Atrial Fibrillation
Polypharmacy in Elderly Patients With Non-Valvular Atrial Fibrillation ― The Trail to Adverse Events ―
2023 Volume 87 Issue 1 Pages 17-19
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2023 Volume 87 Issue 1 Pages 17-19
Atrial fibrillation (AF) is a common arrhythmia in clinical practice and it causes serious adverse events such as stroke and systemic embolic events (SEE). Oral anticoagulation (OAC) with non-vitamin K oral anticoagulants (NOACs) or warfarin is central to the prevention of stroke/SEE in AF patients. The ANAFIE registry is a multicenter, prospective, observational study that has enrolled more than 30,000 elderly (≥75 years old) patients with non-valvular AF (NVAF) in Japan. The study investigated the current status, prognosis, clinical problems, real-world use of anticoagulants, and risk factors associated with adverse events in elderly NVAF patients.1 The initial results have been recently published, demonstrating that stroke/SEE, major bleeding, and all-cause death were observed less frequently in patients on NOACs than in those on warfarin; the absence of OAC was associated with worse outcomes, except for bleeding events.2
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Polypharmacy (≥5 medications) is becoming more prevalent in contemporary, guideline-driven practice, and is an economic health problem as Japan’s society continues to age. In this Issue of the Journal, a subanalysis of the ANAFIE registry by Yamashita et al3 reports the effect of polypharmacy on adverse events in elderly NVAF patients. Their results demonstrated that the prevalence of polypharmacy was 61.2% (Table). Polypharmacy did not independently increase the risk of stroke/SEE in multivariate analysis but it did increase the incidence of extracranial — not intracranial — adverse bleeding. NOACs showed superior efficacy and safety to warfarin even in this aged population with polypharmacy.3
| Piccini et al4 | Jaspers Focks et al5 | Chen et al6 | Yamashita et al3 | |
|---|---|---|---|---|
| Study design | Post-hoc RCT (ROCKET-AF) |
Post-hoc RCT (ARISTOTLE) |
Retrospective database |
Prospective registry (ANAFIE) |
| Follow-up period, years | 1.9 | 1.8 | 2.1 | 1.9 |
| Region | Worldwide | Worldwide | USA | Japan |
| No. of patients, n | 14,264 | 18,201 | 338,810 | 32,726 |
| Age, years | 73 | 70 | 83 | 82 |
| Male, % | 60 | 65 | 49 | 57 |
| CHADS2 score, pts | 3.5 | 2.1 | N/A | 2.9 |
| Anticoagulants | Riv WF |
Api WF |
Dab/Riv/Api WF |
Dab/Riv/Api/Edo WF |
| Polypharmacy, % | 64 | 62 | 52 | 61 |
| Adverse events | ||||
| Stroke/SEE | → | ↑ | → | → |
| Major bleeding | ↑ | ↑ | ↑ | ↑ |
| Gastrointestinal bleeding | N/A | ↑ | N/A | ↑ |
| Intracranial hemorrhage | ↑ | → | N/A | → |
| All-cause death | ↑ | ↑ | N/A | ↑ |
Api, apixaban; Dab, dabigatran; Edo, edoxaban; N/A, not available; NVAF, non-valvular atrial fibrillation; RCT, randomized controlled trial; Riv, rivaroxaban; SEE, systemic embolic events; WF, warfarin.
