Evaluation of a multi-target direct thrombin inhibitor dosing and titration guideline for patients with suspected heparin-induced thrombocytopenia
Authors: James F. Gilmore, Christopher D. Adams, Rachel M. Blum, John Fanikos, Beth Anne Hirning, Lina Matta
Journal: American Journal of Hematology (2015)

To the Editor: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can occur in patients receiving heparinoid therapy 1, 2. Management of HIT consists of discontinuation of the heparinoid and anticoagulation using a direct thrombin inhibitor (DTI), such as argatroban and bivalirudin. Institutions have implemented dosing guidelines for initial DTI dosing and titration. Standardization of DTI dosing and titration using a nursing driven guideline titrating to an activated partial thromboplastin time (aPTT) goal of 50–80 has been shown to reduce time and number of titrations to therapeutic aPTT 3. An analysis of two dosing guidelines for argatroban achieved an aPTT goal of 50–70 4. To our knowledge, currently no published bivalirudin dosing guideline exists that allows for a more stringent aPTT goal. Brigham and Women's Hospital instituted a dosing and titration guideline for argatroban and bivalirudin that allowed the prescriber to select between three therapeutic aPTT goals: 50–80, 50–70, or 60–80 (Table 1). The protocol provided guidance for agent selection and dosing strategy based on age, organ function, and clinical condition. We hypothesized that a standardized dosing and titration guideline for DTIs improve achievement of therapeutic goals in patients with proven or suspected HIT. We conducted a single center, prospective, observational evaluation of patients treated with a DTI according to a dosing and titration guideline compared to a historic control of patients treated prior to protocol implementation. The local IRB approved the study prior to data collection. The protocol was added as a supplemental tool to an existing institutional HIT management guideline that guided clinicians on HIT diagnosis with the 4Ts Score, the IgG-Specific Platelet Factor 4 ELISA (PF4 IgG; Genetics Testing Institute, Waukesha, WI) 5, and if necessary the Serotonin Release Assay (SRA) 6. Our protocol recommended the use of a percentage-based titration model for dose adjustments. Patients included were >18-years old and treated for suspected HIT with a DTI from July 2012 to February 2013. Patients were identified using DTI charging data. Patients were excluded if they had received the DTI for a non-suspected HIT indication or if they were monitored with thrombin time. Patients were collected consecutively and divided into a historical control and protocol treatment group. Each group was planned a priori to contain 50 patients. The primary outcome was the achievement of a therapeutic aPTT value. For patients in both groups, goal aPTT values were specified by the covering prescriber or pharmacist. Other outcomes assessed included percentage of patients who achieved goal aPTT with the initial DTI dose, number of titrations to reach therapeutic aPTT, initial DTI dose, length of DTI therapy, incidence of thromboembolism after DTI initiation, the occurrence of major bleeding, critical aPTT values, and mortality. Categorical data were compared using the Fisher's exact test or Chi-square test. Continuous variables were compared using the Student t test. Non-parametric data were assessed with Mann–Whitney U-test. All tests were two-tailed. A P-value <0.05 was considered statistically significant. A total of 134 patients were identified and evaluated for inclusion. After evaluating for exclusions, both the PRE and POST implementation arms were made up of 50 patients (Fig. 1). Patient enrollment. Therapeutic goal achievement. Baseline characteristics can be found in Table 2. PF4 testing was done in 98% of patients in the PRE and 94% of patients in the POST, and SRA testing was done in 22% of patients in the PRE and 16% of patients in the POST. Positive PF4 values were seen in only 16% of all patients in the PRE and 22% of all patients in the POST, with a SRA positive result in only 2% of all patients in the PRE group and 4% of all patients in the POST. Patients in the POST group achieved an aPTT within therapeutic goal range more than in the PRE group, 92% vs. 72%. (P < 0.01, Figure 2). Achievement of an aPTT value at goal on the initial dosing was also improved after guideline implementation, 44% vs. 16% (P < 0.02). Data related to treatment course can be seen in Table 3. Of the patients to achieve a therapeutic aPTT value, mean number of DTI titrations to reach goal aPTT was decreased after guideline implementation (3.14 ± 3.02 vs. 1.85 ± 2.78, P < 0.05). Observed safety endpoints can be seen in Table 4. The success of this guideline is likely attributable to multiple factors when compared to the historical control. Guidance on initial dosing was provided to the prescriber based on age, end-organ function, and clinical condition, and this is what likely led to a significant increase in the starting dose of bivalirudin prescribed. The monitoring strategy recommended by the guideline advocated for an aggressive monitoring schedule to identify aPTT values that were out of range. The guideline then offered standardized guidance for dosing adjustments based on a percentage factor of the running dose in an attempt to standardize dosing strategies amongst prescribers of different disciplines. The reduction in titrations required to reach a therapeutic aPTT goal showed the superiority over an empiric, prescriber-based strategy. There were no significant differences in the safety endpoints; however, our study was not designed or powered for these outcomes. This is the first published protocol to compare DTI therapy following a guideline that allows prescribers to choose between three therapeutic aPTT goals vs. a historic control and demonstrate an improvement in achievement of therapeutic goal values. There are several limitations to our study. Our analysis was observational in nature and as such unable to account for all forms of bias that may have affected the results. Unlike previously published guidelines that have been nurse-managed, our dosing guideline requires diligence of the prescriber to follow-up and order each dose change and subsequent monitoring frequency. Dosing titrations were enforced by clinical pharmacy staff. The implementation of a direct thrombin inhibitor dosing and titration guideline was associated with an increase in patients who achieved therapeutic aPTT goal, as well as achieving therapeutic aPTT goal on initial dose when compared to a historic cohort of patients managed by the prescriber. These findings were presented in abstract form at the 43rd Society of Critical Care Medicine Annual Congress and received the Hematology Specialty Award. James F. Gilmore,* Christopher D. Adams, Rachel M. Blum, John Fanikos, Beth Anne Hirning, and Lina Matta Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts