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Utility of HAS-BLED and CHA2DS2-VASc Scores Among Patients With Atrial Fibrillation and Imaging Evidence of Cerebral Amyloid Angiopathy

Open AccessPublished:August 20, 2020DOI:https://doi.org/10.1016/j.mayocp.2020.03.034

      Abstract

      Objective

      To determine the utility of the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly) and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age, Diabetes, previous Stroke/transient ischemic attack–VAScular disease) scores among patients on anticoagulation (AC) therapy for atrial fibrillation (AF) who have evidence of cerebral amyloid angiopathy (CAA).

      Patients and Methods

      Patients older than 55 years with a diagnosis of AF who had a nontraumatic intracerebral hemorrhage (ICH) while on AC therapy between 1995 and 2016 were identified using the Rochester Epidemiology Project Database. Medical records were reviewed, including imaging of the brain, to identify baseline characteristics, AC use, and outcomes.

      Results

      A total of 65 patients were identified (mean age, 81.3 years); 35 (53.8%) had evidence of possible/probable CAA. Mean HAS-BLED score in the CAA group was significantly lower (2.1) than that of the non-CAA group (2.9; P<.001). Mortality after ICH, adjusted for HAS-BLED scores, was not significantly different among patients with and without CAA. Sixteen patients restarted on AC therapy after ICH; CHA2DS2-VASc scores were no different between this group and those who were not restarted. Among patients with CAA, the overall rate of ICH recurrence was 8.6% over 93.5 person-years of follow-up. Among patients with CAA, the rate of ICH recurrence was 3.2 per 100 patient-years, higher than their HAS-BLED scores would predict (1.9 bleeds/100 patient-years).

      Conclusion

      HAS-BLED scores were lower in patients who had evidence of CAA compared with those without, suggesting underestimation of ICH risk in patients with CAA. CHA2DS2-VASc scores did not affect resumption of AC therapy. ICH recurrence was higher in patients with CAA than their HAS-BLED scores predicted. Current risk assessment scoring systems do not accurately account for CAA in patients with AF on AC.

      Abbreviations and Acronyms:

