PROACT Xa – A Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely on Apixaban

Overview

Currently, warfarin is the only approved anticoagulation for patients with mechanical valves. The purpose of this study is to determine if participants with an On-X Prosthetic Heart Valve / On-X aortic valve can be maintained safely and effectively on apixaban. Both the On-X aortic valve and apixaban have been approved for use by the US Food and Drug Administration (FDA) but they have not been approved to be used together.

Full Title of Study: “A Prospective, Randomized, Active (Warfarin) Controlled, Parallel-arm Clinical Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely and Effectively on Apixaban”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 12, 2022

Detailed Description

There is an unmet clinical need for an alternative to warfarin, such as a direct oral anticoagulant (DOAC), as anticoagulation in participants with an aortic mechanical prosthetic valve. Some participants may be genetically hyper- or hypo-responsive to warfarin, which makes management difficult. Another small group of participants is allergic to warfarin. A much larger group of participants has difficulty maintaining warfarin control due to dietary and drug interactions. Finally, the requirement for routine blood testing makes people reluctant to take warfarin. All of these factors drive younger participants in need of aortic valve replacement (AVR) toward selection of a tissue valve instead of a mechanical valve. Despite multiple studies (randomized, matched and risk adjusted) that show that tissue valves are associated with worse outcomes, younger participants choose this type of valve to avoid warfarin. In addition, multiple clinical studies have shown valve reoperation rates are higher for tissue valves used in these younger participants. Providing an alternative to warfarin anticoagulation may lead younger participants to choose a mechanical valve with greater durability and better clinical outcomes.

Interventions

  • Drug: Apixaban 5 MG
    • For patients that do NOT meet the following criteria age ≥ 80 years weight ≤ 60 kilograms creatinine ≥ 1.5 mg/dL (133 micromol/L)
  • Drug: Apixaban 2.5 MG
    • For patients that meet at least 2 of the following criteria age ≥ 80 years weight ≤ 60 kilograms creatinine ≥ 1.5 mg/dL (133 micromol/L)
  • Drug: Warfarin
    • Active Control Intervention
  • Device: On-X Aortic Mechanical Valve
    • Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago.

Arms, Groups and Cohorts

  • Experimental: Apixaban
    • Apixaban 5 mg twice daily(BID) or 2.5 mg BID
  • Active Comparator: Warfarin
    • Patients randomized to the warfarin arm will continue warfarin in the INR range of (2.0-3.0)

Clinical Trial Outcome Measures

Primary Measures

  • Composite of Valve Thrombosis and Valve-related Thromboembolism
    • Time Frame: through study closure, a median follow-up of 13.5 months
    • Valve thrombosis was defined as any thrombus, not caused by infection, attached to or near an implanted On-X valve that occluded part of the blood-flow path, interfered with valve function, or was sufficiently large to warrant treatment other than continued oral anticoagulation. Valve-related thromboembolism was defined as any thromboembolic stroke, transient ischemic attack, myocardial infarction, or arterial thromboembolism to an organ or limb that was not associated with infection or an intracardiac tumor and was definitely or possibly related to the valve.
  • Major Bleeding
    • Time Frame: through study closure, a median follow-up of 13.5 months
    • Major bleeding defined as any episode of internal or external bleeding that caused death, hospitalization, or permanent injury or necessitated transfusion, pericardiocentesis, or reoperation.

Participating in This Clinical Trial

Inclusion Criteria

  • Male or female at least 18 years of age at the time of giving informed consent. – Participants currently receiving warfarin anticoagulation and who are able to receive warfarin with a target INR 2.0 to 3.0. – Participants are able to take low-dose aspirin at a dose of 75 -100 mg daily or have a documented contraindication to aspirin use. – Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago. – Female participants of childbearing potential, including those who are less than 2 years post-menopausal, must agree to, and comply with using a highly effective method of birth control (eg, barrier contraceptives [condom or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], intrauterine devices or sexual abstinence) while partaking in this study. In addition, all women of childbearing potential must agree to continue to use birth control throughout the study until last study visit. – Informed of the full nature and purpose of the study, including possible risks and side effects, given ample time and opportunity to read and understand this information, and sign and date the written informed consent before inclusion in the study. Exclusion Criteria:

