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Advanced Age, Anticoagulation Intensity, and Risk for Intracranial Hemorrhage among Patients Taking Warfarin for Atrial Fibrillation

Margaret C. Fang, MD, MPH; Yuchiao Chang, PhD; Elaine M. Hylek, MD, MPH; Jonathan Rosand, MD; Steven M. Greenberg, MD, PhD; Alan S. Go, MD; and Daniel E. Singer, MD
[+] Article and Author Information

From University of California, San Francisco, San Francisco, and Kaiser Permanente of Northern California, Oakland, California; and Massachusetts General Hospital, Boston, Massachusetts.


Acknowledgments: The authors thank Susan Regan, PhD, for her invaluable assistance with the Anticoagulation Management Services database; Robert A. Hughes, MD, and Walter J. Moulaison Jr., RN, MSN, MBA, directors of the Massachusetts General Hospital Anticoagulation Management Services, for facilitating research using the unit; and Drs. Shawn Murphy and Henry Chueh and the Partners Health Care Research Patient Data Registry group for facilitating use of their database.

Grant Support: By National Research Service Award 5T32-HP-11001-14, Public Health Services research grant AG15478 from the National Institute on Aging, and the Eliot B. Shoolman Fund of the Massachusetts General Hospital.

Potential Financial Conflicts of Interest: Honoraria: E.M. Hylek (Bristol-Myers Squibb); Grants received: E.M. Hylek (Bristol-Myers Squibb), D.E. Singer (DuPont Pharma).

Requests for Single Reprints: Margaret C. Fang, MD, MPH, Division of General Internal Medicine, Hospitalist Group, University of California, San Francisco, 533 Parnassus Avenue, Box 0131, San Francisco, CA 94143; e-mail, mfang@medicine.ucsf.edu.

Current Author Addresses: Dr. Fang: Division of General Internal Medicine, Hospitalist Group, University of California, San Francisco, 533 Parnassus Avenue, Box 0131, San Francisco, CA 94143.

Drs. Chang, Hylek, and Singer: General Medicine Division, Clinical Epidemiology Unit, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.

Drs. Rosand and Greenberg: Neurology Clinical Trials Unit, Massachusetts General Hospital, ACC-836, 15 Parkman Street, Boston, MA 02114.

Dr. Go: Division of Research, Kaiser Permanente of Northern California, 2000 Broadway Street, 3rd Floor, Oakland, CA 94612.

Author Contributions: Conception and design: M.C. Fang, E.M. Hylek, D.E. Singer.

Analysis and interpretation of the data: M.C. Fang, Y. Chang, A.S. Go, D.E. Singer.

Drafting of the article: M.C. Fang, D.E. Singer.

Critical revision of the article for important intellectual content: E.M. Hylek, J. Rosand, S.M. Greenberg, A.S. Go, D.E. Singer.

Final approval of the article: E.M. Hylek, J. Rosand, S.M. Greenberg, A.S. Go, D.E. Singer.

Provision of study materials or patients: J. Rosand, S.M. Greenberg.

Statistical expertise: Y. Chang, D.E. Singer.

Obtaining of funding: D.E. Singer.

Administrative, technical, or logistic support: D.E. Singer.

Collection and assembly of data: M.C. Fang


Ann Intern Med. 2004;141(10):745-752. doi:10.7326/0003-4819-141-10-200411160-00005
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To our knowledge, this is the largest study to date to examine risk factors for warfarin-associated intracranial hemorrhage and the only study to specifically address intracranial hemorrhage risk in patients receiving anticoagulation for atrial fibrillation. The odds of intracranial hemorrhage increased with age but increased most sharply at 85 years of age or older. We also found that the odds of intracranial hemorrhage, in particular intracerebral hemorrhage, increased at INRs of 3.5 and higher. International normalized ratios less than 2.0 were not associated with a lower risk for intracranial hemorrhage compared with INRs of 2.0 to 3.0. Combined with previous work, the results of our study do not support the use of target INRs less than 2.0 for atrial fibrillation, since the risk for and mortality associated with ischemic stroke increase substantially at these lower values without a corresponding decrease in the risk for intracranial hemorrhage (16, 28).

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Figures

Grahic Jump Location
Figure 1.
Adjusted relative odds of intracranial hemorrhage by age in 145 case-patients and 870 controls, overall (top) and stratified by hemorrhage (bottom).