      AF (atrial fibrillation), AC (anticoagulation), CAA (cerebral amyloid angiopathy), CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack–vascular disease), CT (computed tomography), ICH (intracerebral hemorrhage), IRB (Institutional Review Board), HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), MRI (magnetic resonance imaging), REP (Rochester Epidemiology Project)
      Atrial fibrillation (AF) is a common arrhythmia that predisposes patients to stroke.
      • Wolf P.A.
      • Abbott R.D.
      • Kannel W.B.
      Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.
      • Morin D.P.
      • Bernard M.L.
      • Madias C.
      • Rogers P.A.
      • Thihalolipavan S.
      • Estes 3rd, N.A.
      The state of the art: atrial fibrillation epidemiology, prevention, and treatment.
      • Chugh S.S.
      • Havmoeller R.
      • Narayanan K.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      Oral anticoagulants are used to reduce the risk for ischemic stroke, but increase the risk for intracerebral hemorrhage (ICH).
      • Lopes R.D.
      • Guimaraes P.O.
      • Kolls B.J.
      • et al.
      Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy.
      ,
      • Hart R.G.
      • Pearce L.A.
      • Aguilar M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      Clinicians are often presented with the challenge of balancing cardioembolic stroke prevention with the risk for ICH. Scoring schemata have been developed to help guide these decisions in clinical practice. Two in particular are heavily relied on in the United States. The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score was developed to predict 1-year risk for a major bleed in patients with AF on oral anticoagulation (AC) therapy.
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • de Vos C.B.
      • Crijns H.J.
      • Lip G.Y.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      ,
      • Lip G.Y.
      • Frison L.
      • Halperin J.L.
      • Lane D.A.
      Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score.
      The CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack–vascular disease) score was developed to predict 1-year risk for stroke in patients with AF who are not on AC therapy.
      • Friberg L.
      • Rosenqvist M.
      • Lip G.Y.
      Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.
      • Okumura K.
      • Inoue H.
      • Atarashi H.
      • Yamashita T.
      • Tomita H.
      • Origasa H.
      J-RHYTHM Registry Investigators
      Validation of CHA(2)DS(2)-VASc and HAS-BLED scores in Japanese patients with nonvalvular atrial fibrillation: an analysis of the J-RHYTHM Registry.
      • Dzeshka M.S.
      • Lane D.A.
      • Lip G.Y.
      Stroke and bleeding risk in atrial fibrillation: navigating the alphabet soup of risk-score acronyms (CHADS2, CHA2 DS2-VASc, R2 CHADS2, HAS-BLED, ATRIA, and more).
      • Lip G.Y.
      • Nieuwlaat R.
      • Pisters R.
      • Lane D.A.
      • Crijns H.J.
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation.
      Cerebral amyloid angiopathy (CAA) is a common cause of lobar ICH in the elderly, particularly among those on AC therapy.
      • Samarasekera N.
      • Smith C.
      • Al-Shahi Salman R.
      The association between cerebral amyloid angiopathy and intracerebral haemorrhage: systematic review and meta-analysis.
      Intracerebral hemorrhage on AC therapy has a high mortality rate.
      • Cervera A.
      • Amaro S.
      • Chamorro A.
      Oral anticoagulant-associated intracerebral hemorrhage.
      ,
      • Grysiewicz R.
      • Gorelick P.B.
      Incidence, mortality, and risk factors for oral anticoagulant-associated intracranial hemorrhage in patients with atrial fibrillation.
      A CAA-related ICH has a higher risk for recurrence compared with hypertensive-related ICH.
      • Biffi A.
      • Halpin A.
      • Towfighi A.
      • et al.
      Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy.
      Due to the higher risk for recurrence, some studies have recommended discontinuing AC therapy after lobar ICH,
      • Eckman M.H.
      • Rosand J.
      • Knudsen K.A.
      • Singer D.E.
      • Greenberg S.M.
      Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis.
      leading to complicated decision-making scenarios.
      • Murthy S.B.
      • Gupta A.
      • Merkler A.E.
      • et al.
      Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis.
      ,
      • Hawkes M.A.
      • Rabinstein A.A.
      Anticoagulation for atrial fibrillation after intracranial hemorrhage: a systematic review.
      Concern about the risk for ICH may lead to underuse of AC therapy in a subset of patients.
      • Vasishta S.
      • Toor F.
      • Johansen A.
      • Hasan M.
      Stroke prevention in atrial fibrillation: physicians’ attitudes to anticoagulation in older people.
      ,
      • Mas Dalmau G.
      • Sant Arderiu E.
      • Enfedaque Montes M.B.
      • Sola I.
      • Pequeno Saco S.
      • Alonso Coello P.
      Patients’ and physicians’ perceptions and attitudes about oral anticoagulation and atrial fibrillation: a qualitative systematic review.
      There is wide variety in the practice of resuming AC therapy in patients with AF after an ICH among practitioners
      • Xu Y.
      • Shoamanesh A.
      • Schulman S.
      • et al.
      Oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: global survey of the practices of neurologists, neurosurgeons and thrombosis experts [erratum in Correction: oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: global survey of the practices of neurologists, neurosurgeons and thrombosis experts. PLoS One. 2018].
      and a lack of well-supported recommendations in current guidelines. Clinicians often rely on the HAS-BLED and CHA2DS2-VASc scores to make individualized decisions based on presumed risk for repeat ICH and ischemic stroke.
      It is currently unknown how a diagnosis of CAA may affect the risks associated with oral AC therapy in patients with AF. The objectives of our population-based study were to: (1) describe the HAS-BLED and CHA2DS2-VASc scores in relation to ICH occurrence and underlying CAA findings and (2) determine the outcomes (mortality and ICH recurrence) among patients with AF on oral AC therapy who experienced a nontraumatic ICH, comparing those with possible/probable CAA vs those without CAA. Our hypothesis was that the scores would have worse predictive performance in patients with CAA.

