A Multicomponent Intervention To Prevent Major Bleeding Complications in Older Patients Receiving Warfarin

Bleeding is the major side effect of warfarin and is a major deterrent to its use, especially in older patients. Older people are widely thought to be at increased risk for warfarin-related bleeding (1-8), and they are less likely to be treated with warfarin, even when it has been proven efficacious, in part because of concern about risk for bleeding (9-13). Efforts that reduce the frequency of major warfarin-related bleeding not only will increase the net benefit of therapy but also will facilitate more appropriate and widespread use of warfarin therapy in older patients. Methods for identifying patients at highest risk for bleeding have recently advanced (5-7, 14-21), and experience with specialized programs that coordinate the management of anticoagulant therapy suggests that clinical outcomes may be improved (6, 14, 18, 22-27). However, there is little controlled or experimental evidence on how to optimize management of anticoagulant therapy in older patients and prevent bleeding. We developed a multicomponent comprehensive program for management of warfarin therapy aimed at improving control of the anticoagulant effect and reducing events (such as use of an interacting medicine) that might precipitate bleeding. We hypothesized that this intervention would be acceptable to most elderly persons starting warfarin therapy and would reduce the frequency of warfarin-related major bleeding. Methods Patients Patients hospitalized at University Hospitals of Cleveland, a 900-bed teaching hospital, between September 1992 and October 1995 who were 65 years of age or older and were receiving 10 000 units or more of intravenous unfractionated heparin every 24 hours were screened daily. Of these patients, we identified 426 persons who were 65 years of age or older, who resided in Cuyahoga County, Ohio, and for whom treatment with warfarin was planned for 10 or more days (Figure 1). Patients were excluded if they had been treated with warfarin at any time during the previous 6 months, were admitted from a nursing home, were enrolled in another clinical trial, were too ill to give consent and had no available surrogate, were discharged prematurely, or did not speak English; if their private physician refused to participate; or if no random allocation was taking place (for example, during vacations or holidays). Eligible patients who were enrolled did not differ significantly from those who were not enrolled with regard to age, ethnicity, sex, or indication for therapy. Figure 1. Eligibility and random assignment of patients. Patients were stratified according to their baseline risk for major bleeding by using the Outpatient Bleeding Risk Index (20). This index includes four independent risk factors for major bleeding: age 65 years or older, history of gastrointestinal bleeding, history of stroke, and one or more of four specific comorbid conditions (recent myocardial infarction, hematocrit<30%, creatinine concentration>133 mol/L [1.5 mg/dL], or diabetes mellitus). Patients with one or two risk factors were classified as intermediate risk, and those with three or more risk factors were classified as high risk; estimated frequencies of major bleeding in 6 months were 6% and 35%, respectively. After stratification, patients were randomly assigned to receive usual care or intervention. Informed consent for observation and data collection was then sought from both groups, and informed consent to participate in the intervention was sought from the intervention group. This method, initially proposed by Zelen (28), allows the study to test the effectiveness of offering the intervention rather than simply the efficacy of the intervention in patients who consent to participation before random assignment. The sample size was calculated to provide 80% power and an level of 0.05. The study protocol and informed consent procedures were approved by the hospital's institutional review board. Intervention The intervention had two main components. The first component consisted of a guideline-based consultation that assessed the patient's indications for therapy and potential risk factors for warfarin-related bleeding. We used this method previously to reduce the frequency of anticoagulant-related bleeding during hospitalization (27). Specific recommendations about modifiable risk factors, such as use of nonsteroidal anti-inflammatory drugs, were made and implemented. The study investigators directed warfarin dosing and international normalized ratio (INR) testing after hospital discharge. The second component included patient education, coaching, and self-monitoring of prothrombin time; this component was grounded in social learning theory (29-31) and experimental evidence (32, 33) showing that increasing participation of patients in their care can improve clinical outcomes but that increasing patient knowledge alone is insufficient (34, 35). Patient education consisted of one-on-one