RE-DUAL

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Cannon CP, et al. "Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation". The New England Journal of Medicine. 2017. 377(16):1513-1524.
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Clinical Question

In patients with nonvalvular atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) for coronary artery disease, is dual therapy with a thienopyridine antiplatelet and dabigatran associated with less bleeding when compared to triple therapy with aspirin, a thienopyridine antiplatelet, and dabigatran? Is dual therapy associated a higher rate of thrombosis?

Bottom Line

In patients with nonvalvular AF undergoing PCI for coronary artery disease, dual therapy with a thienopyridine antiplatelet and dabigatran is associated with an 11.5% absolute reduction in major and clinically relevant non-major bleeding when compared to triple therapy. Dual therapy was also associated with overall similar rates of thrombosis, although a pooled analysis including both doses of dabigatran dual therapy revealed a modest and non-significant 1.1% absolute increase in thromboembolic events or death.

Major Points

Anti-thrombotic management of patients with nonvalvular AF undergoing PCI represents a clinical challenge, as therapeutic anticoagulation is known to prevent ischemic stroke while dual anti-platelet therapy (DAPT) with aspirin and a thienopyridine (e.g., clopidogrel, ticagrelor) is generally considered standard of care to prevent stent thrombosis in the post-PCI period. At the same time, so called "triple therapy" with aspirin, a thienopyridine, and an oral anticoagulant has been shown to result in high rates of clinical bleeding.[1] In an effort to refine the balance of antithrombotic protection and risk of bleeding, there has been significant interest in assessing the safety and efficacy of several intermediate anti-thrombotic regimens in this population.

The 2013 WOEST trial demonstrated that dual therapy with warfarin and clopidogrel post-PCI resulted in a 25% absolute reduction in bleeding events when compared to triple therapy. Thrombosis rates were similar in both groups, although the trial was not adequately powered for thrombosis events. The ISAR-TRIPLE trial demonstrated that a shorter duration of triple therapy (6 weeks as opposed to 6 months) was also associated with a lower rate of bleeding with similar rates of thrombosis. More recently, the PIONEER-AF-PCI trial randomized patients with AF to triple therapy using warfarin, triple therapy using a very low dose of the direct-acting oral anticoagulant (DOAC) rivaroxaban, and dual therapy using a thienopyridine and full-dose rivaroxaban. PIONEER-AF-PCI demonstrated that both triple therapy using very low dose rivaroxaban and dual therapy using full-dose rivaroxaban were both associated with significantly less major bleeding then triple therapy using warfarin, with similar thrombosis rates among all three groups. Largely based on the the results of WOEST, current ACC/AHA guidelines provide a class IIb recommendation ("reasonable") for dual therapy using clopidogrel and oral anticoagulation without aspirin in patients with AF and elevated stroke risk following PCI.

The 2017 Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL PCI) trial randomized 2725 patients with AF undergoing PCI (for acute coronary syndrome in 51% of cases) to a) triple therapy using aspirin, thienopyridine (plavix or ticagrelor), and warfarin (goal INR 2-3), b) dual therapy using thienopyridine and dabigatran 150MG twice daily, and c) dual therapy using thienopyridine and dabigatran 110MG twice daily, and assessed for a primary outcome of major or clinically relevant nonmajor bleeding. Due to labeling recommendations for dose adjustment only present outside the US, elderly patients outside the US were randomized only to triple therapy including warfarin or dual therapy using dabigatran 110MG twice daily. Patients receiving triple therapy were given aspirin for 1-3 months post-PCI and all patients received a thienopyridine for 12 months post-PCI. At mean follow-up 14 months, triple therapy was associated with an 11.5% absolute increase in the primary outcome over the dabigatran 110MG twice daily dual therapy group and a 5.5% absolute increase over the dabigatran 150MG twice daily dual therapy group (which did not include elderly patients outside the US). In secondary efficacy analyses assessing for thrombotic events, rates of myocardial infarction, stroke, systemic embolism, death, or unplanned revascularization were similar across the three groups, although a pooled analysis combining both doses of dabigatran dual therapy demonstrated a modest and non-significant 1.1% absolute increase in thrombotic events or death compared to the triple therapy group.

