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Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong Chung-Wah Siu, MD,* Gregory Y.H. Lip, MD,† Kwok-Fai Lam, PhD,‡ Hung-Fat Tse, MD, PhD* From the *Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China, †University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom, and ‡Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong SAR, China. BACKGROUND Current risk schemes to predict ischemic stroke and intracranial hemorrhage (ICH) in atrial fibrillation (AF) are derived primarily using a Caucasian population. OBJECTIVE The purpose of this study was to describe the risk of ischemic stroke and ICH in a large contemporary “real world” cohort of Chinese AF patients in Hong Kong with detailed long-term follow-up. METHODS This observational study used a hospital-based cohort of Chinese patients with nonvalvular AF. RESULTS Among 9727 patients with nonvalvular AF (age 76.9 ⫾ 12.5 years, 52.1% female), 3881 patients (39.9%) did not receive antithrombotic therapy, 3934 patients (40.4%) were taking aspirin, and 1912 (19.7%) were taking warfarin. After mean follow-up of 3.19 years, 847 patients (21.8%) without antithrombotic therapy developed ischemic strokes (annual risk 9.28%, 95% confidence interval [CI] 8.89%–9.70%). There was a progressively increase in annual risk of ischemic stroke with increasing CHADS2 and CHA2DS2VASc scores. The c-statistics revealed that CHA2DS2-VASc scores (0.525, 95% CI 0.509–0.541, P ¼ .017) was better than CHADS2 scores (0.506, 95% CI 0.490–0.522, P ¼ .584) in predicting ischemic stroke. Use of aspirin and of warfarin were associated with reduced annual risk of ischemic stroke by 18.7% and 52.7%,
Introduction Long-term oral anticoagulant (OAC) for stroke prevention is the cornerstone of atrial fibrillation (AF) management.1 Although the prevalence of AF in China has been consistently reported to be lower than in Caucasian countries,3–5 the overall disease burden in Chinese is much higher because of the huge, and proportionally larger, aged population.6 The utilization of OAC for stroke prevention in AF in China is low at approximately 15%.7 Such a discrepancy between evidence from randomized control trials and reported practice reflects the challenge of balancing the benefit of stroke The study is partially supported by an unrestricted research grant from Bayer HealthCare Pharmaceuticals. Address reprint requests and correspondence: Dr. Chung-Wah Siu, Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
respectively (P o.05). The annual incidence of ICH in patients taking aspirin and warfarin was 0.77% per year and 0.80% per year, respectively. The adjusted net clinical benefit favored warfarin over aspirin or no therapy for almost all Chinese AF patients CHA2DS2VASc score Z1. CONCLUSION Chinese AF patients are at high risk for ischemic stroke. Analysis of the net clinical benefit favors the use of warfarin over aspirin or no therapy for stroke prevention in a broad range of Chinese AF patients. KEYWORDS CHADS2 score; CHA2DS-VASc score; Atrial fibrillation; Ischemic stroke; Intracranial hemorrhage ABBREVIATIONS AF ¼ atrial fibrillation; CHADS2 ¼ Congestive heart failure, Hypertension, Age Z75 years, Diabetes, previous Stroke; CHA2DS-VASc ¼ CHA2DS2-Vascular disease, Age ¼ 65–74 years, Sex category; HAS-BLED ¼ Hypertension, Abnormal Renal/ Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (Age 465 years), Drugs/Alcohol concomitantly; ICH ¼ intracranial hemorrhage; OAC ¼ oral anticoagulant (Heart Rhythm 2014;0:-1–8) rights reserved.
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2014 Heart Rhythm Society. All
risk reduction with the risk of intracranial hemorrhage (ICH) consequent to OAC therapy. This is of particular relevance to the Chinese population because limited clinical observations suggest that Chinese have a lower rate of stroke attributable to AF6,8,9 but a higher baseline rate of ICH,10–12 thus undermining the potential benefit of any antithrombotic therapy. Also, there is a perception that aspirin is effective and is safer than warfarin. The CHADS2 (Congestive heart failure, Hypertension, Age Z75 years, Diabetes, previous Stroke) and, more recently, CHA2DS2-VASc (CHA2DS2-Vascular disease, Age = 65–74 years, Sex category) are increasingly being adopted in clinical practice for stroke risk stratification of AF.1–3 In addition, the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (Age 465 years), Drugs/Alcohol concomitantly) score is well validated for http://dx.doi.org/10.1016/j.hrthm.2014.04.021
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bleeding risk assessment.13,14 These schemes were nonetheless derived and validated primarily in a Caucasian population, and their relevance to other ethnic groups has been questioned. Prior cross-sectional studies suggested that the annual stroke risk determined by CHADS2 and CHA2DS2VASc for Chinese AF patients appeared to differ from the corresponding value in Caucasians.9,16 The objectives of our study were to describe the risk of stroke and ICH in a large contemporary “real world” cohort of Chinese AF patients with detailed long-term follow-up and to assess the prognostic performance of CHADS2, CHA2DS2-VASc, and HAS-BLED scores in this population. The net clinical benefit of aspirin and warfarin, balancing the risk of stroke against ICH, also was determined.
Methods Patients and study design Between July 1997 and December 2011, a total of 10,195 Chinese patients with a diagnosis of AF at Queen Mary Hospital, Hong Kong, were identified from a computerbased clinical management system.17 Patients were excluded if they had significant valvular heart disease including previous valvular surgery, valvular disease with planned surgical correction, and any degree of mitral stenosis, or incomplete clinical and/or follow-up data. The final analysis included 9727 patients, who were categorized according to antithrombotic therapy, and CHADS2, CHA2DS2-VASc and HAS-BLED score calculated. This was an observational study, and the study protocol was approved by the local Institutional Review Board. Demographic data, cardiovascular risk factors, and medications were recorded at baseline. The primary and secondary end-points were hospital admission with stroke and ICH during the follow-up period, respectively. The adjusted net clinical benefit of aspirin and warfarin for stroke and ICH in relation to CHA2DS2-VASc and HASBLED scores was estimated by subtracting the annual number of ICH events (with a weight of 1.5) attributable to treatment with aspirin or warfarin from the annual number of stroke events prevented by the same treatment.18,19
Statistical analysis Details of the statistical analysis are provided in the Online Supplemental Data.
Results Patients We studied 9727 Chinese patients (age 76.9 ⫾ 12.5 years, 52.1% female) with nonvalvular AF. The clinical characteristics of the study population are summarized in Table 1. The mean CHADS2 and CHA2DS2-VASc score were 2.1 ⫾ 1.4 and 3.7 ⫾ 1.8, respectively. Of this cohort, 3881 patients (39.9%) received no aspirin or warfarin (no therapy), 3934 patients (40.4%) were prescribed aspirin (80–160 mg daily), and 1912 patients (19.7%) were taking warfarin.
Heart Rhythm, Vol 0, No 0, Month 2014
Ischemic stroke After a mean follow-up of 3.19 ⫾ 3.43 years (31,028 patientyears), 2179 patients developed a stroke. Of these, 847 strokes occurred in patients with no therapy (21.8%, annual stroke risk 9.28%). Increasing age, hypertension, diabetes mellitus, and female gender were also significantly associated with subsequent stroke, as was previous vascular disease and prior stroke (Table 2). For the 3881 patients prescribed no antithrombotic therapy, mean CHADS2 and CHA2DS2-VASc scores were 1.8 ⫾ 1.3 and 3.3 ⫾ 1.7, respectively. There was a progressive increase in annual stroke risk with increasing CHADS2 and CHA2DS2VASc score (Figure 1). The annual stroke risk for patients with CHA2DS2-VASc ¼ 0 was 2.41%, and increased to 13.18% for those with CHA2DS2-VASc Z6. Kaplan–Meier analyses revealed a significantly higher incidence of stroke in patients with increased CHADS2 (log-rank 71.6, P o.0001) and CHA2DS2-VASc scores (log-rank 86.6, P o.0001l; Figures 1C and 1D). The sensitivity of CHA2DS2-VASc (98.0% with optimal cutoff at 1) was the highest compared with other baseline demographic factors as a single criterion (sensitivity range 20.1%–89.9%; Online Supplemental Table 1). The c-statistic of CHA2DS2-VASc score as a predictor of subsequent strokes was 0.525 (0.509–0.541).