  • Mechanical valve in any position other than aortic valve. – Any cardiac surgery in the three months (90 days) prior to enrollment. – Need to be on aspirin >100 mg daily or a P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel, or ticlopidine). – Known hypersensitivity or other contraindication to apixaban. – On dialysis or a creatinine clearance < 25 mL/min. – Ischemic stroke or intracranial hemorrhage within 3 months. – Active pathological bleeding at the time of screening for enrollment. – Active endocarditis at the time of screening for enrollment. – Pregnant, plan to become pregnant, or are breast feeding. – On concomitant combined strong P-gp and CYP3A4 inducers or inhibitors. – History of non-compliance with recommended monthly INR testing.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Artivion Inc.
  • Collaborator
    • Duke Clinical Research Institute
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Lars Svensson, MD, PhD, Study Chair, Steering Committee
    • John Alexander, MD, Study Chair, Steering Committee

References

Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL, Takkenberg JJ, David TE, Butchart EG, Adams DH, Shahian DM, Hagl S, Mayer JE, Lytle BW; Councils of the American Association for Thoracic Surgery; Society of Thoracic Surgeons; European Assoication for Cardio-Thoracic Surgery; Ad Hoc Liaison Committee for Standardizing Definitions of Prosthetic Heart Valve Morbidity. Guidelines for reporting mortality and morbidity after cardiac valve interventions. J Thorac Cardiovasc Surg. 2008 Apr;135(4):732-8. doi: 10.1016/j.jtcvs.2007.12.002. No abstract available.

Bourguignon T, Lhommet P, El Khoury R, Candolfi P, Loardi C, Mirza A, Boulanger-Lothion J, Bouquiaux-Stablo-Duncan AL, Marchand M, Aupart M. Very long-term outcomes of the Carpentier-Edwards Perimount aortic valve in patients aged 50-65 years. Eur J Cardiothorac Surg. 2016 May;49(5):1462-8. doi: 10.1093/ejcts/ezv384. Epub 2015 Nov 2.

Chambers JB, Pomar JL, Mestres CA, Palatianos GM. Clinical event rates with the On-X bileaflet mechanical heart valve: a multicenter experience with follow-up to 12 years. J Thorac Cardiovasc Surg. 2013 Feb;145(2):420-4. doi: 10.1016/j.jtcvs.2011.12.059. Epub 2012 Feb 17.

Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206-14. doi: 10.1056/NEJMoa1300615. Epub 2013 Aug 31.

Glaser N, Jackson V, Holzmann MJ, Franco-Cereceda A, Sartipy U. Aortic valve replacement with mechanical vs. biological prostheses in patients aged 50-69 years. Eur Heart J. 2016 Sep 7;37(34):2658-67. doi: 10.1093/eurheartj/ehv580. Epub 2015 Nov 11.

Goldstone AB, Chiu P, Baiocchi M, Lingala B, Patrick WL, Fischbein MP, Woo YJ. Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement. N Engl J Med. 2017 Nov 9;377(19):1847-1857. doi: 10.1056/NEJMoa1613792.

Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.

Head SJ, Mylotte D, Mack MJ, Piazza N, van Mieghem NM, Leon MB, Kappetein AP, Holmes DR Jr. Considerations and Recommendations for the Introduction of Objective Performance Criteria for Transcatheter Aortic Heart Valve Device Approval. Circulation. 2016 May 24;133(21):2086-93. doi: 10.1161/CIRCULATIONAHA.115.020493.

Head SJ, Celik M, Kappetein AP. Mechanical versus bioprosthetic aortic valve replacement. Eur Heart J. 2017 Jul 21;38(28):2183-2191. doi: 10.1093/eurheartj/ehx141.

IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol. 2014 Feb 18;14:25. doi: 10.1186/1471-2288-14-25.

