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Warfarin and Antiplatelet Combination Use Among Commercially Insured Patients Enrolled in an Anticoagulation Management Service^*

^* From the Clinical Pharmacy Anticoagulation Service (Drs. Johnson, Witt, and Eddy) and Clinical Pharmacy Research Team (Dr. Delate), Kaiser Permanente Colorado, Aurora, CO.

Correspondence to: Samuel G. Johnson, PharmD, BCPS, Kaiser Permanente of Colorado, 16601 E Centretech Pkwy, Aurora, CO 80011; e-mail: samuel.g.johnson{at}kp.org

Abstract

Background: Although warfarin and antiplatelet medications have documented efficacy for prevention of primary and secondary cardiovascular events, the appropriateness of warfarin and antiplatelet combination therapy is not well described in national consensus guidelines.

Methods and results: Cross-sectional data from 4,557 Kaiser Permanente Colorado members 18 years old who were receiving warfarin anticoagulation therapy were used to quantify the prevalence of warfarin and antiplatelet agent (ie, aspirin, clopidogrel, dipyridamole, and/or dipyridamole/aspirin) combination therapy as of September 30, 2005, and to identify characteristics of patients receiving combination therapy. The prevalence of warfarin and any antiplatelet combination therapy was 385/1,000 (95% confidence interval [CI], 371/1,000 to 399/1,000). The majority of combination therapy was warfarin and aspirin (prevalence, 378/1,000) with a daily dose of aspirin, 81 mg, being the most reported dose (prevalence, 328/1,000). Patients receiving combination therapy were more likely to be male (63.6% vs 46.4%; adjusted odds ratio, 1.5; 95% CI, 1.3 to 1.7) and have a comorbidity of heart failure (29.0% vs 15.6%; adjusted odds ratio, 1.2; 95% CI, 1.1 to 1.5), coronary artery disease (62.4% vs 17.5%; adjusted odds ratio, 7.6; 95% CI, 6.5 to 8.8), and/or stroke/transient ischemic attack (5.2% vs 1.6%; adjusted odds ratio, 3.5; 95% CI, 2.3 to 5.3).

Conclusion: Nearly 4 of 10 patients receiving warfarin management care were receiving warfarin and antiplatelet combination therapy. The findings suggest that this practice is widespread, especially among patients with established cardiovascular disease, and involves a substantially higher number of patients than previously reported. The clinical outcomes associated with this practice require further investigation.

Key Words: anticoagulation • aspirin • pharmacy

Both warfarin and antiplatelet medications (eg, aspirin, clopidogrel) have established efficacy for prevention of primary and secondary ischemic events.¹² Given different mechanisms of action, combining these agents holds the potential for additive and perhaps even synergistic reductions in thromboembolic morbidity and mortality. Conversely, for some patients, combination therapy may increase the risk of clinically significant hemorrhage.³

The risks and benefits of warfarin and antiplatelet combination therapy (usually aspirin) have been evaluated previously.^{34567891011121314151617} However, a precise estimate of the true bleeding risk associated with this practice remains difficult to determine for several reasons. Contrary to routine clinical practice, randomized controlled trials often exclude patients at high risk for bleeding, including elderly patients, patients with a history of hemorrhage or recent trauma and/or surgery, and patients with severe renal or hepatic dysfunction.^5691213 Observational cohorts may be biased by underestimation of aspirin use due to its over-the-counter status and inconsistency of medical record documentation. Lower anticoagulation target ranges (international normalized ratio [INR] target ranges) than those used in clinical practice with warfarin monotherapy have been used in clinical trials^3591213 evaluating combination therapy. Thus, standard clinical practice has not been validated by controlled studies. Finally, patient adherence has been shown to be greater in controlled studies when compared to that usually observed in clinical practice. This potentially results in unrealistic estimates of therapeutic INR control, a principal metric influencing the reported safety of oral anticoagulation therapy.¹

