Original Research Paper
Antithrombotic therapy for ischaemic stroke patients with AF/RHD in West China daily practice Deren Wang1, Junfeng Liu1, Zilong Hao1, Ming Liu1, Ge Tan1, Xiaoqun Jiang1,2, Wendan Tao1 1
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China, 2Department of Neurology, Chengdu Fifth People’s Hospital, China Background and Objective: Although, current evidence-based guidelines advocate anticoagulation as a strong recommendation in IS patients with AF/RHD, the underuse of anticoagulation in IS patients with AF/RHD has been found in clinical practice worldwide. Nevertheless, there was little information about implementation of antithrombotic therapy to prevent stroke for patients with AF and/or RHD in daily practice in West China. Our study determined to clarify the patterns, adherence and comparative effect of antithrombotic treatment during 1-year follow-up in IS patients with AF and/or RHD. Method: Consecutive patients with acute IS and AF/RHD admitted to Department of Neurology, West China Hospital from November 2010 to October 2011 were included in the study. Results: 155 consecutive patients were analysed in this study. One hundred thirteen patients have been diagnosed as AF and/or RHD before admission. Of these, 49 (43.4%) patients were receiving antithrombotic therapy before the time of admission, including nine (8.0%) patients receiving warfarin. At 12 months after stroke onset, 109 (81.3%) patients were on antithrombotics, and 46 (34.3%) patients were on warfarin alone. The persistence rate of warfarin use at 1 year was 77.8%. Moreover, there were 80 (81.6%) patients never starting to use warfarin. Compared with no antithrombotic therapy, anti-platelets and warfarin reduced death risk significantly during 1-year after stroke onset (P 5 0.005). Conclusion: Our study suggests that overall real-world use of warfarin in IS patients with AF and/or RHD is low before and after admission in West China. Implementation study on this respect should be conducted in this area to improve the daily practice. Keywords: Antithrombotic therapy, Ischaemic stroke, Atrial fibrillation, Rheumatic heart disease, Comparative research
Introduction Currently, China has a higher relative stroke burden overall with higher relative mortality1–3 compared to western countries. Ischaemic stroke (IS) accounts for 85% of all strokes,3 among which, 12–31% are cardioembolic strokes.4 The most common cause of cardioembolic stroke in China is rheumatic heart disease (RHD) and atrial fibrillation (AF),5,6 which often accounts for more than 60% of such strokes.4 Worldwide, population- or hospital-based studies have indicated that stroke patients with RHD and AF had a higher proportion of disability and death than other stroke patients.7–10 Both oral anticoagulants and antiplatelet agents have been proven effective for stroke prevention in most patients at high risk for vascular events.
Correspondence to: Ming Liu, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37, GuoXue Xiang, Chengdu 610041, Sichuan Province, China. Email: [email protected]
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However, oral anticoagulation treatment (OAT) for prevention of cardioembolic stroke in patients with AF is much more effective than antiplatelet therapy, which has been identified by large clinical trials.11,12 Current evidence-based guidelines advocate anticoagulation use as a strong recommendation in IS patients with RHD/AF,9,13,14 as well. Despite the compelling evidence exists, it has been found that anticoagulation among such patients in clinical practice is underused and disparate in different regions worldwide.15 Due to less developed and more rural in West China, these regional differences of anticoagulation may be much more apparent compared to other areas in China. Little is known about implementation of antithrombotic therapy to prevent stroke for patients with AF and/or RHD in daily practice in West China. Therefore, we aimed to examine patterns of antithrombotic treatment before and after admission, and to assess the adherence of antithrombotic therapy in secondary prevention in IS patients with
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AF and/or RHD; finally, we aimed to assess the comparative effects of antithrombotic treatment for 1-year stroke prognosis.
