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(Stroke. 2004;35:2362.)
© 2004 American Heart Association, Inc.

Original Contributions

Combined Anticoagulant–Antiplatelet Use and Major Bleeding Events in Elderly Atrial Fibrillation Patients

Theresa I. Shireman, PhD RPh; Patricia A. Howard, PharmD; Timothy F. Kresowik, MD Edward F. Ellerbeck, MD MPH

From the Pharmacy Practice Department (T.I.S.), University of Kansas School of Pharmacy, Lawrence, Kan; the Departments of Pharmacy Practice and Medicine (P.A.H.), University of Kansas Schools of Pharmacy & Medicine, Kansas City, Kan; the Department of Surgery (T.F.K.), University of Iowa College of Medicine, Iowa City, Iowa; the Department of Preventive Medicine and Internal Medicine (E.F.E.), University of Kansas School of Medicine, Kansas City, Kan.

Correspondence to Theresa I. Shireman, PhD, RPh, Pharmacy Practice Department, University of Kansas School of Pharmacy, 1251 Wescoe Hall Drive, Lawrence, KS 66045. E-mail Shireman{at}ku.edu

	Abstract

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Background and Purpose— Bleeding risks from combined antiplatelet-warfarin therapy have not been well-described in clinical practice. We examined antiplatelet therapy among warfarin users and the impact on major bleeding rates.

Methods— Retrospective cohort analysis of persons discharged on warfarin after an atrial fibrillation admission using data from Medicare’s National Stroke Project. Data included Medicare claims, enrollment information, and medical record abstracted data. Logistic regression and Cox proportional hazards models were used to predict concurrent antiplatelet use and hospitalization with a major acute bleed within 90 days after discharge from the index AF admission.

Results— 10 093 warfarin patients met inclusion criteria with a mean age of 77 years; 19.4% received antiplatelet therapy. Antiplatelet use was less common among women, older persons, and persons with cancer, terminal diagnoses, dementia, and bleeding history. Persons with coronary disease were more likely to receive an antiplatelet agent. Antiplatelets increased major bleeding rates from 1.3% to 1.9% (P=0.052). In the multivariate analysis, factors associated with bleeding events included age (OR, 1.03; 95% CI, 1.002 to 1.05), anemia (OR, 2.52; 95% CI, 1.64 to 3.88), a history of bleeding (OR, 2.40; 95% CI, 1.71 to 3.38), and concurrent antiplatelet therapy (OR, 1.53; 95% CI, 1.05 to 2.22).

Conclusions— Although concerns about increased bleeding risk with combined warfarin-antiplatelet therapy are not unfounded, the risk of bleeding is moderately increased. The decision to use concurrent antiplatelet therapy appears to be tempered by cardiac and bleeding risk factors.

Key Words: anticoagulants • atrial fibrillation • blood • platelet aggregation inhibitors

	Introduction

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Atrial fibrillation (AF) occurs commonly in elderly individuals with underlying heart disease.¹ Warfarin has been proven to be the most effective antithrombotic agent for stroke prophylaxis in elderly AF patients and those with additional risk factors.² Although no additional benefit has been shown from combining antiplatelet drugs with warfarin for stroke prophylaxis in AF patients, common concomitant conditions including coronary heart disease (CHD) and cerebrovascular disease are indications for antiplatelet drugs. Little is known about which AF patients receive concurrent warfarin-antiplatelet therapy and the influence of advanced age and additional bleeding risk factors.

The impact of combined warfarin-antiplatelet therapy on bleeding risk remains unclear because of inconsistencies between randomized trial designs and clinical practice. These limitations include exclusion of many elderly patients and those with known bleeding risks from randomized trials. Additionally, clinical trials evaluating efficacy often minimized potential bleeding risks by using lower warfarin doses than those commonly seen in clinical practice. Thus, current evidence is insufficient to support clinical decision-making for AF patients requiring standard warfarin regimens combined with antiplatelet drugs.

Well-designed observational analyses have been shown to address these types of clinical questions in real-world practice.^3–5 In a previous study, we found that 20% of AF patients receive combined warfarin-antiplatelet therapy.⁶ The goals of the current study in elderly AF patients are to examine the influence of patient-specific factors on concomitant warfarin-antiplatelet therapy and the potential impact of combined therapy on major bleeding risk.