      Patients and Methods

      A retrospective review of data from all patients who presented to medical facilities within Olmsted County, Minnesota, between January 1, 1995, and December 31, 2016, was conducted. The study was approved by the Mayo Clinic in Rochester and Olmsted Medical Center institutional review boards (IRBs); Mayo Clinic IRB #: 17-07542, and Olmsted Medical Center IRB #: 056-OMC-17. Given the nature of the study, informed consent was waived.
      Data were extracted from the Rochester Epidemiology Project (REP).
      • Rocca W.A.
      • Yawn B.P.
      • St Sauver J.L.
      • Grossardt B.R.
      • Melton 3rd, L.J.
      History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population.
      The REP database contains medical records for all patients within Olmsted County and codifies their diagnoses using International Classification of Diseases codes and a unique internal research code.
      • St Sauver J.L.
      • Grossardt B.R.
      • Yawn B.P.
      • Melton 3rd, L.J.
      • Rocca W.A.
      Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester Epidemiology Project.
      • St Sauver J.L.
      • Grossardt B.R.
      • Yawn B.P.
      • et al.
      Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system.
      • St Sauver J.L.
      • Grossardt B.R.
      • Leibson C.L.
      • Yawn B.P.
      • Melton 3rd, L.J.
      • Rocca W.A.
      Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project.
      A reliable record of prescribed medications for each patient is also maintained since 2003.
      All patients older than 55 years presenting between 1995 and 2016 with a diagnosis of nontraumatic ICH, AF, and concomitant AC therapy use were identified. Patients with hemorrhage secondary to trauma, hemorrhagic conversion of an ischemic stroke, and those with a known intracranial vascular lesion or tumor were excluded. Traumatic vs nontraumatic cause of the hemorrhage was evaluated through chart and imaging review. Further, patients who were not on AC therapy at the time of their ICH were excluded.
      Medical records were reviewed to gather the cause of ICH, baseline characteristics, data for restarting of AC therapy, and mortality and ICH recurrence outcomes. Computed tomography (CT) and magnetic resonance imaging (MRI; when available) were reviewed by a neurologist (S.E.) using the modified Boston criteria to determine characteristics consistent with possible or probable CAA.
      • Knudsen K.A.
      • Rosand J.
      • Karluk D.
      • Greenberg S.M.
      Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria.
      ,
      • Linn J.
      • Halpin A.
      • Demaerel P.
      • et al.
      Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy.
      Patients with evidence on CT of lobar hemorrhage without MRI were included as possible CAA if no other cause could be identified. Similarly, patients who underwent MRI without hemosiderin-sensitive sequences, patients with isolated cerebellar ICH, or patients with convexal subarachnoid hemorrhage were included as possible CAA if no other causes were identified. Hemosiderin-sensitive sequences include gradient recalled echo and susceptibility weighted imaging sequences.
      Baseline characteristics were used to calculate HAS-BLED and CHA2DS2-VASc scores. HAS-BLED and CHA2DS2-VASc scores were then used to estimate the predicted risk for major hemorrhage and ischemic stroke after the incident ICH, based on their respective validation cohorts. Predicted risk, based on these scores, was compared with actual outcomes in our cohort.
      Outcomes and end points included recurrent ICH, ischemic stroke, and death. These were adjudicated by chart and imaging review. Recurrent ICH was defined as a new ICH outside of the expected evolution of the initial ICH based on clinical context and imaging. Ischemic stroke was recorded when chart review was consistent with a new neurologic deficit in the setting of imaging evidence of new infarction. Death included all-cause mortality.
      Continuous variables are presented as mean ± SD, and categorical variables, as frequency (percentage). Comparisons between dichotomous subgroups were carried out using Pearson χ2 test for categorical variables and Student t test for continuous variables. The 7- and 30-day mortality were analyzed using logistic regression. Cox proportional hazard models were used to model long-term outcomes. The Kaplan-Meier method was used to evaluate survival. P<.05 was considered statistically significant. Statistical analyses were completed using SAS, version 9.4 (SAS Institute, Inc).

