ANTIPLATELET THERAPY IN CAD
















  • Only applies to patients who have completed a year of DAPT without a major ischemic or bleeding event
  • Reference [4]
DAPT score
The benefits of extended DAPT in patients with a score ≥ 2 may outweigh the risks
Risk Factor Score
Age ≥ 75 years -2
Age 65 - <75 years -1
Age < 65 0
Cigarette smoking 1
Diabetes 1
MI at presentation 1
Prior PCI or prior MI 1
Paclitaxel-eluting stent 1
Stent diameter < 3 mm 1
CHF or LVEF < 30% 2
Vein graft stent 2










  • C = Clopidogrel | P = Prasugrel | T = Ticagrelor
  • P2Y12 = P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor)
  • CoCr-EES - cobalt-chromium everolimus-eluting stent
DAPT STUDIES
C = Clopidogrel | P = Prasugrel | T = Ticagrelor
1 - 3 MONTH(S) VS 12 MONTHS OF DAPT
Study Patient population DAPT comparisons Outcomes
STOPDAPT-2
[PubMed]
JAMA (2019)
PCI with CoCr-EES stent for stable CAD or ACS
(N=3045)
  • Group 1: ASA + C or P for 1 month then C only
  • Group 2: ASA + C for 12 months
  • Death/CVD event/Bleed: Group 1 - 2.36% | Group 2 - 3.7% (p=0.04)
  • Stent thrombosis: Group 1 - 0.13% | Group 2 - 0.07% (p=0.57)
  • Major bleed: Group 1 - 0.20% | Group 2 - 1.07% (p=0.01)
  • Overall mortality: Group 1 - 1.42% | Group 2 - 1.21% (p=0.61)
OPTIMIZE
[PubMed]
JAMA (2013)
Low-risk PCI patients
(N=3211)
  • Group 1: ASA + C for 3 months then ASA only
  • Group 2: ASA + C for 12 months
  • Death/CVD event/Bleed: Group 1 - 6% | Group 2 - 5.8% (p=0.84)
  • Stent thrombosis: Group 1 - 0.8% | Group 2 - 0.8% (p=0.86)
  • Major bleed: Group 1 - 0.6% | Group 2 - 0.9% (p=0.41)
  • Overall mortality: Group 1 - 2.8% | Group 2 - 2.9% (p=0.82)
TWILIGHT
[PubMed]
NEJM (2019)
High-risk PCI patients who had completed 3 months of ASA + T without issue
(N=9006)
  • Group 1: T + Placebo for 12 months
  • Group 2: T + ASA for 12 months
  • Death/CVD event: Group 1 - 3.9% | Group 2 - 3.9% (p>0.05)
  • Stent thrombosis: Group 1 - 0.4% | Group 2 - 0.6% (p>0.05)
  • Major bleed: Group 1 - 4% | Group 2 - 7.1% (p<0.001)
  • Overall mortality: Group 1 - 1.0% | Group 2 - 1.3% (p>0.05)
SMART-CHOICE
[PubMed]
JAMA (2019)
Undergoing PCI for CAD
(N=2993)
  • Group 1: DAPT for 3 months then P2Y12 only
  • Group 2: DAPT for 12 months
  • Death/CVD event: Group 1 - 2.9% | Group 2 - 2.5% (p>0.05)
  • Stent thrombosis: Group 1 - 0.2% | Group 2 - 0.1% (p=0.65)
  • Major bleed: Group 1 - 0.8% | Group 2 - 1.0% (p=0.72)
  • Overall mortality: Group 1 - 1.4% | Group 2 - 1.2% (p=0.61)
6 MONTHS VS 12 MONTHS OF DAPT
Study Patient population DAPT comparisons Outcomes
SMART-DATE
[PubMed]
Lancet (2018)
ACS undergoing PCI
(N=2712)
  • Group 1: ASA + C,P, or T for 6 months
  • Group 2: ASA + C,P, or T for ≥ 12 months
  • Death/CVD event: Group 1 - 4.7% | Group 2 - 4.2% (p=0.51)
  • Stent thrombosis: Group 1 - 1.1% | Group 2 - 0.7% (p=0.32)
  • Major bleed: Group 1 - 0.5% | Group 2 - 0.8% (p=0.33)
  • Overall mortality: Group 1 - 2.6% | Group 2 - 2.9% (p=0.90)
DAPT-STEMI
[PubMed]
BMJ (2018)
STEMI patients who completed 6 months of DAPT without issue
(N=870)
  • Group 1: ASA only
  • Group 2: ASA + C,P, or T for 6 months
  • Death/CVD event/Bleed: Group 1 - 4.8% | Group 2 - 6.6% (p=0.26)
  • Stent thrombosis: Group 1 - 0.7% | Group 2 - 0.9% (p=0.72)
  • Major bleed: Group 1 - 0.2% | Group 2 - 0.5% (p=0.58)
  • Overall mortality: Group 1 - 0.7% | Group 2 - 1.4% (p=0.33)
≥ 12 MONTH OF DAPT
Study Patient population DAPT comparisons Outcomes
DAPT
[PubMed]
NEJM (2014)
Completed 12 months of DAPT without issue
(N=9961)
  • Group 1: ASA + C or P for 18 months
  • Group 2: ASA + Placebo
  • Stent thrombosis: Group 1 - 0.4% | Group 2 - 1.4% (p<0.001)
  • CVD events: Group 1 - 4.3% | Group 2 - 5.9% (p<0.001)
  • Bleeding: Group 1 - 2.5% | Group 2 - 1.6% (p=0.001)
  • Overall mortality: Group 1 - 2% | Group 2 - 1.5% (p=0.05)
ISAR-REACT
[PubMed]
NEJM (2019)
ACS patients with planned intervention
(N=4018)
  • Group 1: T + ASA for 12 months
  • Group 2: P + ASA for 12 months
  • CVD events: Group 1 - 9.3% | Group 2 - 6.9% (p=0.006)
  • Stent thrombosis: Group 1 - 1.1% | Group 2 - 0.6%
  • Bleeding: Group 1 - 5.4% | Group 2 - 4.8% (p=0.46)
  • Overall mortality: Group 1 - 4.5% | Group 2 - 3.7% (p>0.05)