Intracranial hemorrhage In total, 46 of 3881 patients (1.19%, 0.5% per year) prescribed no antithrombotic therapy developed ICH: 29 intracerebral hemorrhage (63.1%), 11 subdural hemorrhage (23.9%), and 6 subarachnoid hemorrhage (13.0%). Prior ICH, prior stroke, and hypertension were the most significant predictors for subsequent ICH (Online Supplemental Table 2). The annual ICH risk was 0% for HAS-BLED score ¼ 0, 0.51% for HAS-BLED ¼ 1, 0.44% for HASBLED ¼ 2, and 0.81% for HAS-BLED Z3 (Online Supplemental Figure 1). The c-statistic of the HAS-BLED score to predict ICH was 0.552 (0.537–0.568). In our cohort, 2.4% of patients prescribed aspirin and 1.5% of patients prescribed warfarin developed ICH during the same period. The annual ICH incidence in patients taking aspirin and warfarin was 0.77% per year and 0.80% per year, respectively. The c-statistics of the HAS-BLED score to predict ICH in patients prescribed aspirin and warfarin were 0.552 (0.504–0.600) and 0.574 (0.518–0.629), respectively.
Net clinical benefit of aspirin and warfarin Compared with 3934 patients who received aspirin and 1912 patients taking warfarin, patients prescribed no therapy were less likely to have comorbidities (P o.0001), as reflected by their much lower mean CHADS2 and CHA2DS2-VASc scores (Table 1). Although they had higher CHADS2 and CHA2DS2-VASc scores, the patients taking aspirin or warfarin had a substantially lower annual stroke risk than did patients prescribed no therapy (Figure 1). Across all CHADS2 strata, the average reduction in annual stroke risk was 18.7% (range 12.8%–37.4%) for patients receiving
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Table 1
Ischemic Stroke and ICH in Chinese AF Patients
3
Baseline characteristics of the study population
Age Mean age (years) Age 65–75 years Age Z75 years Female Hypertension Diabetes mellitus Smoker Hyperthyroidism Renal failure on dialysis Heart failure Coronary artery disease Peripheral arterial disease Prior ischemic stroke/transient ischemic attack Prior intracranial hemorrhage Means CHADS2 CHADS2 0 1 2 3 4 5 6 Mean CHA2DS2-VASc score CHA2DS2-VASc 0 1 2 3 4 5 6 7 8 9 Aspirin Warfarin
All (n ¼ 9727)
No aspirin or warfarin (n ¼ 3881)
Aspirin (n ¼ 3934)
Warfarin (n ¼ 1912)
P value
76.9 ⫾ 12.5 2,290 (23.5) 6,178 (63.5) 5,064 (52.1) 5,321 (54.7) 2,144 (22.0) 3,389 (34.8) 642 (6.6) 188 (1.9) 2,215 (22.8) 1,770 (18.2) 337 (3.5) 2,295 (23.1) 254 (2.6) 2.1 ⫾ 1.4
77.2 ⫾ 13.3 855 (22.0) 2,512 (64.7) 2,076 (53.5) 1,845 (47.5) 704 (18.1) 1,355 (34.9) 263 (6.8) 67 (1.7) 728 (18.8) 320 (8.2) 52 (1.3) 675 (17.4) 114 (2.9) 1.8 ⫾ 1.3
78.3 ⫾ 11.3 842 (21.4) 2,700 (68.6) 2,085 (53.0) 2,409 (61.2) 980 (24.9) 1,386 (35.2) 243 (6.2) 86 (2.2) 1,028 (26.1) 991 (25.2) 164 (4.2) 1,054 (26.8) 95 (2.4) 2.3 ⫾ 1.4
73.1 ⫾ 12.4 593 (31.0) 966 (50.5) 903 (47.2) 1,067 (55.8) 460 (24.1) 648 (33.9) 136 (7.1) 35 (1.8) 459 (24.0) 460 (24.1) 121 (6.3) 566 (29.6) 40 (2.1) 2.1 ⫾ 1.5
o.0001 o.0001 o.0001 o.0001 o.0001 o.0001 .597 .340 .315 o.0001 o.0001 o.0001 o.0001 .143 o.0001
1,311 (13.5) 2,371 (24.4) 2,466 (25.4) 1,896 (19.5) 1,076 (11.1) 107 (2.8) 118 (1.2) 3.7 ⫾ 1.8
638 (16.4) 1,115 (28.7) 990 (25.5) 673 (17.3) 329 (8.5) 268 (6.8) 29 (0.7) 3.3 ⫾ 1.7
374 (9.5) 834 (21.2) 1,039 (26.4) 837 (21.3) 515 (13.1) 114 (6.0) 67 (1.7) 4.1 ⫾ 1.8
299 (15.6) 422 (22.1) 437 (22.9) 386 (20.2) 232 (12.1) 489 (5.0) 22 (1.2) 3.7 ⫾ 2.0
o.0001
395 (4.1) 772 (7.9) 1,392 (14.3) 1,956 (20.1) 1,989 (20.4) 1,620 (16.7) 969 (10.0) 430 (4.4) 169 (1.7) 35 (0.4) 3,943 (40.5) 1,912 (19.7)
190 (4.9) 358 (9.2) 681 (17.5) 896 (23.1) 806 (20.8) 552 (14.2) 276 (7.1) 86 (2.2) 31 (0.8) 5 (0.1) 0 (0) 0 (0)
102 (2.6) 232 (5.9) 458 (11.6) 711 (18.1) 837 (21.3) 741 (18.8) 494 (12.6) 243 (6.2) 95 (2.4) 21 (0.5) 3,934 (100) 0 (0)
103 (5.4) 182 (9.5) 253 (13.2) 349 (18.3) 346 (18.1) 327 (17.1) 199 (1.4) 101 (5.3) 43 (2.2) 9 (0.5) 0 (0) 1,912 (100)
o.0001
o.0001
— —
Values are given as n (%) or mean ⫾ SD. CHADS2 score ¼ Congestive heart failure, Hypertension, Age Z75 years, Diabetes, previous Stroke score; CHA2DS2-VASc score ¼ CHA2DS2-Vascular disease, Age 65–74 years, Sex category score.
aspirin and 52.7% (44.3%–68.6%) for those taking warfarin (Figure 2). At different CHA2DS2-VASc scores, the reduction in annual stroke risk with aspirin ranged from 24.5% to 38.1% (except for CHA2DS2-VASc ¼ 0) and with warfarin ranged from 37.9% to 71.2% (Figure 2). For aspirin therapy, the net clinical benefit was almost zero or even negative (net clinical disadvantage) in patients at low stroke and bleeding risk (CHA2DS2-VASc ¼ 0 and HAS-BLED o2; Table 3). For patients with a moderate-tohigh risk of stroke (CHA2DS2-VASc Z1), aspirin therapy had a net clinical benefit that ranged from 1.54 to 3.97 fewer events per 100 patient-years, except for those at moderate stroke risk and bleeding risk (CHA2DS2VASc ¼ 1 and HASBLED ¼ 2; Table 3). The net-clinical-benefit analysis favored warfarin therapy across the remaining whole spectrum of stroke risk and bleeding risk. The best net benefit from warfarin therapy was
found in those with high stroke and bleeding risk. In these high-risk patients, warfarin therapy conferred 4.39 to 6.55 fewer events per 100 patient-years compared with patients who received no OAC therapy. The net-clinical–benefit outcomes favored switching almost all patients from aspirin to warfarin (Table 3).