	Materials and Methods

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The study was a retrospective cohort analysis drawn from Medicare’s National Stroke Project.⁷ The Health Care Financing Administration (now known as the Centers for Medicare & Medicaid Services [CMS]) authorized data collection on patients discharged with AF from 52 US states and territories. The sample consisted of 750 randomly sampled, inpatient, fee-for-service Medicare beneficiaries per state or territory, discharged during a 6-month period between April 1, 1998 and March 31, 1999 from acute-care hospitals with a principal or secondary diagnosis of AF (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 427.31) as identified through National Claims History Files.

Data Sources
Four data sources were linked for this study: (1) initial claims data identifying the index AF hospitalization; (2) the Medicare enrollment database to identify dates of death and managed care enrollment; (3) medical record data abstracted for the index AF hospitalization; and (4) 90-day follow-up Medicare Part A hospitalization administrative claims. The medical record-abstracted data were compiled as part of the National AF Project,⁷ and the reliability of the data has been established as varying between 80% and 95%, with a median of 95%.⁸

Inclusion and Exclusion Criteria
Patient inclusion was based on confirmed AF during chart review, age 65 years or older, and warfarin discharge therapy. Patients were excluded if they were transferred to another acute-care hospital, died during hospitalization, or were discharged against medical advice. We also excluded subjects with managed care enrollment during the 90-days postindex AF hospitalization because CMS did not routinely process these hospitalization claims. Medicare beneficiary identification numbers were cross-referenced to track the cohort over time and ensure complete extraction of claims data.

Study Variables
The first outcome variable was antiplatelet drug use after discharge. Antiplatelets included aspirin, ticlopidine (Ticlid), and clopidogrel (Plavix). This variable was the major independent variable in the analysis of the second outcome. The second outcome was hospitalization with a major acute bleed within 90 days after discharge from the index AF admission. Acute major bleeds included gastrointestinal and intracranial hemorrhages (ICH) that resulted in an inpatient admission. We identified gastrointestinal hemorrhages by screening claims for diagnosis-related grouping codes 174 and 175 (gastrointestinal hemorrhage with and without complications).⁹ Because the diagnosis-related grouping codes for stroke events included both hemorrhagic and ischemic events, ICH were identified using the ICD-9-CM codes subarachnoid hemorrhage (430), intracerebral hemorrhage (431), and other intracerebral hemorrhage (432). Only the first episode of a major bleed per cohort member during the study period was included in the outcome analysis.

The independent variables ascertained from the medical record abstracted data were: age, gender, major comorbid conditions, bleeding risk factors, and warfarin use before admission. Major comorbid conditions considered were CHD, valvular heart disease, diabetes, previous cerebrovascular event, hypertension, and congestive heart failure. Bleeding risk factors aside from antiplatelet use included previous bleeding history, anemia during the index hospitalization (HCT <30%), ulcer, risk for falls, alcohol use, hepatic disease, dementia, cancer, and concurrent medications. Patients with terminal status were identified based on a prognosis of <6 months. Two pharmacists independently reviewed discharge medications to identify drugs with the potential to increase bleeding risks. These drugs were grouped as antibiotics, nonsteroidal antiinflammatory drugs, and other medications, including amiodarone, omeprazole, sertraline, phenytoin, heparin, and cisapride.⁶

Data Analyses
Descriptive statistics and bivariate relationships were compiled for all variables. The decision to use an antiplatelet was modeled using logistic regression, and the occurrence of major bleeding events was analyzed using Cox proportional hazards regression, adjusting for age, gender, and previous warfarin use. Bleeding risk factors and cardiac comorbidities were included in the antiplatelet use model. Comorbidities and bleeding risk factors were tested in the bleeding risk model using a backward elimination technique (P<0.05 to enter; P<0.10 to remain). Times to major bleeding events were plotted using survival analysis from the Cox regression. All statistical analyses were conducted using SPSS version 11.1 (SPSS, Inc).

The University of Kansas Advisory Committee on Human Experimentation approved the research protocol.

