Heparin resistance is defined as the need for more than 35,000 units/day of heparin to reach a therapeutic activated partial thromboplastin time (aPTT), which is 68 to 104 seconds. Among the factors that have been associated with heparin resistance are antithrombin deficiency, congenital deficiencies, disseminated intravascular coagulation, increased heparin clearance, use of extracorporeal circulation, and asparaginase therapy.
Recently it was observed that patients who use IV drugs (PWIDs) may require higher heparin doses. However, there is a paucity of literature evaluating continuous heparin infusion rates in patients with a history of IV drug use.
The purpose of this multicenter, retrospective chart review was to evaluate whether patients with a documented history of IV drug initiated on weight-based heparin infusions required higher than expected infusion rates to achieve a therapeutic aPTT.
Investigators identified patients who had an ICD-9 code for amphetamine and other psychostimulant dependence (304.40), hallucinogen dependence (304.50), nondependent opioid abuse (305.50), and nondependent cocaine abuse (305.60). In addition, they identified ICD-10 codes for opioid abuse–mild or in early or sustained remission (F11.10), cocaine-use disorder–mild or in early or sustained remission (F14.10), amphetamine-type substance use–mild or in early or sustained remission (F15.10), and phencyclidine-use disorder–mild or in early or sustained remission (F16.10) who were admitted at seven acute care facilities between October 1, 2015, and September 30, 2020.
To be included in the study, patients had to be aged 18 years or older, used IV drugs within the past 6 months, and received a weight-based heparin infusion during the above specified dates. Patients were excluded if they were pregnant, of child-bearing age without a negative pregnancy test, if they received a noncontinuous heparin infusion, if heparin was administered for fewer than 48 consecutive hours, or if they were treated in a facility outside of the network.
The primary outcome of the study was to describe therapeutic heparin infusion rates in patients who have used IV drugs within the past 6 months. Secondary outcomes included determining the average time to reach therapeutic aPTT and to identify patients who experienced moderate to severe bleeding (as defined by the International Society of Thrombosis and Haemostasis [ISTH]) secondary to increased heparin infusion rates.
Of the 41 study patients, 39 achieved a therapeutic aPTT after an average time of 35.5 hours. The average maintenance infusion rate needed to have a sustained therapeutic aPTT was 27.6 units/kg/hr, which was 150% or 9.6 units/kg/hr higher than the initial heparin infusion rate to reach a therapeutic status. When the median infusion rate to maintain a therapeutic aPTT was calculated for 24 hours, 85% of patients met the definition of heparin resistance.
The ISTH defined major bleeding in nonsurgical patients as fatal bleeds; bleeds in a critical area such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, intrapericardial, or intramuscular with compartment syndrome; and bleeds that result in a decrease in hemoglobin by more than 2 g/dL. No patients met the first two criteria for a major bleed; however, one patient did have a gastrointestinal bleed with a significant hemoglobin drop of more than 2 g/dL.
While there is a lack of information of the pharmacokinetics of heparin in PWIDs, the authors pointed out that there is a significant decrease in antithrombin activity in heroin users. Heparin depends on the presence of antithrombin to exert its therapeutic effect.
It is theorized that since illicit drug users have an increase in the secretion of acute phase reactants, such as C-reactive protein and serum amyloid A, and since heparin binds to acute-phase reactants, this nonspecific binding accounts for variability in anticoagulant response. The authors hypothesized that PWIDs in this study had reduced antithrombin activity that may explain the heparin resistance observed.
The investigators recommended using anti-Xa assays in PWIDs as it provides superior results compared with the use of aPTT. The target anti-Xa assay level is 0.3 to 0.7 IU/mL. Unfortunately, anti-Xa assay results were not available in this trial.
The authors caution that due to the retrospective nature of this study, the inability to control for confounders, no control group, and the lack of anti-Xa assay results, this study is hypothesis-generating. Nonetheless, pharmacists should be aware of the potential alterations in heparin dosing requirement in PWIDs given that we are still in the throes of an opioid epidemic.
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