EDITORIAL COMMENT
Ethnic Disparity in Intracranial Hemorrhage Among Anticoagulated Patients With Atrial FibrillationAn Answer in Search of a Question?*
Rodney H. Falk, MD, FRCP, FACC*
Department of Cardiology, Harvard Vanguard Medical Associates, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts.
* Reprint requests and correspondence: Dr. Rodney H. Falk, Department of Cardiology, Harvard Vanguard Medical Associates, 133 Brookline Avenue, Boston, Massachusetts 02215. (Email: rfalk{at}partners.org).
Stroke due to intracranial hemorrhage (ICH) carries a higher morbidity and mortality than ischemic stroke, and it has been estimated that among persons 45 to 64 years of age, 8% to 12% of ischemic strokes and 37% to 38% of hemorrhagic strokes result in death within 30 days (1). The risk of ICH is increased among patients receiving heparin or warfarin, and the mortality of anticoagulant-associated ICH is approximately double that of spontaneous ICH (1–4). Atrial fibrillation (AF) is an independent risk factor for ischemic stroke. It increases stroke risk about 5-fold, and this risk is significantly reduced by warfarin.
In the last decade, based on robust clinical trials, there has been an increasing use of warfarin for prevention of ischemic stroke, resulting in a reduction in the incidence of AF-associated ischemic stroke. However, complication rates in clinical trials do not always translate into clinical practice. In a survey in the greater Cincinnati area between 1988 and 1999, Flaherty et al. (5) reported an increase in anticoagulant-associated ICH from 5% of all patients with ICH in 1988 to 17% in 1999. This was accompanied by an approximately 4-fold increase in warfarin use, and the authors attributed the rise in ICH to increasing warfarin use, predominantly among patients with AF. On the basis of such data, it has been estimated that approximately 12% to 24% of intracerebral bleeds are warfarin-related and that as many as 10,000 anticoagulant-related intracerebral hemorrhages occur annually in the U.S. (2–7).
In this issue of the Journal, Shen et al. (8) report on the prevalence of ICH among 18,867 patients, hospitalized for the first time with AF and followed for a median of approximately 3 years. The study was retrospective, and diagnosis was based on the International Classification of Diseases (ICD)-9 codes 430 to 432, which include both intracerebral and subarachnoid hemorrhage. During follow-up, 58.4% took warfarin for at least part of the time. One hundred seventy-five spontaneous ICHs occurred, the majority of them in patients who were taking warfarin when the bleed occurred. Although there was no difference in the prevalence of ICH among racial groups who were not receiving warfarin, nonwhite patients receiving warfarin had a significantly higher risk of ICH, with a hazard ratio, compared with whites, of 2.05 for blacks, 2.06 for Hispanics, and 4.1 for Asians. The findings of this study warrant careful examination, because they have the potential to modify practice and, if the results are incorrectly interpreted, any change in practice could be detrimental to patient care. To understand their significance, several questions need to be addressed. For example, are the findings related to overanticoagulation in minorities due to increased warfarin sensitivity or is the increased ICH rate with warfarin in minorities a function of their greater risk of ICH regardless of warfarin therapy? And, if minorities have a greater ICH risk with warfarin, might this reflect a higher prevalence of intracranial pathology or is it a feature of a greater prevalence of risk factors for ICH such as hypertension? Finally, should these results affect the prescribing of warfarin in minorities, particularly for Asians, who had the highest rate of this devastating condition?