Discussion To the best of our knowledge, this is the largest, real-world cohort of Chinese patients with AF for which we report the following. First, we showed that AF-related stroke risk was substantial and comparable to that reported for Caucasians. Second, OAC with warfarin in Chinese AF patients significantly reduced the stroke risk compared with aspirin or no therapy. Third, Chinese AF patients treated with warfarin or aspirin were at higher ICH risk than Caucasians, but,
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Table 2
Heart Rhythm, Vol 0, No 0, Month 2014 Associations between baseline factors and ischemic stroke in Chinese AF patients without any antithrombotic therapy (n ¼ 3882) Univariate analysis
Age o65 years 65–75 years 475 years Female Hypertension Diabetes mellitus Smoker Hyperthyroidism Renal failure on dialysis Heart failure Coronary artery disease Peripheral arterial disease Prior ischemic stroke Prior intracranial hemorrhage
Multivariate analysis
No. of ischemic strokes
HR (95% CI)
P value
HR (95% CI)
P value
71 233 543 504 428 170 273 64 16 128 75 11 148 24
Reference 2.30 (1.76–3.01) 2.54 (1.98–3.27) 1.16 (1.02–1.34) 1.58 (1.38–1.81) 1.38 (1.17–1.64) 0.87 (0.76–1.00) 0.74 (0.58–0.96) 1.29 (0.79–2.12) 1.19 (0.99–1.44) 1.19 (0.92–1.49) 2.59 (1.43–4.71) 1.49 (1.25–1.78) 1.12 (0.75–0.17)
o.0001* o.0001* .026 o.0001* o.0001* .872 .023* .312 .067 .191 .002* o.0001* .58
Reference 2.09 (1.60–2.75) 2.23 (1.72–2.90) 1.03 (0.88–1.20) 1.34 (1.16–1.55) 1.18 (0.99–1.40) 0.90 (0.77–1.05) 0.81 (0.62–1.05) 1.39 (0.84–2.29) 1.06 (0.87–1.28) 0.96 (0.75–1.22) 2.10 (1.15–3.84) 1.28 (1.06–1.53) 1.09 (0.72–1.65)
o.0001* o.0001* .723 o.0001* .069 .185 .108 .199 .583 .734 .016* .010* .683
AF ¼ atrial fibrillation; CI ¼ confidence interval; HR ¼ hazard ratio. * P o.05.
importantly, warfarin and aspirin were associated with similar ICH risk. Fourth, net-clinical-benefit analysis revealed that the stroke risk in Chinese AF patients without antithrombotic therapy exceeded the ICH risk with either aspirin or warfarin in almost all combinations of stroke and ICH risks. Thus, the net clinical benefit was highest among those at high risk for
W E B 4 C / F P O
both stroke and ICH, and warfarin was preferred to aspirin for all combinations of stroke and ICH risk.
Ischemic stroke The decision for and choice of antithrombotic therapy for stroke prevention in AF is influenced by several factors: the
Figure 1 Relation between CHADS2 (A) and CHA2DS2-VASc (B) scores, and the annual risk of ischemic stroke in Chinese atrial fibrillation (AF) patients with no antithrombotic therapy, aspirin, and warfarin. Kaplan–Meier estimates of ischemic stroke-free survival in Chinese AF patients with no antithrombotic therapy stratified according to CHADS2 (C) and CHA2DS2-VASc (D) score.
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Ischemic Stroke and ICH in Chinese AF Patients
5
Figure 2 Relative effects of aspirin and warfarin on ischemic stroke in Chinese atrial fibrillation patients stratified according to CHADS2 (A, B) and CHA2DS2-VASc (C, D) score. Horizontal lines represent 95% confidence interval (CI) around point estimates.
risk of stroke and ICH, and the efficacy and safety of antithrombotic agents. Prior small studies reported a much lower incidence of stroke among Chinese AF patients that resulted in a prevailing perception that the stroke risk in Chinese AF patients is lower than in Caucasians.8,9 A recent small cohort study in China demonstrated that the risk of stroke and thromboembolism in Chinese was comparable with or even higher than that of Caucasians.16 In our study, the overall stroke risk among Chinese AF patients not receiving antithrombotic therapy was 9.28% per year, which is substantially higher than all previously published Chinese data and is comparable with or even higher than that of the largest published “real world” AF registry.20 These findings are in accordance with the fact that, globally, China is among the countries with the highest stroke.21 As in previously published Caucasian studies20,22 as well as Chinese16 series, individual components of the CHADS2 score, such as increasing age Z75 years, hypertension, diabetes, and prior stroke, were predictive of subsequent stroke in our study. Similar to results from the largest AF registry,20 history of heart failure in our cohort was not associated with an increased stroke risk. Although moderate-to-severe left ventricular systolic dysfunction is an unequivocal risk factor of stroke in AF,23,24 many patients with symptomatic AF often labeled heart failure may not actually have left ventricular impairment, thus undermining the predictive power.20 Importantly, the 3 components incorporated in
the CHA2DS2-VASc score, including age 65–74 years, female gender, and history of other vascular disease, that were listed as “less validated risk factors” for stroke in the 2006 ACC/AHA/ESC guidelines were found to be predictive of stroke in our cohort.25 As in previous Chinese cohorts, peripheral vascular disease seems to be an important driver of stroke risk in AF patients.9,16 Furthermore, stroke risk increased with increasing CHADS2 and CHA2DS2-VASc score as in previous Caucasian studies.20,22,26 Compared with corresponding rates published for Caucasians,22,26 Chinese AF patients with lowto-moderate CHADS2 (r2) or CHA2DS2-VASc (r3) score were at much higher risk for stroke (3–4 times).22,26 Nonetheless, at a higher CHADS2 (Z4) and CHA2DS2-VASc (Z6) score, stroke risk was comparable to or lower than that of Caucasians.20,22,26 Given the relative high stroke risk in Chinese AF patients with low CHADS2 and CHA2DS2VASc scores, the CHA2DS2-VASc score appears to be more sensitive in identifying low-risk stroke patients and therefore should be the score of choice for stroke risk stratification in Chinese AF patients. In agreement with previous randomized control trials in predominantly Caucasian populations, warfarin significantly reduced stroke risk compared with aspirin and no therapy.27 Across all strata of CHADS2 and CHA2DS2-VASc scores, warfarin appeared to be effective in reducing stroke risk. The overall stroke risk reduction was nevertheless much lower
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Table 3
Heart Rhythm, Vol 0, No 0, Month 2014 Net clinical benefit of aspirin and warfarin: ischemic stroke vs intracranial hemorrhage
Net benefit of aspirin (prevented ischemic strokes with aspirin per year minus excess intracranial hemorrhage with aspirin per year with a weight of 1.5) HAS-BLED
CHA2DS2-VASc 0 1 2 3 4 5 6–9
0
1
2
3–6
0.12 — — — — — —
0.47 4.82 2.95 3.37 — — —
-1.71 -0.71 1.54 3.49 3.64 — —
— — — — — — 3.97
Net benefit of warfarin (prevented ischemic strokes with aspirin per year minus excess intracranial hemorrhage with warfarin per year with a weight of 1.5) HAS-BLED
CHA2DS2-VASc 0 1 2 3 4 5 6–9
0
1
2
3–6
— 2.13 — — — — —
— — 3.43 5.85 — — —
— — 4.14 6.27 6.10 4.39 —
— — — — 6.55 6.43 5.46
Net benefit of switching aspirin to warfarin (prevented ischemic strokes per year minus excess intracranial hemorrhage per year with a weight of 1.5) HAS-BLED
CHA2DS2-VASc 0 1 2 3 4 5 6–9
0
1
2
3–6
— — — — — — —
— — 0.48 2.48 — — —
— — 2.60 2.78 2.46 — —
— — — — — — 1.49
than that seen in randomized controlled trials in Caucasians (52.7% vs 64.0%).27 A plausible explanation may be the notoriously low time in the therapeutic range in Asian countries, an important determinant of adverse outcome.28 Unfortunately, we lacked access to international normalized ratio data, which precluded further analysis. In contrast, the benefit of aspirin in stroke prevention for AF remains controversial. In 1 meta-analysis,27 aspirin compared with no therapy resulted in a borderline nonsignificant stroke risk reduction of 19%, essentially driven by 1 single positive study that prescribed aspirin 325 mg daily.29 In our study, although patients treated with aspirin (80–160 mg daily) had a similar overall reduction in stroke risk of 18.7%, no stroke risk reduction was observed in patients at the lowest level of CHADS2 and CHA2DS2-VASc scores.
