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

Aortic Valve Stenosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04142658
• Other study ID #: ONX1801.000-C
• Status: Terminated
• Phase: Phase 3
• Start date: May 1, 2020
• Est. completion date: December 12, 2022

Study information

• Verified date: March 2024
• Source: Artivion Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 863
• Est. completion date: December 12, 2022
• Est. primary completion date: December 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Aortic Valve Disease
• Aortic Valve Failure
• Aortic Valve Stenosis

Intervention

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)
• 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)
• 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.

Locations

Country	Name	City	State
United States	Lehigh Valley Hospital Allentown	Allentown	Pennsylvania
United States	University of Michigan Health	Ann Arbor	Michigan
United States	Emory University Hospital	Atlanta	Georgia
United States	Piedmont Atlanta Hospital	Atlanta	Georgia
United States	John's Hopkins University	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Atrium Health Carolinas Medical Center (CMC)	Charlotte	North Carolina
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Baycare Health / Morton Plant Hospital	Clearwater	Florida
United States	Cleveland Clinic	Cleveland	Ohio
United States	William P. Clements Jr. University Hospital	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	TCU School of Medicine	Fort Worth	Texas
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	Shands Hospital (University of Florida Health)	Gainesville	Florida
United States	Hartford Hospital	Hartford	Connecticut
United States	Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	Franciscan Health Indianapolis	Indianapolis	Indiana
United States	Indiana University Health Methodist Hospital	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	CHI St. Vincent Heart Institute	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Wellstar Kennestone Hospital	Marietta	Georgia
United States	Abbott Northwestern Hospital	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota
United States	Tristar Centennial Medical Center	Nashville	Tennessee
United States	Yale- New Haven Hospital	New Haven	Connecticut
United States	Mount Sinai- St. Luke's Hospital	New York	New York
United States	NewYork-Presbyterian Hospital	New York	New York
United States	NewYork-Presbyterian/ Weill Cornell Medical Center	New York	New York
United States	Oklahoma Heart Hospital	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	AdventHealth Orlando	Orlando	Florida
United States	Stanford University Medical Center	Palo Alto	California
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	UPMC Shadyside	Pittsburgh	Pennsylvania
United States	The Heart Hospital at Baylor Plano	Plano	Texas
United States	Maine Medical Center	Portland	Maine
United States	Vassar Brothers Medical Center	Poughkeepsie	New York
United States	Henrico Doctors' Hospital	Richmond	Virginia
United States	Carilion Roanoke Memorial Hospital	Roanoke	Virginia
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	OSF Cardiovascular Institute	Rockford	Illinois
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Washington University Medical Center	Saint Louis	Missouri
United States	University of Utah Hospital	Salt Lake City	Utah
United States	Sharp Memorial	San Diego	California
United States	Swedish Medical Center	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Avera Health / North Central Heart	Sioux Falls	South Dakota
United States	Tacoma General Hospital	Tacoma	Washington
United States	Tallahassee Research Institute	Tallahassee	Florida
United States	University of South Florida	Tampa	Florida
United States	ProMedica Toledo Hospital	Toledo	Ohio
United States	Tucson Heart Center	Tucson	Arizona
United States	Medical College of Wisconsin	Wauwatosa	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Artivion Inc.	Duke Clinical Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (20)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of Valve Thrombosis and Valve-related Thromboembolism	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.	through study closure, a median follow-up of 13.5 months
Primary	Major Bleeding	Major bleeding defined as any episode of internal or external bleeding that caused death, hospitalization, or permanent injury or necessitated transfusion, pericardiocentesis, or reoperation.	through study closure, a median follow-up of 13.5 months