      Results

      A total of 6045 patients older than 55 years with AF on AC therapy were identified. Among those patients, 262 (4.3%) were identified with any type of intracranial hemorrhage. A total of 65 patients had a nontraumatic ICH while on AC therapy; 61 patients were taking warfarin, 3 were taking direct oral anticoagulants, and 1 was taking heparin. Among those 65 cases, 44 had MRI available whereas 21 had only CT available for review. Of the 44 patients with MRI, 34 had hemosiderin-sensitive sequences to detect microbleeds and superficial siderosis.
      Mean ± SD age was 81.3±7.2 years; 36 were women (55%), and 35 (54%) were identified as having evidence of possible or probable CAA based on revised Boston criteria (Table 1). Mortality after ICH was 26.2% (n=17) at 7 days, 36.9% (n=24) at 30 days, 40.0% (n=26) at 90 days, 41.5% (n=27) at 182 days, 44.6% (n=29) at 1 year, 47.9% (n=31) at 2 years, and 63.1% (n=41) at 5 years (Figures 1 and 2). Baseline HAS-BLED scores ranged from 1 to 5 (score: 1, 19% [n=12]; 2, 35% [n=23]; 3, 32% [n=21]; 4, 12% [n=8]; and 5, 2% [n=1]). Mean baseline HAS-BLED scores among patients with evidence of possible/probable CAA was significantly lower (2.1) than mean scores among patients without evidence of CAA (2.9; P<.001). Logistic regression showed that HAS-BLED score was not a significant predictor of mortality at 7 and 30 days after ICH (P=.29 and P=.22, respectively). Cox proportional hazard models adjusted for possible/probable CAA showed that HAS-BLED score was not a significant predictor of mortality (P=.06).
      Table 1Baseline Patient Characteristics
      VariableOverall (N=65)No Evidence of CAAa (n=30)Possible/Probable CAA (n=35)P
      Age (y), mean ± SD81.3±7.280.9±8.481.8±6.0.63
      Sex, n (%).76
       Male29 (45)14 (47)15 (43)
       Female36 (55)16 (53)20 (57)
      Race, n (%).18
       White63 (97)30 (100)33 (94)
       Asian2 (3)0 (0)2 (6)
      Obesity, n (%)24 (37)12 (40)12 (34).63
      Tobacco use, n (%).68
       No use31 (48)16 (53)15 (43)
       Past use32 (49)13 (43)19 (54)
       Current2 (3)1 (3)1 (3)
      Alcohol use, n (%).81
       No use41 (63)20 (67)21 (60)
       Past use11 (17)5 (17)6 (17)
       Current13 (20)5 (17)8 (23)
      Diabetes mellitus, n (%)16 (25)9 (30)7 (20).45
      Hyperlipidemia, n (%)40 (61)19 (63)21 (60).30
      Hypertension, n (%)53 (82)23 (77)30 (86).08
      Coronary artery disease, n (%)22 (34)8 (27)14 (40).30
      Chronic kidney disease, n (%)6 (9)3 (10)3 (9).84
      Peripheral vascular disease, n (%)6 (9)2 (7)4 (11).51
      Stroke/TIA, n (%)21 (32)10 (33)11 (31).87
      Obstructive sleep apnea, n (%)11 (17)5 (17)6 (17).99
      Rate control, n (%)55 (85)22 (73)33 (94).02
      Rhythm control, n (%)5 (8)5 (17)0 (0).01
      Prior ablation, n (%)4 (6)2 (7)2 (6).87
      HAS-BLED score, mean ± SD2.4±1.02.9±0.92.1±0.9<.001
      HAS-BLED score > 2, n (%)30 (46)18 (60)12 (34).04
      CHA2DS2-VASc score, mean ± SD4.3±1.34.2± 1.34.5±1.4.33
      Hemorrhage type, n (%)
       Clinical hemorrhage65 (100)30 (100)35 (100)
      Hemorrhage location, n (%)<.001
       Deep27 (42)26 (87)0 (0)
       Lobar30 (46)1 (3)30 (86)
       Cerebellar5 (8)0 (0)5 (14)
       Primary IVH3 (5)3 (10)0 (0)
      CAA = cerebral amyloid angiopathy; CHA2DS2-VASc = congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack–vascular disease; HAS-BLED = hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; IVH = intraventricular hemorrhage; TIA = transient ischemic attack.
      Figure thumbnail gr1
      Figure 1Kaplan-Meier mortality curve. CAA = cerebral amyloid angiopathy.
      Figure thumbnail gr2
      Figure 2Kaplan-Meier mortality curve, 0 to 3 months. CAA = cerebral amyloid angiopathy.
