulants is increasing due to aging of the population.2 Temporary cessation and resumption of anticoagulants after the initial treatment is reported to have clinical benefits,3–5 but the optimal timing for resumption is still controversial.6 The timing for resumption should be determined based on the known risk factors for hemorrhagic and thrombotic events such as CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism-vascular disease, age 65-74 years, and sex category) score and HAS-BLED (hypertension, abnormal renal/liver function, stroke-bleeding history or predisposition, labile international normalized ratio, elderly [>65 years], and drugs/alcohol concomitantly) score.7
Background: Patients with intracerebral hemorrhage taking anticoagulants are increasingly common in Japan due to the aging population. The clinical benefit of restarting anticoagulants is established, but the optimal timing of resumption is controversial. Risk factors for hemorrhagic and cardioembolic events in the acute phase are also unknown. This study investigated hemorrhagic and cardioembolic events and risk factors in intracerebral hemorrhage patients taking anticoagulants. Methods: The clinical data of 65 consecutive intracerebral hemorrhage patients taking anticoagulants were retrospectively reviewed. Hemorrhagic and cardioembolic complications and risk factors were analyzed. Results: Lobar hemorrhage was the most frequent (21 of 65 cases, 32.3%). At discharge, 31 patients (47.7%) showed severe disability or had died. Eight (18.6%) of 43 patients who restarted anticoagulants after initial treatment developed hemorrhagic events, including recurrent intracerebral hemorrhage in 3. HAS-BLED score was 2-3 in these 3 patients. Six (15.8%) of 38 patients who took anticoagulants for cardiogenic factors suffered cardioembolism. Systemic inflammatory response syndrome was significantly more common in the cardioembolic group (66.7%) compared with the noncardioembolic group (21.9%, P < .05). CHA₂DS₂-VASc score was paradoxically high in the noncardioembolic group (3 versus 5, P < .05). Conclusion: HAS-BLED score and CHA₂DS₂-VASc score were not useful for risk assessment for hemorrhagic events, recurrent intracerebral hemorrhage, and cardioembolism in the acute phase. Inflammatory response might be important in the occurrence of cardioembolic events.
American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy
2018, Blood Advances
Citation Excerpt :
We included eligible studies from the most recent systematic review for patients who did and did not resume anticoagulation therapy after surviving an episode of gastrointestinal tract bleeding (GIB).216 The search was updated from 2014 onward and expanded to include ICH, yielding a total of 17 observational studies.217-233 Most studies compared outcomes for patients who did and did not resume anticoagulation therapy following a GIB or ICH episode.
In July 2022, these guidelines were reviewed by an expert work group convened by ASH. Review included limited searches for new evidence and discussion of the search results. Following this review, the ASH Committee on Quality agreed to continue monitoring the supporting evidence rather than revise or retire these guidelines at this time. Limited searches and expert review will be repeated annually going forward until these guidelines are revised or retired.
Background: Clinicians confront numerous practical issues in optimizing the use of anticoagulants to treat venous thromboembolism (VTE).
Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the use of anticoagulants in the management of VTE. These guidelines assume the choice of anticoagulant has already been made.
Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment.
Results: The panel agreed on 25 recommendations and 2 good practice statements to optimize management of patients receiving anticoagulants.
Conclusions: Strong recommendations included using patient self-management of international normalized ratio (INR) with home point-of-care INR monitoring for vitamin K antagonist therapy and against using periprocedural low-molecular-weight heparin (LMWH) bridging therapy. Conditional recommendations included basing treatment dosing of LMWH on actual body weight, not using anti–factor Xa monitoring to guide LMWH dosing, using specialized anticoagulation management services, and resuming anticoagulation after episodes of life-threatening bleeding.
Delphi-RAND consensus of the Spanish Society of Internal Medicine on the controversies in anticoagulant therapy and prophylaxis in medical diseases. INTROMBIN Project (Uncertainty in thromboprophylaxis in internal medicine)
2018, Revista Clinica Espanola
El objetivo de este estudio ha sido conocer la opinión de los internistas sobre el manejo de la anticoagulación y profilaxis tromboembólica en escenarios clínicos complejos en los que el balance riesgo/beneficio de la intervención es estrecho y elaborar un documento de consenso sobre el uso de fármacos anticoagulantes en este grupo de pacientes. Para ello, se identificaron por consenso las áreas clínicas de mayor incertidumbre, se elaboró una encuesta con 20 escenarios desplegados en 40 preguntas clínicas y se realizó una revisión bibliográfica específica. La encuesta se distribuyó entre los internistas de la Sociedad Española de Medicina Interna (SEMI) y fue cumplimentada por 290 de sus miembros. El proceso de consenso se desarrolló mediante una modificación del método Delphi-RAND de adecuación en un proceso anonimizado de doble ronda que permite al panel de expertos identificar áreas de acuerdo y de incertidumbre. En nuestro caso, además, se incorporaron al panel los resultados de la encuesta, innovación metodológica que permite aportar información adicional de la práctica clínica habitual. El resultado del proceso es un conjunto de 19 recomendaciones formuladas por expertos de la SEMI que permite establecer pautas de actuación sobre el tratamiento anticoagulante en escenarios complejos (alto riesgo o hemorragia activa, corta expectativa vital, coexistencia de tratamiento antiagregante o comorbilidades como enfermedad renal, hepática, etc.), que no son infrecuentes en la práctica clínica habitual.
The aim of this study was to determine the opinion of internists on the management of anticoagulation and thromboembolism prophylaxis in complex clinical scenarios in which the risk-benefit ratio of surgery is narrow and to develop a consensus document on the use of drugs anticoagulant therapy in this patient group. To this end, we identified by consensus the clinical areas of greatest uncertainty, a survey was created with 20 scenarios laid out in 40 clinical questions, and we reviewed the specific literature. The survey was distributed among the internists of the Spanish Society of Internal Medicine (SEMI) and was completed by 290 of its members. The consensus process was implemented by changing the Delphi-RAND appropriateness method in an anonymous, double-round process that enabled an expert panel to identify the areas of agreement and uncertainty. In our case, we also added the survey results to the panel, a methodological innovation that helps provide additional information on the standard clinical practice. The result of the process is a set of 19 recommendations formulated by SEMI experts, which helps establish guidelines for action on anticoagulant therapy in complex scenarios (high risk or active haemorrhage, short life expectancy, coexistence of antiplatelet therapy or comorbidities such as kidney disease and liver disease), which are not uncommon in standard clinical practice.
Reintroduction of anticoagulant therapy after intracranial haemorrhage: If and when?
2018, Blood Reviews
Intracranial haemorrhage is a devastating complication of anticoagulation. In surviving patients, physicians will be faced with the dilemma of if and when treatment should be reintroduced. There is little evidence to support this decision making and guidelines refrain from making specific recommendations. Existing data relates almost exclusively to vitamin K antagonists and is entirely retrospective.
There appears to be an overall benefit to reintroducing anticoagulation in most patients; although, this may not be advocated in those at the highest risk of recurrent bleeding. The issue of when to reintroduce treatment is more controversial. The literature suggests timing could be anywhere between 7 days and 30 weeks; however there is no overall consensus.
This review summarises what evidence is currently available to support decision making and suggests pragmatic management options based on a risk-benefit assessment of thromboembolism and recurrent bleeding; however, it should be acknowledged this may not be entirely evidence-based.