Methods Consecutive patients with acute IS and AF (or RHD) admitted within 1 month since stroke onset to Department of Neurology, West China Hospital from November 2010 to October 2011 were included in the study. All patients had a clinical diagnosis of stroke according to World Health Organisation criteria,16 further confirmed by computed tomography or magnetic resonance imaging scan. Informed consent was obtained from participants or their guardians. This study was approved by the Scientific Research Department of our hospital, which also conformed to the local ethic criteria. Details of patient demographics, time of stroke onset, stroke severity on admission, risk factors, prior antithrombotic, diagnostic tests, neurological imaging, treatment administered, stroke-related complications during hospitalisation and discharge medicine/interventions were recorded at the time of assessment using a standardised structured form. Patients were followed up at 3, 6 months and 1 year after stroke onset by telephone interviews or letter inquiries to assess current medicine use and clinical outcomes. Atrial fibrillation was defined as a history of persistent AF or paroxysmal AF, supported by past ECG or diagnosed by the attending physicians based on ECG and/or 24-hour ECG monitoring during admission.6 Rheumatic heart disease was diagnosed according to International Classification of Diseases, 10th edition, criteria and further confirmed by echocardiography.6 Data were also collected for other vascular risk factors, including hypertension, diabetes mellitus, hyperlipidaemia, coronary heart disease, previous transient ischaemic attacks, history of stroke and current smoking and alcohol consumption, which have been described in previous reports.6,17 Stroke severity on admission was measured using the National Institutes of Health Stroke scale (NIHSS).18 The outcome measures were death, disability, death/disability and recurrence at 3, 6 months and 1 year after stroke. Disability was measured according to the modified Rankin Scale score and was defined as a score of 3–5.19 Results for categorical variables were compared between different groups using chi-squared or Fisher exact tests. Results of continuous variables were compared using ANOVA or Mann–Whitney U tests. The impact of prior to stroke antithrombotic on stroke severity in the acute stage was analysed according to NIHSS score on admission categorised by two cut-off points (j6 vs w6 and j15 vs w15).18 Binary logistic regression was used to evaluate the association between
Antithrombotics for stroke with AF/RHD in West China
antithrombotic therapy started within 3 months and outcomes. Cumulative 1-year survival and recurrence rates were estimated using the Kaplan–Meier product limit method and the results for different groups were compared using log rank tests. A two-tailed value of P v 0.05 was defined as the threshold of statistical significance. All statistical analyses were performed using SPSS (version 16).
Results Baseline characteristics During the enrolment period from November 2010 to October 2011, 155 consecutive IS patients with AF and/or RHD were analysed in this study, of them 54.2% (84/155) were females and the mean age was 68.3 + 12.5 years at stroke onset. Of these, five patients (3.2%) were with only RHD, 105 (67.8%) with only AF, and 45 (29.0%) with both RHD and AF. The baseline characteristics of the patients are listed in Table 1. Ultimately, 134 patients were alive at 1-year post-stroke during the follow-up (Fig. 1). Of the 150 patients with AF, 90 (60.0%) were known to have AF and 60 (40.0%) were diagnosed with AF for the first time due to current stroke presentation. Among the 90 patients with AF diagnosed previously, 56 (62.2%) patients were diagnosed due to cardiac manifestation, 10 (11.1%) patients were diagnosed due to previous stoke, and the remaining 24 (26.7%) were diagnosed according to other manifestation.
Preadmission antithrombotic therapy use and impact on stroke severity One hundred thirteen patients have been diagnosed as AF and/or RHD before the time of admission. Prior to stroke, of those with known AF/RHD, 43.4% were on antithrombotic therapy, including nine receiving Table 1 Baseline characteristics of ischaemic stroke (IS) patients with rheumatic heart disease (RHD)/atrial fibrillation (AF) Characteristic Age, years Mean ^ SD Range Sex, n (%) Male Female Risk factors, n (%) Hypertension Diabetes mellitus Hyperlipidaemia Coronary heart disease Current smoking Alcohol consumption Previous TIA History of stroke Stroke severity on admission National Institutes of Health Stroke scale (NIHSS) score, median
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68.3 ^ 12.5 29–89 71 (45.8) 84 (54.2) 69 (44.5) 24 (15.5) 3 (1.9) 21 (13.5) 29 (18.7) 18 (11.6) 1 (0.6) 32 (20.6) 8
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Figure 1 The total number of patients in each stage during follow-up.
warfarin, and 40 receiving anti-platelets treatment. Use of anti-platelets or warfarin before stroke was not associated with a mild or moderate stroke severity on admission (NIHSS j 6: P 5 0.601; NIHSS j 15: P 5 0.889) and was not associated with death at discharge (P 5 0.803).
Antithrombotic use at discharge and during 1-year follow-up period As shown in Table 2, 123 (84.8%) patients were on antithrombotic therapy at discharge. One hundred fifteen (82.1%), 117 (85.4%), and 109 (81.3%) patients were on antithrombotic medication therapy at 3, 6 months and 1 year post-stroke, respectively. Among the 134 patients alive at 12 months since stroke onset, those who received warfarin at discharge (n 5 36), eight (22.2%) patients were taken off warfarin, whereas those who did not receive warfarin at discharge (n 5 98), 18 patients (18.4%) were started on warfarin. The persistence rate of warfarin use at 1 year was 77.8% (of the patients who were discharged and remained on warfarin at 1 year); and of the patients Table 2 Rates of antithrombotic use at discharge, and during 1-year follow-up period
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Time since stroke
Alive (n)
Warfarin (n)
At discharge 3 Months 6 Months 1 Year
145 140 137 134
37 (25.5%) 42 (30.0%) 48 (35.0%) 46 (34.3%)
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86 (59.3%) 73 (52.1%) 69 (50.4%) 63 (47.0%)
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who did not receive warfarin at discharge, 80 (81.6%) never started warfarin during this 1-year period.