Intracranial hemorrhage ICH remains the greatest barrier to OAC for stroke prevention in AF. It is postulated that Chinese may have a higher baseline ICH risk than Caucasians.6,30 In our study, the overall annual ICH incidence in 3881 Chinese AF patients with no therapy was 0.5% per year, comparable to published rates in Caucasian AF patients (n = 33,486, 0.6% per year).20 Nonetheless, such risk among Chinese prescribed either aspirin or warfarin (0.77% per year and 0.80% per year, respectively) was higher than that of Caucasians (aspirin: n ¼ 48,599, 0.6% per year; warfarin: n ¼ 61,396, 0.6% per year; Online Supplemental Figure 2).20 Our findings suggest that instead of a higher baseline ICH risk, Chinese patients may indeed be more susceptible to ICH when prescribed antithrombotic therapy with aspirin or warfarin. This concurs with the subanalyses of the RE-LY
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Ischemic Stroke and ICH in Chinese AF Patients
trial31 and the ROCKET-AF trial that Asian AF patients32,33 treated with warfarin were at higher ICH risk compared with their non-Asian counterparts. Importantly, the ICH risk among patients treated with aspirin was similar to that warfarin; therefore, aspirin does not offer a “safer” alternative to warfarin in reducing ICH. Similar to data from previous Caucasian series, the ICH risk increased with the HAS-BLED score in our cohort (Online Supplemental Figure 2). Among individual components that compose the HAS-BLED score, prior stroke and hypertension were significant predictors of ICH. Whereas prior ICH conferred the highest risk among all risk factors for subsequent ICH, history of other major bleeding did not have any statistically significant association with subsequent ICH. This concurs with the largest AF registry in which ICH conferred a 2–3 times higher risk for subsequent ICH than any other form of severe bleeding.18
7 large “real world” cohort data serve as a good alternative. In addition, although we carefully ascertained all strokes and ICHs by careful examination of hospitalization records and laboratory and imaging results, patients with milder forms of stroke and/or ICH who were not hospitalized were not included.
Conclusion Chinese AF patients are at high risk for stroke. CHA2DS2VASc and HAS-BLED scores appear to be the appropriate risk stratification tools for stroke risk and ICH, respectively, for Chinese. Analysis of the net clinical benefit favors warfarin over aspirin and no therapy for stroke prevention in a broad range of Chinese AF patients.
Uncited reference 15
Net clinical benefits and the choice of antithrombotic agents In concordance with a previous study in a Caucasian population, the stroke risk in Chinese AF patients prescribed no antithrombotic therapy exceeded the ICH risk with warfarin at all combinations of CHA2DS2-VASc and HASBLED score.18 In the net-clinical-benefit analysis, the optimal antithrombotic therapy for Chinese AF patients clearly favored warfarin over aspirin and no therapy in almost all combinations of CHA2DS2-VASc and HASBLED scores, primarily driven by the substantial stroke risk reduction. Although aspirin provides a modest net-clinicalbenefit over no therapy in moderate- to-high-risk patients, given the similar ICH risk inferred by aspirin and warfarin, aspirin should not be used as the primary agent for stroke prevention in Chinese AF patients. Given the much higher annual incidence of stroke among Chinese AF patients even with CHA2DS2-VASc ¼ 0 compared with Caucasians (2.4% vs 0.2%), it is possible that OAC may be beneficial.18 Unfortunately, because of the lack of an adequate number of patients with a very low score (CHA2DS2-VASc ¼ 0) and prescribed warfarin, any net clinical benefit among these “low-risk” patients could not be demonstrated. Moreover, several novel OACs, including dabigatran, rivaroxaban, and apixaban, confer a much lower risk for ICH than warfarin but have comparable or superior efficacy in stroke prevention. In the subanalyses, Asian AF patients receiving warfarin tended to have a higher ischemic stroke risk and a higher ICH risk compared with Caucasian counterpart but at the same time had a poorer time in the therapeutic range. These agents may have a much higher overall net benefit in Chinese AF.
Study limitations This study is limited by its cohort-based and single-center observational design in primarily hospital-based patients. The gold standard for demonstrating treatment effects is a randomized placebo-controlled trial, which is not ethically possible given the well-documented benefit of OAC. Thus,
Appendix Supporting data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2014.04.021.
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14. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093–1100. 15. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–2429. 16. Guo Y, Apostolakis S, Blann AD, Wang H, Zhao X, Zhang Y, Zhang D, Ma J, Wang Y, Lip GY. Validation of contemporary stroke and bleeding risk stratification scores in non-anticoagulated Chinese patients with atrial fibrillation. Int J Cardiol 2013;168:904–909. 17. Siu CW, Tse HF. Net clinical benefit of warfarin therapy in very elderly chinese patients with atrial fibrillation. Circulation Arrhythmia and electrophysiology 2014;7:300–306. 18. Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 2012;125:2298–2307. 19. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;151:297–305. 20. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012;33:1500–1510. 21. Kim AS, Johnston SC. Global variation in the relative burden of stroke and ischemic heart disease. Circulation 2011;124:314–323. 22. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, Selmer C, Ahlehoff O, Olsen AM, Gislason GH, Torp-Pedersen C. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 23. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 2007;69: 546554. 24. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998;158:1316–1320.