Current practice standards for patients with or at high risk for coronary artery disease (CAD) advocate the use of antiplatelet therapy—principally aspirin, 75 to 325 mg/d—for prevention of ischemic coronary events.¹⁸¹⁹ In addition, evidence supports the use of antiplatelet therapy to prevent thrombosis following intracoronary stent implantation and to reduce the complications of peripheral arterial disease.²⁰²¹ Adjusted-dose warfarin is an effective alternative for primary or secondary CAD prevention therapy but is used less than antiplatelet therapy due to safety concerns and difficulty associated with therapeutic management.¹⁸ Despite widespread clinical use, the appropriateness of warfarin and antiplatelet combination therapy is not well described in national consensus guidelines. The goals of this investigation were to quantify the prevalence of warfarin and antiplatelet (ie, aspirin, clopidogrel, dipyridamole, and/or dipyridamole/aspirin) combination therapy and to identify patient characteristics associated with combination therapy in a population of commercially insured patients.

Materials and Methods

Setting
This study was conducted at Kaiser Permanente Colorado (KPCO), a group-model, health-maintenance organization providing integrated medical care to approximately 450,000 patients in the Denver-Boulder metropolitan area. All phases of the study were approved by the KPCO Institutional Review Board.

The KPCO Clinical Pharmacy Anticoagulation Service (CPAS) provides comprehensive services for approximately 6,800 KPCO patients requiring anticoagulation therapy. Working collaboratively with referring physicians, CPAS clinical pharmacists initiate anticoagulation therapy, order relevant laboratory tests, and adjust anticoagulation medications as necessary. As part of a concerted effort to improve documentation of self-reported aspirin use, an annual patient survey process was instituted 6 months prior to this study. As part of this ongoing survey, patients presenting (randomly) for follow-up were contacted by telephone in order to confirm aspirin use or nonuse. Pharmacists in the CPAS now routinely verify and document patient-reported antiplatelet medication use annually and document in an electronic database (Dawn-AC; 4S Systems; Cumbria, UK).²² For example, once aspirin use had been verified verbally by a CPAS pharmacist, the date and time of the interaction, along with aspirin dose, would be documented within the electronic database, and the electronic reminder system was then scheduled out for 1 year from that date. One year later, the CPAS pharmacist would then requery the patient and document that aspirin was either continued or discontinued along with the applicable dates; this would, theoretically, allow tracking of duration or interruptions in therapy to correspond with complications of therapy. At the time of this study, all but 1,442 patients had been successfully queried regarding their aspirin use.

Study Population
This study included all KPCO members 18 years old who were receiving warfarin therapy monitored by CPAS and had documented self-reported use or nonuse of aspirin therapy, and/or had purchased a prescription antiplatelet medication from a KPCO pharmacy. Patients receiving warfarin for venous thromboembolic (VTE) prophylaxis following orthopedic surgery were excluded because the duration of warfarin therapy in this setting is typically 6 weeks.

Data Collection
A cross-sectional study design was utilized to collect pertinent data. Patients receiving warfarin therapy on the extraction date (September 30, 2005) were identified via a query of the Dawn-AC database. Information on target INR range, length of warfarin therapy (in years since initiation), primary indication for warfarin therapy, patient-reported use or nonuse, and daily dosage of aspirin were also extracted from this database.

Generic product identifier numbers (85158020100320 for clopidogrel, 85150030000310, 85150030000320, 85150030000330, 32200010000305, 32200010000310, and 32200010000315 for dipyridamole, and 85159902206920 for dipyridamole/aspirin) were used to query the electronic KPCO pharmacy database to obtain information on prescription antiplatelet utilization during the 3 months prior to the extraction date. Ticlopidine utilization was not queried because use of this agent in the KPCO system is negligible due to its nonformulary status.

Electronic, integrated ambulatory and inpatient medical record databases were queried to identify patient age, gender, and the presence or absence during the 12 months prior to the extraction date of comorbid disease states that could influence the decision to use antiplatelet therapy (CAD, peripheral vascular disease, angina, and/or history of coronary artery bypass graft or percutaneous transluminal coronary angioplasty; diabetes mellitus [DM]; stroke or transient ischemic attack [cerebrovascular accident]; hypertension; chronic kidney disease [CKD]; cardiomyopathy; and heart failure [HF]). Specific International Classification of Diseases, Ninth Revision [ICD-9] codes are given in the ^Appendix. Patients in whom the primary indication for warfarin therapy was similar to an identified comorbidity were coded as "no" for that specific comorbidity. For example, if a patient had had a primary indication for warfarin therapy of CAD in the Dawn-AC database and diagnoses for DM and CAD in his medical record, this patient would be coded "yes" for a primary indication of CAD, "yes" for a comorbidity of DM, but "no" for a comorbidity of CAD.