Impact of antithrombotic use started within three months on stroke outcomes As shown in Table 3, in patients with warfarin therapy started within 3 months since stroke onset, the 12-month death rate was 2.0%, in patients with antiplatelets started within 3 months was 7.5% and in patients with no antithrombotic therapy within 3 months was 25.0%. The death rates in patients with antithrombotic therapy were significantly lower than in patients with no antithrombotic therapy at the end of 3-month (P 5 0.014), 6-month (P 5 0.008) and 1-year (P 5 0.019) follow-up. However, after adjusting for age, sex and NIHSS on admission, the death risk in patients with antithrombotic therapy started within 3 months was similar to that in patients with no antithrombotic therapy within 3 months (95%CI, 0.040–1.049, P 5 0.057), whereas the death risk in patients with antithrombotic therapy started within 3 months was significantly lower than at 6 months (95%CI, 0.056–0.799, P 5 0.022) and at 1 year (95%CI, 0.094–0.890, P 5 0.031). One-year survival curves demonstrated warfarin and anti-platelets therapy were associated with a significantly higher cumulative survival rates at 1-year after stroke onset compared to no antithrombotic therapy (98.0 vs 92.5% vs 75.0%, P 5 0.005, log rank test) (Fig. 2). The three groups did not differ significantly in disability rates at 3 months (p 5 0.232), 6 months
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Table 3 Rates of death, disability and combined death and disability in patients with ischaemic stroke (IS) and atrial fibrillation (AF)/rheumatic heart disease (RHD) Outcome Death 3 Months 6 Months 12 Months Disability 3 Months 6 Months 12 Months Death þ disability 3 Months 6 Months 12 Months
No
Anti-platelets
Warfarin
P
3/16 (18.8) 4/16 (25.0) 4/16 (25.0)
1/80 (17.7) 3/80 (3.8) 6/80 (7.5)
1/49 (2.0) 1/49 (2.0) 1/49 (2.0)
0.014† 0.008† 0.019†
8/13 (61.5) 6/12 (50.0) 6/12 (50.0)
34/79 (43.0) 28/77 (36.4) 27/74 (36.5)
17/78 (35.4) 16/48 (33.3) 14/48 (29.2)
0.232* 0.562* 0.373*
11/16 (68.8) 10/16 (62.5) 10/16 (62.5)
35/80 (43.8) 31/80 (38.8) 33/80 (41.3)
18/49 (36.7) 17/49 (34.7) 15/49 (30.6)
0.081* 0.135* 0.073*
*Chi-squared test, †Fisher exact test.
Figure 2 Kaplan–Meier estimates of 1-year survival curves for IS patients with RHD/AF. Curves for the three groups were significantly different (P 5 0.005, log rank test).
(P 5 0.562) or 12 months (P 5 0.373; Table 2). When death and disability rates were combined into an aggregate measure of poor outcomes, there was also no significantly difference among three groups at 3 (P 5 0.081), 6 (P 5 0.135) or 12 months (P 5 0.073; Table 3). As to recurrence, by 12 months, stroke had recurred in 20 patients (12.9%). Kaplan–Meier estimates of 1-year cumulative stroke recurrence showed similar results for patients with and without antithrombotic therapy (P 5 0.814, log rank test).
Discussions Stroke attributable to AF or RHD is common in the Chinese population and China is still facing an epidemic of AF and AF/RHD related stroke, the prevalence of which increases significantly with age.3,5,6 Despite that, little information on implementation of antithrombotic therapy to prevent stroke for
patients with AF and/or RHD in daily practice in West China is currently available. In the present study, we provided insights on this respect based on a prospective cohort of hospitalised patients’ population in West China, found overall real-world use of warfarin is low in IS patients with AF/RHD, and IS patients with AF and/or RHD in West China prefer antiplatelet therapy to anticoagulation therapy in daily secondary prevention. Moreover, warfarin and anti-platelets therapy were significantly associated with a reduction in the odds of death at 1-year after stroke onset in routine medical context. Only 8% of our study population had been receiving warfarin therapy at stroke presentation. This is much lower than that reported by other studies conducted in western countries, which ranged from 21.9 to 37%.20–24 There were two possible reasons for underusing oral anticoagulants in our study. First, when physicians recommended patients to use warfarin, and meanwhile
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told them the bleeding risk, and benefits of warfarin, most of the patients in West China refused to accept it immediately because of overestimating the risk of bleeding, and underestimating the risk of stroke and the benefit of warfarin. Second, the inconvenience and high economic burden in monitoring and adjusting INR was another barrier. Moreover, prestroke warfarin therapy in our study is also lower than that one study from China National Stroke Registry (16.2%).25 This might be related to the less developed, low education, and more rural in West China. Above all, these suggest that the frequency of warfarin therapy before stroke onset can vary greatly by geographic region, not only in different countries with different economic level but also in different areas within the same country. Although the percentage of warfarin therapy in our study rose up from 25.5% at discharge to 34.3% at 1-year after stroke onset, which is also much poorer than Lopes, R. D. et al. study (49.1–44.3%).26 In addition, in our research, 86(59.3%) patients accepted antiplatelet therapy at discharge and 63 (47.0%) at 1-year follow-up. These data suggested that IS patients