Selecting a Direct Oral Anticoagulant for the Geriatric Patient with Nonvalvular Atrial Fibrillation
Journal of Clinical Outcomes Management. 2015 December;22(12)
References
Therapeuti Drug Monitoring
Collectively, the data on assessment of the anticoagulant activity of DOACs using coagulation assays is evolving. These tests include but are not limited to prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TT), dilute TT, activated clotting time (ACT), anti factor Xa, and ecarin clotting time (ECT) assays. Although routine monitoring is not desirable, the ability to assess degree of anticoagulation in select patient populations may prove beneficial. Future studies are essential to confirm whether assessing DOAC activity using coagulation assays in vulnerable populations such as the elderly improves clinical outcomes. Several reviews on this subject matter have been published [51–55]. The reader is encouraged to review these data as there are significant limitations to currently available assays and incorrect interpretation may lead to suboptimal treatment decisions.
Renal and Hepatic Dysfunction
Depending on the specific agents, DOACs renal clearance varies from 27% to 80% [56–59]. Clinical trials often use the Cockcroft-Gault formula (CG) based on actual body weight to estimate renal function. Landmark trials evaluating the DOACs differed in their strategy for estimation of renal function using CG. For example, RE-LY and ROCKET-AF used actual body weight for the estimation of renal function, while ARISTOTLE did not specify which body weight to use. Estimation of renal function or glomerular filtration rate (GFR) by CG is frequently in discordance with actual renal function in the elderly [60]. MDRD (modification of diet in renal disease) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) are also common estimations that provide an estimate of GFR. In a cross-sectional study, comparing the CG, MDRD, and EPI formulas in a clinical setting, data from potential kidney donors and adult patients who underwent a GFR measurement revealed that MDRD has the smallest mean bias. The influence of age was the absolute bias for estimation of renal function for all formulas. CG is additionally influenced by body weight and body mass index. When compared to CG, MDRD actually reported more accurate predictor of GFR in adults < 70 years old [61]. However, package inserts recommend dose adjustments based on estimation of CrCl using CG formula. This poses a problem in adjusting DOAC doses in elderly patients who are subject to overestimation of renal function with this antiquated equation. Among elderly patients with renal impairment, discordance between estimated and actual renal function was higher for dabigatran and rivaroxaban than for apixaban dosages [61].
Only 27% of apixaban is renally cleared, and the manufacturer does not indicate dose adjustments for patients with renal insufficiency [57]. Therefore, apixaban is the favorable anticoagulant in the elderly population with renal disease. Prescribing information recommends reducing the dose from 5 mg twice daily to 2.5 mg twice daily for nonvalvular AF patients, if patients meet 2 of the following criteria: age ≥ 80 years of age, body weight ≤ 60 kg, and serum creatinine ≥ 1.5 mg/dL ( Table 5 ) [57]. In patients with end-stage renal disease (ESRD) maintained on hemodialysis, the recommended dose of apixaban is 5 mg twice daily, unless the patient is ≥ 80 years or has a body weight ≤ 60 kg, in which case the dose should be reduced to 2.5 mg twice daily. Clinicians should consider the source of the aforementioned dosing strategy as patients with a CrCl < 25 mL/min were excluded from the ARISTOTLE study. Dosing in hemodialysis is supported by a small study that showed an increase in AUC of 36% after a single dose. The extent of drug accumulation is unknown and dialysis only clears a small portion of apixaban (~14%).
Renal excretion of unchanged dabigatran is the predominant pathway for elimination (~80%) [58]. The FDA-approved dosing strategy in the US for dabigatran is 150 mg twice daily in patients with a CrCl ≥ 30 mL/min, 75 mg twice daily in patients with severe renal impairment (CrCl 15–30 mL/min), and is contraindicated in patients with a CrCl < 15 mL/min [58]. By comparison, the Canadian and the European Medicines Agency have listed patients with a CrCl < 30 mL/min (severe renal impairment) as a contraindication for use. The US-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model [62,63]. The dosage was estimated by pharmacokinetic simulation to provide similar C max and C min concentrations compared to the 150 mg twice-daily dosage in moderate renal impairment. Compared to patients with CrCl ≥ 80 mL/min, there was a 1.29- and a 1.47-fold increase in dabigatran trough plasma concentration in the CrCl 50–80 mL/min patients and the CrCl 30–50 mL/min patients, respectively. There have been many postmarketing reports of hemorrhage with dabigatran [36,84,85]. Although reporting bias is likely due to the novelty of the agent, clinicians may take key clinical pearls away from these reports. Patients often had risk factors, including low body weight, renal impairment, and polypharmacy with interacting drugs (eg, amiodarone). These risk factors are also important with the other DOACs.
