WOEST

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Dewilde WJM, et al. "Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An open-label, randomised, controlled trial". The Lancet. 2013. 381(9872):1107-1115.
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Clinical Question

In patients on oral anticoagulation undergoing PCI, does using clopidogrel alone reduce the risk of bleeding compared with clopidogrel plus aspirin?

Bottom Line

In patients on oral anticoagulation undergoing PCI, use of clopidogrel alone (double therapy) was associated with a significant reduction in bleeding complications compared to patients receiving clopidogrel with aspirin (triple therapy).

Major Points

Antiplatelet therapy and oral anticoagulant (OAC) therapy each increase risk of bleeding. 20-30% of patients with an indication for long-term oral anticoagulation (OAC) have concomitant ischemic heart disease that requires PCI with stenting. In these cases, the 2006 ACC/AHA/ESC guidelines recommended dual antiplatelet therapy with aspirin and clopidogrel in addition to OAC (triple therapy) [Class IIb, level C recommendation] [1]. However, it was known that triple therapy increases the risk of both fatal and non-fatal bleeding events[2][3]. No prospective, randomized controlled data was available to guide the decision to use dual vs. triple therapy in patients on OAC undergoing PCI.

Published in 2013, the What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial randomized 573 patients with need for long-term OAC to double (OAC+clopidogrel) or triple therapy (OAC+clopidogrel+ASA) in an open-label fashion. At 1-year follow-up, bleeding events were lower in the double therapy group (19.4% vs. 44.4%; P<0.0001; NNT 4). This was driven by reductions in minor bleeding. The combined secondary endpoints (death, MI, revascularization, stroke, stent thrombosis) was likewise lower for the double therapy group (11.1% vs. 17.6%; P=0.025; NNT 15). Interestingly, all-cause mortality was lower in the double therapy group, which was driven by non-cardiac mortality.

There are several limitations of this trial. The trial was underpowered to detect differences in thrombotic events. There was a greater incidence of bleeding events than expected, which may be in part due to the lower-than-expected use of PPIs.[4][5] (PPIs were shown to reduce bleeding in patients undergoing PCI in the 2010 COGENT trial.) The reduction in bleeding events was driven by minor bleeding, which may not be clinically-meaningful.[6] Finally, the trial was not blinded.

Despite these limitations, practice guidelines were changed in 2014 to recommend double therapy in patients on OAC undergoing PCI.

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)[7]

  • In patients with nonvalvular AF with prior stroke, TIA, or CHA2DS2-VASc score ≥2, recommend oral anticoagulation with:
    • Warfarin, goal INR 2-3 (class I, level A)
    • Dabigatran (class I, level B)
    • Rivaroxaban (class I, level B)
    • Apixaban (class I, level B)
  • In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
  • In patients with nonvalvular AF with moderate or severe CKD with CHA2DS2-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
  • In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
  • In patients with a mechanical heart valve, do not use dabigatran (class III, level B)
  • Following coronary revascularization (percutaneous or surgical) in patients with AF and a CHA2DS2-VASc score of 2 or greater, it may be reasonable to use clopidogrel (75 mg once daily) concurrently with OAC but without aspirin (Class IIb, Level B)

Design

  • Multicenter, open-label, randomized, controlled trial
  • N=563
    • Double Therapy (n=279)
    • Triple Therapy (n=284)
  • Setting: 15 sites in the Netherlands and Belgium
  • Enrollment: 2008-2011
  • Follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: Any bleeding by year 1

Population

Inclusion Criteria

  • Age 18-80
  • An indication for OAC for ≥1 year after the study
  • A severe coronary lesion (at least 75% stenosis on angiography or FFR<0.80) with an indication for PCI as according to the US and European guidelines

Exclusion Criteria

  • Prior intracranial bleeding
  • Cardiogenic shock
  • Contraindication to use of the study medications
  • Peptic ulcer in the prior 6 months
  • Thrombocytopenia (platelet concentration lower than 50×109/L)
  • TIMI major bleeding in the prior 12 months
  • Pregnancy

Baseline Characteristics

From the double therapy group.

  • Demographics: Age 70 years, male 77%
  • Health data: BMI 27.5 kg/m2
  • Risk Factors: ACS 25%, DM 24%, HTN 69%, HLD 68%, current smoker 22%, family history of CAD 42%, MI 34%, HF 25%, CVA 18%
  • PSH: PCI 31%, CABG 20%
  • Meds: Beta blocker 76%, ACE-inhibitor or ARB 69%, CCB 27%, diuretic 46%, statin 70%, digoxin 11%, nitrate 29%, ASA 27%, clopidogrel 44%, insulin 8%, oral DM medication 21%, fibrate 3%, PPI use 34%
  • Other PMH: GI Bleed 5%, renal failure 18%
  • CHADS2 if AF:
  • Indication for OAC: Afib/flutter 69%, mechanical valve 10%, other (eg, apical aneurysm or PE) 20%
    • 1: 12%
    • 2: 32%
    • 3: 32%
    • 4: 16%
    • 5: 7%
    • >5: 1%
  • LVEF: 46%
    • LVEF <30%: 21%

Interventions

  • All patients pretreated with 75mg clopidogrel daily x5 days
  • A pre-PCI loading dose clopidogrel was given (300mg if >24 hours or 600mg if >4 hours before PCI)
    • Double therapy - Clopidogrel 75mg daily
    • Triple therapy - Clopidogrel 75mg + ASA 80-100mg daily
  • Follow-up:
    • Bare metal stent for stable CAD:
      • Clopidogrel continued for minimum 1 month and up to 1 year (at the discretion of attending physician)
    • Drug-eluting stent:
      • Clopidogrel continued for at least 1 year
  • OACs were continued, targeting an INR of 2.0

Outcomes

Presented as double vs. triple therapy.