with AF and/or RHD in West China prefer antiplatelet therapy to anticoagulation therapy in daily secondary prevention. It might be because of the use of antiplatelet agents for stroke prevention in these patients who fear to be on warfarin because of the bleeding risk. This unrealistic fear of bleeding is common among Chinese patients, especially in rural areas. It was surprising to see no association between preadmission antithrombotic therapy use and stroke severity on admission and death at discharge in our study. This finding is contrary to several other studies, which suggested preadmission antithrombotic therapy was associated with less severe stroke and lower mortality.22–24 One possible interpretation is that the sample of our study is small and the proportion of patients on antithrombotic therapy at stroke presentation is lower than other studies. For example, O’Donnell, M. et al. included 948 consecutive patients with acute IS and AF using data from the Registry of the Canadian Stroke Network (2003–05) and found 37% patients were receiving Warfarin and 31% were on anti-platelets.24 Similarly to previous randomised controlled trials,14,27,28 we found warfarin and anti-platelets therapy could significantly reduce the death risk at 1-year after stroke onset in routine medical context. By contrast, we did not find significant association between antithrombotic therapy and 1-year stroke recurrence or disability in our study. This may be explained by the small sample of our study and more severe stroke in individuals with AF resulting in greater risk of death before stroke can recurrent.17 Despite that, our study still shows there is overall benefit for antithrombotic therapy in IS
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patients with AF and/or RHD during 1-year follow-up period after stroke onset in routine medical context. Our study has several limitations. First, it is a single centre, hospital-based study, so the study population may not be representative of other populations in West China or of the general population of stroke patients with RHD and/or AF. Some stroke patients may not present to hospital, especially those with mild symptoms or those who died before they could be admitted. Second, the follow-up visits were conducted by telephone and mail rather than in person. This decision was based on the fact that many patients at our hospital travel from the distant areas in West China to be treated, making in-person follow-up difficult. Previous studies have shown that face-to-face assessment of mRS is impractical, follow-up by telephone or letter can lead to good follow-up rates and reliable results with low bias.29,30 In conclusion, our study suggests that IS patients with AF and/or RHD in West China prefer antiplatelet therapy to anticoagulation therapy in daily secondary prevention, and overall real-world use of warfarin in West China is low before and after admission of IS patients with AF and/or RHD. More implementation researches on antithrombotic therapy in such patients in West China should be conducted.
Disclaimer Statements Contributors DW and JL contributed equally to this work. Funding This study was sponsored by research grants from the National Natural Science Foundation of China (Grant No.81371282 and Grant No.81400964). The agency did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Conflicts of interest The authors declare no financial or other conflict of interests. Ethics approval This study was approved by the Scientific Research Department of our hospital which also conformed to the local ethic criteria.
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with atrial fibrillation in a Chinese hospital-based stroke study. Cerebrovasc Dis. 2011;31:419–26. Wang D, Liu M, Hao Z, Tao W, Lin S, Zhang S, et al. Features of acute ischemic stroke with rheumatic heart disease in a hospitalized Chinese population. Stroke. 2012;43:2853–7. Lamassa M, Di Carlo A, Pracucci G, Basile AM, Trefoloni G, Vanni P, et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (the European community stroke project). Stroke. 2001;32:392–8. Marini C, De Santis F, Sacco S, Russo T, Olivieri L, Totaro R, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke. 2005;36:1115–9. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, 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;31:2369–3429. Steger C, Pratter A, Martinek-Bregel M, Avanzini M, Valentin A, Slany J, et al. Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian stroke registry. Eur Heart J. 2004;25:1734–40. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2005;3:CD001927. Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007;3:CD006186. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA 3rd, et al. ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2011;123:104–23. Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American heart association/American stroke association. Stroke. 2011;42:227–76. Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(638–645):e634. Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T. Cerebrovascular disease in the community: results of a WHO collaborative study. Bull World Health Organ. 1980;58:113–30. Wang D, Liu M, Hao Z, Tao W. Association between reduced kidney function and clinical outcomes after ischaemic stroke with atrial fibrillation. Eur J Neurol. 2014;21:160–6.
