Is it time to replace warfarin with novel oral anticoagulants (NOACs) for treating thrombotic disorders?

Charles Ng, C. Daniel Mullins, PhD

Background• Warfarin has been the gold standard for venous thromboembolism

(VTE) treatment and stroke/systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).1,2

• Within the past few years, NOACs such as edoxaban, apixaban, rivaroxaban, and dabigatran have emerged as the preferred treatment due to their favorable pharmacokinetics, pharmacodynamics, and minimal adverse events.1,2

• Currently, the majority of clinical guidelines prefer warfarin over NOACs. However, these guidelines overlook the issue of cost, which should to be incorporated into decision making.

PurposeTo determine whether NOACs should be considered first-line treatments alongside warfarin for both VTE treatment and stroke/systemic embolism prophylaxis in patients with NVAF from a clinical and cost-effective viewpoint.

Methods• A decision tree was constructed for each of the indications: VTE

treatment and stroke/systemic embolism prophylaxis in NVAF patients.

• Each tree compared five therapies: edoxaban, apixaban, rivaroxaban, dabigatran, and warfarin.

• The transition probabilities were derived from their respective phase 3 clinical trials.

• Costs were derived from various literature sources with a one-year time frame.

Summary of Clinical Trials

Table 1. VTE clinical efficacy and safety summaries derived from NOAC’s respective phase 3 trials Table 2. NVAF clinical efficacy and safety summaries derived from NOAC’s respective phase 3 clinical trials

Model Inputs

Table 4. Data derived from NOAC’s respective phase 3 clinical trials and various literature sources Table 3. Data derived from NOAC’s respective phase 3 clinical trials and various literature sourcesCRNMB: Clinically relevant non-major bleeding

Decision Tree

Results: NVAF Treatment

• Apixaban had the lowest average yearly cost of $7,755.91, followed by warfarin ($7,864.46), dabigatran ($8,903.02), edoxaban ($9,557.37), and rivaroxaban($10,630.41).

• Effectiveness was measured by treatment response without a major bleeding or CRNMB event. Warfarin had the lowest efficacy of 0.87, followed by rivaroxaban(0.88), edoxaban (0.89), dabigatran (0.91), and apixaban (0.94).

• Apixaban is the most cost-effective option due to its superior price and efficacy profile.

• From a clinical viewpoint, the NOACs are non-inferior to warfarin but are currently less utilized in practice.

• When cost-effectiveness analyses are integrated into clinical decision making, a need for change in the clinical guidelines is established due to the greater cost effectiveness of the NOACs compared to warfarin.

Results: VTE Treatment

• Warfarin had the lowest average yearly cost of $1,119.71, followed by edoxaban ($3,596.70), dabigatran ($4,110.33), apixaban ($4,385.71), and rivaroxaban ($4,438.61).

• The effectiveness was treatment response without a major bleeding event. Warfarin and edoxaban had the lowest efficacy of 0.90, followed by rivaroxaban (0.91), dabigatran (0.92), and apixaban (0.94).

• The incremental cost-effectiveness ratio of dabigatran versus warfarin and apixaban versus dabigatran was $175,918.82 and $12,517.27 per additional treatment response without a major bleeding event, respectively.

• Apixaban is the most efficacious option, but warfarin is the least expensive option.

References

Contact

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369:1406-1415. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1306638 4. Agnelli G, Buller HR, Cohen A, et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2013, Aug 29: 369:799-808. Available at:

http://www.nejm.org/doi/pdf/10.1056/NEJMoa13025075. Prins et al.: Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized

studies. Thrombosis Journal 2013 11:216. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009, Dec 10: 2342-52. Available at:

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http://www.nejm.org/doi/full/10.1056/NEJMoa1310907 8. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011, Sep 15: 365:981-992. Available at:

http://www.nejm.org/doi/full/10.1056/NEJMoa1107039 9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011, Sep 8: 365:883-891. Available at:

http://www.nejm.org/doi/full/10.1056/NEJMoa1009638 10.Connolly SJ, Ezekowitz MD, Phil D, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009, Sep 7: 361:1139-1151. Available at:

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Patients with Nonvalvular Atrial Fibrillation and Venous Thromboembolism in the U.S. J Hematol Thrombo Dis 3: 209. doi:10.4172/2329-8790.100020912.Biskupiak J, Ghate SR, Jiao T, et al. Cost implications of formulary decisions on oral anticoagulants in nonvalvular atrial fibrillation. J Manag Care Pharm. 2013 Nov-

Dec;19(9):789-98. Available at: http://www.amcp.org/WorkArea/DownloadAsset.aspx?id=17308 13.Magnuson EA, Vilain K, Wang K, et al. Cost-effectiveness of edoxaban vs warfarin in patients with atrial fibrillation based on results of the ENGAGE AF-TIMI 48 trial. Am Heart

J. 2015 Dec;170(6):1140-50. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26678636 14.Amin A, Lingohr-Smith M, Bruno A, Trocio J, Lin J (2015) Economic Evaluations of Medical Cost Differences: Use of Targeted-Specific Oral Anticoagulants vs. Warfarin among

Patients with Nonvalvular Atrial Fibrillation and Venous Thromboembolism in the U.S.. J Hematol Thrombo Dis 3: 209. doi:10.4172/2329-8790.100020915.REDBOOK [Internet]. Greenwood Village, Colorado: Thomson Reuters (Healthcare) Inc. 1974 – [cited 2016 Apr 26]. Available from

http://www.micromedexsolutions.com/proxy-hs.researchport.umd.edu/micromedex2/librarian/CS/8840FB/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/D7A020/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/redbook.FindRedBook?navitem=topRedBook&isToolPage=true

Charles Ng: CharlesNg58@gmail.com; 443-939-8431; www.linkedin.com/in/CharlesNg58

Conclusions