In summary, RE-DUAL PCI adds to accumulating evidence suggesting that "triple therapy" with aspirin, a thienopyridine antiplatelet agent, and full-dose oral anticoagulation is associated with higher rates of bleeding without clear evidence of improved thrombotic protection (either stroke or MI/stent thrombosis) in patients with AF after PCI. Similar to previous studies, RE-DUAL PCI was underpowered to robustly assess for thrombotic outcomes and a pooled analysis involving both dual therapy groups did suggest a small signal towards possible increased thrombosis rates. Notably, however, the rate of thromboembolic events or death was actually lower in the 150MG dabigatran dual therapy group when compared to the corresponding triple therapy group, suggesting that the signal towards more thrombosis may be driven solely by dual therapy using 110MG dabigatran. On balance, these findings suggest that dual therapy with a thienopyridine antiplatelet agent and oral anticoagulation without aspirin appears to be a reasonable compromise between providing adequate thrombotic protection and minimizing bleeding risk in appropriately selected patients. Importantly, triple therapy using aspirin, a thienopyridine, and very low dose DOAC is also another candidate approach that was not assessed in RE-DUAL PCI. Further study is necessary to define the optimal OAC dosing strategy and duration of antiplatelet therapy in this population.

Guidelines

As of January 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label, randomized, controlled trial
  • N=2725
    • Triple therapy (aspirin, clopidogrel or ticagrelor, warfarin)
    • 150MG dual therapy (clopidogrel or ticagrelor, dabigatran 150MG twice daily)
    • 110MG dual therapy (clopidogrel or ticagrelor, dabigatran 110MG twice daily)
  • Setting: 414 sites in 41 countries
  • Enrollment: July 21, 2014 - October 31, 2016
  • Mean follow-up: 14 months
  • Analysis: Intention-to-treat
  • Primary Outcome: ISTH major bleeding or clinically relevant non-major bleeding

Population

Inclusion Criteria

  • Age ≥ 18 years
  • Non-valvular atrial fibrillation
  • Stable or unstable coronary disease treated with PCI

Exclusion Criteria

  • Mechanical or biological heart valve prosthesis
  • Cardiogenic shock
  • Use of fibrinolytic agents within 24 hours prior to randomization resulting in prohibitive bleeding risk
  • Stroke within 1 month
  • Major surgery within 1 month
  • Organ transplant or awaiting organ transplant
  • History of intraocular, spinal, retroperitoneal, or traumatic intra-articular bleeding (unless causative factor addressed)
  • GI hemorrhage within 1 month (unless causative factor addressed)
  • Major bleeding episode within 1 month
  • Hemorrhagic disorder or bleeding diathesis
  • Anemia or thrombocytopenia
  • Severe renal impairment (eCrCl < 30 mL/min)
  • Acute liver disease or known active hepatitis
  • Recent malignancy or radiation therapy, unless life expectancy is > 36 months
  • Treatment with a CYP inhibitor or activator, NSAIDs
  • Known allergy or contraindication to study drug
  • Premenopausal women who are pregnant, breast-feeding, not surgically sterile, or not practicing 2 acceptable methods of birth control
  • Participation in another clinical trial within 30 days
  • Unable to unwilling to comply with the protocol
  • Life expectancy shorter than study duration

Baseline Characteristics

From triple therapy group.

  • Demographics: Age 71.7 years, male 76.5%
  • Comorbidities: DM 37.9%, stroke 10.2%, CrCl 75.4 mL/min
  • Cardiac: previous MI 27.3%, previous PCI 35.4%, previous CABG 11.3%, stable angina 43.7%, acute coronary syndrome 48.4%, DES placed 84.6%, BMS placed 13.6%
  • AF: Persistent 18.2%, permanent 32.4%, paroxsymal 49.4%, CHADS2-VASc score 3.8, HAS-BLED score 2.8

Interventions

  • Patients randomized 1:1:1
    • Triple therapy with warfarin (N=981)
    • Dual therapy with dabigatran 150MG twice daily (N=763)
    • Dual therapy with dabigatran 110MG twice daily (N=981)
  • Elderly patients outside the US only eligible for dual therapy with dabigatran 110MG twice daily or triple therapy with warfarin
    • Due to labeling recommendations outside of the US affecting these patients
    • Randomization stratified in this subset
  • In the triple therapy group, aspirin discontinued after 1 month (in patients with BMS) and after 3 months (in patients with DES)
  • All patients were to receive either clopidogrel or ticagrelor for at least 12 months after randomization, with choice of agent at the discretion of the investigator
  • The dose of warfarin was adjusted to ensure INR 2-3
  • Follow-up performed every 3 months with a conclusion visit during which the trial anticoagulant was discontinued
  • The trial continued until all patients had a minimum of 6 months of follow-up and the target number of end-point events was anticipated to be reached

