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

Overview

About this study

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.  Currently, warfarin is the only approved anticoagulation for patients with mechanical valves.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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 (e.g., 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.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Rochester, Minn.

Mayo Clinic principal investigator

Alberto Pochettino, M.D.

Closed for enrollment

More information

Publications

  • Vitamin K antagonists are the only approved oral anticoagulants for long-term prophylaxis against valve thrombosis and thromboembolism in patients with a mechanical heart valve. Despite the proven efficacy and safety of anticoagulation with the oral direct factor Xa inhibitor apixaban compared with warfarin in high-risk populations including subjects with atrial fibrillation or with venous thromboembolism, it remains unknown whether patients with a mechanical heart valve can be safely managed with apixaban. The On-X Aortic Heart Valve and On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft may have lower rates of valve thrombosis and thromboembolism than conventional bileaflet and tilting disc valves due its unique pyrolytic carbon composition and flared inlet design. DESIGN: PROACT Xa is a randomized, multicenter, open-label, active-controlled trial comparing apixaban with warfarin in patients with an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. The study will randomize approximately 1,000 patients from approximately 60 sites in North America who underwent aortic valve replacement at least 3 months prior. Patients will be randomized 1:1 to receiving apixaban 5 mg twice daily or warfarin with a target international normalized ratio of 2.0-3.0. The last randomized participant will be followed for at least 2 years. The primary efficacy outcome is the composite of valve thrombosis and valve-related thromboembolism, and the primary safety outcome is major bleeding. Assuming the primary outcome occurs in warfarin-anticoagulated patients at a rate of 1.75%/patient-year, the study has more than 90% power to assess noninferiority of apixaban treatment with an absolute noninferiority margin of 1.75%/patient-year. A second co-primary analysis is to compare the hazard rate for the apixaban arm to twice the objective performance criterion for thromboembolism and valve thrombosis, that is, 3.4%/patient-year. SUMMARY: PROACT Xa will determine whether patients with an On-X Aortic Heart Valve can be anticoagulated with apixaban as an alternative to warfarin. Read More on PubMed
  • The burden oral anticoagulation is a limitation of mechanical valve prostheses. Read More on PubMed
  • In patients undergoing aortic-valve or mitral-valve replacement, either a mechanical or biologic prosthesis is used. Biologic prostheses have been increasingly favored despite limited evidence supporting this practice. Read More on PubMed
  • Mechanical valves used for aortic valve replacement (AVR) continue to be associated with bleeding risks because of anticoagulation therapy, while bioprosthetic valves are at risk of structural valve deterioration requiring reoperation. This risk/benefit ratio of mechanical and bioprosthetic valves has led American and European guidelines on valvular heart disease to be consistent in recommending the use of mechanical prostheses in patients younger than 60 years of age. Despite these recommendations, the use of bioprosthetic valves has significantly increased over the last decades in all age groups. A systematic review of manuscripts applying propensity-matching or multivariable analysis to compare the usage of mechanical vs. bioprosthetic valves found either similar outcomes between the two types of valves or favourable outcomes with mechanical prostheses, particularly in younger patients. The risk/benefit ratio and choice of valves will be impacted by developments in valve designs, anticoagulation therapy, reducing the required international normalized ratio, and transcatheter and minimally invasive procedures. However, there is currently no evidence to support lowering the age threshold for implanting a bioprosthesis. Physicians in the Heart Team and patients should be cautious in pursuing more bioprosthetic valve use until its benefit is clearly proven in middle-aged patients. Read More on PubMed
  • Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical heart valves, yet optimal therapy to maximize anticoagulation and minimize bleeding complications requires routine coagulation monitoring, possible dietary restrictions, and drug interaction monitoring. As alternatives to warfarin, oral direct acting factor Xa inhibitors are currently approved for the prophylaxis and treatment of venous thromboembolism and reduction of stroke and systemic embolization. However, no in vivo preclinical or clinical studies have been performed directly comparing oral factor Xa inhibitors such as apixaban to warfarin, the current standard of therapy. Read More on PubMed
  • The objective was to investigate the long-term all-cause mortality in patients aged 50-69 years after aortic valve replacement (AVR) with bioprosthetic or mechanical valves. Read More on PubMed