Genetic variations play a role in determining the maintenance dose of warfarin and, among patients with mutations that result in a low warfarin maintenance dose, overanticoagulation during the initial phases of warfarin treatment is quite common (9). Rieder et al. (10) estimated that 21% to 25% of the maintenance dose of warfarin can be explained by variance in the gene-encoding vitamin K epoxide reductase complex 1. Five common haplotypes were identified, 2 of which resulted in the need for a lower warfarin dose. Haplotypes predictive of a low maintenance dose of warfarin were present in 35% of whites compared with 89% of Asians but only 14% of blacks; these findings have been subsequently confirmed in populations attending anticoagulation clinics in several different areas of the world (9,11–14). Warfarin sensitivity, partly mediated by genetic variation, is associated with an increased bleeding risk. This risk clusters in the early period of therapy, when excessively high international normalized ratio (INR) measurements might occur and greatly lessens during maintenance therapy once a therapeutic INR is achieved (9). Thus genetic differences in warfarin sensitivity would be expected to manifest themselves as differences in early bleeding rates. In the current study, reference to the authors’ figure demonstrates that, rather than a cluster of bleeding risk early after warfarin therapy, excess bleeding risk among minorities persisted over several years. Data on anticoagulation intensity are presented and do not suggest that overanticoagulation accounted for excess ICH in minorities. Indeed, among blacks, there was a tendency toward underanticoagulation. Thus, although genetic variation might explain Asian sensitivity to warfarin, it would not account for excessive ICH rates in the Asian population and would certainly not explain the increased risk in blacks.
Hypertension is a major risk factor for ICH, and the risk of ICH is related to hypertension severity and consistency of blood pressure control (15–18). Blacks have a higher prevalence of hypertension than whites, and hypertension in this population might be more severe and more difficult to control. In the current study, 77.5% of the population had hypertension, but the black population had the highest prevalence. The nature of the study did not allow the severity of hypertension to be assessed, and hypertension was analyzed as a dichotomous variable, so it is conceivable that blacks had both a higher prevalence and more severe hypertension, potentially explaining some of their risk. However, there is inadequate information to be certain, and the precise role of poorly controlled hypertension remains intriguing but uncertain.
Cerebral amyloid angiopathy (CAA) is characterized by the deposition of congophilic amyloid beta protein in cortical and leptomeningeal vessels (3,19,20) and is associated with lobar hemorrhage in elderly patients. Patients with CAA have a 4-fold increase in warfarin-associated intracranial bleeding, and several gene polymorphisms are associated with both the presence and severity of this condition (19). The authors do not indicate whether there was a predominance of lobar hemorrhage (which would suggest CAA), but other studies have addressed this issue. In a study in northern Manhattan, blacks and Hispanics were found to have an increased risk of all types of ICH, with nonlobar hemorrhage predominating (6), and in an autopsy series of Chinese patients, the prevalence of CAA was found to be much lower than expected in whites, despite a higher incidence of intracerebral hemorrhage in this population (21). Thus CAA is unlikely to explain the ethnic differences in the current study.
None of the aforementioned mechanisms give a satisfactory answer to the findings in this study. Therefore, rather than focus the question on why warfarin might have caused an increased ICH risk in minorities, it is worthwhile stepping back and asking whether ethnic variation in ICH occurs in the absence of warfarin. If so, then the results might well be explained by an increased overall ICH risk among warfarin-treated patients regardless of ethnicity. In the present study, minorities with AF did not have a statistically significant excess ICH risk unless they were using warfarin. This might suggest that the drug is the culprit rather than the existence of intrinsic interethnic variations in ICH prevalence that are exaggerated by anticoagulation. However, extensive data in published reports suggest that this is not the case. Age standardized mortality rates in the U.S. between 1995 and 1998 for ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage were all higher among blacks than whites, and death rates from intracerebral hemorrhage but not ischemic stroke was higher among Asians and Pacific islanders than among whites (22). In a much larger study than the current one, also from Kaiser Permanente of California, black patients had a relative risk of intracerebral hemorrhage of 1.9 compared with whites, and Asians had a relative risk of 1.6 (23). Although information is not available about the rhythm in these patients or their anticoagulant use, this was a relatively young population, and it is unlikely that many were using anticoagulants. Finally, in a recently published study of a similar number of anticoagulant-associated ICH, almost one-half of whom had AF, Flaherty et al. (4) found no evidence of excess warfarin-related ICH risk in black patients compared with whites.
The risk of ischemic stroke is high among most patients with AF, and it would require overwhelmingly convincing data to result in a recommendation to withhold warfarin in minorities with AF. The present study does not offer such data, but the findings do underscore the importance of developing an approach to therapy that should include a consideration of ethnicity when choosing a dose of warfarin to initiate therapy. In addition, the data underscore the necessity for a vigorous approach to treating risk factors for ICH, particularly hypertension, which might be more common and more severe in minority populations.