Primary Outcomes

Any bleeding by year 1
19.4% vs. 44.4% (HR 0.36; 95% CI 0.26-0.50; P<0.0001; NNT 4)

Secondary Outcomes

TIMI bleeding
Major: 3.2% vs. 5.6% (HR 0.56; 95% CI 0.25-1.27; P=0.159)
Major and minor: 14.0% vs. 31.3% (HR 0.40; 95% CI 0.27-0.58; P<0.0001; NNT 6)
GUSTO risk score
Severe: 1.4% vs. 3.5% (HR 0.40; 95% CI 0.12-1.27; P=0.119)
Severe and moderate: 5.4% vs. 12.3% (HR 0.42; 95% CI 0.23-0.76; P=0.003; NNT 14)
BARC bleeding score
BARC 3: 6.5% vs. 12.7% (HR 0.49; 95% CI 0.28-0.86; P=0.011; NNT 16)
BARC 2: 8.2% vs. 20.8% (HR 0.36; 95% CI 0.23-0.59; P<0.0001; NNT 8)
BARC 1: 6.5% vs. 15.8% (HR 0.38; 95% CI 0.22-0.66; P=0.0004; NNT 11)
Any blood transfusion
3.9% vs. 9.5% (OR 0.39; 95% CI 0.17-0.84; P=0.011)
Combined secondary endpoint
Death, myocardial infarction, target-vessel revascularisation, stroke or stent thrombosis.
11.1% vs. 17.6% (HR 0.60; 95% CI 0.38-0.94; P=0.025; NNT 15)
Death
2.5% vs. 6.3% (HR 0.39; 95% CI 0.16-0.93; P=0.027; NNT 26)
Cardiac: 1.1% vs. 2.5% (HR 0.43; 95% CI 0.11-1.66; P=0.207)
Non-cardiac: 1.4% vs. 3.9% (HR 0.36; 95% CI 0.11-1.13; P=0.069)
Myocardial infarction
3.2% vs. 4.6% (HR 0.69; 95% CI 0.29-1.60; P=0.382)
STEMI: 0.4% vs. 1.1% (HR 0.34; 95% CI 0.04-3.25; P=0.325)
NSTEMI: 2.9% vs. 3.5% (HR 0.79; 95% CI 0.31-2.01; P=0.625)
Target-vessel revascularisation
PCI or CABG: 7.2% vs. 6.7% (HR 1.05; 95% CI 0.56-1.97; P=0.876)
PCI: 6.1% vs. 5.6% (HR 1.06; 95% CI 0.54-2.10; P=0.869)
CABG: 1.1% vs. 1.1% (HR 1.0; 95% CI 0.20-4.90; P=0.998)
Stroke
1.1% vs. 2.8% (HR 0.37; 95% CI 0.10-1.40; P=0.128)
Ischemic: 0.7% vs. 2.8% (HR 0.25; 95% CI 0.05-1.17; P=0.056)
Hemorrhagic: 0.4% vs. 0% (P=0.321)
Disabling: 0.7% vs. 0.7% (HR 0.99; 95% CI 0.14-6.99; P=0.988]
Non-disabling: 0.4% vs. 2.5% (HR 0.14; 95% CI 0.02-1.16; P=0.034)
Stent Thrombosis
1.4% vs. 3.2% (HR 0.44; 95% CI 0.14-1.44; P=0.165)
Definite: 0.4% vs. 1.1% (HR 0.33; 95% CI 0.03-3.22; P=0.319)
Probable: 0% vs. 0.7% (P=0.161)
Possible: 1.1% vs. 1.4% (HR 0.75; 95% CI 0.17-3.30; P=0.708)

Criticisms

  • Unclear why the bleeding rates were so high in this study[4][6]
  • Underpowered to detect differences in stent thrombotic events[4]
  • This study did not compare novel OACs[4]
  • Bleeding differences were mainly driven by minor bleeding, which may not represent clinically-meaningful bleeding[6]
  • The low use of PPIs may have increased bleeding rates[5]
  • It is unclear why there were differences in non-cardiac mortality[6]
  • The antiplatelet therapy used was more aggressive than those in the European guidelines[5]
  • No placebo group
  • Not blinded

Funding

  • Antonius Ziekenhuis Foundation and Strect Foundation
  • No declared conflicts of interest

Further Reading

  1. Fuster et al. "ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation—Executive Summary." Circulation. 2006;114:700-752.
  2. P.P. Karjalainen, P. Porela, A. Ylitalo, et al. "Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting." Eur Heart J. 2007 Mar;28(6):726-32.
  3. J.L. Orford, P. Fasseas, S. Melby, et al. "Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation". Am Heart J. 2004 Mar;147(3):463-7.
  4. 4.0 4.1 4.2 4.3 Brott BC. "ACP Journal Club: Adding aspirin to clopidogrel worsened outcomes in PCI patients receiving oral anticoagulants." Annals of Internal Medicine. 2013;158(12):JC6.
  5. 5.0 5.1 5.2 Fox KA. "Comment: Dual or single antiplatelet therapy with anticoagulation?" The Lancet. 2013;381(9872):1080-1081.
  6. 6.0 6.1 6.2 6.3 Multiple authors. "Correspondence: Antiplatelet therapy and anticoagulants." The Lancet. 2013;382(9886):24-25.
  7. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.