Dosing challenges with direct oral anticoagulants in the elderly: a retrospective analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) provide patients with attractive options for anticoagulation in atrial fibrillation (AF). However, dosing these agents in the elderly can be challenging due to factors such as drug interactions, reduced renal function, and less frequent monitoring. This study addressed this challenge by reviewing the dosing of three commonly used DOACs (i.e. apixaban, dabigatran, and rivaroxaban) in elderly patients managed at a pharmacist-run anticoagulation clinic. METHODS: This was a single-center, retrospective cohort study. A total of 98 cases of DOAC therapy in patients with AF aged 75 years or older receiving care at a large urban healthcare center were identified via chart review. Dosing of each DOAC was assessed at therapy initiation and throughout treatment whenever a serum creatinine was reported, using the Cockcroft-Gault equation to estimate creatinine clearance (CrCl). Dose excursions (defined as instances where patients were exposed to non-Food and Drug Administration (FDA)-approved doses) were documented in each case. Rationales for dose excursions were determined by study investigators via review of progress notes and categorized using clinical judgement. RESULTS: Upon therapy initiation apixaban was dosed in accordance with FDA recommendations in 92.9% of patient cases, dabigatran in 91.2% of cases, and rivaroxaban in 86.1% of cases (p = 0.70). FDA-recommended dosing was maintained throughout treatment at the highest rates with dabigatran (88.2% versus 78.6% with apixaban and 58.3% with rivaroxaban; p = 0.01, p = 0.005 for dabigatran versus rivaroxaban). The most common rationales for dose excursion were fluctuation in estimated CrCl near the dosing cutoff, and recommendations from nonpharmacist providers co-managing the patient. CONCLUSIONS: Prescribing and maintaining FDA-recommended doses of DOAC agents in the elderly is more challenging than initially perceived. Fluctuations in renal function, comorbidities, and concomitant antiplatelet use may necessitate more individualized dosing strategies with these agents.

Bridging for an isolated subtherapeutic INR: an evaluation of clinical practice patterns, outcomes, and costs from an anticoagulation clinic.

No formal recommendations support bridging patients taking warfarin for a subtherapeutic international normalized ratio (INR). This study aimed to: (1) characterize practices at one anticoagulation clinic, (2) evaluate adverse events, and (3) compare cost of bridging versus withholding bridging for subtherapeutic INR. A retrospective chart review of 320 patients having 546 isolated subtherapeutic INR episodes included patients with an INR below their therapeutic range, preceded by two INRs within or above range. Bridged episodes required more frequent follow-up visits to achieve therapeutic INR (2.5 ± 1.0 vs. 2.2 ± 0.6; P = 0.097), but fewer days until the INR returned to therapeutic range (6.8 ± 5.0 vs. 18.9 ± 16.0; P < 0.0001). The strongest predictor of bridging was the magnitude the INR fell below the therapeutic range, where those with a severely-low INR were 30-fold more likely to be bridged (P < 0.0001), and moderately-low INR episodes were 6-fold more likely to be bridged compared with mildly-low INR (P < 0.0001). Those at high thromboembolic risk were more likely to be bridged than at low-risk (OR 3.39 [1.50-7.68]; P = 0.0034). Increasing age reduced the likelihood of being bridged (OR 0.97 [0.95-0.99]; P = 0.0118). Adverse events were infrequent in both the bridged and non-bridged; thrombosis (2.0 vs. 0.7%), major bleeding (2.0 vs. 1.3%), minor bleeding (4.1 vs. 3.1%) and bruising (18.4 vs. 3.6%). Incremental cost difference of bridging was significantly greater for total cost ($967.13) and its components, direct medical ($951.32), transportation ($2.73) and productivity cost ($13.08). It is unclear if bridging for an isolated subtherapeutic INR reduces thrombosis risk, but it is associated with higher costs.

Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic.