Heart Rhythm, Vol 0, No 0, Month 2014 785 25. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College 786 of Cardiology/American Heart Association Task Force on Practice Guidelines 787 and the European Society of Cardiology Committee for Practice Guidelines 788 (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European 789 Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114: 790 e257–e354. 791 26. Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J 2010;31:967–975. 792 27. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to 793 prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–867. 794 28. Singer DE, Hellkamp AS, Piccini JP, et al. ROCKET AF Investigators. Impact of 795 global geographic region on time in therapeutic range on warfarin anticoagulant 796 therapy: data from the ROCKET AF clinical trial. J Am Heart Assoc 2013;2: e000067. 797 29. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84: 798 527–539. 799 30. Chong BH, Chan KH, Pong V, Lau KK, Chan YH, Zuo ML, Lui WM, Leung GK, Lau CP, Tse HF, Pu JK, Siu CW. Use of aspirin in Chinese after recovery 800 from primary intracranial haemorrhage. Thromb Haemost 2012;107:241–247. 801 31. Hori M, Connolly SJ, Zhu J, et al. Investigators tR-L. Efficacy and safety of Q12 802 dabigatran versus warfarin in patients with atrial fibrillation: analysis in Asian population in RE-LY trial. Cerebrovascular Disease 2012;34(Suppl 1):9. 803 32. Hankey GJ, Stevens S, Piccini JP, et al. Predictors of intracranial hemorrhage 804 among anticoagulated patients with atrial fibrillation: insights from the Rivarox805 aban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation 806 (ROCKET AF). Stroke 2012;43:A152. 807 33. Tanahashi N, Hori M, Matsumoto M, et al. Rivaroxaban versus warfarin in 808 Japanese patients with nonvalvular atrial fibrillation for the secondary prevention of stroke: a subgroup analysis of J-ROCKET AF. J Stroke Cerebrovasc Dis 809 2013;22:1317–1325. 810
Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong Chung-Wah Siu, MD,* Gregory Y.H. Lip, MD,† Kwok-Fai Lam, PhD,‡ Hung-Fat Tse, MD, PhD* From the *Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China, †University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom, and ‡Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong SAR, China. BACKGROUND Current risk schemes to predict ischemic stroke and intracranial hemorrhage (ICH) in atrial fibrillation (AF) are derived primarily using a Caucasian population. OBJECTIVE The purpose of this study was to describe the risk of ischemic stroke and ICH in a large contemporary “real world” cohort of Chinese AF patients in Hong Kong with detailed long-term follow-up. METHODS This observational study used a hospital-based cohort of Chinese patients with nonvalvular AF. RESULTS Among 9727 patients with nonvalvular AF (age 76.9 ⫾ 12.5 years, 52.1% female), 3881 patients (39.9%) did not receive antithrombotic therapy, 3934 patients (40.4%) were taking aspirin, and 1912 (19.7%) were taking warfarin. After mean follow-up of 3.19 years, 847 patients (21.8%) without antithrombotic therapy developed ischemic strokes (annual risk 9.28%, 95% confidence interval [CI] 8.89%–9.70%). There was a progressively increase in annual risk of ischemic stroke with increasing CHADS2 and CHA2DS2VASc scores. The c-statistics revealed that CHA2DS2-VASc scores (0.525, 95% CI 0.509–0.541, P ¼ .017) was better than CHADS2 scores (0.506, 95% CI 0.490–0.522, P ¼ .584) in predicting ischemic stroke. Use of aspirin and of warfarin were associated with reduced annual risk of ischemic stroke by 18.7% and 52.7%,
Introduction Long-term oral anticoagulant (OAC) for stroke prevention is the cornerstone of atrial fibrillation (AF) management.1 Although the prevalence of AF in China has been consistently reported to be lower than in Caucasian countries,3–5 the overall disease burden in Chinese is much higher because of the huge, and proportionally larger, aged population.6 The utilization of OAC for stroke prevention in AF in China is low at approximately 15%.7 Such a discrepancy between evidence from randomized control trials and reported practice reflects the challenge of balancing the benefit of stroke The study is partially supported by an unrestricted research grant from Bayer HealthCare Pharmaceuticals. Address reprint requests and correspondence: Dr. Chung-Wah Siu, Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
respectively (P o.05). The annual incidence of ICH in patients taking aspirin and warfarin was 0.77% per year and 0.80% per year, respectively. The adjusted net clinical benefit favored warfarin over aspirin or no therapy for almost all Chinese AF patients CHA2DS2VASc score Z1. CONCLUSION Chinese AF patients are at high risk for ischemic stroke. Analysis of the net clinical benefit favors the use of warfarin over aspirin or no therapy for stroke prevention in a broad range of Chinese AF patients. KEYWORDS CHADS2 score; CHA2DS-VASc score; Atrial fibrillation; Ischemic stroke; Intracranial hemorrhage ABBREVIATIONS AF ¼ atrial fibrillation; CHADS2 ¼ Congestive heart failure, Hypertension, Age Z75 years, Diabetes, previous Stroke; CHA2DS-VASc ¼ CHA2DS2-Vascular disease, Age ¼ 65–74 years, Sex category; HAS-BLED ¼ Hypertension, Abnormal Renal/ Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (Age 465 years), Drugs/Alcohol concomitantly; ICH ¼ intracranial hemorrhage; OAC ¼ oral anticoagulant (Heart Rhythm 2014;0:-1–8) rights reserved.
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2014 Heart Rhythm Society. All
risk reduction with the risk of intracranial hemorrhage (ICH) consequent to OAC therapy. This is of particular relevance to the Chinese population because limited clinical observations suggest that Chinese have a lower rate of stroke attributable to AF6,8,9 but a higher baseline rate of ICH,10–12 thus undermining the potential benefit of any antithrombotic therapy. Also, there is a perception that aspirin is effective and is safer than warfarin. The CHADS2 (Congestive heart failure, Hypertension, Age Z75 years, Diabetes, previous Stroke) and, more recently, CHA2DS2-VASc (CHA2DS2-Vascular disease, Age = 65–74 years, Sex category) are increasingly being adopted in clinical practice for stroke risk stratification of AF.1–3 In addition, the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (Age 465 years), Drugs/Alcohol concomitantly) score is well validated for http://dx.doi.org/10.1016/j.hrthm.2014.04.021
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73
2 74Q5 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118Q6 119 120 121 122 123 124 125 T1 126 127 128 129 130
bleeding risk assessment.13,14 These schemes were nonetheless derived and validated primarily in a Caucasian population, and their relevance to other ethnic groups has been questioned. Prior cross-sectional studies suggested that the annual stroke risk determined by CHADS2 and CHA2DS2VASc for Chinese AF patients appeared to differ from the corresponding value in Caucasians.9,16 The objectives of our study were to describe the risk of stroke and ICH in a large contemporary “real world” cohort of Chinese AF patients with detailed long-term follow-up and to assess the prognostic performance of CHADS2, CHA2DS2-VASc, and HAS-BLED scores in this population. The net clinical benefit of aspirin and warfarin, balancing the risk of stroke against ICH, also was determined.
Methods Patients and study design Between July 1997 and December 2011, a total of 10,195 Chinese patients with a diagnosis of AF at Queen Mary Hospital, Hong Kong, were identified from a computerbased clinical management system.17 Patients were excluded if they had significant valvular heart disease including previous valvular surgery, valvular disease with planned surgical correction, and any degree of mitral stenosis, or incomplete clinical and/or follow-up data. The final analysis included 9727 patients, who were categorized according to antithrombotic therapy, and CHADS2, CHA2DS2-VASc and HAS-BLED score calculated. This was an observational study, and the study protocol was approved by the local Institutional Review Board. Demographic data, cardiovascular risk factors, and medications were recorded at baseline. The primary and secondary end-points were hospital admission with stroke and ICH during the follow-up period, respectively. The adjusted net clinical benefit of aspirin and warfarin for stroke and ICH in relation to CHA2DS2-VASc and HASBLED scores was estimated by subtracting the annual number of ICH events (with a weight of 1.5) attributable to treatment with aspirin or warfarin from the annual number of stroke events prevented by the same treatment.18,19
Statistical analysis Details of the statistical analysis are provided in the Online Supplemental Data.
