How does apixaban versus warfarin compare for mechanical heart valve replacement patients?

Comment by InpharmD Researcher

There is little clincal data on the use of apixaban as an alternative to warfarin in patients with mechanical heart valves. A current ongoing trial, PROACT Xa, aims to evaluate the safety and efficacy of apixaban versus warfarin in patients with an aortic valve replacement; however, it is estimated to be completed in 2023. Until that is published, only a case report and animal data exist.
Background

Per the 2020 American College of Cardiology and American Heart Association guideline on the management of patients with valvular heart disease, use of direct oral anticoagulants (DOACs), such as apixaban, is not recommended in patients with a mechanical heart valve due to lack of data to support its use. Warfarin is the preferred agent for anticoagulation. Patients with an aortic valve replacement have an INR goal of 2.5 with no additional risk factors (atrial fibrillation, previous thromboembolism, left ventricular dysfunction, hypercoagulable state) and an INR goal of 3 if additional risk factors are present. Patients with a mitral valve replacement have an INR goal of 3 regardless of risk factors. Warfarin is also used in bioprosthetic valves with an INR goal of 2.5. [1]

Major direct oral anticoagulants (DOACs) studies, such as ARISTOTLE, excluded patients with mechanical heart valves. The RE-ALIGN trial evaluated dabigatran in human patients with mechanical heart valves. This study concluded that dabigatran should not be used in patients with mechanical heart valves. Clinical trials in humans regarding direct oral anticoagulants are lacking aside from the RE-ALIGN trial comparing dabigatran against warfarin. Based on these results, most authors advise against the use of direct oral anticoagulants (DOACs) in patients with mechanical valves. [2], [3]

An animal study used pig models to compare apixaban and warfarin for thromboprophylaxis of mechanical heart valves. The animals were randomized to 4 groups with no anticoagulation, apixaban oral 1 mg/kg twice a day, warfarin oral 0.04 to 0.08 mg/kg daily, and apixaban infusion. There were no adverse bleeding events found in the apixaban group. The study concluded that apixaban is a promising candidate and may be a useful alternative to warfarin for patients with mechanical heart valves; however, this study is not human data and needs more evidence to support use in humans. [4]

PROACT Xa (ClinicalTrials.gov no. NCT04142658) is an ongoing phase 3 study evaluating the safety and efficacy of apixaban versus warfarin in patients with an aortic valve replacement, specifically an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. Patients will be randomized 1:1 to receive apixaban 5 mg or 2.5 mg by mouth twice a day or warfarin with an INR goal of 2 - 3. The primary endpoint is the composite of valve thrombosis and valve-related thromboembolism with a safety outcome of major bleeding. Patients will be followed for 2 years with an estimated study completion date of December 2023. [5], [6]

References:

[1] Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2021 Feb 2;143(5):e228] [published correction appears in Circulation. 2021 Mar 9;143(10):e784]. Circulation. 2021;143(5):e35-e71. doi:10.1161/CIR.0000000000000932
[2] Anderson SL, Marrs JC. Direct Oral Anticoagulant Use in Valvular Heart Disease. Clinical Medicine Insights: Therapeutics. January 2018. doi:10.1177/1179559X17751638
[3] Aikins J, Koomson A, Ladele M, et al. Anticoagulation and antiplatelet therapy in patients with prosthetic heart valves. Journal of Cardiac Surgery. 2020;35(12):3521-3529.
[4] Lester PA, Coleman DM, Diaz JA, et al. Apixaban Versus Warfarin for Mechanical Heart Valve Thromboprophylaxis in a Swine Aortic Heterotopic Valve Model. Arterioscler Thromb Vasc Biol. 2017;37(5):942-948. doi:10.1161/ATVBAHA.116.308649
[5] Jawitz OK, Wang TY, Lopes RD, et al. Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve. Am Heart J. 2020;227:91-99. doi:10.1016/j.ahj.2020.06.014
[6] ClinicalTrials.gov. PROACT Xa - A Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely on Apixaban. https://clinicaltrials.gov/ct2/show/NCT04142658. Updated February 11, 2021. Accessed February 15, 2021.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

How does apixaban versus warfarin compare for mechanical heart valve replacement patients?

Please see Table 1 for your response.

 

Apixaban for stroke prevention in a patient with a mechanical heart valve

Design

Case report
Case Presentation

A 75-year-old man presented with a fall, left hemiparesis, and dysphasia. His past medical history was significant for mitral heart valve replacement and a coronary bypass graft in 2010 and was on warfarin and aspirin. The patient discontinued his warfarin in 2014 upon reading that warfarin was rat poison.

A computed tomography (CT) scan of the brain revealed an acute left pons ischemic stroke along with bilateral multiple chronic anterior and posterior circulation ischemic strokes. Transthoracic echocardiography revealed a normal functioning mitral valve without any signs of thrombosis. His aspirin dose was increased to 300 mg. 

The patient was counseled on warfarin and how it was the only approved medication for mechanical valves, but he continued to refuse treatment. However, the patient did not object to using direct oral anticoagulants. Two cardiologists and a legal advisor agreed to initiate apixaban if the patient also agreed despite there being a lack of evidence to support its use and the recent premature discontinuation of the RE-ALIGN trial with dabigatran. Approval was obtained and apixaban 5 mg twice daily was initiated. 

The patient has been followed for over 2.5 years and has not had any thromboembolic or hemorrhagic complications and his most recent CT scan revealed no new ischemic lesions.
Study Author Conclusion

Anticoagulation is essential in reducing the risk of thromboembolism in mitral valve replacements. Warfarin is the only agent approved for this indication, reducing the risk of thromboembolism from 4% per year to 1% per year.

When warfarin is not an option, as with this patient, apixaban may be considered due to its lower bleeding profile compared to warfarin. This patient demonstrates the possible use of direct oral anticoagulants in mechanical heart valves as evidenced by his lack of complications since initiating apixaban.

 

References:

Shukla P, Ashraf I, Aghoram P. Apixaban for stroke prevention in a patient with a mechanical heart valve. Br J Hosp Med. 2018;79(11):652-653.