Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation

Kevin Lao, Mercer University College of Pharmacy

The 2016 European Society of Cardiology guidelines recommend a short period of triple therapy (oral anticoagulant [OAC], aspirin, clopidogrel) for patients with atrial fibrillation (AFib) undergoing percutaneous coronary intervention (PCI) with a stent placement. [1]

Contrary to the European guidelines, the American Heart Association guidelines state that it may be reasonable to use clopidogrel with OAC without aspirin in AFib patients with CHA2DS2-VASc score ≥ 2 following PCI based on evidence that showed higher rates of bleeding with triple therapy. [2] Additionally, one previous trial has shown that dual therapy (warfarin + clopidogrel [P2Y12 inhibitor]) was associated with lower incidence of bleeding without increased rates of stent thrombosis in PCI patients compared to triple therapy. [3]

With the availability of the new oral anticoagulant (NOAC), some evidence suggests that NOAC, instead of warfarin, with a P2Y12 inhibitor (i.e. clopidogrel) may be an effective thromboprophylaxis in PCI patients. Therefore, the RE-DUAL PCI trial aimed to compare the efficacy and safety of dual therapy composed of dabigatran and P2Y12 inhibitor among patients with AFib undergoing PCI. [4]

Dual Antithrombotic Therapy with Dabigatran after percutaneous coronary intervention in Atrial Fibrillation
Design Multicenter, randomized, parallel, stratified trial; N= 2,725
Objective To evaluate dual therapy compared with triple therapy among patients with atrial fibrillation who received percutaneous coronary intervention (PCI)
Study Groups Triple Therapy; n= 981

  • Warfarin
  • P2Y12 (clopidogrel or ticagrelor)
  • Aspirin

Dual Therapy with dabigatran 110 mg; n= 981

  • Dabigatran 110 mg
  • P2Y12 (clopidogrel or ticagrelor)

Dual Therapy with dabigatran 150 mg; n= 763

  • Dabigatran 150 mg
  • P2Y12 (clopidogrel or ticagrelor)
Methods Patients were randomized based on age group and location

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

Inclusion Criteria

  • ≥ 18 years of age
  • Nonvalvular atrial fibrillation who successfully undergone PCI with a bare-metal or drug-eluting stent within the previous 120 hours
  • Nonvalvular atrial fibrillation could be paroxysmal, persistent, or permanent
  • Patients who had been receiving treatment with an oral anticoagulant before PCI
  • Patients who had not received oral anticoagulation
  • Indication for PCI could be either an acute coronary syndrome or stable coronary-artery disease

Exclusion Criteria

  • Presence of bioprosthetic or mechanical heart valves
  • Severe renal insufficiency (creatinine clearance [CrCl], < 30 ml per minute)
  • Cardiogenic shock during current hospitalization
  • Use of fibrinolytics within 24 hrs of randomization that, in the investigator’s opinion, will put patient at high risk of bleeding
  • Stroke or major bleeding event within 1 month prior to screening visit
  • Other major coexisting conditions

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

Duration July 21, 2014 to October 31, 2016
Primary Outcome Measure The first major or clinically relevant non-major bleeding event during follow-up

  • Major bleed is when patient meets ≥ 1 of following criteria:
    • Symptomatic bleeding in a critical area or organ
    • Bleeding associated with a reduction in hemoglobin of ≥ 2 g/dl (1.24 mmol/l) or leading to transfusion of ≥ 2 U blood or packed cells
    • Fatal bleed
  • Clinically relevant nonmajor bleeding event
    • A clinically overt bleed that does not meet the criteria for a major bleed but results in ≥ 1 of the following clinical responses:
      • hospital admission
      • physician-guided medical or surgical treatment
      • physician-guided change, interruption (more than omitting 1 dose), or discontinuation of the study drug
Baseline Characteristics
Characteristic DT w/

Dabigatran 110 mg

(n= 981)

TT

(n= 981)

DT w/

Dabigatran

150 mg

(n= 763)

Corresponding TT

(n= 764)†

Age, years 71.5±8.9 71.7±8.9 68.6±7.7 68.8±7.7
Elderly age group, n (%) 225 (22.9) 225 (22.9) 8 (1.0) 8 (1.0)
Male sex,
n (%)
728 (74.2) 750 (76.5) 592 (77.6) 594 (77.7)
Diabetes mellitus 362/981 (36.9) 371/980 (37.9) 260/763 (34.1) 303/763 (39.7)
Previous stroke 74/981 (7.5) 100/980 (10.2)

52/763 (6.8)

77/763 (10.1)
CHA2DS2-VASc score 3.7±1.6 3.8±1.5 3.3±1.5 3.6±1.5
HAS-BLED score 2.7±0.7 2.8±0.8 2.6±0.7 2.7±0.8
Creatinine clearance

(mL/min)

76.3±28.9 75.4±29.1 83.7±31.0 81.3±29.6
Previous myocardial infarction

n (%)

