The Weight-based Heparin Dosing Nomogram Compared with a Standard Care Nomogram

Heparin therapy improves clinical outcomes in patients with thromboembolic disorders [1-4], but the determination of appropriate heparin dosing is often problematic. Physicians' dosing decisions vary widely, as do their therapeutic goals [5]. Practice audits reveal frequent underdosing, with delays in achieving therapeutic anticoagulation leading to suboptimal clinical outcomes [6, 7]. Recent research offers hope that clarification of treatment goals and specific dosing guidelines may improve outcomes. Hull and colleagues [3] reported that rapidly exceeding a therapeutic threshold (APTT, 1.5 times the control) reduced the rate of recurrent thromboembolism from 25% to 2%, a finding confirmed in other studies [4, 8-12]. In addition, a retrospective analysis suggested that an initial heparin infusion dose of 1000 units per hour is often insufficient [13], and the most recent American College of Chest Physicians Consensus Conference on Antithrombotic Therapy recommends an initial infusion of at least 1250 units per hour [14, 15]. Finally, dosing nomogramswhich specify heparin dose adjustments in response to any given APTT levelhave shown promising results [16, 17]. Despite these advances, uncertainties remain. Randomized controlled studies have not compared higher initial heparin doses with 1000 units per hour, and many physicians continue to follow this clinical tradition [5]. Because the relation between bleeding complications and excessive APTT values is controversial [3, 10, 16, 18-24], so is the optimal upper limit of the therapeutic range [5, 14, 25]. For this reason, Hull and colleagues [14] and Hirsh [25] have recently de-emphasized the value of the therapeutic range and have stressed the need to minimize recurrent thromboembolism by rapidly exceeding the therapeutic threshold. Measured against that standard, Hull's nomogram succeeded in 98% of patients; however, heparin infusions were routinely started at 1670 units per hour and nearly half of the patients had excessive APTT levels that persisted for 24 hours or more [16]. The generalizability of this nomogram is limited by its dependence on an APTT test reagent that yields markedly prolonged APTT compared with reagents commonly used in the United States [16, 17, 26, 27]. (Activated partial thromboplastin times vary greatly depending on laboratory method used [14-16, 25-27], analogous to the variability of prothrombin times that prompted development of the International Normalized Ratio.) We agree with Hull and colleagues that heparin nomograms relentlessly direct the heparin dosage and drive the APTT into the therapeutic range [16]. We hypothesized that a patient-specific nomogram, based on total body weight (the single best predictor of individual heparin requirements [28, 29]) would achieve high success rates without the need for prescribing excessive heparin doses. Our study, using the most generalizable APTT test system in North America, compares the performance of our weight-based heparin nomogram with another nomogram reflecting a prevalent standard of practice. Our report is the first to describe a weight-based heparin nomogram, the first to compare two nomograms prospectively, and the first nomogram study to have easily generalizable results. Methods Study Design In a randomized, controlled trial, we compared two nomograms for intravenous heparin dosing in patients with venous thromboembolism, unstable angina, or arterial thromboembolism. During the first 48 hours of anticoagulation, the appropriate nomogram determined all dosing decisions (Tables 1, 2), and warfarin was withheld. We defined two primary outcomes. The first was the time elapsed between initiating heparin therapy and surpassing the therapeutic threshold (APTT, 1.5 times the control), considered the minimum acceptable level of anticoagulation. The second was the time elapsed before achieving therapeutic range (APTT, 1.5 to 2.3 times the control), the optimal goal for intravenous anticoagulation. Table 1. Standard Care Nomogram Table 2. Weight-based Nomogram We did our study simultaneously at two community teaching hospitals: a 700-bed regional referral center in Phoenix, Arizona, and a 250-bed, inner-city hospital in Rochester, New York. Both hospitals are major teaching affiliates of university medical schools, and each maintains a large, accredited internal medicine residency program. Patients Patients admitted between May 1991 and January 1992 were deemed eligible if they were to receive intravenous heparin for one of the following indications: 1) pulmonary embolism, diagnosed clinically and confirmed by a high-probability lung scan or pulmonary arteriography; 2) proximal deep vein thrombosis, confirmed by ascending venography, impedance plethysmography, or Doppler ultrasonography; 3) unstable angina, diagnosed clinically by an attending cardiologist using the Braunwald criteria [30]; or 4) acute noncoronary arterial ischemia. Exclusion