Outcomes
The primary outcome measure was the prevalence of warfarin and antiplatelet combination therapy use per 1,000 patients enrolled in CPAS as of the extraction date. Prevalence of combination therapy use was determined for each individual antiplatelet agent and for important subgroups (eg, atrial fibrillation patients), also. Secondary outcomes included the comparison of patient characteristics between patients who were (combination cohort) and were not (warfarin cohort) receiving antiplatelet and warfarin combination therapy. Predictors of antiplatelet and warfarin combination therapy were also identified.

Data Analysis
The analysis for this study was primarily descriptive. Patient characteristics were reported as means and SDs for interval-level variables (eg, age, length of warfarin therapy) and proportions for categorical variables (eg, gender, combination use of antiplatelet therapy, presence of comorbid disease states). Prevalence of warfarin and antiplatelet combination therapy use was calculated by dividing the number of patients receiving combination therapy by the total number of warfarin-only patients receiving care from the CPAS and reported as combination therapy users per 1,000 warfarin-therapy patients. Independent-sample t tests and ² tests of association were used to assess differences between antiplatelet and warfarin cohorts for interval-level and categorical variables, respectively. Patient characteristic variables were entered into a multivariate logistic regression model with the cohort variable to identify predictors of combination therapy. The target INR range variable was not entered into the model owing to the lack of meaningful differences between the cohorts in the proportions of patients in all levels. The level was set at 0.05.

Results

A total of 6,015 patients were identified as receiving warfarin pharmacotherapy as of September 30, 2005. Of these patients, 16 were excluded for receiving warfarin as VTE prophylaxis following an orthopedic surgery. An additional 1,442 patients were excluded due to as-yet undocumented aspirin use or nonuse. Thus, a total of 4,557 patients were included in the study. Patients were primarily males (53.0%) and mature (mean age, 70.6 ± 12.6 years), and had been receiving warfarin therapy for > 4 years. The most common indications for warfarin use were atrial fibrillation (47.8%) and VTE (27.4%) [Table 1 ].

Multivariate modeling indicated that having had a primary indication of CAD (odds ratio, 21.97; 95% CI, 13.87 to 34.83 compared to a primary indication of VTE) and a comorbidity of CAD (odds ratio, 7.56; 95% CI, 6.50 to 8.82) were the strongest predictors of receiving combination therapy regimen (Table 3 ). In addition, being male, having had less time since warfarin initiation, and having had a comorbidity of DM, cerebrovascular accident, HF, or hypertension was associated with receiving any antiplatelet combination therapy. Furthermore, compared to a primary indication of VTE, a primary indication for warfarin therapy of stroke or transient ischemic attack, cardiomyopathy, heart valve disorder, atrial fibrillation, or another indication was associated with receiving any warfarin and antiplatelet combination therapy.

To our knowledge, this is the first systematic investigation to describe the prevalence of warfarin and antiplatelet combination therapy within a commercially insured patient population managed by an anticoagulation service. Results of this investigation suggest that this practice is widespread in anticoagulation management care: approximately 4 of 10 patients surveyed were receiving warfarin and antiplatelet combination therapy. Our finding is particularly interesting given that a much higher proportion of patients (38.5%) were receiving combination therapy than previously reported (19.4%).⁷ This may be partially due to our inclusion of patients receiving warfarin therapy for any indication except VTE prophylaxis following orthopedic surgery. Additionally, we speculate that the observed widespread use of combination therapy in patients with documented CAD may be driven in part by KPCO initiatives designed to promote the use of aspirin following myocardial infarction.