	Results

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From the original National Stroke Project database (n=38 924), we identified 10 093 cases meeting the inclusion criteria. Most exclusions were because of a lack of confirmatory AF (n=11 250), managed care enrollment (n=3122), and not discharged on warfarin (n=11 283 after other exclusions applied). The cohort was evenly divided between men and women with a mean age of 77.2 years (Table 1). The majority had CHD, hypertension, and congestive heart failure. Previous cerebrovascular events and diabetes were common. Approximately one-fifth had a previous bleeding event, and many were discharged on an antibiotic or other medication associated with bleeding. Approximately one-fifth (19.4%) of AF patients discharged on warfarin were simultaneously discharged on an antiplatelet agent, principally aspirin alone (89.7%), aspirin plus clopidogrel or ticlopidine (6.1%), or clopidogrel or ticlopidine alone (4.2%).

View this table: [in this window] [in a new window]   TABLE 1. Comparison of Descriptive Statistics Between Warfarin-Treated AF Patients With or Without Concurrent Antiplatelet Therapy

Multivariate Analysis: Factors Predicting Use of Concurrent Antiplatelet
In the multivariable model, women were 20% less likely to be prescribed an antiplatelet drug with warfarin, and concurrent antiplatelet use declined by 1% per year with each year of increasing age (Table 2). Those using warfarin before the index hospitalization and patients with terminal status were less likely to be discharged on an antiplatelet drug. CHD increased the odds of antiplatelet therapy and based on maximum likelihood estimates was the major driving factor for antiplatelet use. Bleeding risk factors that lowered the odds of concurrent therapy were a bleeding history, dementia, cancer, and discharge antibiotic. Concomitant use of nonsteroidal antiinflammatory drugs or other medications that may increase bleeding risk was associated with higher odds of antiplatelet use.

View this table: [in this window] [in a new window]   TABLE 2. Factors Predicting the Use of Concurrent Antiplatelets Among Warfarin Users

Impact of Combined Warfarin–Antiplatelet Therapy on Major Bleeding Events
In the bivariate analysis (Table 1), major bleeding events during 90 days after discharge occurred in 1.3% of the warfarin-only users versus 1.9% on combined warfarin–antiplatelet therapy (OR, 1.46; 95% CI, 0.998 to 2.12). The major difference was seen in ICH, which occurred 3x more frequently in the combined group. When we extended the follow-up period to 180 days, major bleeding rates were 2.0% for the warfarin-only group and 2.8% for the combined group; the 3-fold difference in ICH remained (0.3% versus 0.9%; OR, 2.95; 95% CI, 1.58 to 5.51).

In the multivariate Cox regression model (Table 3), age, combined warfarin–antiplatelet use, anemia, and bleeding history were significantly associated with a major bleed in the 90 days postdischarge. These factors remained in the model with the addition of terminal status, dementia, and miscellaneous medications associated with bleeding. Each 1-year increase in age was associated with a 3% increase in bleeding rate. Persons using combined therapy were 1.53x more likely to bleed, and those with anemia or a bleeding history were nearly 2.5x more likely to bleed. The survival curve for the adjusted model is shown in Figure.

View this table: [in this window] [in a new window]   TABLE 3. Factors Predicting Probability of a Major Bleeding Event Within 90 Days: Results of Cox Regression Analysis

View larger version (8K): [in this window] [in a new window]   Survival graph comparing time to bleeding events for warfarin users stratified by antiplatelet use.

	Discussion

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Almost 20% of AF patients using warfarin were discharged on antiplatelet therapy that appeared to be clinically driven by the presence of CHD. After accounting for other risk factors, combined warfarin–antiplatelet therapy increased the risk of a major bleeding event 50% during the 90-day follow-up period.

