Prospective Randomized On-X Anticoagulation Clinical Trial: Reduced Anticoagulation for a Mechanical Heart Valve - PROACT

Apr 05, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
On-X Life Technologies, Inc., manufacturers of the On-X valve
Date Presented:
01/01/2011
Date Updated:
04/05/2011
Original Posted Date:
04/05/2011
References

Description:

Current guidelines recommend an international normalized ratio (INR) goal of 2-3 in patients with bileaflet mechanical or Medtronic Hall valves (2.5-3.5 if risk factors are present). On-X is a new pure carbon valve with a different design, as compared with currently available valves. The current trial was a Food and Drug Administration investigational device exemption (FDA IDE) trial to study the safety and efficacy of lower dose anticoagulation in patients who underwent valve replacement with the On-X valve.

Hypothesis:

Low-dose anticoagulation would be noninferior compared with standard therapy in patients who have undergone valve replacement with the On-X valve.

Study Design

  • Randomized
  • Parallel

Patient Populations:

  • Age >18 years
  • Isolated AVR and MVR or with other concomitant cardiac surgery

    Number of enrollees: 435
    Duration of follow-up: 1.6 years
    Mean patient age: 55.2 years
    Percentage female: 21%
    NYHA class: I (20%), II (38%), III (28%), IV (6%)

Exclusions:

  • Multiple valve replacement (MV repair allowed)
  • Active endocarditis
  • Terminal illness
  • Emergency cases
  • Inability to return for follow-up
  • Persons unable to give adequate consent

Primary Endpoints:

  • Sum of thromboembolism, thrombosis, and bleeding events, defined per American Association for Thoracic Surgery/Society of Thoracic Surgeons guidelines

Secondary Endpoints:

  • Echo results, New York Heart Association (NYHA) class, and other valve-related adverse events

Concomitant Medications:

All patients received standard anticoagulation therapy for 90 postoperative days, as well as aspirin 81 mg daily. Following this, they were randomized to either low-dose anticoagulation or standard therapy (as per American College of Cardiology/American Heart Association recommendations) for 3 months.

The low-dose groups were comprised of three separate populations: low-risk aortic valve replacement (AVR) (clopidogrel 75 mg daily + aspirin 325 mg daily), high-risk AVR (warfarin with a goal INR of 1.5-2.0, plus aspirin 81 mg daily), and mitral valve replacement (MVR) (warfarin with a goal INR of 2.0-2.5, plus aspirin 81 mg daily). Aspirin 81 mg daily was also continued in the standard therapy patients. All patients received home INR monitoring after 3 months.

Principal Findings:

A total of 861 patients were enrolled in the trial; this preliminary report outlines results for 435 high-risk AVR patients. Of these, 185 patients were enrolled in the low-dose arm, and 190 in the standard therapy arm, while 60 were withdrawn/removed. Criteria for high-risk AVR included clinical features (chronic atrial fibrillation, history of cerebrovascular accident, women on estrogen replacement therapy), echo parameters (left ventricular ejection fraction <30%, left atrial diameter >5 mm, spontaneous echo contrast in left atrium, ventricular aneurysm), and laboratory measurements (hypercoagulability, inadequate platelet response to aspirin and clopidogrel). About 31% of patients were classified as being high risk based on clinical parameters only. The major native valve pathology in these patients was calcific or congenital, with about 52% having aortic stenosis, 21% having aortic insufficiency, and 23% both. Overall mortality prior to randomization at 3 months was 1.8%.

The mean INR was 1.89 versus 2.49 in the low-dose and standard-dose arms, respectively (p < 0.0001), with in-range values being reported in about 69% of patients in both arms. More patients in the low-dose arm reported INR values >3 (25.7% vs. 14.5%, p < 0.05). No difference was noted between the low-dose and standard therapy arms at 1.6 years of follow-up, including mortality (2.1%/patient-year [PY] vs. 1.3%/PY, p = 0.45), major bleed (2.8%/PY vs. 4.2%/PY, p = 0.36), minor bleed (3.1%/PY vs. 4.8%/PY, p = 0.3), stroke (1.4%/PY vs. 0.3%/PY, p = 0.16), peripheral thromboembolic event (0.69%/PY vs. 0.32%/PY, p = 0.52), thrombosis (0% in both arms), or a major event, defined as major bleed, stroke, or thrombosis (4.2%/PY vs. 4.5%/PY, p = 0.84).

Interpretation:

The interim results of the high-risk AVR subgroup of the PROACT trial indicate that low-dose anticoagulation 3 months after AVR may be noninferior to standard-dose anticoagulation in patients undergoing AVR with the On-X mechanical valve. These results are interesting, and the final full analysis of all three cohorts, over a longer period of follow-up, is eagerly awaited.

References:

Presented by Dr. John Puskas at the ACC.11/i2 Summit, New Orleans, LA, New Orleans, April 5, 2011.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention

Keywords: Heart Valve Prosthesis, Stroke, Heart Atria, Follow-Up Studies, Blood Platelets, Risk Factors, Estrogen Replacement Therapy, Carbon, International Normalized Ratio, Thrombophilia, United States Food and Drug Administration, Thrombosis, Cardiac Surgical Procedures


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