This study evaluated whether novel oral anticoagulants (NOACs) such as apixaban, edoxaban, dabigatran, and rivaroxaban should replace warfarin as the standard treatment for venous thromboembolism (VTE) and stroke prevention in atrial fibrillation based on clinical efficacy and cost-effectiveness. Decision tree models compared the five treatments using data from phase 3 clinical trials. For atrial fibrillation, apixaban had the lowest average yearly cost and highest efficacy, making it the most cost-effective option. For VTE, apixaban was most efficacious but warfarin was least expensive. The study concludes that clinical guidelines should

1. 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.
Purpose
To 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 sourcesTable 3. Data derived from NOAC’s respective phase 3 clinical trials and various literature sources
CRNMB: 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
1. Venous Thromboembolism (Blood Clots) [Internet]. [cited 2016 May 4]. Available from: http://www.cdc.gov/ncbddd/dvt/data.html
2. Atrial Fibrillation Fact Sheet [Internet]. [cited 2016 May 4]. Available from: http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm
3. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med. 2013, Oct 10:
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/NEJMoa1302507
5. 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 11:21
6. 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:
http://www.nejm.org/doi/pdf/10.1056/NEJMoa0906598
7. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2013, Nov 28: 369:2093-2104. Available at:
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:
http://www.nejm.org/doi/full/10.1056/NEJMoa0905561
11.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:10.4172/2329-8790.1000209
12.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:10.4172/2329-8790.1000209
15.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/ev
idencexpert/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
Presented at American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting 2016 at the Mandalay Bay Convention Center
in Las Vegas, NV, December 4-8, 2016