PROACT - Reduced INR goal (1.5-2) with On-X mechanical aortic valve

Puskas J, et al Reduced anticoagulation after mechanical aortic valve replacement: interim results from the prospective randomized on-x valve anticoagulation clinical trial randomized Food and Drug Administration investiational device exemption trial. J Thorac Cardiovasc Surg. 2014;147:1202-10. 

 

Clinical Question

In patients with isolated aortic valvular replacement (AVR) with On-X mechanical valve treated with standard target warfarin (INR 2-3) + ASA x3 months, does lowering the chronic INR target to 1.5-2.0 increase the risk of thromboembolic events?

 

Bottom Line

In a population of patients with isolated AVR with On-X mechanical valve at generally low thromboembolic risk, warfarin with a lower INR target of 1.5-2.0 was not as good as INR target 2-3 at preventing thromboembolism when added to ASA. Although this trial demonstrated a 1.8%/year reduction in major bleeding with the lower INR target, it was also unable to rule-out a 2%/year greater risk of thromboembolic events.

Notably, despite the substantial limitations noted below, the FDA approved an expanded label for use of the On-X valve for isolated AVR with a target INR 1.5-2.0 (+ ASA 81 mg/d).

 

Design

Unblinded non-inferiority RCT with high loss-to-follow-up/analysis with differences between groups (24% vs 13%) that was stopped early & analyzed using modified intention-to-treat population.

 

Non-inferiority trial details:

  • Non-inferiority margin: 1.5% PER YEAR absolute risk increase in 1o outcome (composite of thromboembolism/thrombus/bleed) with intervention vs control
    • No minimum clinically important difference provided
  • Final sample size calculation of 800 patient-years of follow-up/group would have provided 80% power for non-inferiority with 1-sided alpha of 0.05 (actual follow-up ~755 and ~675 pt-y/group)

 

Patients and Setting

  • 33 centres in Canada + US
  • Enrolled from June 2006 to October 2009, followed to March 1, 2013
  • Inclusion criteria:
    1. Adult (18+ y/o)
    2. Isolated AVR
    3. 1+ risk factor for thromboembolism, including:
      • Hx of neurologic events
      • Chronic AF
      • LV ejection fraction <30%
      • Left or right ventricular aneurysm
      • Enlarged left atrium (diameter >50 mm)
      • + bubble study (spontaneous echo contrast in left atrium), indicating right-to-left shunt
      • Hypercoagulability (as determined by testing for factor V Leiden, prothrombin mutation, antithrombin III, protein C, S & factor VIII activity, LDL)
      • Vascular pathologic features
      • Lack of platelet response to ASA or clopidogrel
      • Women receiving estrogen replacement therapy
    4. Received warfarin with target INR 2-3 + ASA 81 mg/d for the first 3 months post-op
    5. No thromboembolism during first 3 months post-AVR
  • Key exclusion criteria:
    • Note: Did not exclude if concomitant cardiac surgery such as CABG or mitral/tricuspid repair, ascending aortic replacement, maze procedure
    • Double left-sided valve replacement (i.e. also had MVR)
    • Right-sided valve replacement
    • Active endocarditis at implantation
  • 425 screened -> 375 randomized -> 306 analyzed as part of "intention-to-treat" analysis
  • Average patient:
    • 55 y/o
    • 20% female
    • Race: ?
    • Concomitant procedures during AVR
      • CABG 27%
      • Aortic aneurysm repair 14%
      • Other 25%
    • Valve characteristics
      • Etiology: Calcified ~2/3, bicuspid ~1/3
      • Lesion: Stenosis (~50%), regurgitation (~25%), both (~25%)
    • Risk factors
      • Hx neurologic event 3-5%
      • AF <5%
      • LVEF <30% 5%
      • Enlarged left atrium ~10%
      • Estrogen replacement therapy 1-2%
      • Abnormal labs
        • Antithrombin III activity 15%
        • Other hypercoagulable states (<5% each)
        • P2Y12 inhibition ~25%
        • Urine thromboxane ~35-45%

 

Intervention and Control

  • Co-interventions common to both groups:
    • 1st 3 months post-AVR: Both groups treated with warfarin to target INR 2.0-3.0 + ASA 81 mg/d
    • Patients in both groups received a home "point-of-care" INR monitor & instructed to check INR q1week
      • >80% of patients checked their INR at least 3x/month
    • Warfarin dose adjustment made by study sites (rather than by family doctor or other local anticoagulation service)
  • Intervention: Lower INR target
    • Starting 3 months post-AVR: Warfarin to target INR 1.5-2.0 + ASA 81 mg/d
      • Time in therapeutic range (INR 1.5-2.0): 63.6%
      • Mean INR: 1.9 +/- 0.5
      • Patients who experienced a thromboembolic event had their INR target increased to 2.0-3.0
  • Control: Standard INR target
    • 3 months post-AVR: Continue warfarin to target INR 2.0 to 3.0 + ASA 81 mg/d
      • Mean INR 2.5 +/- 0.6
      • Time in therapeutic range (INR 2.0-3.0): 69.8%

 

Outcomes

  • Average patient followed up for 3.8 years
    • Intervention group: 675.2 patient-years
    • Control: 755.7 patient-years
  • Thromboembolism: Non-inferiority NOT demonstrated
    • Study did not report any formal non-inferiority statistical testing; stated "similar" rates of thromboembolic events between groups
    • Calculation of raw numbers shows that upper limit of 95% confidence interval crosses the 1.5%/y non-inferiority margin
      • 5.2% (risk of primary outcome in control group) * 0.4 (upper end of 95% CI) = 2.1%/y
  • Bleeding: Statistically-significant 1.8%/year lower risk of major bleed with lower INR target

PROACT outcomes

Key Considerations

The study did not demonstrate non-inferiority of the lower INR target

  • The absolute difference in the primary outcome PER YEAR based on the 95% confidence interval could be anywhere from a 2.4% lower risk to a 2.1 HIGHER risk, which is greater than the 1.5%/y non-inferiority margin.
  • Notably, the 1.5%/y non-inferiority margin was not based on any statistically appropriate criteria or an agreed-upon minimum clinically important difference (MCID)
  • Additional problems with this non-inferiority analysis:
    • Primary outcome included competing events (thrombosis & bleed). Inclusion of bleeding events in this composite outcome attenuates any difference between groups in favor of the lower target INR group, biasing the results towards non-inferiority
    • Unplanned interim analysis
    • Absolute instead of relative non-inferiority margin
    • Done on mITT population only (non-inferiority trials should report ITT + per-protocol analyses)
  • More plainly, the results of this trial suggest that loosening the INR target from 2.0-3.0 to 1.5-2.0 may increase the risk of the primary outcome by up to 8% over ~4 years.

Generalizability: Most patients in this trial did not have typical high-risk features for thromboembolism, These risk factors (including AF, enlarged LA, reduced LVEF, hypercoagulability, vascular disease or history of embolism) were each present in <10% of the study population. Therefore, these results only truly apply to patients with On-X AVR at relatively low risk of thromboembolism.

Internal validity: Unclear/high risk of bias in multiple domains likely underestimate differences between groups in terms of thromboembolic events, & overestimate differences in favor of the lower-target group for bleeding events.

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD

Summary date: 30 May 2016