Polypharmacy presumably reduces the efficacy and safety of medical treatment by altering the pharmacokinetics and pharmacodynamics due to complex drug-drug interactions. Nevertheless, in this study3 it was not independently associated with the risk of stroke/SEE irrespective of the type of anticoagulant (NOACs or warfarin). The subanalyses of the ROCKET-AF trial (using rivaroxaban and warfarin) and another database study (using dabigatran, rivaroxaban, apixaban, and warfarin) also demonstrated similar results, implying that OAC is essential for stroke/SEE prevention even with polypharmacy.4,5 In contrast, a subanalysis of the ARISTOTLE trial (using apixaban and warfarin) demonstrated that polypharmacy increased the incidence of stroke/SEE in NVAF patients (Table).6
Polypharmacy increased the risk of major bleeding in this study, a finding consistent with previous reports (Table).3–6 Controlling factors associated with bleeding risk is particularly important in elderly NVAF patients with polypharmacy. On the one hand, clinicians should attempt to reduce the number of drugs as much as possible. On the other hand, because several drugs are usually prescribed for each comorbid disease regardless of the patient’s age, polypharmacy is a surrogate marker of multimorbidity. In general, elderly patients suffer from multiple comorbid diseases and so require multiple medications. Therefore, withdrawal of some concomitant medications may exacerbate disease conditions. In this study, antihyperlipidemic drugs significantly decreased the risk of major bleeding.3 A previous Asian study has also demonstrated that concurrent use of atorvastatin with NOACs decreased the risk of major bleeding regardless of the type of anticoagulant.7 In this study, antihypertensive drugs significantly decreased the risk of all-cause death.3 In general, appropriate control of blood pressure reduces the risk of major bleeding. Such medications should be prioritized to control lifestyle diseases and arteriosclerosis. Nevertheless, the half-lives and maximum blood concentrations of drugs usually increase in the aged population and dose adjustment is an alternative to avoid adverse events. The risk-benefit of discontinuation and dose adjustment of each drug should be carefully evaluated in this population.
Polypharmacy was not independently associated with the risk of intracranial hemorrhage (ICH) in the multivariate analysis of this study although the incidence increased in the Kaplan-Meier analysis.3 In the ANAFIE registry most of the patients (≥60%) were anticoagulated with NOACs. The result may be, at least partly, attributable to the ICH-avoidable safety nature of NOACs.8 In previous studies, apixaban did not increase the incidence of ICH in NVAF patients with polypharmacy whereas rivaroxaban showed a higher risk of ICH in patients treated with at least 10 medications (Table).4,5 There are conflicting results on the relationship between polypharmacy and adverse events, which would be attributable to differences in patient demographics, study design, definition of adverse events, control of comorbid diseases, and the profiles of anticoagulants among studies.
Polypharmacy reduces physical function in elderly patients associated with multimorbidity (frailty). Frail patients have a higher chance of falls and fractures with serious traumatic bleeding, especially subdural hematoma. A North European study using a large-scale database has shown that a higher incidence of subdural hematoma was related to an increased prescription rate of anticoagulants in NVAF patients. The most frequent reason for nonprescription of OACs is falls/frailty and high bleeding risk in elderly patients with multimorbidity.9 However, frail patients with NVAF are also at increased risk of stroke/SEE so any discontinuation and nonprescription of OAC should be carefully assessed in this population. In this study, psychotropic drugs were independently associated with the risk of major bleeding, likely because of the increased chance of fall and fracture.3 A previous study reported that an antiepileptic drug (phenytoin) increased the risk of ICH in NVAF patients with NOACs.7 Concurrent use of these drugs with NOACs and warfarin should be done with caution. Percutaneous left atrial appendage occlusion is an alternative in elderly NVAF patients with a remarkably higher bleeding risk who cannot tolerate OAC.
Polypharmacy is also associated with poor drug adherence, especially in people with geriatric mental conditions (i.e., cognitive dysfunction, depression, and poor literacy), which limits their pharmacological control options (e.g., rhythm control with antiarrhythmic drugs), and would increase the risk of adverse events. Easy and simple drug-intake methods (e.g., from TID to BID/QD, one-dose package, fixed-dose combination, adhesive drug) may help to improve the poor drug adherence associated with polypharmacy.
Polypharmacy, multimorbidity, and frailty synergistically contribute to the risk of adverse events (Figure) and management of this vicious triad is a challenge in the aged population; the ANAFIE registry has shed light on the warning trail to adverse events and provide clues to avoiding it. Physicians sometimes face difficulty in applying guideline-directed medical therapy in this group and therefore should define the goals and limitations of medical treatment based on what matters most to a patient with a narrow range of risk-benefit management. Shared decision-making is particularly important for choosing the therapeutic options that meets a patient’s needs and rejecting those that do not, thereby helping to decrease adverse events and improve patient outcomes.
Polypharmacy, multimorbidity, and frailty synergistically contribute to the risk of adverse events in elderly patients with non-valvular atrial fibrillation.
M.H. received speaker fees from Nippon Boehringer Ingelheim, Daiichi-Sankyo, Bristol-Myers Squibb.