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18 Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–70. 19 de Haan R, Limburg M, Bossuyt P, van der Meulen J, Aaronson N. The clinical meaning of rankin ’handicap’ grades after stroke. Stroke. 1995;26:2027–30. 20 Haeusler KG, Konieczny M, Endres M, Villringer A, Heuschmann PU. Impact of anticoagulation before stroke on stroke severity and long-term survival. Int J Stroke. 2012;7: 544–50. 21 Schwammenthal Y, Bornstein N, Schwammenthal E, Schwartz R, Goldbourt U, Tsabari R, et al. Relation of effective anticoagulation in patients with atrial fibrillation to stroke severity and survival (from the national acute stroke israeli survey [nasis]). Am J Cardiol. 2010;105:411–6. 22 Johnsen SP, Svendsen ML, Hansen ML, Brandes A, Mehnert F, Husted SE. Preadmission oral anticoagulant treatment and clinical outcome among patients hospitalized with acute stroke and atrial fibrillation: a nationwide study. Stroke. 2014;45: 168–75. 23 Kwok CS, Skinner J, Metcalf AK, Potter JF, Myint PK. Prior antiplatelet or anticoagulant therapy and mortality in stroke. Heart. 2012;98:712–7. 24 O’Donnell M, Oczkowski W, Fang J, Kearon C, Silva J, Bradley C, et al. Preadmission antithrombotic treatment and stroke severity in patients with atrial fibrillation and acute ischaemic stroke: an observational study. Lancet Neurol. 2006;5:749–54. 25 Wang C, Yang Z, Wang Y, Zhao X, Liu L, Wang DZ, et al. Significant underuse of warfarin in patients with nonvalvular atrial fibrillation: results from the China national stroke registry. J Stroke Cerebrovasc Dis. 2014;23(5):1157–63. 26 Lopes RD, Shah BR, Olson DM, Zhao X, Pan W, Bushnell CD, et al. Antithrombotic therapy use at discharge and 1 year in patients with atrial fibrillation and acute stroke: results from the avail registry. Stroke. 2011;42:3477–83. 27 Saxena R, Koudstaal P. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack. Cochrane Database Syst Rev. 2004;4:CD000187. 28 Saxena R, Koudstaal PJ. Anticoagulants for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischaemic attack. Cochrane Database Syst Rev. 2004;2:CD000185. 29 Bruno A, Akinwuntan AE, Lin C, Close B, Davis K, Baute V, et al. Simplified modified rankin scale questionnaire: reproducibility over the telephone and validation with quality of life. Stroke. 2011;42:2276–9. 30 Dennis M, Mead G, Doubal F, Graham C. Determining the modified rankin score after stroke by postal and telephone questionnaires. Stroke. 2012;43:851–3.
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Antithrombotic therapy for ischaemic stroke patients with AF/RHD in West China daily practice Deren Wang1, Junfeng Liu1, Zilong Hao1, Ming Liu1, Ge Tan1, Xiaoqun Jiang1,2, Wendan Tao1 1
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China, 2Department of Neurology, Chengdu Fifth People’s Hospital, China Background and Objective: Although, current evidence-based guidelines advocate anticoagulation as a strong recommendation in IS patients with AF/RHD, the underuse of anticoagulation in IS patients with AF/RHD has been found in clinical practice worldwide. Nevertheless, there was little information about implementation of antithrombotic therapy to prevent stroke for patients with AF and/or RHD in daily practice in West China. Our study determined to clarify the patterns, adherence and comparative effect of antithrombotic treatment during 1-year follow-up in IS patients with AF and/or RHD. Method: Consecutive patients with acute IS and AF/RHD admitted to Department of Neurology, West China Hospital from November 2010 to October 2011 were included in the study. Results: 155 consecutive patients were analysed in this study. One hundred thirteen patients have been diagnosed as AF and/or RHD before admission. Of these, 49 (43.4%) patients were receiving antithrombotic therapy before the time of admission, including nine (8.0%) patients receiving warfarin. At 12 months after stroke onset, 109 (81.3%) patients were on antithrombotics, and 46 (34.3%) patients were on warfarin alone. The persistence rate of warfarin use at 1 year was 77.8%. Moreover, there were 80 (81.6%) patients never starting to use warfarin. Compared with no antithrombotic therapy, anti-platelets and warfarin reduced death risk significantly during 1-year after stroke onset (P 5 0.005). Conclusion: Our study suggests that overall real-world use of warfarin in IS patients with AF and/or RHD is low before and after admission in West China. Implementation study on this respect should be conducted in this area to improve the daily practice. Keywords: Antithrombotic therapy, Ischaemic stroke, Atrial fibrillation, Rheumatic heart disease, Comparative research
Introduction Currently, China has a higher relative stroke burden overall with higher relative mortality1–3 compared to western countries. Ischaemic stroke (IS) accounts for 85% of all strokes,3 among which, 12–31% are cardioembolic strokes.4 The most common cause of cardioembolic stroke in China is rheumatic heart disease (RHD) and atrial fibrillation (AF),5,6 which often accounts for more than 60% of such strokes.4 Worldwide, population- or hospital-based studies have indicated that stroke patients with RHD and AF had a higher proportion of disability and death than other stroke patients.7–10 Both oral anticoagulants and antiplatelet agents have been proven effective for stroke prevention in most patients at high risk for vascular events.