criteria included 1) anticoagulant or thrombolytic therapy in the previous 7 days, 2) active hemorrhage, 3) acute major cerebral vascular event, 4) history of heparin-induced thrombocytopenia, and 5) known allergy to heparin. A power analysis revealed that a total study size of 100 patients would have 90% power (with a type I error of 0.05) to detect a 6-hour difference in the mean time needed to achieve the primary outcomes. The Nomograms The standard practice nomogram (Table 1) was based on the mode for each of the responses to a survey of 61 internists at our hospitals regarding their usual practices of heparin administration [5]. The initial bolus and infusion doses were identical to those recommended by the American College of Chest Physicians at the time the study was done [13], and dose adjustments in response to APTT results were similar to those of subsequently published nomograms [16, 17]. We constructed the weight-based nomogram Table 2 after we reviewed the literature and did a preliminary dosing study. Many reports have described bolus doses ranging from 50 to 150 units per kg body weight and infusion doses from 15 to 25 units per kg per hour [8, 28, 29, 31, 37]. In one study, 78% of patients achieved therapeutic goals rapidly after receiving a bolus of 75 units per kg and an initial infusion of 17 units per kg per hour [34]. In our preliminary dosing study, the mean dose of heparin required to achieve two consecutive therapeutic APTT values in 24 patients with unstable angina was 17.3 4.0 units per kg per hour [38]. The initial heparin doses we chose for our weight-based nomogram (bolus, 80 units per kg; infusion, 18 units per kg per hour) supplied 511 units per kg per day, consistent with reports that daily heparin requirements in venous thromboembolism range from 480 to 600 units per kg [7, 39, 40]. Subsequent infusion adjustments in the nomogram were designed to minimize delay in attaining the therapeutic range. All doses in the weight-based nomogram were calculated based on actual body weight rather than ideal weight. Intervention After informed consent was obtained, patients were randomized to one of the two nomograms, and preprinted orders for implementation of the appropriate nomogram were charted. Staff nurses, who were not blinded, weighed each patient, calculated doses, and adjusted the infusion rate accordingly. Although the nurses could not influence the results of APTT measurements, several indices of nomogram implementation were monitored to detect any unintended co-interventions. Patients randomized to standard heparin therapy received a 5000-unit bolus of intravenous heparin followed by an infusion dose of 1000 units per hour. Patients in the weight-based heparin group received an intravenous bolus of 80 units per kg, followed by an infusion dose of 18 units per kg per hour. At both hospitals, heparin sodium (pork derived, Schein Pharmaceuticals Inc.; New York, New York) was diluted in 5% dextrose solution and administered with infusion pumps. Stat APTT levels were drawn every 6 hours. (This interval approximates four half-lives of heparin, the time required to achieve steady-state kinetics.) When the staff nurses received the APTT results, they consulted the nomogram and adjusted the heparin dose. No adjustments were made if blood for the APTT was drawn less than 4 hours after the last heparin dose adjustment was made. Measurements All blood specimens for APTT were collected in siliconized Vacutainer tubes (Bectin-Dickinson Company; Rutherford, New Jersey) containing buffered citrate. Both our hospital laboratories use plain Dade actin thromboplastin (Baxter Healthcare Corporation, Dade Division; Miami, Florida) and automated coagulation systems (MLA Electra 700 and 1000 series, Medical Laboratory Automation Inc.; Pleasantville, New York) to determine APTT values. The correlation coefficient for APTT performed with plain Dade actin thromboplastin on these two automated systems, using mean values reported for all plasma samples in the 1992 College of American Pathologists' data [27], is 0.999. The normal range for APTT (mean APTT 2 SD in patients having no known coagulopathy and not receiving anticoagulants) at both hospitals was 20 to 30 seconds. In the absence of published consensus regarding the definition of control APTT, we used the upper limit of the normal range (30 seconds) as our control APTT in all patients, assuming that 97.5% of patients' individual APTT control values would be 30 seconds or less. The primary outcome variables were elapsed time from initiation of heparin therapy until achievement of the two primary outcomes: an APTT value exceeding the therapeutic threshold of 45 seconds (1.5 times the control APTT) and an APTT within the therapeutic range of 46 to 70 seconds (1.5 to 2.3 times the control APTT). This therapeutic range is consistent with others published [2, 7, 10, 13, 16, 25] and correlates with heparin levels of 0.38 to 0.57 by anti-factor Xa activity (performed at the University of Okla