teaching by a lay educator using a specifically formatted workbook for older adults to teach them about warfarin, indications for its use, drug and food interactions, and the signs and symptoms of bleeding. The lay educator reviewed the workbook and was taught how to use the prothrombin time monitor by one of the authors but had no formal medical training. Coaching was aimed to increase patients' participation in their care and to improve information-seeking skills. Patients were trained and encouraged to communicate more effectively with physicians and other health personnel about a range of issues, such as health concerns, drug interactions, or changes in lifestyle or diet. Finally, patients were taught to self-monitor the prothrombin time by using a home portable monitor (Coumatrak Protime Test System, Biotrack, Inc., Mountain View, California). The monitor uses a fingerstick to obtain a blood sample and has well-established accuracy (36-38). Patients were initially assessed, educated, and taught to use the portable monitor while hospitalized; training lasted 30 minutes to 1 hour. They were seen daily while hospitalized, warfarin therapy was adjusted as needed, and any concerns or questions about anticoagulant therapy were addressed. Within 3 days of discharge from the hospital, the lay educator or study investigator made a home visit to assess patients' use of the portable monitor and to check the prothrombin time. In general, patients were instructed to check their prothrombin time three times during the first week after hospital discharge, weekly for the remainder of the first month, and monthly thereafter depending on their results. Patients phoned in their results to the coach, who reviewed the results with one of the investigators and provided same-day follow-up, including recommendations for dose and subsequent INR testing. Patients were instructed to call whenever they had questions or concerns about their warfarin management or possible side effects, if they were hospitalized for any reason, or if they began receiving new medications. After the 6-month intervention period, management and dosing of warfarin therapy reverted back to patients' personal physicians. Patients assigned to usual care received medical care, including management, dosing, and medical information, according to the discretion and practices of their personal physician. Data Collection Trained abstractors who were not involved with the intervention component of the study collected data from the medical chart at the start of anticoagulant therapy; at each subsequent hospitalization; and by blinded interview at enrollment and 1, 3, and 6 months after enrollment and every 6 months thereafter. Data elements included demographic characteristics, clinical history including comorbid diagnoses, indications for therapy, potential risk factors for bleeding, functional status, and new illnesses or comorbid conditions that developed after enrollment. Surveillance for bleeding and thromboembolism was conducted identically in the intervention and control groups and consisted of 12 items inquiring about bleeding and thromboembolism at each follow-up interview. Whenever an event was reported, the clinical characteristics of the bleeding or thromboembolic episode were determined by review of the relevant medical record and abstracted without identifying patient information onto a standard form. All dates of death were confirmed by death certificates, and all causes of death were confirmed by review of death certificates and medical records. Follow-up was complete for all patients. End Points The primary end point was the first major bleeding event during the 6-month intervention period. Using explicit criteria in the Bleeding Severity Index (39) for the amount, rate, and consequences of bleeding, we defined major bleeding as overt bleeding that led to the loss of at least 2.0 units of blood in 7 days or less or was otherwise life-threatening (for example, intracranial bleeding). Bleeding was classified without information about possible risk factors or randomization status. Two author-reviewers who were blinded to group assignment adjudicated bleeding events; their agreement was high ( statistic, 0.97). Secondary outcomes were death and recurrent venous thromboembolism at 6 months; major bleeding after 6 months; and control of anticoagulant therapy during the first 6 months of therapy, as measured by the INR. The therapeutic range of the INR was defined as 2.5 to 3.5 for persons with mechanical heart valves and 2.0 to 3.0 for persons with all other indications (40). Therapeutic quality control was assessed by using the patient-time approach, described by Rosendaal and colleagues (41), for three time periods after discharge from the hospital: 0 to 1 month, 1 to 3 months, and 3 to 6 months of therapy. This approach estimates the amount of time a patient is in the therapeutic range based on the actual INRs measured, assuming a linear relationship between consecutive INRs. Patients with only one INR