Results Patients We studied 9727 Chinese patients (age 76.9 ⫾ 12.5 years, 52.1% female) with nonvalvular AF. The clinical characteristics of the study population are summarized in Table 1. The mean CHADS2 and CHA2DS2-VASc score were 2.1 ⫾ 1.4 and 3.7 ⫾ 1.8, respectively. Of this cohort, 3881 patients (39.9%) received no aspirin or warfarin (no therapy), 3934 patients (40.4%) were prescribed aspirin (80–160 mg daily), and 1912 patients (19.7%) were taking warfarin.
Heart Rhythm, Vol 0, No 0, Month 2014
Ischemic stroke After a mean follow-up of 3.19 ⫾ 3.43 years (31,028 patientyears), 2179 patients developed a stroke. Of these, 847 strokes occurred in patients with no therapy (21.8%, annual stroke risk 9.28%). Increasing age, hypertension, diabetes mellitus, and female gender were also significantly associated with subsequent stroke, as was previous vascular disease and prior stroke (Table 2). For the 3881 patients prescribed no antithrombotic therapy, mean CHADS2 and CHA2DS2-VASc scores were 1.8 ⫾ 1.3 and 3.3 ⫾ 1.7, respectively. There was a progressive increase in annual stroke risk with increasing CHADS2 and CHA2DS2VASc score (Figure 1). The annual stroke risk for patients with CHA2DS2-VASc ¼ 0 was 2.41%, and increased to 13.18% for those with CHA2DS2-VASc Z6. Kaplan–Meier analyses revealed a significantly higher incidence of stroke in patients with increased CHADS2 (log-rank 71.6, P o.0001) and CHA2DS2-VASc scores (log-rank 86.6, P o.0001l; Figures 1C and 1D). The sensitivity of CHA2DS2-VASc (98.0% with optimal cutoff at 1) was the highest compared with other baseline demographic factors as a single criterion (sensitivity range 20.1%–89.9%; Online Supplemental Table 1). The c-statistic of CHA2DS2-VASc score as a predictor of subsequent strokes was 0.525 (0.509–0.541).
Intracranial hemorrhage In total, 46 of 3881 patients (1.19%, 0.5% per year) prescribed no antithrombotic therapy developed ICH: 29 intracerebral hemorrhage (63.1%), 11 subdural hemorrhage (23.9%), and 6 subarachnoid hemorrhage (13.0%). Prior ICH, prior stroke, and hypertension were the most significant predictors for subsequent ICH (Online Supplemental Table 2). The annual ICH risk was 0% for HAS-BLED score ¼ 0, 0.51% for HAS-BLED ¼ 1, 0.44% for HASBLED ¼ 2, and 0.81% for HAS-BLED Z3 (Online Supplemental Figure 1). The c-statistic of the HAS-BLED score to predict ICH was 0.552 (0.537–0.568). In our cohort, 2.4% of patients prescribed aspirin and 1.5% of patients prescribed warfarin developed ICH during the same period. The annual ICH incidence in patients taking aspirin and warfarin was 0.77% per year and 0.80% per year, respectively. The c-statistics of the HAS-BLED score to predict ICH in patients prescribed aspirin and warfarin were 0.552 (0.504–0.600) and 0.574 (0.518–0.629), respectively.
Net clinical benefit of aspirin and warfarin Compared with 3934 patients who received aspirin and 1912 patients taking warfarin, patients prescribed no therapy were less likely to have comorbidities (P o.0001), as reflected by their much lower mean CHADS2 and CHA2DS2-VASc scores (Table 1). Although they had higher CHADS2 and CHA2DS2-VASc scores, the patients taking aspirin or warfarin had a substantially lower annual stroke risk than did patients prescribed no therapy (Figure 1). Across all CHADS2 strata, the average reduction in annual stroke risk was 18.7% (range 12.8%–37.4%) for patients receiving
131 132 133 134 135 136 137 T2138 139 140 141 142 F1143 144 145 146 147 148 149 150 151 152 Q7153 154 155 156 157 158 159 160 161 162 163 Q8 164 165 166 Q9 167 168 169 170 171 172 Q10 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187
Siu et al 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 F2 230 231 232 233 234 235 236 T3 237 238 239 240 241 242 243 244
Table 1
Ischemic Stroke and ICH in Chinese AF Patients
3
Baseline characteristics of the study population
Age Mean age (years) Age 65–75 years Age Z75 years Female Hypertension Diabetes mellitus Smoker Hyperthyroidism Renal failure on dialysis Heart failure Coronary artery disease Peripheral arterial disease Prior ischemic stroke/transient ischemic attack Prior intracranial hemorrhage Means CHADS2 CHADS2 0 1 2 3 4 5 6 Mean CHA2DS2-VASc score CHA2DS2-VASc 0 1 2 3 4 5 6 7 8 9 Aspirin Warfarin
All (n ¼ 9727)
No aspirin or warfarin (n ¼ 3881)
Aspirin (n ¼ 3934)
Warfarin (n ¼ 1912)
P value
76.9 ⫾ 12.5 2,290 (23.5) 6,178 (63.5) 5,064 (52.1) 5,321 (54.7) 2,144 (22.0) 3,389 (34.8) 642 (6.6) 188 (1.9) 2,215 (22.8) 1,770 (18.2) 337 (3.5) 2,295 (23.1) 254 (2.6) 2.1 ⫾ 1.4
77.2 ⫾ 13.3 855 (22.0) 2,512 (64.7) 2,076 (53.5) 1,845 (47.5) 704 (18.1) 1,355 (34.9) 263 (6.8) 67 (1.7) 728 (18.8) 320 (8.2) 52 (1.3) 675 (17.4) 114 (2.9) 1.8 ⫾ 1.3
78.3 ⫾ 11.3 842 (21.4) 2,700 (68.6) 2,085 (53.0) 2,409 (61.2) 980 (24.9) 1,386 (35.2) 243 (6.2) 86 (2.2) 1,028 (26.1) 991 (25.2) 164 (4.2) 1,054 (26.8) 95 (2.4) 2.3 ⫾ 1.4
73.1 ⫾ 12.4 593 (31.0) 966 (50.5) 903 (47.2) 1,067 (55.8) 460 (24.1) 648 (33.9) 136 (7.1) 35 (1.8) 459 (24.0) 460 (24.1) 121 (6.3) 566 (29.6) 40 (2.1) 2.1 ⫾ 1.5
o.0001 o.0001 o.0001 o.0001 o.0001 o.0001 .597 .340 .315 o.0001 o.0001 o.0001 o.0001 .143 o.0001
1,311 (13.5) 2,371 (24.4) 2,466 (25.4) 1,896 (19.5) 1,076 (11.1) 107 (2.8) 118 (1.2) 3.7 ⫾ 1.8
638 (16.4) 1,115 (28.7) 990 (25.5) 673 (17.3) 329 (8.5) 268 (6.8) 29 (0.7) 3.3 ⫾ 1.7
374 (9.5) 834 (21.2) 1,039 (26.4) 837 (21.3) 515 (13.1) 114 (6.0) 67 (1.7) 4.1 ⫾ 1.8
299 (15.6) 422 (22.1) 437 (22.9) 386 (20.2) 232 (12.1) 489 (5.0) 22 (1.2) 3.7 ⫾ 2.0
o.0001
395 (4.1) 772 (7.9) 1,392 (14.3) 1,956 (20.1) 1,989 (20.4) 1,620 (16.7) 969 (10.0) 430 (4.4) 169 (1.7) 35 (0.4) 3,943 (40.5) 1,912 (19.7)
190 (4.9) 358 (9.2) 681 (17.5) 896 (23.1) 806 (20.8) 552 (14.2) 276 (7.1) 86 (2.2) 31 (0.8) 5 (0.1) 0 (0) 0 (0)
102 (2.6) 232 (5.9) 458 (11.6) 711 (18.1) 837 (21.3) 741 (18.8) 494 (12.6) 243 (6.2) 95 (2.4) 21 (0.5) 3,934 (100) 0 (0)
103 (5.4) 182 (9.5) 253 (13.2) 349 (18.3) 346 (18.1) 327 (17.1) 199 (1.4) 101 (5.3) 43 (2.2) 9 (0.5) 0 (0) 1,912 (100)
o.0001
o.0001
— —
Values are given as n (%) or mean ⫾ SD. CHADS2 score ¼ Congestive heart failure, Hypertension, Age Z75 years, Diabetes, previous Stroke score; CHA2DS2-VASc score ¼ CHA2DS2-Vascular disease, Age 65–74 years, Sex category score.