BACKGROUND: There is growing evidence that kidney disease affects hepatically cleared drugs. Accordingly, we hypothesized that chronic kidney disease (CKD) would disrupt anticoagulation of warfarin-treated patients and thereby increase the amount of management required to maintain appropriate anticoagulation. Specifically, we anticipated that more dose manipulations (both dose changes and transient dose adjustments) and shorter times between scheduled clinic visits would be required for anticoagulation patients with CKD. OBJECTIVES: To determine how CKD affected warfarin maintenance dose, anticoagulation stability, the proportion of clinic visits that necessitated a dose manipulation (either a change in the prescribed weekly dose or a transient dose adjustment), and the length of time between scheduled visits in 2 pharmacist-managed anticoagulation clinics. METHODS: Our retrospective, cohort chart review investigated warfarin response in anticoagulation clinic patients. From the clinic database of patients with an international normalized ratio (INR) target range of 2.0-3.0, we matched 20 of 24 patients with CKD (estimated creatinine clearance less than 60 mL per minute) to 20 comparison group patients (estimated creatinine clearance greater than 60 mL per minute) based on parameters demonstrated to affect warfarin dose: ethnicity, gender, age, body surface area, and simvastatin use. We calculated the average weekly dose used to maintain target INR (assessment period range=116-1,408 days). To evaluate anticoagulation stability and patient management, we quantified several parameters, including the percentage of total time in therapeutic range, the proportion of clinic visits that required a dose change, and the time between scheduled visits. We compared group means using t-tests, and categorical data were compared using Fisher's exact test. RESULTS: Our population was predominantly female (75%) and of African ancestry (95%); average age 60 years. Patients with CKD required a 24% lower dose than the comparison group (mean [SD]=35.9 [10.7] vs. 47.0 [11.2] mg per week, P=0.003) and spent less time in therapeutic range required increased clinic management versus the comparison group, as indicated by a significantly higher proportion of clinic visits at which dose changes occurred (22% vs. 12%, P<0.001) and a decreased time between scheduled visits (mean [SD] of 16.0 [3.2] days vs. 19.7 [3.4] days, respectively, P=0.001). CONCLUSIONS: CKD was associated with both decreased warfarin maintenance dose and decreased anticoagulation stability which, in turn, required more frequent and intensive anticoagulation clinic management.

Warfarin maintenance dose in older patients: higher average dose and wider dose frequency distribution in patients of African ancestry than those of European ancestry.

Studies report that warfarin doses required to maintain therapeutic anticoagulation decrease with age; however, these studies almost exclusively enrolled patients of European ancestry. Consequently, universal application of dosing paradigms based on such evidence may be confounded because ethnicity also influences dose. Therefore, we determined if warfarin dose decreased with age in Americans of African ancestry, if older African and European ancestry patients required different doses, and if their daily dose frequency distributions differed. Our chart review examined 170 patients of African ancestry and 49 patients of European ancestry cared for in our anticoagulation clinic. We calculated the average weekly dose required for each stable, anticoagulated patient to maintain an international normalized ratio of 2.0 to 3.0, determined dose averages for groups <70, 70-79, and >80 years of age and plotted dose as a function of age. The maintenance dose in patients of African ancestry decreased with age (P<0.001). In addition, older patients of African ancestry required higher average weekly doses than patients of European ancestry: 33% higher in the 70- to 79-year-old group (38.2+/-1.9 vs. 28.8+/-1.7 mg; P=0.006) and 52% in the >80-year-old group (33.2+/-1.7 vs. 21.8+/-3.8 mg; P=0.011). Therefore, 43% of older patients of African ancestry required daily doses >5mg and hence would have been under-dosed using current starting-dose guidelines. The dose frequency distribution was wider for older patients of African ancestry compared to those of European ancestry (P<0.01). The higher doses required by older patients of African ancestry indicate that strategies for initiating warfarin therapy based on studies of patients of European ancestry could result in insufficient anticoagulation and thereby potentially increase their thromboembolism risk.