The Risk for and Severity of Bleeding Complications in Elderly Patients Treated with Warfarin

Warfarin is prescribed for more than 1 million persons in the United States, many of whom are elderly and take the drug indefinitely. The pooled results of five randomized trials document that warfarin reduced the incidence of stroke by 68% in persons with atrial fibrillation, a benefit that substantially outweighs the risk for bleeding that accompanies warfarin therapy [1-6]. Atrial fibrillation is present in 4% of persons older than 60 years of age and 10% of persons older than 80 years of age [7]. Paradoxically, many studies have found that elderly persons are at higher risk for hemorrhagic complications than are younger patients [8-17]. It has been suggested that older patients are more prone to bleeding because they metabolize warfarin more slowly [18-20]; they have an elevated risk for drug interactions because of polypharmacy [21]; and they often have chronic illnesses, such as renal insufficiency [22], heart failure [9], cancer [10, 22], and cerebrovascular disease [23], that increase the risk for bleeding during warfarin therapy. On the other hand, numerous studies have not found elderly persons to be at greater risk for bleeding [24-31]. These discrepant findings have not been adequately explained. Because of the clinical importance of this problem, we analyzed data from six sites to determine whether elderly patients who were receiving warfarin had a higher incidence of complications than similar younger patients who were also receiving warfarin. Methods We collected our data in two phases. The first phase involved a retrospective review of medical records from 1980 to 1990; other results from this review have been reported previously [30]. In the second phase, we analyzed data collected prospectively between 1990 and 1993, including the results from a multicenter, randomized trial of a computerized scheduling system for patients receiving warfarin [32]. Study Setting and Patients Our study was done in the six anticoagulation clinics that make up the National Consortium of Anticoagulation Clinics. These clinics represent a mix of geographic locations, practice settings, and patient populations. Clinic personnel were responsible for managing anticoagulation therapy for all patients throughout the study, although in two clinics, personnel also provided primary medical care [33]. The sites were the University of California at Davis, Sacramento, California; Jefferson Medical College, Philadelphia, Pennsylvania; the University of Virginia, Charlottesville, Virginia; the Veterans Affairs Medical Center, Buffalo, New York; the Veterans Affairs Medical Center, Palo Alto, California; and the Veterans Affairs Medical Center, Seattle, Washington. Because Jefferson Medical College did not join the Consortium until 1992, data from that site were used only in the prospective phase of the study, which followed completion of the randomized trial of computerized scheduling. Retrospective Data Collection During the retrospective phase of our study, we abstracted the medical records of all patients who were currently receiving anticoagulation therapy and all patients whose anticoagulation therapy had been discontinued within the previous 18 to 24 months. If patients had received multiple courses of warfarin (that is, if there were extended periods during which a patient did not receive warfarin), we abstracted data from all courses. All patients were eligible for inclusion unless they had received warfarin for 6 weeks or less. We have described our data collection methods in detail elsewhere [30]. Trained abstractors reviewed inpatient and outpatient records using standard forms that have been extensively tested for reliability. All records from inpatient admissions and visits to the anticoagulation clinic; other medical, surgical, and urgent care clinics (excluding visits made for psychiatric reasons); and emergency departments were abstracted. We also reviewed any records that were maintained separately from the formal medical record by a practitioner responsible for anticoagulation therapy. At each of the three Veterans Affairs medical centers, data were also retrieved from the hospital's information system. We excluded seven patients whose charts were missing. Indications for anticoagulation therapy were organized into seven main categories and 29 subcategories. For patients who had more than one indication, the most serious problem (the one that required the greatest intensity or longest duration of therapy) was deemed the primary indication. During the retrospective phase of our study, only one of the five medical centers reported results using the international normalized ratio. Because the international sensitivity index values of the thromboplastins used at some of the participating centers were unavailable before 1988, we analyzed all results using the prothrombin time ratio. However, we contacted each laboratory to determine whether the international sensitivity