      Baseline CHA2DS2-VASc scores ranged from 2 to 8 (score: 2, 8% [n=5]; 3, 15% [n=10]; 4, 37% [n=24]; 5, 25% [n=16]; 6, 8% [n=5]; 7, 6% [n=4]; and 8, 1% [n=1]). Mean scores were not significantly different between patients with evidence of CAA (4.5) and those without (4.2; P=.33). Logistic regression models showed that CHA2DS2-VASc score was not a significant predictor of mortality at 7 and 30 days (P=.18 and P=.18, respectively). Cox proportional hazards models adjusted for possible/probable CAA showed that CHA2DS2-VASc score was not a significant predictor of mortality (P=.09).
      Mean HAS-BLED scores for patients with CAA (2.1) correlated to an estimated future hemorrhage risk of 3.6% overall and 1.9 bleeds per 100 patient-years, whereas mean HAS-BLED scores for patients without CAA (2.9) correlated to an estimated future hemorrhage risk of 5.8% overall and 3.7 bleeds per 100 patient-years.
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • de Vos C.B.
      • Crijns H.J.
      • Lip G.Y.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      ,
      • Lip G.Y.
      • Frison L.
      • Halperin J.L.
      • Lane D.A.
      Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score.
      A CHA2DS2-VASc score of 4 correlated to an estimated future annual risk for stroke of 4.8% and a score of 5 correlated to an estimated annual risk of 7.2% among patients not on AC therapy.
      • Friberg L.
      • Rosenqvist M.
      • Lip G.Y.
      Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.
      • Okumura K.
      • Inoue H.
      • Atarashi H.
      • Yamashita T.
      • Tomita H.
      • Origasa H.
      J-RHYTHM Registry Investigators
      Validation of CHA(2)DS(2)-VASc and HAS-BLED scores in Japanese patients with nonvalvular atrial fibrillation: an analysis of the J-RHYTHM Registry.
      • Dzeshka M.S.
      • Lane D.A.
      • Lip G.Y.
      Stroke and bleeding risk in atrial fibrillation: navigating the alphabet soup of risk-score acronyms (CHADS2, CHA2 DS2-VASc, R2 CHADS2, HAS-BLED, ATRIA, and more).
      • Lip G.Y.
      • Nieuwlaat R.
      • Pisters R.
      • Lane D.A.
      • Crijns H.J.
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation.
      Of the 65 patients, 16 were re-initiated on AC therapy after their ICH (39% of 41 patients who were alive 30 days after the index ICH). Baseline CHA2DS2-VASc scores were not different between patients who were restarted on AC therapy (4.2) compared with those who were not (4.4; P=.06). Ten (63%) of the 16 patients restarted on AC therapy had possible/probable CAA. Among the 16 re-initiated on AC therapy, 1 (6%) experienced a second ICH and 1 (6%) experienced an ischemic stroke. Among the 49 who did not restart AC therapy, 2 (4%) experienced a second ICH (3335 and 2176 days after the index ICH; Figure 3) and 1 (2%) experienced an ischemic stroke. Kaplan-Meier curve for all outcomes is shown in Figure 4. The 3 patients who experienced a second ICH had HAS-BLED scores less than 3 and all 3 had imaging suggestive of possible/probable CAA. Among 35 patients with possible/probable CAA, the rate of ICH recurrence was 8.6% (n=3) overall, over a mean of 2.7 years and 93.45 total person-years of follow-up, with 3.2 bleeds per 100 patient-years (Table 2).
      Figure thumbnail gr3
      Figure 3Kaplan-Meier curve: recurrent intracerebral hemorrhage (ICH). CAA = cerebral amyloid angiopathy.
      Figure thumbnail gr4
      Figure 4Kaplan-Meier curve: death, recurrent intracerebral hemorrhage (ICH), and ischemic stroke. CAA = cerebral amyloid angiopathy.
      Table 2Predicted Risk for Hemorrhage and Actual Recurrence of ICH by CAA Status
      Evidence of CAANo CAA
      Average HAS-BLED score2.12.9
      Predicted risk for hemorrhage1.9/100 patient-y3.7/100 patient-y
      Actual recurrence of ICH3.2/100 patient-y0
      CAA = cerebral amyloid angiopathy; HAS-BLED = hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; ICH = intracerebral hemorrhage.

