NOACs in nonvalvular atrial fibrillation with multimorbidity: Where does apixaban stand?

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice, affecting millions of people globally. Stroke is one of its devastating complications, with the risk steeply increasing with advancing age. Additionally, AF is associated with more than a tripling of the risk of systemic embolic (SE) events. [J Am Heart Assoc 2020;9:e016724]

Multimorbidity common in AF
Patients with nonvalvular AF (NVAF) often have multimorbidity, defined as 3 or more comorbid conditions. In a UK study of over 5 million people with a median follow-up of 10.3 years, two in five patients had 3 or more comorbidities at the time of AF diagnosis. [Lancet Reg Health Eur 2021;7:100157]

Importantly, multiple comorbid conditions increase the risks of polypharmacy, cerebrovascular events, and other adverse patient outcomes. For each comorbidity added, the risk of major bleeding (MB) increases by 15 percent. [Am Heart J 2019;208:123-131] 

The associated risks are even magnified in AF patients with long-term conditions, which further increase the complexity of patient management. Oral anticoagulation therapy is central to minimizing the risk. 

The vitamin K antagonist warfarin is commonly prescribed for AF, but it has a complex dose-response relationship that makes safe and effective use a challenge. Routine international normalized ratio (INR) monitoring and frequent dose adjustments make warfarin less appealing to patients and clinicians. 

Non-vitamin K antagonist oral anticoagulants (NOACs) offer a safe and efficacious treatment option for stroke prevention in patients with NVAF, without the drawbacks associated with conventional therapy like warfarin. [Lancet 2014;383:955-962; J Am Coll Cardiol 2019;74:104-132] 

The scarcity of studies comparing NOACs vs warfarin in patients with NVAF and multimorbidity made the ARISTOPHANES (Anticoagulants for Reduction in Strokes: Observational Pooled Analysis on Health Outcomes and Experience of Patients) subanalysis more relevant. 

NOACS vs warfarin in multimorbid AF population
In the ARISTOPHANES substudy, researchers evaluated the prevalence of multimorbidity among older patients with AF who were prescribed NOACs or warfarin, including its impact on adverse clinical outcomes, specifically stroke/SE and MB. Data were culled from the US Centers for Medicare & Medicaid Services and four insurance claims databases in the US. Propensity score matching (1:1) was conducted between NOAC and warfarin cohorts and between the NOAC cohorts. [Adv Ther 2021;doi:org/10.1007/s12325-021-01724-8] 

Among 466,991 patients with NVAF on NOACs or warfarin, 155,959 (33.4 percent) had multimorbidity. The mean number of comorbidities were between 7.5 and 7.8 across the cohorts. 

The unadjusted incidence rates of stroke/SE (per 100 person-years) were 3.7 for warfarin, 2.4 for apixaban, 2.8 for dabigatran, and 2.4 for rivaroxaban. The unadjusted rate for MB (per 100 person-years) was lower with apixaban at 6.9 compared with 11.5 for warfarin, 7.2 for dabigatran, and 10.5 for rivaroxaban. 

Stroke/SE, MB risks lower with apixaban
Overall, NOACs were associated with varying risks of stroke/SE and MB. However, compared with warfarin, apixaban (Eliquis, Pfizer) was associated with a lower risk of stroke/SE (hazard ratio [HR], 0.63, 95 percent confidence interval [CI], 0.54-0.74; p<0.001). Similarly, the risk of MB was also lower with  apixaban vs warfarin (HR, 0.61, 95 percent CI, 0.56-0.67; p<0.001). 

Compared with dabigatran, apixaban was associated with a lower risk of stroke/SE (HR, 0.81, 95 percent CI, 0.65-1.00) and MB (HR, 0.82, 95 percent CI, 0.69-0.98). Apixaban was also associated with a lower risk of MB vs rivaroxaban (HR, 0.57, 95 percent CI, 0.52-0.63; p<0.001). 

Comorbidities & impact on treatment
In the subanalyses looking at the number of comorbidities and their impact on OAC treatment, patients with 6-8 comorbidities had a greater reduction in MB risk vs those with 9+ comorbidities at least for apixaban vs warfarin users (Table 1). The same was true for apixaban vs rivaroxaban (Table 2). 

In terms of stroke/SE, the risks were similar for apixaban and rivaroxaban in those with 6-8 comorbidities but appeared lower for apixaban than rivaroxaban in patients with 9+ comorbidities (Table 2). 

Take-away messages
·       Multimorbidity is frequent in NVAF. With it goes higher risks of stroke and bleeding. In this largest study thus far of oral anticoagulants in multimorbid patients with NVAF, NOACs were associated with varying risks of stroke/SE and MB vs warfarin.

·       Apixaban preserved its safety and efficacy over warfarin in this unique subgroup of patients. Overall, the results will inform treatment decisions on the best anticoagulation therapy for multimorbid patients with NVAF.