The referent group was patients 70 to 74 years of age. Data points are plotted at the midpoints of each age interval; vertical bars represent 95% CIs.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Adjusted relative odds of intracranial hemorrhage by international normalized ratio (INR) in 145 case-patients and 870 controls, overall (top) and stratified by hemorrhage (bottom).

The referent group was patients with an INR of 2.0 to 3.0. Data points are plotted at the midpoints of each INR interval; vertical bars represent 95% CIs.

Grahic Jump Location

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Risk of intracerebral hemorrhage is increased when aspirin is added to warfarin
Posted on November 17, 2004
Robert Hart
University of Texas Health Science Center
Conflict of Interest: None Declared

The case-control study by Fang et al. excluded 503 cases due to "lack of anticoagulation".(1) Does this refer to "not receiving warfarin" or "no prolongation of the INR"? If it is the latter, the study systematically underestimates the risk of intracerebral hemorrhage at lower INRs. If it is the former, was the determination made with knowledge of the INR, potentially biasing the selection?

Concomitant use of aspirin with anticoagulation did not emerge as a risk factor for intracranial hemorrhage in this study which did not consider duration of antithrombotic therapy, sharply conflicting with a meta-analysis of randomized trials (2), a longitudinal cohort study (3), and bivariate analysis of a under-powered case-control study (4) indicating a 2-3 fold increased risk of intracerebral hemorrhage when aspirin is added to warfarin. Considering all available data, concomitant use of aspirin is likely to increase the risk of warfarin-associated intracerebral hemorrhage, and this is important for clinicians to appreciate.

Finally, the authors' major conclusion that "anticoagulation management should focus on maintaining INRs in the 2.0-3.0 range"¦" is not supported strongly by their data because neither efficacy for thromboembolism prevention nor major extracranial bleeding were assessed.

1. Fang MC, Chang Y, Hylek EM, Rosand J, Greenberg SM, Go AS, Singer DE. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141: 745-52.

2. Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: a meta-analysis and hypothesis. Cerebrovasc Dis 1999; 9: 215-17.

3. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004; 35: 2362-7.

4. Berwaerts J, Webster J. Analysis of risk factors involved in oral- anticoagulant-related intracranial hemorrhages. Q J Med 2000; 93: 513-521.

Conflict of Interest:

None declared

Warfarin or not warfarin?
Posted on November 27, 2004
Francisco J Ruiz-Ruiz
Hospital Clinico de Zaragoza, Spain
Conflict of Interest: None Declared

Warfarin or not warfarin? That is the question. Each day, this dilemma is considered by physicians who treat elderly patients, specially octogenarian. Benefits of warfarin are well known in patients at 75 years of age or older. But, they have a higher risk than younger patients for intracranial hemorrhage and other types of bleeding associated with warfarin.

Fang et al establish the intracranial hemorrhage risk depend on age and INR (1). However, characteristics of these patients are not favourable to prescribe warfarin. INR control is more difficult in patients at 85 years of age or older due to several factors. So, a high percent of them suffer from gait disturbances, neurodegenerative diseases and others prevalent diseases (diabetes, COPD, heart failure, "¦). A lot of them take drugs such as amiodarone, antibiotics, corticoids, statins, omeprazol, NSAID, "¦, which can increase warfarin effect. Other patients present social problems that not guarantee a right monitoring.

Because we treat patients and not percents or relative risk, I think to generalize recommendation about oral anticoagulation in very older patients should be avoided. According to associated diseases, concurrent medications, functional and mental status, "¦ we should individualize prescription of anticoagulation.

REFERENCES 1. Fang MC, Chang Y, Hylek EM, Rosand J, Greenberg SM, Go AS, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141: 745-52

Conflict of Interest:

None declared

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Summary for Patients

What Is the Appropriate Level of Blood-Thinning Medication for Elderly People with Atrial Fibrillation?

The summary below is from the full report titled “Advanced Age, Anticoagulation Intensity, and Risk for Intracranial Hemorrhage among Patients Taking Warfarin for Atrial Fibrillation.” It is in the 16 November 2004 issue of Annals of Internal Medicine (volume 141, pages 745-752). The authors are M.C. Fang, Y. Chang, E.M. Hylek, J. Rosand, S.M. Greenberg, A.S. Go, and D.E. Singer.

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