Correspondence to: Ming Liu, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37, GuoXue Xiang, Chengdu 610041, Sichuan Province, China. Email: [email protected]
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DOI 10.1179/1743132815Y.0000000071
However, oral anticoagulation treatment (OAT) for prevention of cardioembolic stroke in patients with AF is much more effective than antiplatelet therapy, which has been identified by large clinical trials.11,12 Current evidence-based guidelines advocate anticoagulation use as a strong recommendation in IS patients with RHD/AF,9,13,14 as well. Despite the compelling evidence exists, it has been found that anticoagulation among such patients in clinical practice is underused and disparate in different regions worldwide.15 Due to less developed and more rural in West China, these regional differences of anticoagulation may be much more apparent compared to other areas in China. Little is known about implementation of antithrombotic therapy to prevent stroke for patients with AF and/or RHD in daily practice in West China. Therefore, we aimed to examine patterns of antithrombotic treatment before and after admission, and to assess the adherence of antithrombotic therapy in secondary prevention in IS patients with
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AF and/or RHD; finally, we aimed to assess the comparative effects of antithrombotic treatment for 1-year stroke prognosis.
Methods Consecutive patients with acute IS and AF (or RHD) admitted within 1 month since stroke onset to Department of Neurology, West China Hospital from November 2010 to October 2011 were included in the study. All patients had a clinical diagnosis of stroke according to World Health Organisation criteria,16 further confirmed by computed tomography or magnetic resonance imaging scan. Informed consent was obtained from participants or their guardians. This study was approved by the Scientific Research Department of our hospital, which also conformed to the local ethic criteria. Details of patient demographics, time of stroke onset, stroke severity on admission, risk factors, prior antithrombotic, diagnostic tests, neurological imaging, treatment administered, stroke-related complications during hospitalisation and discharge medicine/interventions were recorded at the time of assessment using a standardised structured form. Patients were followed up at 3, 6 months and 1 year after stroke onset by telephone interviews or letter inquiries to assess current medicine use and clinical outcomes. Atrial fibrillation was defined as a history of persistent AF or paroxysmal AF, supported by past ECG or diagnosed by the attending physicians based on ECG and/or 24-hour ECG monitoring during admission.6 Rheumatic heart disease was diagnosed according to International Classification of Diseases, 10th edition, criteria and further confirmed by echocardiography.6 Data were also collected for other vascular risk factors, including hypertension, diabetes mellitus, hyperlipidaemia, coronary heart disease, previous transient ischaemic attacks, history of stroke and current smoking and alcohol consumption, which have been described in previous reports.6,17 Stroke severity on admission was measured using the National Institutes of Health Stroke scale (NIHSS).18 The outcome measures were death, disability, death/disability and recurrence at 3, 6 months and 1 year after stroke. Disability was measured according to the modified Rankin Scale score and was defined as a score of 3–5.19 Results for categorical variables were compared between different groups using chi-squared or Fisher exact tests. Results of continuous variables were compared using ANOVA or Mann–Whitney U tests. The impact of prior to stroke antithrombotic on stroke severity in the acute stage was analysed according to NIHSS score on admission categorised by two cut-off points (j6 vs w6 and j15 vs w15).18 Binary logistic regression was used to evaluate the association between
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antithrombotic therapy started within 3 months and outcomes. Cumulative 1-year survival and recurrence rates were estimated using the Kaplan–Meier product limit method and the results for different groups were compared using log rank tests. A two-tailed value of P v 0.05 was defined as the threshold of statistical significance. All statistical analyses were performed using SPSS (version 16).
Results Baseline characteristics During the enrolment period from November 2010 to October 2011, 155 consecutive IS patients with AF and/or RHD were analysed in this study, of them 54.2% (84/155) were females and the mean age was 68.3 + 12.5 years at stroke onset. Of these, five patients (3.2%) were with only RHD, 105 (67.8%) with only AF, and 45 (29.0%) with both RHD and AF. The baseline characteristics of the patients are listed in Table 1. Ultimately, 134 patients were alive at 1-year post-stroke during the follow-up (Fig. 1). Of the 150 patients with AF, 90 (60.0%) were known to have AF and 60 (40.0%) were diagnosed with AF for the first time due to current stroke presentation. Among the 90 patients with AF diagnosed previously, 56 (62.2%) patients were diagnosed due to cardiac manifestation, 10 (11.1%) patients were diagnosed due to previous stoke, and the remaining 24 (26.7%) were diagnosed according to other manifestation.
Preadmission antithrombotic therapy use and impact on stroke severity One hundred thirteen patients have been diagnosed as AF and/or RHD before the time of admission. Prior to stroke, of those with known AF/RHD, 43.4% were on antithrombotic therapy, including nine receiving Table 1 Baseline characteristics of ischaemic stroke (IS) patients with rheumatic heart disease (RHD)/atrial fibrillation (AF) Characteristic Age, years Mean ^ SD Range Sex, n (%) Male Female Risk factors, n (%) Hypertension Diabetes mellitus Hyperlipidaemia Coronary heart disease Current smoking Alcohol consumption Previous TIA History of stroke Stroke severity on admission National Institutes of Health Stroke scale (NIHSS) score, median
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68.3 ^ 12.5 29–89 71 (45.8) 84 (54.2) 69 (44.5) 24 (15.5) 3 (1.9) 21 (13.5) 29 (18.7) 18 (11.6) 1 (0.6) 32 (20.6) 8
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Figure 1 The total number of patients in each stage during follow-up.
warfarin, and 40 receiving anti-platelets treatment. Use of anti-platelets or warfarin before stroke was not associated with a mild or moderate stroke severity on admission (NIHSS j 6: P 5 0.601; NIHSS j 15: P 5 0.889) and was not associated with death at discharge (P 5 0.803).