      Discussion

      The main findings of our population-based study are as follows: (1) Among patients with AF on AC therapy who experienced ICH, baseline HAS-BLED scores were significantly P<.001) lower in patients who also had evidence of CAA compared with those without. (2) Baseline HAS-BLED scores were not predictive of mortality following ICH. (3) Baseline CHA2DS2-VASc scores were not significantly different between patients who had evidence of CAA compared with those who did not and were not different between patients who were restarted on AC therapy and those who were not. (4) The recurrence of ICH in patients with evidence of CAA was higher than their HAS-BLED scores would have predicted. (5) All patients who experienced recurrent ICH had evidence of CAA.
      The HAS-BLED score was developed to give clinicians an estimate of the risk for a major bleed in patients with AF who were initiated on AC therapy.
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • de Vos C.B.
      • Crijns H.J.
      • Lip G.Y.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      ,
      • Lip G.Y.
      • Frison L.
      • Halperin J.L.
      • Lane D.A.
      Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score.
      A CAA increases the risk for ICH
      • Samarasekera N.
      • Smith C.
      • Al-Shahi Salman R.
      The association between cerebral amyloid angiopathy and intracerebral haemorrhage: systematic review and meta-analysis.
      ,
      • Biffi A.
      • Halpin A.
      • Towfighi A.
      • et al.
      Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy.
      and yet it is largely unaccounted for in the HAS-BLED scoring system. This is despite series showing a prevalence of pathology-proven CAA in patients with ICH as high as 25% to 83%.
      • Guidoux C.
      • Hauw J.J.
      • Klein I.F.
      • et al.
      Amyloid angiopathy in brain hemorrhage: a postmortem neuropathological-magnetic resonance imaging study.
      • Rosand J.
      • Hylek E.M.
      • O’Donnell H.C.
      • Greenberg S.M.
      Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study.
      • Lin C.M.
      • Arishima H.
      • Kikuta K.I.
      • et al.
      Pathological examination of cerebral amyloid angiopathy in patients who underwent removal of lobar hemorrhages.
      The HAS-BLED score is derived from multiple factors that have little to no bearing on a diagnosis of CAA. Specific features of CAA not accounted for by the HAS-BLED score include lobar vs deep location of an ICH, cortical superficial siderosis, and lobar cerebral microbleeds. Cerebral microbleeds alone have been associated with increased risk for ICH in patients with AF on AC therapy.
      • Wilson D.
      • Ambler G.
      • Shakeshaft C.
      • et al.
      CROMIS-2 collaborators
      Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study.
      Our study demonstrates that among a cohort of patients with AF on AC therapy who experienced an ICH, those with evidence of CAA had statistically significant (p<.001) lower HAS-BLED scores compared with those without CAA. It is possible that in patients with CAA, the HAS-BLED score underestimates their risk for an ICH. Patients with CAA might be prone to experience an ICH at a higher rate than what their HAS-BLED score might otherwise predict, and therefore in the post-ICH group, the clinical utility is questionable. Although most patients with AF older than 55 years will not undergo MRI of the brain evaluating for CAA before starting AC therapy, consideration of CAA status with MRI of the brain after an index ICH may prevent further morbidity associated with recurrent ICH.
      The mean HAS-BLED score for patients in our study with possible or probable CAA was 2.1. That would correspond to an estimated future hemorrhage risk of 3.6% overall and 1.9 bleeds per 100 patient-years.
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • de Vos C.B.
      • Crijns H.J.
      • Lip G.Y.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      ,
      • Lip G.Y.
      • Frison L.
      • Halperin J.L.
      • Lane D.A.
      Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score.
      In contrast, we know that the risk for recurrent ICH after CAA-related lobar hemorrhage is approximately 10% per year.
      • Charidimou A.
      • Imaizumi T.
      • Moulin S.
      • et al.
      Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: a meta-analysis.
      ,
      • Charidimou A.
      • Boulouis G.
      • Gurol M.E.
      • et al.
      Emerging concepts in sporadic cerebral amyloid angiopathy.
      Of the 16 patients in our study who were resumed on AC therapy, 1 (6%) experienced a recurrent ICH, and 8.6% of patients with possible/probable CAA overall experienced a recurrent ICH during a mean of 2.7 years of follow-up. Patients with evidence of CAA in our cohort had an ICH recurrence rate of 3.2 bleeds per 100 patient-years. The risk for a recurrent ICH within our subgroup was much higher than predicted by the mean HAS-BLED scores, albeit with very low overall numbers. This may further suggest the discordance between the predicted risk based on HAS-BLED scores vs risk for a recurrent ICH related to CAA and the need for better risk predictors.
      Baseline HAS-BLED scores were not predictive of mortality after ICH at either 7 or 30 days. The mortality related to ICH at 7 and 30 days is known to be high,
      • Friberg L.
      • Rosenqvist M.
      • Lip G.Y.
      Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.
      ,
      • Okumura K.
      • Inoue H.
      • Atarashi H.
      • Yamashita T.
      • Tomita H.
      • Origasa H.
      J-RHYTHM Registry Investigators
      Validation of CHA(2)DS(2)-VASc and HAS-BLED scores in Japanese patients with nonvalvular atrial fibrillation: an analysis of the J-RHYTHM Registry.
      ,
      • Lip G.Y.
      • Nieuwlaat R.
      • Pisters R.
      • Lane D.A.
      • Crijns H.J.
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation.
      and this was demonstrated again in our study with 7- and 30-day mortality at 26% and 37%, respectively. Although the HAS-BLED score was not intended to predict mortality, it has been validated to estimate the risk for a major hemorrhage, defined as an ICH, a fatal hemorrhage, a hemorrhage requiring a transfusion, or a greater than 2 g/L decrease in hemoglobin level.
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • de Vos C.B.
      • Crijns H.J.
      • Lip G.Y.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      ,
      • Lip G.Y.
      • Frison L.
      • Halperin J.L.
      • Lane D.A.
      Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score.
      Therefore, clinicians should not use HAS-BLED to estimate mortality risk when discussing with patients with AF whether to use AC therapy.
      In our cohort, there was no difference in baseline CHA2DS2-VASc scores between patients with possible/probable CAA vs those without. This would be expected because CAA should not significantly affect CHA2DS2-VASc scores. Our study showed no difference in baseline scores between patients who were restarted on AC therapy after their ICH compared with those who were not restarted, highlighting the lack of consensus on the correct score threshold for restarting AC therapy, especially in the setting of CAA.
      Baseline CHA2DS2-VASc scores were not predictive of overall mortality after ICH in our study. The average baseline CHA2DS2-VASc score among patients who were not restarted on AC therapy was high at 4.4. Despite this, there was no difference in recurrent ischemic stroke between patients who were restarted on AC therapy compared with those who were not, albeit with low numbers in both categories and a high mortality rate limiting length of follow-up. There was only 1 instance of ischemic stroke in the group that was not restarted on AC therapy despite their average CHA2DS2-VASc score of 4.4, which would correlate to an estimated annual risk for ischemic stroke between 4.8% and 7.2%.
      • Friberg L.
      • Rosenqvist M.
      • Lip G.Y.
      Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study.
      Overall, our study suggests that more investigation is needed to better estimate the risks and benefits of AC therapy in patients with CAA. The current most commonly used risk predictors do not take into account CAA status and may be inappropriate for use in patients with CAA. Given the wide prevalence of AF and increasing findings of CAA,
      • Chugh S.S.
      • Havmoeller R.
      • Narayanan K.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      the clinical scenario of a patient with both is going to become more common. Clinicians will need better tools to estimate the potential downside of AC therapy to make informed decisions.
      The main strengths of our study are its population-based design and the completeness of follow-up data, which offers a unique cohort. However, our study has limitations, chief among them being the relatively small numbers of events and particularly recurrent events that compromise the power of our statistical analysis. Not all patients with ICH had MRI of the brain for review, which may have led to underdiagnosis of CAA. The prescription data contained in the REP database is not complete before 2003 because of limitations in the electronic record keeping before this date and therefore our study may have underestimated the number of patients on AC therapy between 1995 and 2003.

      Conclusion

      The main clinical message of this study is that the HAS-BLED score may be insufficient to estimate the risk for ICH in patients with AF who are older than 55 years. When these patients have underlying CAA, they may have a higher risk for ICH than predicted by the HAS-BLED score. Further research is needed to optimize ICH risk prediction in older patients.

      Acknowledgements

      Drs Ponamgi and Ward contributed equally to this work and are co-first authors.

      Supplemental Online Material

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      Linked Article

      • Predicting Who Will Experience Cerebral Hemorrhage When Anticoagulated
        Mayo Clinic ProceedingsVol. 95Issue 10
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          The most feared hemorrhagic complication of anticoagulating patients with atrial fibrillation is intracerebral hemorrhage (ICH). However, not anticoagulating high-risk patients with atrial fibrillation can lead to cardioembolic stroke, another disastrous outcome. Physicians may tend to avoid blame by inaction, which can result in underprescribing. Such clinical inertia is not unique to anticoagulating patients with atrial fibrillation. Clinical inertia has been noted in the treatment of several common chronic conditions, such as treating blood pressure in patients with hypertension and treating hyperglycemia in patients with diabetes mellitus.
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