Cost/benefit of direct oral anticoagulants

Warfarin? DOACs and, if so, which ones? An examination of the latest options, pros and cons for anticoagulation treatment

Clinicians commonly encounter medical conditions that require anticoagulation. It’s no wonder; up to 6.1 million people in the U.S. have  atrial fibrillation (AF or AFib), the most common type of heart arrhythmia . And as the population continues to age, the prevalence of AF grows accordingly. The CDC reports that AF is attributed to more than 750,000 hospitalizations each year and 130,000 deaths; the death rate from AF as the primary or a contributing cause of death has been rising for more than two decades.

Annual direct expenses for nonvalvular atrial fibrillation (NVAF) have been assessed at nearly $7 billion, including $3 billion to $4 billion for hospitalizations. This blog discusses the incremental cost-effectiveness of direct oral anticoagulants (such as rivaroxaban, apixaban, edoxaban, dabigatran) as part of your treatment decisions.

Direct oral anticoagulants (DOAC) have gained an increased share over warfarin for the prevention and treatment of thromboembolic disease. These DOACs extend the benefits of fewer drug-drug interactions, an absence of significant dietary effects, no requirement for regular international normalized ratio monitoring, and less risk of intracranial bleeding when compared with warfarin. Nevertheless, patients receiving these agents still need follow-up to ensure proper use and adherence to therapy.

Warfarin sodium, an inhibitor of vitamin K-dependent clotting factors, has been the cornerstone of oral anticoagulation. Unlike warfarin, DOACs don’t require routine testing to check blood level, and consequently expanded their usage as an alternative to the older drug.

Comparing approved DOACs

Four direct-acting oral anticoagulants (DOAC) — the thrombin inhibitor dabigatran, and factor Xa inhibitors rivaroxaban, apixaban, edoxaban — are approved for non-valvular atrial fibrillation and venous thromboembolism treatment (all four), secondary VTE prevention (rivaroxaban, apixaban, dabigatran), prophylaxis from venous thromboembolism after knee or hip replacement (dabigatran, rivaroxaban, apixaban). A fifth DOAC, betrixaban, received FDA approval in 2017 for extended thromboprophylaxis in acutely ill medical patients.

Labeled indications have included the treatment of DVT and PE, prevention of recurrent DVT and PE, the prevention of stroke in patients with nonvalvular atrial fibrillation, and prophylaxis after joint replacement surgery. DOACs — in particular, apixaban — reduce the risk of major bleeds in comparison with warfarin in both patients with and without AF.

Available DOACs act on two specific clotting factors. Dabigatran is a direct thrombin inhibitor, whereas rivaroxaban, apixaban and edoxaban are factor Xa inhibitors. DOACs are cleared by the kidney and other routes of metabolism, such as the liver and enteric secretion. They have a shorter half-life (8 to 17 hours) compared with vitamin K antagonist (36 to 42 hours.) The peak level of all DOACs is reached in 1 to 4 hours. As DOACs are metabolized through the cytochrome pathway, they tend to interact primarily with CYP3A4 or P-glycoprotein (P-gp) inhibitors and inducers.

There’s a lack of standardization on how systematic reviews of cost-effectiveness studies are conducted; future studies are needed to accurately compare and summarize the cost-effectiveness among DOACs for healthcare providers and decision-makers in practices, including formulary decisions. However, it appears that the higher cost of DOACs dominates by the value of their advantages of the minimized need for monitoring and the superior efficacy and safety profiles. The objective of this systematic review is to summarize and compare the primary cost-effectiveness outcomes in studies comparing DOAC agents.

Economic implications of DOACs

Various studies using clinical trial data and Markov decision models have revealed that DOACs are cost-effective alternatives to warfarin depending on the payer (healthcare systems vs. patient), with apixaban presenting the most cost-effectiveness compared with dabigatran, rivaroxaban and warfarin. Nevertheless, insufficient real-world data is available such as lack of adherence data and uncertainty about diagnoses of outcomes to accurately evaluate healthcare cost.

When selecting an anticoagulant, clinicians must take into account class- and drug-specific precautions and contraindications. For instance, some anticoagulants may require dosing adjustments for those with renal impairment, whereas others may be correlated with more significant risks of bleeding or possess specific drug interactions. Moreover, circumstances such as patient preferences, issues of adherence, and required weekly lab testing may result in favoring one drug over another without associating cost.