aspirin and 52.7% (44.3%–68.6%) for those taking warfarin (Figure 2). At different CHA2DS2-VASc scores, the reduction in annual stroke risk with aspirin ranged from 24.5% to 38.1% (except for CHA2DS2-VASc ¼ 0) and with warfarin ranged from 37.9% to 71.2% (Figure 2). For aspirin therapy, the net clinical benefit was almost zero or even negative (net clinical disadvantage) in patients at low stroke and bleeding risk (CHA2DS2-VASc ¼ 0 and HAS-BLED o2; Table 3). For patients with a moderate-tohigh risk of stroke (CHA2DS2-VASc Z1), aspirin therapy had a net clinical benefit that ranged from 1.54 to 3.97 fewer events per 100 patient-years, except for those at moderate stroke risk and bleeding risk (CHA2DS2VASc ¼ 1 and HASBLED ¼ 2; Table 3). The net-clinical-benefit analysis favored warfarin therapy across the remaining whole spectrum of stroke risk and bleeding risk. The best net benefit from warfarin therapy was
found in those with high stroke and bleeding risk. In these high-risk patients, warfarin therapy conferred 4.39 to 6.55 fewer events per 100 patient-years compared with patients who received no OAC therapy. The net-clinical–benefit outcomes favored switching almost all patients from aspirin to warfarin (Table 3).
Discussion To the best of our knowledge, this is the largest, real-world cohort of Chinese patients with AF for which we report the following. First, we showed that AF-related stroke risk was substantial and comparable to that reported for Caucasians. Second, OAC with warfarin in Chinese AF patients significantly reduced the stroke risk compared with aspirin or no therapy. Third, Chinese AF patients treated with warfarin or aspirin were at higher ICH risk than Caucasians, but,
245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301
4 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358
Table 2
Heart Rhythm, Vol 0, No 0, Month 2014 Associations between baseline factors and ischemic stroke in Chinese AF patients without any antithrombotic therapy (n ¼ 3882) Univariate analysis
Age o65 years 65–75 years 475 years Female Hypertension Diabetes mellitus Smoker Hyperthyroidism Renal failure on dialysis Heart failure Coronary artery disease Peripheral arterial disease Prior ischemic stroke Prior intracranial hemorrhage
Multivariate analysis
No. of ischemic strokes
HR (95% CI)
P value
HR (95% CI)
P value
71 233 543 504 428 170 273 64 16 128 75 11 148 24
Reference 2.30 (1.76–3.01) 2.54 (1.98–3.27) 1.16 (1.02–1.34) 1.58 (1.38–1.81) 1.38 (1.17–1.64) 0.87 (0.76–1.00) 0.74 (0.58–0.96) 1.29 (0.79–2.12) 1.19 (0.99–1.44) 1.19 (0.92–1.49) 2.59 (1.43–4.71) 1.49 (1.25–1.78) 1.12 (0.75–0.17)
o.0001* o.0001* .026 o.0001* o.0001* .872 .023* .312 .067 .191 .002* o.0001* .58
Reference 2.09 (1.60–2.75) 2.23 (1.72–2.90) 1.03 (0.88–1.20) 1.34 (1.16–1.55) 1.18 (0.99–1.40) 0.90 (0.77–1.05) 0.81 (0.62–1.05) 1.39 (0.84–2.29) 1.06 (0.87–1.28) 0.96 (0.75–1.22) 2.10 (1.15–3.84) 1.28 (1.06–1.53) 1.09 (0.72–1.65)
o.0001* o.0001* .723 o.0001* .069 .185 .108 .199 .583 .734 .016* .010* .683
AF ¼ atrial fibrillation; CI ¼ confidence interval; HR ¼ hazard ratio. * P o.05.
importantly, warfarin and aspirin were associated with similar ICH risk. Fourth, net-clinical-benefit analysis revealed that the stroke risk in Chinese AF patients without antithrombotic therapy exceeded the ICH risk with either aspirin or warfarin in almost all combinations of stroke and ICH risks. Thus, the net clinical benefit was highest among those at high risk for
W E B 4 C / F P O
both stroke and ICH, and warfarin was preferred to aspirin for all combinations of stroke and ICH risk.
Ischemic stroke The decision for and choice of antithrombotic therapy for stroke prevention in AF is influenced by several factors: the
Figure 1 Relation between CHADS2 (A) and CHA2DS2-VASc (B) scores, and the annual risk of ischemic stroke in Chinese atrial fibrillation (AF) patients with no antithrombotic therapy, aspirin, and warfarin. Kaplan–Meier estimates of ischemic stroke-free survival in Chinese AF patients with no antithrombotic therapy stratified according to CHADS2 (C) and CHA2DS2-VASc (D) score.
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Ischemic Stroke and ICH in Chinese AF Patients
5
Figure 2 Relative effects of aspirin and warfarin on ischemic stroke in Chinese atrial fibrillation patients stratified according to CHADS2 (A, B) and CHA2DS2-VASc (C, D) score. Horizontal lines represent 95% confidence interval (CI) around point estimates.
