Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention - RE-DUAL PCI

May 22, 2019
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Author/Summarized by Author:
Anthony A. Bavry, MD,MPH,FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Summary Supplemental Reviewer:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
Boehringer Ingelheim
Date Presented:
11/14/2017
Date Published:
05/14/2019
Date Updated:
05/22/2019
Original Posted Date:
08/27/2017
References

Contribution To Literature:

The RE-DUAL PCI trial showed that dual therapy with dabigatran was superior to triple therapy with warfarin at preventing bleeding.

Description:

The goal of the trial was to evaluate dual therapy compared with triple therapy among patients with atrial fibrillation undergoing coronary revascularization. Triple therapy usually consists of aspirin, an ADP receptor antagonist, and warfarin; however, this approach is associated with increased bleeding.


Study Design

  • Randomized
  • Parallel
  • Stratified

Patients with atrial fibrillation undergoing coronary revascularization were randomized to dual therapy with dabigatran at a dose of 110 mg twice daily (n = 981) vs. dual therapy with dabigatran at a dose of 150 mg twice daily (n = 763) vs. triple therapy with warfarin (n = 981).

In the dual therapy group, participants received clopidogrel or ticagrelor in addition to one of two doses of dabigatran.

In the triple therapy group, participants received aspirin plus clopidogrel or ticagrelor in addition to warfarin. The duration of aspirin was 1 month after a bare-metal stent (BMS) and 3 months after a drug-eluting stent (DES).

Outside the United States, elderly participants were not eligible for the dabigatran 150 mg dose.

  • Total number of enrollees: 2,725
  • Duration of follow-up: minimum of 6 months
  • Mean patient age: 72 years
  • Percentage female: 26%
  • Percentage with diabetes: 37%

Inclusion criteria:

  • Patients with stable or unstable coronary artery disease undergoing coronary revascularization
  • Nonvalvular atrial fibrillation

Exclusion criteria:

  • Bioprosthetic or mechanical heart valve
  • Severe renal insufficiency

Other salient features/characteristics:

  • Acute coronary syndrome (ACS): 52%
  • DES: 82%
  • Approximately 10% received ticagrelor as their ADP receptor antagonist

Principal Findings:

The primary safety outcome, incidence of major or clinically relevant nonmajor bleeding events, occurred in 15.4% of the dual therapy with dabigatran 110 mg group vs. 26.9% of the triple therapy group (p for noninferiority < 0.001, p for superiority < 0.001). Thrombolysis in Myocardial Infarction (TIMI) major bleeding was also lower in the dual vs. triple therapy group.

The primary safety outcome, incidence of major or clinically relevant nonmajor bleeding events, occurred in 20.2% of the dual therapy with dabigatran 150 mg group vs. 25.7% of the corresponding triple therapy group (excluding elderly participants outside the United States) (p for noninferiority < 0.001). TIMI major bleeding was also lower in the dual vs. triple therapy group.

The primary efficacy outcome, incidence of death, MI, stroke, systemic embolism, or unplanned revascularization, occurred in 13.7% of the two dual therapy groups vs. 13.4% of the triple therapy group (p for noninferiority = 0.005).

Secondary outcomes:

  • MI: 4.5% with dual therapy 110 mg group vs. 3.0% with triple therapy (p = 0.09), and 3.4% with dual therapy 150 mg group vs. 2.9% with triple therapy (p = 0.61)
  • Definite stent thrombosis: 1.5% with dual therapy 110 mg group vs. 0.8% with triple therapy (p = 0.15), and 0.9% with dual therapy 150 mg group vs. 0.9% with triple therapy (p = 0.98)

Subgroup analyses: Approximately 50% of patients presented with an ACS. DES were used in 83% of patients. Patients who received ticagrelor (12%) more often had ACS as the index event. Patients who were on ticagrelor had higher bleeding compared with clopidogrel, with and without dabigatran.