Antithrombotic use at discharge and during 1-year follow-up period As shown in Table 2, 123 (84.8%) patients were on antithrombotic therapy at discharge. One hundred fifteen (82.1%), 117 (85.4%), and 109 (81.3%) patients were on antithrombotic medication therapy at 3, 6 months and 1 year post-stroke, respectively. Among the 134 patients alive at 12 months since stroke onset, those who received warfarin at discharge (n 5 36), eight (22.2%) patients were taken off warfarin, whereas those who did not receive warfarin at discharge (n 5 98), 18 patients (18.4%) were started on warfarin. The persistence rate of warfarin use at 1 year was 77.8% (of the patients who were discharged and remained on warfarin at 1 year); and of the patients Table 2 Rates of antithrombotic use at discharge, and during 1-year follow-up period
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Time since stroke
Alive (n)
Warfarin (n)
At discharge 3 Months 6 Months 1 Year
145 140 137 134
37 (25.5%) 42 (30.0%) 48 (35.0%) 46 (34.3%)
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86 (59.3%) 73 (52.1%) 69 (50.4%) 63 (47.0%)
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who did not receive warfarin at discharge, 80 (81.6%) never started warfarin during this 1-year period.
Impact of antithrombotic use started within three months on stroke outcomes As shown in Table 3, in patients with warfarin therapy started within 3 months since stroke onset, the 12-month death rate was 2.0%, in patients with antiplatelets started within 3 months was 7.5% and in patients with no antithrombotic therapy within 3 months was 25.0%. The death rates in patients with antithrombotic therapy were significantly lower than in patients with no antithrombotic therapy at the end of 3-month (P 5 0.014), 6-month (P 5 0.008) and 1-year (P 5 0.019) follow-up. However, after adjusting for age, sex and NIHSS on admission, the death risk in patients with antithrombotic therapy started within 3 months was similar to that in patients with no antithrombotic therapy within 3 months (95%CI, 0.040–1.049, P 5 0.057), whereas the death risk in patients with antithrombotic therapy started within 3 months was significantly lower than at 6 months (95%CI, 0.056–0.799, P 5 0.022) and at 1 year (95%CI, 0.094–0.890, P 5 0.031). One-year survival curves demonstrated warfarin and anti-platelets therapy were associated with a significantly higher cumulative survival rates at 1-year after stroke onset compared to no antithrombotic therapy (98.0 vs 92.5% vs 75.0%, P 5 0.005, log rank test) (Fig. 2). The three groups did not differ significantly in disability rates at 3 months (p 5 0.232), 6 months
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Table 3 Rates of death, disability and combined death and disability in patients with ischaemic stroke (IS) and atrial fibrillation (AF)/rheumatic heart disease (RHD) Outcome Death 3 Months 6 Months 12 Months Disability 3 Months 6 Months 12 Months Death þ disability 3 Months 6 Months 12 Months
No
Anti-platelets
Warfarin
P
3/16 (18.8) 4/16 (25.0) 4/16 (25.0)
1/80 (17.7) 3/80 (3.8) 6/80 (7.5)
1/49 (2.0) 1/49 (2.0) 1/49 (2.0)
0.014† 0.008† 0.019†
8/13 (61.5) 6/12 (50.0) 6/12 (50.0)
34/79 (43.0) 28/77 (36.4) 27/74 (36.5)
17/78 (35.4) 16/48 (33.3) 14/48 (29.2)
0.232* 0.562* 0.373*
11/16 (68.8) 10/16 (62.5) 10/16 (62.5)
35/80 (43.8) 31/80 (38.8) 33/80 (41.3)
18/49 (36.7) 17/49 (34.7) 15/49 (30.6)
0.081* 0.135* 0.073*
*Chi-squared test, †Fisher exact test.
Figure 2 Kaplan–Meier estimates of 1-year survival curves for IS patients with RHD/AF. Curves for the three groups were significantly different (P 5 0.005, log rank test).
(P 5 0.562) or 12 months (P 5 0.373; Table 2). When death and disability rates were combined into an aggregate measure of poor outcomes, there was also no significantly difference among three groups at 3 (P 5 0.081), 6 (P 5 0.135) or 12 months (P 5 0.073; Table 3). As to recurrence, by 12 months, stroke had recurred in 20 patients (12.9%). Kaplan–Meier estimates of 1-year cumulative stroke recurrence showed similar results for patients with and without antithrombotic therapy (P 5 0.814, log rank test).
