Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

基于DEA方法的华法林抗凝分级管理模式的效率评价

目的:通过小范围的临床实践,使用数据包络分析(data envelopment analysis,DEA)方法对基于全程化抗栓药学服务模式的华法林抗凝管理工作效率进行评价。方法:选取2021年7-12月南京大学医学院附属鼓楼医院心胸外科瓣膜置换术后使用华法林抗凝的患者。将患者分为实验组和对照组,实验组由临床药师利用基于分级管理的全程化抗栓药学服务模式进行抗凝管理和药学监护,对照组由临床药师按照无差别监护模式进行抗凝管理和监护,记录2种模式下药师工作内容和工作成效,通过DEA方法分析比较2种抗凝管理模式的效率。结果:研究最终纳入服用华法林的患者233人(实验组116人,对照组117人),实验组的单位患者管理时间显著减少[(27.8±9.7)min vs.(34.8±11.4)min]。经模型计算后,实验组的总体效率值为1,说明其投入和产出最优,且效率高于对照组。结论:全程化抗栓药学服务模式下药师管理单位抗凝患者需要的时间更少,管理效率更高。     

Utility of INR For Prediction of Delayed Intracranial Hemorrhage Among Warfarin Users with Head Injury

BackgroundIncidence of delayed intracranial hemorrhage (DICH) in patients on warfarin has been controversial. No previous literature has reported the utility of international normalized ratio (INR) in predicting traumatic DICH.ObjectivesUtilizing INR to risk stratify head trauma patients who may be managed without repeat imaging.MethodsThis was a retrospective study at a Level II trauma center. All patients on warfarin with head injuries from March 2014 to December 31, 2017 were included. Each patient underwent an initial head computed tomography scan (HCT) and subsequent repeat HCT 12 h after. Patients presenting > 12 h after head injury received only one HCT. Two blinded neuroradiologists reviewed each case of DICH. Statistical analysis evaluated Glasgow Coma Scale (GCS), Injury Severity Score (ISS), heart rate, systolic blood pressure (SBP), age, and platelet count.ResultsThere were 395 patients who qualified for the protocol; 238 were female. Average age was 79 years. Seventy-seven percent of patients underwent repeat HCT. Five resulted in DICH (INR 2.6–3.0), three of which might have been present on initial HCT; incidence rate of 0.51–1.27%. One patient required neurosurgical intervention. Among 80 patients with INR < 2, no DICH was identified, resulting in high sensitivity, but with a wide confidence interval; sensitivity of 100% (95% confidence interval [CI] 47.8–100), specificity 21% (95% CI 16.6–28.9). Correlation of factors: ISS (p = 0.039), GCS (p = 0.978), HR (p = 0.601), SBP (p = 0.198), age (p = 0.014), and platelets (p = 0.281).ConclusionNo patient with INR < 2 suffered DICH, suggesting that warfarin users presenting with INR < 2 may be managed without repeat HCT. For INR > 2, patients age and injury severity can be used for shared decision-making to discharge home with standard head injury precautions and no repeat HCT.     

Quality of oral anticoagulation control in Chinese patients with non-valvular atrial fibrillation: a prospective controlled study

Abstract

Objective

The sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT₂R₂) Score; the sex, age, medical history, treatment, tobacco use, genotype combination (SAMe-TT₂G₂) Score; and the so-called modified SAMe-TT₂R₂ scores have been proposed to predict the anticoagulation quality for patients with non-valvular atrial fibrillation (NVAF). The data from a prospective controlled study is used to validate the SAMe-TT₂R₂ and SAMe-TT₂G₂ scores in Chinese NVAF patients treated with warfarin and to evaluate the association of factors with time in therapeutic range (TTR) to predict the quality of oral anticoagulation control.     

Structural Modeling Insights into Human VKORC1 Phenotypes

Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- and indandione-based vitamin K antagonists (VKA) used in the prevention and therapy of thromboembolism. Patients with these mutations require greater doses of VKA for stable anticoagulation than patients without mutations. The second phenotype, a very rare autosomal-recessive bleeding disorder caused by combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) arises from a homozygous Arg98Trp mutation. The bleeding phenotype can be corrected by vitamin K administration. Here, we summarize published experimental data and in silico modeling results in order to rationalize the mechanisms of VKA resistance and VKCFD2.