WOEST study - VKA + Plavix + ASA vs VKA + Plavix in Patients on Anticoagulants Undergoing PCI, Lancet (2013) [PubMed abstract]
  • The WOEST study enrolled 573 patients with an indication for oral anticoagulation who were to undergo PCI
Main inclusion criteria
  • Indication for long-term anticoagulant therapy (until at least 1 year after the study)
  • Severe coronary lesion with indication for PCI
Main exclusion criteria
  • History of intracranial bleeding
  • Major bleeding in past 12 months
Baseline characteristics
  • Average age 70 years
  • Indication for anticoagulation: Atrial fibrillation - 69% | Mechanical heart valve - 11% | Other (apical aneurysm, PE, PAD, ejection fraction < 30%) - 20%
  • CHADS₂ score ≥ 2: 88% of patients
Randomized treatment groups
  • Group 1 (279 patients): Anticoagulation + clopidogrel (loading dose then 75 mg daily) after stent placement
  • Group 2 (284 patients): Anticoagulation + clopidogrel (loading dose then 75 mg daily) + aspirin (loading dose then 80 - 100 mg daily) after stent placement
  • For patients receiving bare metal stents (32% of patients), clopidogrel was continued for at least one month and up to one year. For patients who received drug-eluting stents (65% of patients), clopidogrel was to be administered for at least one year.
  • The authors do not state which anticoagulants were given in the study. The study was performed in Europe where several vitamin K antagonists are available. Patients were treated to the recommended INR for their indication.
  • Study treatment was open-label
Primary outcome: Any bleeding episode within one year of PCI
Results

Duration: 1 year
Outcome Group 1 Group 2 Comparisons
Primary outcome 19.4% 44.4% HR 0.36 [0.26 - 0.50] p<0.0001
Blood transfusion performed 3.9% 9.5% OR 0.39 [0.17 - 0.84], p=0.011
Composite of death, heart attack, stroke, target-vessel revascularization, and stent thrombosis 11.1% 17.6% HR 0.60 [0.38 - 0.94], p=0.025
All-cause mortality 2.5% 6.3% HR 0.39 [0.16 - 0.93], p=0.027