Discussions Stroke attributable to AF or RHD is common in the Chinese population and China is still facing an epidemic of AF and AF/RHD related stroke, the prevalence of which increases significantly with age.3,5,6 Despite that, little information on implementation of antithrombotic therapy to prevent stroke for
patients with AF and/or RHD in daily practice in West China is currently available. In the present study, we provided insights on this respect based on a prospective cohort of hospitalised patients’ population in West China, found overall real-world use of warfarin is low in IS patients with AF/RHD, and IS patients with AF and/or RHD in West China prefer antiplatelet therapy to anticoagulation therapy in daily secondary prevention. Moreover, warfarin and anti-platelets therapy were significantly associated with a reduction in the odds of death at 1-year after stroke onset in routine medical context. Only 8% of our study population had been receiving warfarin therapy at stroke presentation. This is much lower than that reported by other studies conducted in western countries, which ranged from 21.9 to 37%.20–24 There were two possible reasons for underusing oral anticoagulants in our study. First, when physicians recommended patients to use warfarin, and meanwhile
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told them the bleeding risk, and benefits of warfarin, most of the patients in West China refused to accept it immediately because of overestimating the risk of bleeding, and underestimating the risk of stroke and the benefit of warfarin. Second, the inconvenience and high economic burden in monitoring and adjusting INR was another barrier. Moreover, prestroke warfarin therapy in our study is also lower than that one study from China National Stroke Registry (16.2%).25 This might be related to the less developed, low education, and more rural in West China. Above all, these suggest that the frequency of warfarin therapy before stroke onset can vary greatly by geographic region, not only in different countries with different economic level but also in different areas within the same country. Although the percentage of warfarin therapy in our study rose up from 25.5% at discharge to 34.3% at 1-year after stroke onset, which is also much poorer than Lopes, R. D. et al. study (49.1–44.3%).26 In addition, in our research, 86(59.3%) patients accepted antiplatelet therapy at discharge and 63 (47.0%) at 1-year follow-up. These data suggested that IS patients with AF and/or RHD in West China prefer antiplatelet therapy to anticoagulation therapy in daily secondary prevention. It might be because of the use of antiplatelet agents for stroke prevention in these patients who fear to be on warfarin because of the bleeding risk. This unrealistic fear of bleeding is common among Chinese patients, especially in rural areas. It was surprising to see no association between preadmission antithrombotic therapy use and stroke severity on admission and death at discharge in our study. This finding is contrary to several other studies, which suggested preadmission antithrombotic therapy was associated with less severe stroke and lower mortality.22–24 One possible interpretation is that the sample of our study is small and the proportion of patients on antithrombotic therapy at stroke presentation is lower than other studies. For example, O’Donnell, M. et al. included 948 consecutive patients with acute IS and AF using data from the Registry of the Canadian Stroke Network (2003–05) and found 37% patients were receiving Warfarin and 31% were on anti-platelets.24 Similarly to previous randomised controlled trials,14,27,28 we found warfarin and anti-platelets therapy could significantly reduce the death risk at 1-year after stroke onset in routine medical context. By contrast, we did not find significant association between antithrombotic therapy and 1-year stroke recurrence or disability in our study. This may be explained by the small sample of our study and more severe stroke in individuals with AF resulting in greater risk of death before stroke can recurrent.17 Despite that, our study still shows there is overall benefit for antithrombotic therapy in IS
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patients with AF and/or RHD during 1-year follow-up period after stroke onset in routine medical context. Our study has several limitations. First, it is a single centre, hospital-based study, so the study population may not be representative of other populations in West China or of the general population of stroke patients with RHD and/or AF. Some stroke patients may not present to hospital, especially those with mild symptoms or those who died before they could be admitted. Second, the follow-up visits were conducted by telephone and mail rather than in person. This decision was based on the fact that many patients at our hospital travel from the distant areas in West China to be treated, making in-person follow-up difficult. Previous studies have shown that face-to-face assessment of mRS is impractical, follow-up by telephone or letter can lead to good follow-up rates and reliable results with low bias.29,30 In conclusion, our study suggests that IS patients with AF and/or RHD in West China prefer antiplatelet therapy to anticoagulation therapy in daily secondary prevention, and overall real-world use of warfarin in West China is low before and after admission of IS patients with AF and/or RHD. More implementation researches on antithrombotic therapy in such patients in West China should be conducted.
Disclaimer Statements Contributors DW and JL contributed equally to this work. Funding This study was sponsored by research grants from the National Natural Science Foundation of China (Grant No.81371282 and Grant No.81400964). The agency did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Conflicts of interest The authors declare no financial or other conflict of interests. Ethics approval This study was approved by the Scientific Research Department of our hospital which also conformed to the local ethic criteria.
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