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Footnotes
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* Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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1. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2007;115:e69-e171.[Free Full Text]2. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion Mayo Clin Proc 2007;82:82-92.[Abstract/Free Full Text] 3. Ferro JM. Update on intracerebral haemorrhage J Neurol 2006;253:985-999.[CrossRef][Web of Science][Medline] 4. Flaherty ML, Haverbusch M, Sekar P, et al. Location and outcome of anticoagulant-associated intracerebral hemorrhage Neurocrit Care 2006;5:197-201.[CrossRef][Web of Science][Medline] 5. Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage Neurology 2007;68:116-121.[Abstract/Free Full Text] 6. Labovitz DL, Halim A, Boden-Albala B, Hauser WA, Sacco RL. The incidence of deep and lobar intracerebral hemorrhage in whites, blacks, and Hispanics Neurology 2005;65:518-522.[Abstract/Free Full Text] 7. Pautas E, Gouin-Thibault I, Debray M, Gaussem P, Siguret V. Haemorrhagic complications of vitamin K antagonists in the elderly: risk factors and management Drugs Aging 2006;23:13-25.[CrossRef][Web of Science][Medline] 8. Shen AY-J, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation J Am Coll Cardiol 2007;50:309-315.[Abstract/Free Full Text] 9. Lindh JD, Lundgren S, Holm L, Alfredsson L, Rane A. Several-fold increase in risk of overanticoagulation by CYP2C9 mutations Clin Pharmacol Ther 2005;78:540-550.[CrossRef][Web of Science][Medline] 10. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose N Engl J Med 2005;352:2285-2293.[Abstract/Free Full Text] 11. Lee SC, Ng SS, Oldenburg J, et al. Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population Clin Pharmacol Ther 2006;79:197-205.[CrossRef][Web of Science][Medline] 12. Li T, Lange LA, Li X, et al. Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation J Med Genet 2006;43:740-744.[Abstract/Free Full Text] 13. Moridani M, Fu L, Selby R, et al. Frequency of CYP2C9 polymorphisms affecting warfarin metabolism in a large anticoagulant clinic cohort Clin Biochem 2006;39:606-612.[CrossRef][Web of Science][Medline] 14. Schalekamp T, Brasse BP, Roijers JF, et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation Clin Pharmacol Ther 2006;80:13-22.[CrossRef][Web of Science][Medline] 15. Song YM, Sung J, Smith GD, Ebrahim S. Blood pressure, haemorrhagic stroke, and ischaemic stroke: the Korean national prospective occupational cohort study BMJ 2004;328:831-836. 16. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas Stroke 2005;36:1588-1593.[Abstract/Free Full Text] 17. Huber J, Stollberger C, Finsterer J, Schneider B, Langer T. Quality of blood pressure control and risk of cerebral bleeding in patients with oral anticoagulation Acta Med Austriaca 2003;30:6-9.[CrossRef][Web of Science][Medline] 18. Lip GYH, Frison L, Grind M. Effect of hypertension on anticoagulated patients with atrial fibrillation Eur Heart J 2007;28:752-759.[Abstract/Free Full Text] 19. Yamada M. Cerebral amyloid angiopathy and gene polymorphisms J Neurol Sci 2004;226:41-44.[CrossRef][Web of Science][Medline] 20. Smith EE, Eichler F. Cerebral amyloid angiopathy and lobar intracerebral hemorrhage Arch Neurol 2006;63:148-151.[Free Full Text] 21. Ng TH, Leung SY, Wong MP. Cerebral amyloid angiopathy in Chinese: incidence and significance Clin Neurol Neurosurg 1991;93:19-23.[CrossRef][Web of Science][Medline] 22. Ayala C, Greenlund KJ, Croft JB, et al. Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995–1998 Am J Epidemiol 2001;154:1057-1063.[Abstract/Free Full Text] 23. Klatsky AL, Friedman GD, Sidney S, Kipp H, Kubo A, Armstrong MA. Risk of hemorrhagic stroke in Asian American ethnic groups Neuroepidemiology 2005;25:26-31.[CrossRef][Web of Science][Medline]
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