Relating to cost, in the Deitelzweig et al. (2016) evaluation of DOACs, rivaroxaban patients acquired significantly higher all-cause hospital readmission costs (difference=$413; P=0.003) compared with apixaban patients. Additionally, apixaban was associated with lower all-cause healthcare costs per patient per month (PPPM) and high bleeding-related medical costs compared with warfarin, but significantly lower major bleeding-related costs compared with dabigatran.

As a whole, comparing different studies, outcomes confirmed related total all-cause healthcare costs between warfarin and apixaban patients. But in a study analyzing Medicare data, patients taking warfarin were found to have significantly higher healthcare costs compared with patients taking apixaban. The discrepancy in results can be credited to the potential underestimation of pharmacy costs in the data. As more-extensive data becomes accessible and as treatment guidelines change over time, further studies are warranted regarding the comparative economic outcomes of direct oral anticoagulants.

In terms of a patient’s cost, it varies from individual to individual based on insurance coverage. But in general, DOACs are presumably less expensive than the injectable agents but more expensive than warfarin. On the other hand, accounting for the monitoring visits with practitioners, and the dose changes required of warfarin, the overall cost of DOACs may be lower for healthcare systems. Researchers have found that annual U.S. healthcare costs associated with VTE is, conservatively up to $10 billion a year…and increasing faster than general inflation for healthcare services.

Healthcare professionals are rapidly accepting DOACs as viable alternatives to warfarin, as is evident in a report showing that DOACs accounted for 62% of all new anticoagulant prescriptions, with an accompanying 98% of total anticoagulant-related drug costs. Average patient out-of-pocket and insurance spending were more than fivefold and 15-fold higher, respectively, for DOACs compared with warfarin. According to one study, patients’ average monthly out-of-pocket expense for warfarin (including INR monitoring) was $39 compared with $234.38, $238.11, $234.87, and $205.64 for dabigatran, rivaroxaban, apixaban and edoxaban, respectively.

The role of pharmacogenomics

The results of pharmacogenomic (PGx) testing on a patient should additionally be taken into consideration to maximize effectiveness and safety along with the economic implications of any chosen anticoagulants. New guidelines for warfarin have been updated and are presumed to reduce the risk of adverse drug events These pharmacogenomic factors may add to the cost of warfarin administration, but in general, it appears they’re less of a consideration with DOACs.

Conclusion: Cost-effectiveness of DOACs vs. VKAs

In the long run, event-specific cost analysis shows that DOACs can translate into reduced costs based on fewer strokes and less bleeding compared with VKAs. Statistical analyses have attested that direct-acting oral anticoagulants are cost-effective when observed in terms of their overall safety and quality-adjusted life-years despite having higher drug-acquisition costs than traditional treatments. Cost-effectiveness of DOACs is highly dependent on the degree of VKA anticoagulation control, such that there will be no savings for a patient whose condition is well-controlled on VKAs.

Because there have been no head-to-head comparisons among DOACs, choosing one DOAC over another may be driven by cost considerations, including patients’ socioeconomic factors, insurance coverage, and copayments required. Pharmacological factors (including dosing frequency, safety and efficacy data) also will influence therapeutic choices.

This observational review supplements the clinical trial findings on the effectiveness and safety of apixaban relative to warfarin. Moreover, it presents data on the clinical and economic comparisons of apixaban with other DOACs, which will conceivably expedite the provider decision-making process. For patients already taking VKAs, the cost-effectiveness and efficacy benefits of DOACs are likely to be most significant in patients poorly controlled on VKAs. The advantages of DOACs include their limited drug interactions and the fact that there is no need for routine blood testing.

Finally, adherence to therapy is a crucial issue for treatment and overall management for all anticoagulant patients. DOACs will continue to reshape anticoagulation management as additional studies are conducted for new indications, and with specified populations, this will paint a more accurate understanding of determining true cost-effectiveness.

Kristen Engelen, PharmD
Kristen Engelen, PharmD, is the chief pharmacy officer of RxLive and a certified consultant pharmacist; she has over a decade of experience in retail pharmacy settings. Kristen became an RxLive co-founder because of her passion for geriatric pharmacy, with a focus on the intersection of pharmacy and aging.