  • In the United States, new surgical heart valves can be approved on the basis of objective performance criteria (OPC). In contrast, the US Food and Drug Administration traditionally requires stricter criteria for transcatheter heart valve (THV) approval, including randomized, clinical trials. Recent US Food and Drug Administration approval of new-generation THVs based on single-arm studies has generated interest in alternative study approaches for THV device approval. This review evaluates whether THV device approval could follow a pathway analogous to that of surgical heart valves by incorporating OPC and provides several considerations and recommendations. Factors to be taken into account in the construction of OPC include the maturity of THV technology, variability in transcatheter aortic valve replacement practice, end points included as OPC, follow-up terms for specific OPC, patient populations to which these OPC apply, and (statistical) methods for OPC development. We recommend that approval of THV devices in the United States for low- and intermediate-risk patients or for new indications should provisionally rely on data from randomized, clinical trials. However, it is recommended that formal OPC be applied for approval of new-generation THVs for use in high- and extreme-risk patient populations. Read More on PubMed
  • Aortic valve replacement (AVR) using a bioprosthesis remains controversial for patients aged 50-65 years. This cohort study reports the very long-term outcomes of AVR using Carpentier-Edwards Perimount pericardial bioprosthesis in this age group. Read More on PubMed
  • This article summarizes the long-term clinical results of the Food and Drug Administration-approved heart valves, provides current updates to the objective performance criteria (OPC) used to evaluate new heart valve prostheses, and documents the steps that the International Organization for Standardization Committee used to arrive at the updated OPC. Data were extracted from 19 Food and Drug Administration summaries of safety and effectiveness data reports (31 series) and 56 literature articles (85 series) published from 1999 to 2012. The OPC were calculated for five valve-related complications by valve type (mechanical and bioprosthetic) and valve position (aortic and mitral). Read More on PubMed
  • Under Food and Drug Administration investigational device exemption, the Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) has been testing the safety of less aggressive anticoagulation than recommended by the American College of Cardiology/American Heart Association guidelines after implantation of an approved bileaflet mechanical valve. Read More on PubMed
  • The DerSimonian and Laird approach (DL) is widely used for random effects meta-analysis, but this often results in inappropriate type I error rates. The method described by Hartung, Knapp, Sidik and Jonkman (HKSJ) is known to perform better when trials of similar size are combined. However evidence in realistic situations, where one trial might be much larger than the other trials, is lacking. We aimed to evaluate the relative performance of the DL and HKSJ methods when studies of different sizes are combined and to develop a simple method to convert DL results to HKSJ results. Read More on PubMed
  • Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. Read More on PubMed
  • The aim of the study was to establish clinical event rates for the On-X bileaflet mechanical heart valve (On-X Life Technologies Inc, Austin, Tex) using an audit of data from the 3 centers within Europe with the longest history of implanting. Read More on PubMed
  • Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. Read More on PubMed
  • Herein are presented long-term results for the On-X mechanical heart valve. All On-X heart valve recipients since the first implantation worldwide at the University of Bochum in September 1996 were followed retrospectively; the present authors' single-center experience over a period of almost 10 years is reported. Read More on PubMed
  • This study was performed to determine the safety and effectiveness of the On-X valve, a novel mechanical valve substitute. Read More on PubMed
  • The study aim was to evaluate the clinical performance of the On-X heart valve in a socioeconomically disadvantaged population. Most patients were from an indigenous, poorly educated and geographically dispersed segment of the population where anticoagulation therapy was generally erratic. Read More on PubMed
  • This ongoing, longitudinal, multi-center, North American study was designed to evaluate the safety and effectiveness of the On-X valve. Read More on PubMed
  • Anticoagulation can reduce quality of life, and different models of anticoagulation management might have different impacts on satisfaction with this component of medical care. Yet, to our knowledge, there are no scales measuring quality of life and satisfaction with anticoagulation that can be generalized across different models of anticoagulation management. We describe the development and preliminary validation of such an instrument - the Duke Anticoagulation Satisfaction Scale (DASS). Read More on PubMed

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