risk of stroke and ICH, and the efficacy and safety of antithrombotic agents. Prior small studies reported a much lower incidence of stroke among Chinese AF patients that resulted in a prevailing perception that the stroke risk in Chinese AF patients is lower than in Caucasians.8,9 A recent small cohort study in China demonstrated that the risk of stroke and thromboembolism in Chinese was comparable with or even higher than that of Caucasians.16 In our study, the overall stroke risk among Chinese AF patients not receiving antithrombotic therapy was 9.28% per year, which is substantially higher than all previously published Chinese data and is comparable with or even higher than that of the largest published “real world” AF registry.20 These findings are in accordance with the fact that, globally, China is among the countries with the highest stroke.21 As in previously published Caucasian studies20,22 as well as Chinese16 series, individual components of the CHADS2 score, such as increasing age Z75 years, hypertension, diabetes, and prior stroke, were predictive of subsequent stroke in our study. Similar to results from the largest AF registry,20 history of heart failure in our cohort was not associated with an increased stroke risk. Although moderate-to-severe left ventricular systolic dysfunction is an unequivocal risk factor of stroke in AF,23,24 many patients with symptomatic AF often labeled heart failure may not actually have left ventricular impairment, thus undermining the predictive power.20 Importantly, the 3 components incorporated in
the CHA2DS2-VASc score, including age 65–74 years, female gender, and history of other vascular disease, that were listed as “less validated risk factors” for stroke in the 2006 ACC/AHA/ESC guidelines were found to be predictive of stroke in our cohort.25 As in previous Chinese cohorts, peripheral vascular disease seems to be an important driver of stroke risk in AF patients.9,16 Furthermore, stroke risk increased with increasing CHADS2 and CHA2DS2-VASc score as in previous Caucasian studies.20,22,26 Compared with corresponding rates published for Caucasians,22,26 Chinese AF patients with lowto-moderate CHADS2 (r2) or CHA2DS2-VASc (r3) score were at much higher risk for stroke (3–4 times).22,26 Nonetheless, at a higher CHADS2 (Z4) and CHA2DS2-VASc (Z6) score, stroke risk was comparable to or lower than that of Caucasians.20,22,26 Given the relative high stroke risk in Chinese AF patients with low CHADS2 and CHA2DS2VASc scores, the CHA2DS2-VASc score appears to be more sensitive in identifying low-risk stroke patients and therefore should be the score of choice for stroke risk stratification in Chinese AF patients. In agreement with previous randomized control trials in predominantly Caucasian populations, warfarin significantly reduced stroke risk compared with aspirin and no therapy.27 Across all strata of CHADS2 and CHA2DS2-VASc scores, warfarin appeared to be effective in reducing stroke risk. The overall stroke risk reduction was nevertheless much lower
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Table 3
Heart Rhythm, Vol 0, No 0, Month 2014 Net clinical benefit of aspirin and warfarin: ischemic stroke vs intracranial hemorrhage
Net benefit of aspirin (prevented ischemic strokes with aspirin per year minus excess intracranial hemorrhage with aspirin per year with a weight of 1.5) HAS-BLED
CHA2DS2-VASc 0 1 2 3 4 5 6–9
0
1
2
3–6
0.12 — — — — — —
0.47 4.82 2.95 3.37 — — —
-1.71 -0.71 1.54 3.49 3.64 — —
— — — — — — 3.97
Net benefit of warfarin (prevented ischemic strokes with aspirin per year minus excess intracranial hemorrhage with warfarin per year with a weight of 1.5) HAS-BLED
CHA2DS2-VASc 0 1 2 3 4 5 6–9
0
1
2
3–6
— 2.13 — — — — —
— — 3.43 5.85 — — —
— — 4.14 6.27 6.10 4.39 —
— — — — 6.55 6.43 5.46
Net benefit of switching aspirin to warfarin (prevented ischemic strokes per year minus excess intracranial hemorrhage per year with a weight of 1.5) HAS-BLED
CHA2DS2-VASc 0 1 2 3 4 5 6–9
0
1
2
3–6
— — — — — — —
— — 0.48 2.48 — — —
— — 2.60 2.78 2.46 — —
— — — — — — 1.49
than that seen in randomized controlled trials in Caucasians (52.7% vs 64.0%).27 A plausible explanation may be the notoriously low time in the therapeutic range in Asian countries, an important determinant of adverse outcome.28 Unfortunately, we lacked access to international normalized ratio data, which precluded further analysis. In contrast, the benefit of aspirin in stroke prevention for AF remains controversial. In 1 meta-analysis,27 aspirin compared with no therapy resulted in a borderline nonsignificant stroke risk reduction of 19%, essentially driven by 1 single positive study that prescribed aspirin 325 mg daily.29 In our study, although patients treated with aspirin (80–160 mg daily) had a similar overall reduction in stroke risk of 18.7%, no stroke risk reduction was observed in patients at the lowest level of CHADS2 and CHA2DS2-VASc scores.
Intracranial hemorrhage ICH remains the greatest barrier to OAC for stroke prevention in AF. It is postulated that Chinese may have a higher baseline ICH risk than Caucasians.6,30 In our study, the overall annual ICH incidence in 3881 Chinese AF patients with no therapy was 0.5% per year, comparable to published rates in Caucasian AF patients (n = 33,486, 0.6% per year).20 Nonetheless, such risk among Chinese prescribed either aspirin or warfarin (0.77% per year and 0.80% per year, respectively) was higher than that of Caucasians (aspirin: n ¼ 48,599, 0.6% per year; warfarin: n ¼ 61,396, 0.6% per year; Online Supplemental Figure 2).20 Our findings suggest that instead of a higher baseline ICH risk, Chinese patients may indeed be more susceptible to ICH when prescribed antithrombotic therapy with aspirin or warfarin. This concurs with the subanalyses of the RE-LY
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Ischemic Stroke and ICH in Chinese AF Patients
trial31 and the ROCKET-AF trial that Asian AF patients32,33 treated with warfarin were at higher ICH risk compared with their non-Asian counterparts. Importantly, the ICH risk among patients treated with aspirin was similar to that warfarin; therefore, aspirin does not offer a “safer” alternative to warfarin in reducing ICH. Similar to data from previous Caucasian series, the ICH risk increased with the HAS-BLED score in our cohort (Online Supplemental Figure 2). Among individual components that compose the HAS-BLED score, prior stroke and hypertension were significant predictors of ICH. Whereas prior ICH conferred the highest risk among all risk factors for subsequent ICH, history of other major bleeding did not have any statistically significant association with subsequent ICH. This concurs with the largest AF registry in which ICH conferred a 2–3 times higher risk for subsequent ICH than any other form of severe bleeding.18
7 large “real world” cohort data serve as a good alternative. In addition, although we carefully ascertained all strokes and ICHs by careful examination of hospitalization records and laboratory and imaging results, patients with milder forms of stroke and/or ICH who were not hospitalized were not included.
Conclusion Chinese AF patients are at high risk for stroke. CHA2DS2VASc and HAS-BLED scores appear to be the appropriate risk stratification tools for stroke risk and ICH, respectively, for Chinese. Analysis of the net clinical benefit favors warfarin over aspirin and no therapy for stroke prevention in a broad range of Chinese AF patients.
Uncited reference 15
Net clinical benefits and the choice of antithrombotic agents In concordance with a previous study in a Caucasian population, the stroke risk in Chinese AF patients prescribed no antithrombotic therapy exceeded the ICH risk with warfarin at all combinations of CHA2DS2-VASc and HASBLED score.18 In the net-clinical-benefit analysis, the optimal antithrombotic therapy for Chinese AF patients clearly favored warfarin over aspirin and no therapy in almost all combinations of CHA2DS2-VASc and HASBLED scores, primarily driven by the substantial stroke risk reduction. Although aspirin provides a modest net-clinicalbenefit over no therapy in moderate- to-high-risk patients, given the similar ICH risk inferred by aspirin and warfarin, aspirin should not be used as the primary agent for stroke prevention in Chinese AF patients. Given the much higher annual incidence of stroke among Chinese AF patients even with CHA2DS2-VASc ¼ 0 compared with Caucasians (2.4% vs 0.2%), it is possible that OAC may be beneficial.18 Unfortunately, because of the lack of an adequate number of patients with a very low score (CHA2DS2-VASc ¼ 0) and prescribed warfarin, any net clinical benefit among these “low-risk” patients could not be demonstrated. Moreover, several novel OACs, including dabigatran, rivaroxaban, and apixaban, confer a much lower risk for ICH than warfarin but have comparable or superior efficacy in stroke prevention. In the subanalyses, Asian AF patients receiving warfarin tended to have a higher ischemic stroke risk and a higher ICH risk compared with Caucasian counterpart but at the same time had a poorer time in the therapeutic range. These agents may have a much higher overall net benefit in Chinese AF.
Study limitations This study is limited by its cohort-based and single-center observational design in primarily hospital-based patients. The gold standard for demonstrating treatment effects is a randomized placebo-controlled trial, which is not ethically possible given the well-documented benefit of OAC. Thus,
Appendix Supporting data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2014.04.021.
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