An additional finding of interest in our study was that 50 patients received dual-antiplatelet therapy with clopidogrel and aspirin in conjunction with warfarin anticoagulation. In these 50 patients, the primary indications for warfarin therapy were atrial fibrillation (32%), CAD (18%), VTE (26%), peripheral vascular disease (8%), mitral valve replacement (6%), cerebrovascular accident (6%), and cardiomyopathy (4%). One retrospective study³ reported low bleeding rates in patients receiving this three-drug combination (0.09 events per patient-year), but detailed information regarding the safety of this strategy is limited. More recently, a case-control study²³ suggested that the odds of serious upper-GI bleeding may be synergistically increased with the use of combinations of antithrombotic agents.

Warfarin and antiplatelet combination therapy has been associated with increased rates of major and minor hemorrhage, even in patients treated with less aggressive target INR ranges than are typically used with warfarin monotherapy (Table 4 ).^3458910 Dual-antiplatelet regimens, including the combination of aspirin with thienopyridine agents (clopidogrel, ticlopidine), have also been shown to increase the risk of bleeding.³²⁴

Antiplatelet therapy is principally recommended by the ACCP to prevent thrombotic complications of peripheral arterial disease. Current consensus guidelines²¹ recommend against the use of anticoagulants for patients with intermittent claudication. Additionally, a recent abstract²⁷ suggests that addition of warfarin to aspirin in patients with peripheral vascular disease does not reduce the rate of major ischemic events, but does increase the risk of severe bleeding. The investigators in this study²¹ noted that 1.3% (n = 14) of subjects in the combination therapy arm had hemorrhagic strokes, compared to none in the aspirin-only arm.

Attempts to improve the stroke-preventing ability of low-intensity anticoagulation by adding antiplatelet therapy in patients with atrial fibrillation have been disappointing.¹²¹³ When antiplatelet therapy has been added to high-intensity anticoagulation in patients with atrial fibrillation, the risk for hemorrhage outweighed any therapeutic benefits.¹⁴¹⁵ Additionally, in a comparison of dual-antiplatelet therapy with clopidogrel and aspirin to warfarin anticoagulation in high-risk atrial fibrillation patients, patients who received dual-antiplatelet therapy were more likely to have stroke and major hemorrhage than patients receiving oral anticoagulation, further fueling debate regarding the safety of combining antithrombotic agents.²⁸²⁹ Recently revised consensus recommendations³⁰ discourage the combination of anticoagulants with antiplatelet therapy for patients with stable CAD due to increased bleeding risk without incremental improvement in efficacy.

Warfarin and aspirin combination therapy has resulted in significant reductions in thrombotic adverse events for patients with mechanical heart valve prostheses. The addition of aspirin, 100 mg/d, to high-intensity anticoagulation (target INR range, 2.5 to 3.5) resulted in fewer valve thromboses at the expense of a nonsignificant increase in the rate of hemorrhage.¹⁶¹⁷ In fact, current ACCP consensus guidelines recommend combination treatment for patients with caged-ball and caged-disk mechanical prostheses, for patients who have systemic embolism despite a therapeutic INR, and for patients with additional stroke risk factors including atrial fibrillation, myocardial infarction, left atrial enlargement, and low ejection fraction.³¹ However, in studied patients, the time spent in the therapeutic INR range was significantly lower in the anticoagulation-alone control groups, thus possibly confounding the perceived benefits of combination therapy.³¹

We theorize that aspirin therapy was initiated in many of our patients without a thorough evaluation of the benefits and risks involved. When compared to existing national guidelines,^181920213031 KPCO practice patterns for patients with a primary indication for anticoagulation of CAD are largely consistent with regard to combining anticoagulation and antiplatelet therapy. Guidelines suggest that patients with a primary indication for anticoagulation of CAD receive moderate-intensity anticoagulation (INR range, 2 to 3) in combination with antiplatelet therapy. We found that approximately two thirds of patients in our study were being treated in this manner. Practice patterns for KPCO patients with mechanical heart valve prostheses also appear to be consistent with national guidelines. Conversely, > 30% of KPCO patients with an indication for anticoagulation of atrial fibrillation are maintained on moderate-intensity anticoagulation (INR range, 2 to 3) in combination with antiplatelet therapy, inconsistent with national guidelines. It is important to note here that we were unable to determine for the purposes of this study whether patients were receiving antiplatelet therapy as directed by their physician or on their own initiative. As it has been widely publicized that aspirin is beneficial for reducing the risk of heart attack, many patients may have been self-administering aspirin without the knowledge of their physician.