237 (24.2) 268 (27.3) 194 (25.4) 211 (27.6)
Previous PCI n/total (%) 326/981 (33.2) 347/980 (35.4) 239/763 (31.3) 272/763 (35.6)
Previous CABG
n/total (%)
97/981 (9.9) 111/980 (11.3) 79/763 (10.4) 87/763 (11.4)
Type of Atrial Fibrillation, n/total (%):
Persistent 174/981 (17.7) 178/980 (18.2) 132/763 (17.3) 149/763 (19.5)
Permanent 320/981 (32.6) 318/980 (32.4) 250/763 (32.8) 238/763 (31.2)
Paroxysmal 487/981 (49.6) 484/980 (49.4) 380/763 (49.8) 376/763 (49.3)
Indication for PCI n (%):
Stable angina or positive stress test 433 (44.1) 429 (43.7) 320 (41.9) 339 (44.4)
Acute coronary syndrome 509 (51.9) 391 (51.2) 391 (51.2) 369 (48.3)
Staged procedure 156 (15.9) 168 (17.1) 138 (18.1) 134 (17.5)
Other 43 (4.4) 62 (6.3) 65 (8.5) 50 (6.5)
Type of stent, n/total (%):
Drug-eluting 804/979 (82.1) 826/976 (84.6) 621/762 (81.5) 638/759 (84.1)
Bare-metal 148/979 (15.1) 133/976 (13.6) 123/762 (16.1) 107/759 (14.1)
Drug-eluting and bare-metal 19/979 (1.9) 12/976 (1.2) 10/762 (1.3) 9/759 (1.2)
Other 8/979 (0.8) 5/976 (0.5) 8/762 (1.0) 5/759 (0.7)
DT= Dual Therapy
TT = Triple Therapy with warfarin
† The corresponding triple-therapy group included only patients who had been eligible to be assigned to the 150-mg dual-therapy group (i.e., did not include elderly patients outside the United States).
Results
End point DT w/

Dabigatran 110 mg

(n= 981)

TT

(n= 981)

Hazard Ratio

(95% CI)

p Value
n (%)
Primary Endpoint 151 (15.4) 264 (26.9) 0.52 (0.42–0.63) <0.001

(<0.001 for noninferiority)

ISTH major bleeding 49 (5.0) 90 (9.2) 0.52 (0.37–0.74) <0.001
Total bleeding 266 (27.1) 421 (42.9) 0.54 (0.46–0.63) <0.001
Intracranial hemorrhage 3 (0.3) 10 (1.0) 0.30 (0.08–1.07) 0.06
TIMI major bleeding 14 (1.4) 37 (3.8) 0.37 (0.20–0.68) 0.002
TIMI major or minor bleeding 29 (3.0) 69 (7.0) 0.41 (0.26–0.63) <0.001
End point DT w/

Dabigatran 150 mg

(n= 763)

TT

(n= 764)

Hazard Ratio

(95% CI)

p Value
n (%)
Primary Endpoint 154 (20.2) 196 (25.7) 0.72 (0.58–0.88) 0.002

(<0.001 for noninferiority)

ISTH major bleeding 43 (5.6) 64 (8.4) 0.64 (0.43–0.94) 0.02
Total bleeding 254 (33.3) 316 (41.4) 0.72 (0.61–0.84) <0.001
Intracranial hemorrhage 1 (0.1) 8 (1.0) 0.12 (0.02–0.98) 0.047
TIMI major bleeding 16 (2.1) 30 (3.9) 0.51 (0.28–0.93) 0.03
TIMI major or minor bleeding 27 (3.5) 48 (6.3) 0.53 (0.33–0.85 0.009
Adverse Events Common Adverse Events: Not disclosed
Serious Adverse Events: Cardiac failure (4.6%), atrial fibrillation (4.3%), angina pectoris (2.1%), angina unstable (2.0%), pneumonia (2.0%), vascular stent thrombosis (1.9%), acute myocardial infarction (1.8%), cardiac failure congestive (1.7%), chest pain (1.6%), dyspnea (1.4%), acute kidney injury (1.3%) myocardial infarction (1.2%), atrial flutter (1.2%), gastrointestinal hemorrhage (1.0%), syncope (1.0%), hypertensive crisis (0.8%), coronary artery stenosis (0.7%).
Percentage that Discontinued due to Adverse Events: ≥0.4% (treated set)
Study Author Conclusions Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower in dual therapy group compared to  triple therapy. Moreover, dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.

 

The noninferior efficacy of the dual therapy shown in this study combined with improved safety profile regarding the risk of bleeding provide further support of previous trials that this may be a viable option in AFib patients undergoing PCI.

 

References
[1] Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893-2962
[2] January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-76.
[3] Dewilde WJ, Oirbans T, Verheugt FW, 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.Lancet. 2013;381(9872):1107-15
[4] Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377(16):1513-1524.
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