Outcomes

Comparisons are dual therapy vs. (corresponding) triple therapy

Primary Outcomes

ISTH major or clinically relevant nonmajor bleeding (110MG twice daily dabigatran)
151 (15.4%) vs. 264 (26.9%); HR 0.52 (95% CI 0.42-0.63); p < 0.001
ISTH major or clinically relevant nonmajor bleeding (150MG twice daily dabigatran)
154 (20.2%) vs. 196 (25.7%); HR 0.72 (95% CI 0.58-0.88); p = 0.002

Secondary Outcomes

ISTH major bleeding (110MG twice daily dabigatran)
49 (5.0%) vs. 90 (9.2%); HR 0.52 (95% CI 0.37-0.74); p < 0.001
ISTH major bleeding (150MG twice daily dabigatran)
43 (5.6%) vs. 64 (8.4%); HR 0.64 (95% CI 0.43-0.94); p = 0.02
Total bleeding (110MG twice daily dabigatran)
266 (27.1%) vs. 421 (42.9%); HR 0.54 (95% CI 0.46-0.63); p < 0.001
Total bleeding (150MG twice daily dabigatran)
254 (33.3%) vs. 316 (41.4%); HR 0.72 (95% CI 0.61-0.84); p < 0.001
TIMI major bleeding (110MG twice daily dabigatran)
14 (1.4%) vs. 37 (3.8%); HR 0.37 (95% CI 0.20-0.68); p = 0.002
TIMI major bleeding (150MG twice daily dabigatran)
16 (2.1%) vs. 30 (3.9%); HR 0.51 (95% CI 0.28-0.93); p = 0.03
Thromboembolic events, death, or unplanned revascularization (110MG twice daily dabigatran)
149 (15.2%) vs. 131 (13.4%); HR 1.13 (95% CI 0.90-1.43); p = 0.30
Thromboembolic events, death, or unplanned revascularization (150MG twice daily dabigatran)
90 (11.8%) vs. 98 (12.8%); HR 0.89 (95% CI 0.67-1.19); p = 0.44
Thromboembolic events, death, or unplanned revascularization (pooled dual therapy)
237 (13.7%) vs. 131 (13.4%); HR 1.04 (95% CI 0.84-1.29); p = 0.74 / p = 0.005 for noninferiority
Thromboembolic events or death (110MG twice daily dabigatran)
108 (11.0%) vs. 83 (8.5%); HR 1.30 (95% CI 0.98-1.73); p = 0.07
Thromboembolic events or death (150MG twice daily dabigatran)
60 (7.9%) vs. 60 (7.9%); HR 0.97 (95% CI 0.68-1.39); p = 0.88
Thromboembolic events or death (pooled dual therapy)
168 (9.6%) vs. 83 (8.5%); HR 1.17 (95% CI 0.90-1.53); p = 0.25 / p = 0.11 for noninferiority
Definite stent thrombosis (110MG twice daily dabigatran)
15 (1.5%) vs. 13 (1.3%); HR 1.30 (95% CI 0.63-2.67); p = 0.15
Definite stent thrombosis (150MG twice daily dabigatran)
7 (0.9%) vs. 7 (0.9%); HR 0.99 (95% CI 0.35-2.81); p = 0.98

Adverse Events

Serious adverse event (110MG twice daily dabigatran)
42.7% vs. 41.8%
Serious adverse event (150MG twice daily dabigatran)
39.6% vs. 41.8%
Fatal adverse event (110MG twice daily dabigatran)
38 (3.9%) vs. 41 (4.3%)
Fatal adverse event (150MG twice daily dabigatran)
24 (3.2%) vs. 41 (4.3%)

Criticisms

  • Open-label design allows for possible bias in outcomes assessment. The degree of bias is mitigated in this study by outcomes adjudication performed by an independent committee blinded to treatment allocation.
  • The initial goal sample size of 8520 patients (powered to assess for thromboembolic events) was not reached due to feasibility. As a result, the trial is underpowered to robustly assess for thrombotic events.
  • Only 12% of study patients received ticagrelor, limiting generalizability of these findings to use of this drug.

Funding

  • Study sponsor Boehringer Ingelheim provided dabigatran and warfarin, served as the data coordinating center, performed site monitoring, and performed the statistical analysis
  • Authors with multiple ties to industry

Further Reading

  1. Andrade JG et al. Risk of bleeding on triple antithrombotic therapy after percutaneous coronary intervention/stenting: a systematic review and meta-analysis. Can J Cardiol 2013. 29:204-12.