Samsa G, Matchar DB, Dolor RJ, Wiklund I, Hedner E, Wygant G, Hauch O, Marple CB, Edwards R. A new instrument for measuring anticoagulation-related quality of life: development and preliminary validation. Health Qual Life Outcomes. 2004 May 6;2:22. doi: 10.1186/1477-7525-2-22.

Lester PA, Coleman DM, Diaz JA, Jackson TO, Hawley AE, Mathues AR, Grant BT, Knabb RM, Ramacciotti E, Frost CE, Song Y, Wakefield TW, Myers DD Jr. Apixaban Versus Warfarin for Mechanical Heart Valve Thromboprophylaxis in a Swine Aortic Heterotopic Valve Model. Arterioscler Thromb Vasc Biol. 2017 May;37(5):942-948. doi: 10.1161/ATVBAHA.116.308649. Epub 2017 Feb 23.

McNicholas KW, Ivey TD, Metras J, Szentpetery S, Marra SW, Masters RG, Dilling EW, Slaughter MS, Mack MJ. North American multicenter experience with the On-X prosthetic heart valve. J Heart Valve Dis. 2006 Jan;15(1):73-8; discussion 79.

Palatianos GM, Laczkovics AM, Simon P, Pomar JL, Birnbaum DE, Greve HH, Haverich A. Multicentered European study on safety and effectiveness of the On-X prosthetic heart valve: intermediate follow-up. Ann Thorac Surg. 2007 Jan;83(1):40-6. doi: 10.1016/j.athoracsur.2006.08.010.

Puskas J, Gerdisch M, Nichols D, Quinn R, Anderson C, Rhenman B, Fermin L, McGrath M, Kong B, Hughes C, Sethi G, Wait M, Martin T, Graeve A; PROACT Investigators. Reduced anticoagulation after mechanical aortic valve replacement: interim results from the prospective randomized on-X valve anticoagulation clinical trial randomized Food and Drug Administration investigational device exemption trial. J Thorac Cardiovasc Surg. 2014 Apr;147(4):1202-1210; discussion 1210-1. doi: 10.1016/j.jtcvs.2014.01.004. Epub 2014 Jan 12.

Puskas JD, Gerdisch M, Nichols D, Fermin L, Rhenman B, Kapoor D, Copeland J, Quinn R, Hughes GC, Azar H, McGrath M, Wait M, Kong B, Martin T, Douville EC, Meyer S, Ye J, Jamieson WRE, Landvater L, Hagberg R, Trotter T, Armitage J, Askew J, Accola K, Levy P, Duncan D, Yanagawa B, Ely J, Graeve A; PROACT Investigators. Anticoagulation and Antiplatelet Strategies After On-X Mechanical Aortic Valve Replacement. J Am Coll Cardiol. 2018 Jun 19;71(24):2717-2726. doi: 10.1016/j.jacc.2018.03.535.

Tossios P, Reber D, Oustria M, Holland-Letz T, Germing A, Buchwald D, Laczkovics A. Single-center experience with the On-X prosthetic heart valve between 1996 and 2005. J Heart Valve Dis. 2007 Sep;16(5):551-7.

Williams MA, van Riet S. The On-X heart valve: mid-term results in a poorly anticoagulated population. J Heart Valve Dis. 2006 Jan;15(1):80-6.

Wu Y, Butchart EG, Borer JS, Yoganathan A, Grunkemeier GL. Clinical evaluation of new heart valve prostheses: update of objective performance criteria. Ann Thorac Surg. 2014 Nov;98(5):1865-74. doi: 10.1016/j.athoracsur.2014.05.006. Epub 2014 Sep 23.

Jawitz OK, Wang TY, Lopes RD, Chavez A, Boyer B, Kim H, Anstrom KJ, Becker RC, Blackstone E, Ruel M, Thourani VH, Puskas JD, Gerdisch MW, Johnston D, Capps S, Alexander JH, Svensson LG. 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 Sep;227:91-99. doi: 10.1016/j.ahj.2020.06.014. Epub 2020 Jun 25.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.