Findings: Use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events
RE-DUAL PCI - Triple Therapy vs Dabigatran + P2Y12 inhibitor in Patients with A fib and Recent PCI, NEJM (2017) [PubMed abstract]
  • The RE-DUAL study enrolled 2725 patients with atrial fibrillation who had undergone PCI
Main inclusion criteria
  • Nonvalvular atrial fibrillation
  • Successful PCI with a BMS or DES within the previous 120 hours
Main exclusion criteria
  • Bioprosthetic or mechanical heart valve
  • CrCl < 30 ml/min
  • Bleeding disorder
  • Major bleeding episode within a month
Baseline characteristics
  • Average age 71 years
  • PCI indication: ACS - 51% | Stable CAD - 43%
  • Average CHA₂DS₂-VASc score: ∼ 3.6
  • Stent type: DES - 83% | BMS - 15%
  • Average CrCl ∼ 78 ml/min
  • Previous stroke ∼ 8.6%
  • Previous myocardial infarction ∼ 26%
Randomized treatment groups
  • Group 1 (981 patients): Dabigatran 110 mg twice daily + P2Y12 inhibitor (clopidogrel or ticagrelor)
  • Group 2 (763 patients): Dabigatran 150 mg twice daily + P2Y12 inhibitor (clopidogrel or ticagrelor)
  • Group 3 (981 patients): Warfarin + Aspirin (≤ 100 mg/day) + P2Y12 inhibitor (clopidogrel or ticagrelor)
  • Aspirin was discontinued after 1 month in patients who received a BMS and after 3 months in patients with DES
  • All patients were to receive the P2Y12 inhibitor for at least 12 months
  • 88% of patients received clopidogrel
  • The trial continued until all the patients had a minimum of 6 months of follow-up and the target number of end-point events was anticipated to be reached
  • Outside of the United States, elderly patients were not randomized to Group 2 because the higher dabigatran dose was not approved in that age group. For the primary outcome, Group 2 was compared to a subgroup of Group 3 patients which did not include elderly patients outside the United States.
Primary outcome: First major or clinically relevant nonmajor bleeding event, as defined by the International Society on Thrombosis and Hemostasis (ISTH), in a time-to-event analysis
Results

Duration: Average of 14 months
Outcome Group 1 or 2 Group 3 Comparisons
Primary outcome (Group 1 vs Group 3) 15.4% 26.9% p<0.001
Primary outcome (Group 2 vs Group 3) 20.2% 25.7% p=0.002
Composite of thromboembolic events, death, or unplanned revascularization (Group 1 vs Group 3) 15.2% 13.4% p=0.30
Composite of thromboembolic events, death, or unplanned revascularization (Group 2 vs Group 3) 11.8% 12.8% p=0.44
Overall mortality (Group 1 vs Group 3) 5.6% 4.9% p=0.56
Overall mortality (Group 2 vs Group 3) 3.9% 4.6% p=0.44
  • The average duration of treatment with trial anticoagulant was 12.3 months
  • In Group 3, patients had a therapeutic INR (2 - 3) 64% of the time