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: See editorial by Coppens et al. on pages 6-8 in this issue.

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Clinical research - anticoagulationReinitiation of Anticoagulation After Warfarin-Associated Intracranial Hemorrhage and Mortality Risk: The Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) Study

Abstract

Background

Methods

Results

Conclusions

Résumé

Introduction

Méthodes

Résultats

Conclusions

Section snippets

Data sources

Study cohort

Discussion

Funding Sources

Disclosures

Acknowledgements

Am Heart J

Am J Prev Med

Thromb Res

The increasing incidence of anticoagulant-associated intracerebral hemorrhage

Neurology

Oral anticoagulants and intracranial hemorrhageFacts and hypotheses

Stroke

The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage

Arch Int Med

Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment

Stroke

Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study

Stroke

Intracerebral hematomas during anticoagulant treatment

Stroke

Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage

Neurology

Registry of the Canadian Stroke Network: Progress Report 2001-2005

Coding of stroke and stroke risk factors using international classification of diseases, revisions 9 and 10

Stroke

Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation

JAMA

Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk

Arch Neurol

Predictors of outcome in warfarin-related intracerebral hemorrhage

Arch Neurol

Clinical research - anticoagulation
Reinitiation of Anticoagulation After Warfarin-Associated Intracranial Hemorrhage and Mortality Risk: The Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) Study