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Aortic Valve DiseasePhase 3NCT04142658

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

A Phase 3 study testing Apixaban 5 MG, Apixaban 2.5 MG and Warfarin in people with Aortic Valve Disease and Aortic Valve Stenosis, run by Artivion Inc. at 62 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Apixaban 5 MG, Apixaban 2.5 MG and Warfarin
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
863 participants
Where
62 sitesUnited States
Study dates
1 May 2020to 12 Dec 2022
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 11Show fewer
  • 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.

Trial locations and contacts

62 sites in 1 country.

62 sites in 1 country

United States62 sites

  • Lehigh Valley Hospital Allentown

    Allentown, Pennsylvania, 18103

  • University of Michigan Health

    Ann Arbor, Michigan, 48109

  • Piedmont Atlanta Hospital

    Atlanta, Georgia, 30309

  • Emory University Hospital

    Atlanta, Georgia, 30332

  • John's Hopkins University

    Baltimore, Maryland, 21218

  • Brigham and Women's Hospital

    Boston, Massachusetts, 02115

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Atrium Health Carolinas Medical Center (CMC)

    Charlotte, North Carolina, 28203

  • Northwestern Memorial Hospital

    Chicago, Illinois, 60611

  • Baycare Health / Morton Plant Hospital

    Clearwater, Florida, 33756

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • William P. Clements Jr. University Hospital

    Dallas, Texas, 75235

  • Duke University

    Durham, North Carolina, 27708

  • TCU School of Medicine

    Fort Worth, Texas, 76107

  • Shands Hospital (University of Florida Health)

    Gainesville, Florida, 32608

  • Northeast Georgia Medical Center

    Gainesville, Georgia, 30501

  • Hartford Hospital

    Hartford, Connecticut, 06102

  • Penn State Health Milton S. Hershey Medical Center

    Hershey, Pennsylvania, 17033

  • The University of Texas Health Science Center at Houston

    Houston, Texas, 77030

  • Indiana University Health Methodist Hospital

    Indianapolis, Indiana, 46202

  • Franciscan Health Indianapolis

    Indianapolis, Indiana, 46237

  • University of Iowa

    Iowa City, Iowa, 52242

  • Saint Luke's Hospital

    Kansas City, Missouri, 64111

  • CHI St. Vincent Heart Institute

    Little Rock, Arkansas, 72205

  • Loma Linda University Medical Center

    Loma Linda, California, 92354

  • University of Wisconsin

    Madison, Wisconsin, 53792

  • Wellstar Kennestone Hospital

    Marietta, Georgia, 30060

  • Abbott Northwestern Hospital

    Minneapolis, Minnesota, 55407

  • University of Minnesota

    Minneapolis, Minnesota, 55422

  • Tristar Centennial Medical Center

    Nashville, Tennessee, 37203

  • Yale- New Haven Hospital

    New Haven, Connecticut, 06510

  • Mount Sinai- St. Luke's Hospital

    New York, New York, 10029

  • NewYork-Presbyterian Hospital

    New York, New York, 10065

  • NewYork-Presbyterian/ Weill Cornell Medical Center

    New York, New York, 10065

  • Oklahoma Heart Hospital

    Oklahoma City, Oklahoma, 73120

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

  • AdventHealth Orlando

    Orlando, Florida, 32803

  • Stanford University Medical Center

    Palo Alto, California, 94305

  • Hospital of the University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Thomas Jefferson University

    Philadelphia, Pennsylvania, 19107

  • UPMC Shadyside

    Pittsburgh, Pennsylvania, 15232

  • The Heart Hospital at Baylor Plano

    Plano, Texas, 75093

  • Maine Medical Center

    Portland, Maine, 04102

  • Vassar Brothers Medical Center

    Poughkeepsie, New York, 12601

  • Henrico Doctors' Hospital

    Richmond, Virginia, 23229

  • Carilion Roanoke Memorial Hospital

    Roanoke, Virginia, 24014

  • Mayo Clinic Rochester

    Rochester, Minnesota, 55902

  • University of Rochester Medical Center

    Rochester, New York, 14642

  • OSF Cardiovascular Institute

    Rockford, Illinois, 61107

  • University of Utah Hospital

    Salt Lake City, Utah, 84132

  • Sharp Memorial

    San Diego, California, 92123

  • Swedish Medical Center

    Seattle, Washington, 98122

  • University of Washington Medical Center

    Seattle, Washington, 98195

  • Avera Health / North Central Heart

    Sioux Falls, South Dakota, 57108

  • Washington University Medical Center

    St Louis, Missouri, 63105

  • Missouri Baptist Medical Center

    St Louis, Missouri, 63131

  • Tacoma General Hospital

    Tacoma, Washington, 98405

  • Tallahassee Research Institute

    Tallahassee, Florida, 32308

  • University of South Florida

    Tampa, Florida, 33606

  • ProMedica Toledo Hospital

    Toledo, Ohio, 43606

  • Tucson Heart Center

    Tucson, Arizona, 85712

  • Medical College of Wisconsin

    Wauwatosa, Wisconsin, 53226

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Apixaban 5 MG, Apixaban 2.5 MG, Warfarin, On-X Aortic Mechanical Valve
Medical subject headings
Aortic Valve Disease, Aortic Valve Stenosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Apixaban 5 MGDrug

    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 MGDrug

    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)

  • WarfarinDrug

    Active Control Intervention

  • On-X Aortic Mechanical ValveDevice

    Also called On-X Ascending Aortic Prosthesis (AAP)

    Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago.

Study groups in NCT04142658
Study groupRoleWhat they receive
ApixabanExperimentalApixaban 5 mg twice daily(BID) or 2.5 mg BID
Receives: Drug: Apixaban 5 MG; Drug: Apixaban 2.5 MG; Device: On-X Aortic Mechanical Valve
WarfarinActive comparatorPatients randomized to the warfarin arm will continue warfarin in the INR range of (2.0-3.0)
Receives: Drug: Warfarin; Device: On-X Aortic Mechanical Valve

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: through study closure, a median follow-up of 13.5 months

  2. 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.

    Measured: through study closure, a median follow-up of 13.5 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Oct 2019
  2. Study start1 May 2020
  3. Primary completion12 Dec 2022
  4. Study completion12 Dec 2022

Why it stopped: Safety

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Parallel control and treatment arm at a 1:1 ratio.
Masking
None (open label)
Enrolment
863 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04142658
Sponsor's protocol ID
ONX1801.000-C
Status last verified
Mar 2024
First submitted
9 Oct 2019
Last updated
20 Mar 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
Yes

Publications

  • 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.

    PubMed 18374749

  • 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.

    PubMed 26530269

  • 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.

    PubMed 22341654

  • 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.

    PubMed 23991661

  • 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.

    PubMed 26559386

  • 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.

    PubMed 29117490

  • 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.

    PubMed 21870978

  • 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.

    PubMed 27217434

  • 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.

    PubMed 28444168

  • 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.

    PubMed 24548571

  • 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.

    PubMed 15132746

  • 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.

    PubMed 28232327

  • 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.

    PubMed 16480015

  • 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.

    PubMed 17184628

  • 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.

    PubMed 24512654

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Apixaban 5 MG, Apixaban 2.5 MG and Warfarin in people with Aortic Valve Disease and Aortic Valve Stenosis, run by Artivion Inc. at 62 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 20 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 62 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Composite of Valve Thrombosis and Valve-related Thromboembolism (time frame: through study closure, a median follow-up of 13.5 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04142658, which also lists 21 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2024.

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