The risk of the primary safety outcome was reduced with dabigatran dual therapy compared with warfarin triple therapy among patients with ACS (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.35-0.63) for dabigatran 110 mg and (HR 0.67, 95% CI 0.50-0.90) for dabigatran 150 mg; elective percutaneous coronary intervention (PCI) (HR 0.57, 95% CI 0.43-0.76) for dabigatran 110 mg and (HR 0.76, 95% CI 0.56-1.03) for dabigatran 150 mg, receiving ticagrelor (HR 0.46, 95% CI 0.28-0.76) for dabigatran 110 mg and (HR 0.59, 95% CI 0.34-1.04) for dabigatran 150 mg, or receiving clopidogrel (HR 0.51, 95% CI 0.41-0.64) for dabigatran 110 mg and (HR 0.73, 95% CI 0.58-0.91) for dabigatran 150 mg (all interaction p values > 0.1).

Dabigatran dual therapy was similar to warfarin triple therapy for the primary efficacy outcome of death, MI, stroke, systemic embolism, or unplanned revascularization across the subgroups (all interaction p values > 0.10).

Interpretation:

Among patients with atrial fibrillation undergoing coronary revascularization, dual therapy compared with triple therapy was effective at reducing bleeding events. Bleeding was primarily defined as major or clinically relevant nonmajor bleeding; however, there was also a reduction in TIMI major bleeding with dual therapy. Dual therapy consisted of an ADP receptor antagonist (clopidogrel or ticagrelor) and dabigatran (110 mg or 150 mg). Adverse cardiac events were similar between treatment groups; however, there was a numerical increase in MI and definite stent thrombosis in the dual therapy dabigatran 110 group vs. the triple therapy group. No differences were noted for the primary safety or efficacy outcome for dabigatran dual therapy vs. warfarin triple therapy according to ACS vs. elective PCI and ticagrelor vs. clopidogrel.

In summary, several lines of evidence now suggest that it is safe to treat atrial fibrillation patients who undergo coronary revascularization with anticoagulation (warfarin studied in WOEST, rivaroxaban studied in PIONEER AF-PCI, dabigatran studied in RE-DUAL PCI) and clopidogrel monotherapy.

References:

Oldgren J, Steg PG, Hohnloser SH, et al. Dabigatran Dual Therapy With Ticagrelor or Clopidogrel After Percutaneous Coronary Intervention in Atrial Fibrillation Patients With or Without Acute Coronary Syndrome: A Subgroup Analysis From the RE-DUAL PCI Trial. Eur Heart J 2019;40:1553-62.

Editorial: Mehran R, Kalkman DN, Angiolillo DJ. Atrial Fibrillation, With ACS and PCI: Walking a Tightrope. Eur Heart J 2019;40:1563-6.

Presented by Dr. Jonas Oldgren at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 14, 2017.

Cannon CP, Bhatt DL, Oldgren J, et al., on behalf of the RE-DUAL PCI Steering Committee and Investigators. Dual Antithrombotic Therapy With Dabigatran after PCI in Atrial Fibrillation. N Engl J Med 2017;377:1513-24.

Editorial: Piccini JP, Jones WS. Triple Therapy for Atrial Fibrillation After PCI. N Engl J Med 2017;377:1580-2.

Presented by Dr. Christopher P. Cannon at the European Society of Cardiology Congress, Barcelona, Spain, August 27, 2017.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Interventions and ACS, Interventions and Coronary Artery Disease

Keywords: AHA17, AHA Annual Scientific Sessions, Acute Coronary Syndrome, Antithrombins, Aspirin, Atrial Fibrillation, Coronary Artery Disease, Drug-Eluting Stents, Embolism, ESC Congress, ESC2017, Fibrinolytic Agents, Hemorrhage, Myocardial Infarction, Myocardial Revascularization, Purinergic P2Y Receptor Antagonists, Stroke, Thrombosis, Warfarin


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