Several aspects of our investigation warrant comment. Our findings are cross-sectional in nature and, as such, our analysis may have excluded patients who previously stopped taking either warfarin or aspirin due to a bleeding complication. Thus, our prevalence estimates may underestimate the true prevalence of combination therapy. However, we theorize that if this had occurred, it would not have amounted to a significant number of patients discontinuing combination therapy based on our previous research²² that indicated overall hemorrhage rates for patients in the CPAS are low. Our findings may not be generalizable to other health-care settings because patients treated with combined antithrombotic agents may be more likely to be managed by central anticoagulant monitoring services. However, drawing from an anticoagulant service with > 6,500 patients being monitored at the time of the study, we believe that the large cohort of patients described represents a diverse, real-world population of patients receiving warfarin. In addition, the characteristics, in terms of patient age and proportions of male patients and patients with DM, of patients in our study were comparable to a population-based, observational cohort study³² that examined bleeding rates in patients receiving combinations of antithrombotic agents. A conservative list of ICD-9 codes was used to determine comorbidity status. However, we theorize that our list contained the most commonly used codes for these disease states. The reliance on patient-reported information regarding over-the-counter aspirin use may have resulted in recall bias. However, a standardized question was used to obtain this information along with mental prompts to facilitate patient recall of the information. At this time > 1,400 patients remain to be queried as part of an ongoing survey for combination therapy use and were excluded from this study. Most importantly, no clinical outcomes regarding bleeding or thrombosis were reported in this initial descriptive study. Our aim was to document the prevalence of concurrent antiplatelet therapy use in a large, diverse, real-world sample of patients receiving warfarin therapy. Future research efforts will focus on the clinical outcomes associated with this practice.

Mounting evidence indicates that warfarin monotherapy is effective in the primary and secondary prevention of coronary events. Clinicians should carefully weigh the risks and benefits of warfarin and antiplatelet combination therapy to ensure that patients are not unnecessarily exposed to increased bleeding risk. Recent evidence has shown that combining antithrombotic agents does not necessarily reduce the risk of recurrent ischemic events.³³ Patients receiving warfarin therapy should be carefully educated not to take aspirin or other over-the-counter platelet inhibiting medications (eg, nonsteroidal antiinflammatory drugs) unless instructed to do so by their physician.

Appendix

ICD-9 Diagnosis Codes Used To Identify Comorbidities
Diabetes: 250 through 250.93, 275.0, 253.5, 277.7, 362.01, 362.02, 588.1, 648, 790.2, 271.4, 790.6.

Hypertension: 401, 401.0, 401.1, 401.9', 402.0, 402.00, 402.01, 402.1, 402.10, 402.11, 402.9, 402.90, 402.91.

CAD: 410 through 410.92, 411 through 411.89, 412, 413, 413.0, 413.1, 413.9, 414 through 414.9, 429, 429.2, 440.0 through 440.9, 443.0, 443.1,4 43.8, 443.81, 443.9, V45.82, V45.81.

Cardiomyopathy: 425 through 425.9.

Chronic Heart Failure: 428 through 428.43.

Cerebrovascular Disease: 434 through 434.91, 435 through 435.9, 436.0, 437, 437.1.

CKD: 585.

Footnotes

Abbreviations: ACCP = American College of Chest Physicians; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; CPAS = Clinical Pharmacy Anticoagulation Service; DM = diabetes mellitus; HF = heart failure; ICD-9 = International Classification of Diseases, Ninth Revision; INR = international normalized ratio; KPCO = Kaiser Permanente Colorado; VTE = venous thromboembolism

Funding and research support for this endeavor were provided exclusively by the Department of Pharmacy, Kaiser Permanente Colorado.

The authors have no conflicts of interest to disclose.

Received for publication September 26, 2006. Accepted for publication January 12, 2007.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Johnson, S. G. Search for Related Content PubMed PubMed Citation Articles by Johnson, S. G.