index values of the reagents used were known; this information was available from several of the study sites after 1985 and from all sites after 1990. All laboratories used standard North American thromboplastins that had international sensitivity index values ranging from 2.0 to 2.4. Practitioners typically adhered to therapeutic recommendations published by the American College of Chest Physicians (ACCP) in 1986 [34, 35], which set the target range as a prothrombin time ratio of 1.5 to 1.8 (high intensity) for patients with mechanical valves and 1.3 to 1.5 (low intensity) for most other patients. Records from outpatient visits were reviewed to ascertain the reason for the appointment, the occurrence of any intercurrent illnesses, all medications prescribed in addition to warfarin, and the dates on which therapy with each medication was started and stopped [36]. Prospective Study The prospective data collection was done over a 3-year period (1990 to 1993). During the first year of this period, we did a randomized trial of a computerized scheduling intervention [32]. Because the scheduling system produced no statistically significant differences in control of anticoagulation or frequency of complications, we have included data collected during that 1-year period in our present analysis. During the 2 years after completion of the trial, we continued to collect identical information on patients who had participated in the trial and on all eligible patients subsequently enrolled into participating clinics for the management of warfarin therapy. Jefferson Medical College did not participate in the trial of computerized scheduling. Patients who were actively enrolled in one of the six participating clinics or who were newly referred to one of the clinics were eligible for this portion of the study if the total planned duration of their anticoagulation therapy was 6 weeks or longer. Before the start of prospective data collection, we abstracted the medical records of all active eligible patients in each clinic. These data were collected according to the same protocol used in the retrospective study. At the three clinics located in university medical centers, our trial was exempted from requirements for verbal or written informed consent by the local institutional review boards, and all eligible patients were enrolled. At the three Veterans Affairs clinics, the local review boards required informed consent, and we invited the participation of all eligible patients in person or by mail; 5.2% of patients in these clinics declined to participate. At each visit to each anticoagulation clinic during the prospective phase of the study, all data, including those on the prothrombin time ratio (or international normalized ratio) results, warfarin dosage, complications, and follow-up plans, were entered directly into a notebook computer. Classification of Outcomes In both the retrospective and prospective phases of data collection, we used the same detailed scheme to classify bleeding complications as minor (no associated costs or medical consequences), serious (requiring treatment or medical evaluation), life-threatening, or fatal. Minor complications required no additional testing, referrals, or outpatient visits but were remarkable enough to report to the provider. Examples of minor bleeding included mild nosebleeds, bruising, mild hemorrhoidal bleeding, and microscopic hematuria. Examples of serious bleeding included overt gastrointestinal bleeding, occult gastrointestinal bleeding if endoscopic or radiographic studies were done, gross hematuria that prompted cystoscopy or intravenous urography or lasted more than 2 days, and hemoptysis. If blood was transfused, 2 units or fewer were given. Life-threatening bleeding was defined as that leading to cardiopulmonary arrest, surgical or angiographic intervention, or irreversible sequelae, such as myocardial infarction, neurologic deficit consequent to intracerebral hemorrhage, or massive hemothorax. Bleeding was also considered to be life-threatening if it led to at least two of the following consequences: loss of 3 or more units of blood; systolic hypotension (systolic blood pressure less than 90 mm Hg); or critical anemia (hematocrit less than equals 0.20). Fatal bleeding was defined as that leading directly to the death of the patient. All serious, life-threatening, and fatal complications were independently reviewed by a physician investigator at the local site and by three investigators at the coordinating center. Using standardized criteria, we determined whether deaths were related to bleeding caused by warfarin therapy or to thromboembolic complication. Disagreements were resolved by discussion. Deviation in the Prothrombin Time Ratio We previously described [37] a method that can be used to characterize the degree to which a patient's prothrombin time ratios deviate from his or her target prothrombin time ratio over time, and we have shown that the level of variability in the prothrombin time ratio is stati