ARTE - Dual versus single antiplatelet therapy after TAVI

Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) randomized clinical trial. JACC: Cardiovascular Intervention 2017 [online]

Bottom line: In patients undergoing TAVI with no other indication for anticoagulation or DAPT, 3 months of DAPT increases the risk of major/life-threatening bleeding (number needed to harm 14) versus ASA alone without any apparent benefit.


Patients (n=222)

  • Included patients who underwent TAVI (aka TAVR) with Edwards SAPIEN XT or SAPIEN 3 valve (balloon-expandable valve)
  • Excluded patients requiring chronic anticoagulation or dual antiplatelet therapy (DAPT) for other indication, or those who had a major bleed within 3 months before TAVI or any history of intracranial hemorrhage
  • Baseline characteristics
    • Age 79 y
    • Male 58%
    • Indexed AVA 0.4 cm2/m2
    • LVEF 55%
    • Procedural characteristics
      • Femoral approach ~70%
      • SAPIEN XT ~92%, SAPIEN 3 8%
      • Post-TAVI indexed AVA 0.95-1.0 cm2/m2
      • New-onset AF 11%


  • I: DAPT - clopidogrel (300 mg/d load <1 day before/after TAVI, then 75 mg/d) x90 days
  • C: ASA monotherapy
  • In both groups, ASA started >24h before TAVI & continued for 6+ months
  • PPI use not reported (though authors report that all patients with GI bleed were receiving a PPI prior to the event)

Results @ 90 days

  • Types of major/life-threatening bleeds in DAPT group (all occurred in first 30 days): GI bleed (5), peri-operative or access-site bleed (annular rupture, femoral hematoma; 7)



  • This trial represents elderly patients undergoing TAVI with moderate-high risk of peri-operative mortality
    • Although the results of this trial do not apply to those requiring anticoagulation, we would expect an even greater increase in serious bleeds when adding DAPT to an oral anticoagulant
  • These results with the SAPIEN valves are also likely generalizable to self-expanding valves (Medtronic's CoreValve line)

Internal validity

  • Unclear risk of allocation bias (allocation concealment not adequately described)
  • High risk of performance & detection bias (no blinding to treatment)
  • Stopped prematurely due to slow enrolment + loss of funding


Other studies

  • Results from our systematic review of 4 small studies (2 RCTs & 2 cohorts) were consistent with the ARTE trial; DAPT increased the risk of bleeding events without significantly reducing stroke or other ischemic events
  • Notably, none of the studies - alone or in combination - have sufficient power to evaluate the efficacy of DAPT in this setting, though it is likely that the severity and magnitude of harm from bleeds related to DAPT likely exceeds any possible benefit in this patient population
  • Therefore, the existing evidence does not support routine use of DAPT in patients undergoing TAVI

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 investigational device exemption trial. J Thorac Cardiovasc Surg. 2014;147:1202-10. 

Puskas J, et al. Anticoagulation and antiplatelet strategies after On-X mechanical aortic valve replacement. JACC 2018;71:2717-26.

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 2.3%/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).


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: 1.0% PER YEAR absolute risk increase in 1o outcome (composite of thromboembolism/bleed) with intervention vs control
    • No minimum clinically important difference provided
  • Final sample size calculation of 1000 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 (n=374)

  • 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 mechanical 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)
      • Spontaneous echo contrast in left atrium
      • 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 -> 374 analyzed as part of intention-to-treat analysis
  • Average patient:
    • 55 y/o
    • 20% female
    • 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): 66%
      • 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): 55%


  • Median follow-up: Low-target 5.1 years, standard target 5.7 years
  • Major bleeding: Low target 1.6%/year, standard target 3.9%/year (NNT 44/year)
  • Thromboembolism: Non-inferiority NOT demonstrated
    • Study did not report any formal non-inferiority statistical testing; reported as "similar/no different" rates of thromboembolic events between groups
    • Stroke/TIA: Low target 2%, standard target 1.65% (rate ratio 1.22, 95% CI 0.64-2.32)
      • 95% CI crosses the 1.0%/y non-inferiority margin, & cannot rule out 2% absolute increase PER YEAR
    • Peripheral thromboembolism: Low target 0.4%, standard target <0.1% (rate ratio 4.61, 95% CI 0.52-41.28)
    • 12% of patients in the low-target group crossed over to the standard target due to thromboembolism or valve thrombosis

Key Considerations

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

  • Based on the 95% CI, the absolute risk of stroke/TIA could be as much as 2.2% higher per year, which is far greater than the 1.0%/y non-inferiority margin.
    • Notably, theis 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
    • The initial 2014 publication was based on an unplanned interim analysis
    • The non-inferiority margin changed between publications (1.5%/year in the 2014 publication and 1.0%/year in the 2018 publication), and was based on absolute instead of relative risk differences
    • Done on ITT population only (non-inferiority trials should report both ITT & per-protocol analyses)
  • In summary, 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 updated: July 30, 2018