Polypharmacy compromises apixaban efficacy, safety in atrial fibrillation

Concurrent use of multiple drugs in patients with atrial fibrillation (AF) potentially undermines the performance of apixaban, such that there are higher risks of ischaemic stroke and death relative to warfarin and rivaroxaban, respectively, as shown in a study.

“One potential explanation is that apixaban is dosed twice daily, while warfarin and rivaroxaban are dosed once daily,” according to the investigators, pointing out that the dosing frequency influences patient adherence to that prescribed medication.

“Another explanation for our findings could be the use of a warfarin anticoagulation clinic model, which enables frequent prothrombin time/international normalized ratio monitoring and dosing adjustments and has been shown to be associated with higher adherence in prior research,” they added. [Circ Cardiovasc Qual Outcomes 2016;9:182-185]

Using Medicare administrative data, the investigators evaluated the comparative efficacy and safety of oral anticoagulants in AF patients with polypharmacy. They looked at 6,985 apixaban users, 3,838 rivaroxaban users, and 6,639 warfarin users. Patients taking ≤3, 4–8, or ≥9 other prescription medications were categorized as having low, moderate, or high polypharmacy, respectively.

On a three-way propensity-score–matched analysis, the risk of ischaemic stroke did not differ among the three drugs in the low and moderate polypharmacy groups. However, among patients with high polypharmacy, apixaban carried a risk increase when compared with warfarin (adjusted hazard ratio [HR], 2.34, 95 percent confidence interval [CI], 1.01–5.42; p=0.05) but not with rivaroxaban (adjusted HR, 1.38, 95 percent CI, 0.67–2.84; p=0.4). [Stroke 2020;51:2076-2086]

Apixaban was also associated with a higher risk of death relative to rivaroxaban (adjusted HR, 2.03, 95 percent CI, 1.01–4.08; p=0.05) but similar risk relative to warfarin (adjusted HR, 1.46, 95 percent CI, 0.79–2.70; p=0.2) in the high polypharmacy group. Mortality outcome did not differ among the three drugs in the low and moderate polypharmacy groups.

In terms of bleeding risk, a significant difference was observed in only the low polypharmacy group, with apixaban bearing a lower risk compared with warfarin (adjusted hazard ratio, 0.54, 95 percent CI, 0.32–0.90; p=0.02).

In an analysis evaluating reduced doses in the high polypharmacy group, both apixaban 2.5 mg twice daily and rivaroxaban 15 mg daily were associated with lower risk of bleeding compared with warfarin. However, apixaban still posed a greater risk of death relative to rivaroxaban.

The findings indicate that significant polypharmacy is prevalent among AF patients from the US, the investigators said. “Polypharmacy is associated with negative clinical outcomes in several ways.”

For the most part, there is the potential for drug-drug interaction, which can weaken efficacy for a given drug or increase toxicity level. Furthermore, polypharmacy may negatively affect adherence, as the investigators mentioned earlier. Patients may miss their medications or end up taking the wrong dosage or frequency. [Expert Opin Drug Saf 2014;13:57-65; Arch Intern Med 2004;164:722-732]

“The question of whether the higher apixaban mortality in our study is due to medication nonadherence leading to higher stroke risk or caused by drug interaction with strong P-GP inhibitors could not be answered with our analysis and requires further studies,” the investigators said.