Although our findings differ from AF clinical trials reporting no additional risk with combined therapy,^10–11 the use of fixed low-dose warfarin and lower target INR ranges in these trials precludes extrapolation to warfarin regimens using the recommended INR (2.0 to 3.0). Increased bleeding rates were reported with warfarin–aspirin therapy compared with warfarin alone in studies of prosthetic heart valves,^12–14 but target INR were higher than those recommended for AF. Higher bleeding risks with combined warfarin–aspirin therapy compared with monotherapy have been reported in studies of postinfarction patients using target INR ranges up to 2.5,^15–18 and coronary patients receiving standard warfarin doses.^19–21 In exploring factors contributing to a higher risk, we included variables that were reflective of clinical practice as opposed to the randomized trials. Anemia and bleeding history led to a higher bleeding risk, whereas neither nonantiplatelet medications associated with bleeding nor a history of ulcers significantly increased the risk. We cannot rule out the possibility that unknown factors played a role, such as the presence of cerebral arterial disease.²²

Although comorbidities favor the use of antiplatelet drugs in AF patients receiving warfarin, little is known about which patients receive combination therapy. We found that antiplatelets were less likely to be used in women, users of warfarin before admission, persons with a bleeding history, and persons with short life expectancy. Decreased combination therapy in women could result from physician perceptions of increased bleeding risk²³ or a tendency toward less aggressive CHD treatment in women.^24–26 Use of concomitant warfarin–antiplatelet therapy declined with advancing age, a known bleeding risk factor. Surprisingly, other bleeding risk factors were not related to antiplatelet use.

Study limitations include possible misclassification bias. Although the validity of ICD-9-CM codes for stroke-related illnesses have been subject to debate, evidence suggests higher and more reasonable true positive values when using ICD-9-CM codes for hemorrhagic strokes.^27–28 No data are available on the validity of gastrointestinal hemorrhage diagnoses codes in hospitalization claims. We excluded minor bleeding that may be clinically important but requires fewer resources to manage.

We were unable to track medication use after hospitalization. Because we assumed the continued use of discharge medications, if substantial numbers of patients crossed over from one treatment group to another, we would have understated the true risk. Nevertheless, such an "intent-to-treat" analysis is the standard for randomized clinical trials and the method recommended for observational studies.⁵ Additional limitations include the inability to determine INR or aspirin doses and insufficient patient numbers to assess potential increased risk with concomitant aspirin–clopidogrel therapy as previously shown in coronary patients.²⁹ We found that persons using warfarin before admission were less likely to receive aspirin; we did not investigate prescriber decision-making relative to the addition of warfarin for persons receiving aspirin before admission.

A final comment concerning the 90-day follow-up and duration of therapy is warranted. Studies have shown that major bleeding from warfarin often occurs early with the highest rates during the first 3 months of therapy.^30–34 Because almost 40% of our study population had been using warfarin before admission, we were unable to determine the effects of treatment duration directly, although those who were using warfarin before admission did not have different bleeding rates. It is possible that our observed bleeding rates were lower than those commonly seen during initiation of anticoagulant therapy. However, most concerning was our finding of a 3-fold increase in the risk of ICH with combined therapy over time (0.9% versus 0.3% at 180 days).

	Summary

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AF is a major risk factor for stroke and a growing public health problem.³⁵ Previous studies have demonstrated the cost-effectiveness of warfarin in AF, provided that bleeding rates similar to those in the clinical trials are achieved.^36–38 Appropriate antithrombotic therapy in AF patients could prevent 40 000 strokes annually and save an estimated $600 million if bleeding risks were controlled.³⁹ Although practice guidelines encourage physicians to use warfarin for stroke prevention in high-risk AF patients,⁴⁰ the necessity of antiplatelet therapy for comorbidities such as CHD complicates treatment decisions.

Our results reflect AF patients seen in clinical practice, eg, with older age and multiple comorbidities, as compared with randomized clinical trials. Combined warfarin–antiplatelet therapy resulted in a relative increase in major bleeding risks, although absolute rates remained low. These findings suggest that physician concerns about increased bleeding risk with combination therapy are not unfounded and additional study of the benefit/risk ratio is warranted.

	Acknowledgments

 
This project was funded by an American Heart Association Beginning grant-in-aid (0160495Z). The authors acknowledge the assistance of the Iowa Foundation for Medical Care and the CMS in providing data that made this research possible. The conclusions presented are solely those of the authors and do not represent those of Iowa Foundation for Medical Care or CMS.

Received June 8, 2004; revision received July 20, 2004; accepted July 27, 2004.

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