Adherence trajectories of DOACs and warfarin
To date, this is the first study to evaluate the adherence trajectories to DOAC and warfarin among AF patients with HTN, DM, and hyperlipidemia. This study identified three distinct trajectories in DOAC (adherence trajectory, RD, and GD) and warfarin (adherence trajectory, RD, and GA) users. This study found consistently poorer adherence to DOACs than warfarin among AF patients with multimorbidity. Only 39% of DOAC users and 59.4% of warfarin users were adherent for 1 year. Adherence to DOACs and warfarin is lower than other study findings[12–15]. This difference in adherence may be due to increased comorbidity burden, CHA2DS2VASc ≥5, and regimen complexity in this population[15, 16]. Furthermore, comorbidities like diabetes/HTN are associated with suboptimal adherence among AF patients . Approximately 41% of DOAC users were identified to have a gradual decline in adherence. DOACs have a shorter half-life than warfarin, and hence nonadherence to DOACs will result in more significant consequences and worse clinical outcomes. Ease of DOAC use and lack of frequent DOAC monitoring is considered to be advantageous over warfarin. However, in this study, this lack of monitoring may have impacted adherence. Evidence suggests that monitoring of AF patients for a longer duration improves adherence.
Use of concomitant medications in multimorbid AF patients
A higher disease burden among AF patients results in regimen complexity and predisposes them to poor adherence. Inadequate control of INR values and permanent discontinuation of medications were documented among AF patients who were prescribed with a greater number of concomitant drugs. In this study, all patients taking ≥ 4 concomitant medications, including their oral anticoagulant, could impact the risk-benefit profile of DOACs/warfarin. Evidence suggests that a number of concomitant medications are associated with increased stroke, bleeding events, and mortality. Medication regimen complexity impacts the risk-to benefit profile adversely and further decreases the quality of life. Concomitant use of statins among AF reduces CV and all-cause mortality, stroke, intracranial hemorrhage, gastrointestinal hemorrhage, and reduces the risk of dementia[22, 23]. The antithrombotic effect is attributed to ability of statins to alter coagulation and inhibit platelet activation. All the patients in this study had a cardiovascular benefit due to the concomitant use of statins. The drug-drug interactions in this study underscore the need for better pharmacovigilance to reduce the risk of adverse events among high-risk patients. Clinicians should consider prescribing medications that can be safely co-administered with DOACs/warfarin.
Clinical outcomes among multimorbid AF patients
Another major concern in this study is regarding the clinical outcomes among AF patients with multimorbidity. Suboptimal adherence to DOACs significantly increases the incidence of stroke among high stroke risk patients, which is consistent with this study findings[3, 13, 25]. Furthermore, the increased stroke in this study can be attributed to the elevated stroke risk scores and comorbid DM. DM among AF increases the likelihood of thrombus formation through oxidative stress, inflammation, and platelet activation. In this population, bleeding episodes were higher among the DOAC users. Additionally, the unadjusted analysis showed that the bleeding events were similar across the adherent and nonadherent patients. Hence, the use of warfarin/DOACs alone cannot fully explain the increased incidence of bleeding. Increased bleeding events that could not be attributed to warfarin/DOAC exposure may be due to comorbidity burden, increased CHA2DS2VASc scores, and concomitant use of potentially interacting medications. Health care professionals should educate patients about symptoms of drug-drug interactions like bleeding and stroke/transient ischemic attack.
Increased risk of MI among DOAC users is in line with the evidence which suggests that warfarin may be beneficial to reduce the risk of MI[28, 29]. The presence of comorbid HTN and DM in this study may have resulted in increased adverse kidney outcomes among AF patients. This study results are consistent with a prior study that reported warfarin users had more pronounced renal disorders than DOAC users[30, 31]. Elderly AF patients with HTN and DM have reduced glomerular filtration rate (GFR), which may justify the higher rates of renal disorder in this study. Renal impairment among AF patients increases the thromboembolic and cardiovascular complications than AF patients without renal complications. This study result highlights the need for more frequent monitoring of renal function among these high-risk patients with multimorbidity. Finally, the DOAC users appeared to have a lower risk of dementia compared to the warfarin users and is consistent with prior studies[33, 34]. This should be further investigated in future studies. The clinical outcome in the study highlights the need for optimal management of comorbidities.
Drug-drug interactions with DOACs and warfarin
There is a potential need to cautiously monitor DOAC/warfarin users who are prescribed NSAIDs and antiplatelet agents due to the increased bleeding risk[27, 35]. Clinicians may consider prescribing cyclooxygenase-2 (COX-2) over NSAIDs for pain management as it is associated with less bleeding risk. Clinically relevant interactions occur with DOACS/warfarin when they inhibit or induce p-gp and CYP3A4 pathways. Amiodarone, diltiazem, and ketoconazole were the most frequently prescribed p-gp/CYP3A4 inhibitor medications that interact with DOACs/warfarin and increase plasma levels DOACs/warfarin. Patients with AF had significantly higher rates of stroke, systemic embolism, and mortality[39, 40] when they received amiodarone than AF patients who did not take amiodarone. Concurrent use of DOACs and amiodarone was associated with significant increase in bleeding events. Furthermore, co-administration of amiodarone and warfarin increases the risk of stroke and systemic embolism. Despite this evidence, more than one-third of warfarin patients were prescribed with amiodarone. Concurrent administration of DOACs and diltiazem to AF patients significantly increase the bleeding events. Co-prescriptions of ketoconazole and DOACs increase bleeding events . Given the safety concerns related to ketoconazole, clinicians are advised to carefully evaluate such concerns prior to prescribing.
This was an exploratory study. Due to the limitations of sample size, there was a limited scope of carrying out regression analysis across different trajectories. Due to the lack of adequate power, the association between adherence and outcomes could not be carried out. This study was conducted among patients enrolled in the Texas Medicare Advantage plan which limits generalization.