Findings: Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.
AUGUSTUS study - Triple therapy vs VKA or Apixaban + P2Y12 Inhibitor in Patients with A fib and Recent PCI, NEJM (2019) [PubMed abstract]
  • Design: Randomized, 2-factorial, placebo-controlled trial (N=4614 | length = 6 months) in patients with A fib who had ACS or recent PCI
  • Treatment groups:
    • P2Y12 + Apixaban + ASA
    • P2Y12 + Apixaban + Placebo
    • P2Y12 + VKA + ASA
    • P2Y12 + VKA + Placebo
  • Primary outcome: Major or clinically relevant nonmajor bleeding
  • Results:
    • There were no significant interactions between the two randomization factors on the primary or secondary outcomes
    • Primary outcome: Apixaban - 10.5%, VKA - 14.7% (p<0.001)
    • Primary outcome: ASA - 16.1%, Placebo - 9% (p<0.001)
    • Death or ischemic event: Apixaban - 6.7%, VKA - 7.1% (HR 0.93 [0.75–1.16])
    • Death or ischemic event: ASA - 6.5%, Placebo - 7.3% (HR 0.89 [0.71–1.11])
  • Findings: In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both
PIONEER study - VKA + DAPT vs Rivaroxaban 15 mg once daily + P2Y12 inhibitor vs Rivaroxaban 2.5 mg twice daily + DAPT, NEJM (2016) [PubMed abstract]
  • Design: Randomized, multi-factorial, controlled trial (N=2124 | length = 12 months) in patients with A fib who had PCI with stents
  • Treatment: Rivaroxaban 15 mg once daily + P2Y12 inhibitor for 12 months vs Rivaroxaban 2.5 mg twice daily + DAPT for 1, 6, or 12 months vs VKA + DAPT for 1, 6, or 12 months
  • Primary outcome: Clinically significant bleeding (TIMI major or minor bleeding)
  • Results:
    • Primary outcome: Rivaroxaban 15 mg - 16.8%, Rivaroxaban 2.5 mg - 18%, VKA - 26.7% (1 or 2 vs 3 p<0.001)
    • CVD events: Rivaroxaban 15 mg - 6.5%, Rivaroxaban 2.5 mg - 5.6%, VKA - 6% (all comparisons nonsignificant)
  • Findings: In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a VKA plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy.
ENTRUST study - VKA + P2Y12 + ASA vs Edoxaban + P2Y12 in Patients with A fib and Recent PCI, Lancet (2019) [PubMed abstract]
  • Design: Randomized, open-label, controlled trial (N=1506 | length = 12 months) in patients with A fib who had recent PCI for stable CAD or ACS
  • Treatment: Edoxaban 60 mg once daily + P2Y12 inhibitor vs VKA + P2Y12 inhibitor + ASA 100 mg once daily
  • Primary outcomes:
    • Safety: Composite of major or clinically relevant non-major bleeding
    • Efficacy: Composite of cardiovascular death, stroke, systemic embolic events, myocardial infarction, and definite stent thrombosis
  • Results:
    • Primary outcome (safety): Edoxaban - 17%, VKA - 20% (p=0.1154)
    • Primary outcome (efficacy): Edoxaban - 7%, VKA - 6% (HR 1.06, 95%CI [0.71 - 1.69])
  • Findings: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events
ISAR-TRIPLE trial - VKA + Plavix + ASA for 6 weeks vs 6 months in Patients on Anticoagulants with Recent PCI, J Am Coll Cardiol (2015) [PubMed abstract]
  • The ISAR-TRIPLE study enrolled 614 patients on oral anticoagulation who received a drug-eluting stent (DES)
Main inclusion criteria
  • Receiving oral anticoagulation for at least 12 months
  • Receiving DES for stable angina or acute coronary syndrome
Main exclusion criteria
  • DES in left main
  • History of intracranial bleeding
  • Bleeding disorder
Baseline characteristics
  • Average age 73 years
  • Indication for anticoagulation: Atrial fibrillation - 83% | Mechanical heart valve ∼ 7% | Venous thromboembolism ∼ 5%
  • Presenting diagnosis: STEMI - 1% | NSTEMI - 14% | Unstable angina - 16.5% | Stable angina - 67%
  • CHADS₂ score ≥ 2: ∼ 81% of patients
Randomized treatment groups
  • Group 1 (307 patients): Anticoagulation + aspirin 75 - 200 mg once daily + clopidogrel (loading dose then 75 mg daily) for 6 weeks
  • Group 2 (307 patients): Anticoagulation + aspirin 75 - 200 mg once daily + clopidogrel (loading dose then 75 mg daily) for 6 months
  • Aspirin and anticoagulant were continued after clopidogrel was stopped
  • Oral anticoagulation was with warfarin or phenprocoumon. Patients were treated to the lowest recommended INR for their indication.
  • Stents used: everolimus-eluting stent - 38%, biodegradable biolimus-eluting stent - 16%, biodegradable sirolimus-eluting stent - 16%, zotarolimus-eluting stent - 11%, probucol sirolimus-eluting stent - 11%
  • Study treatment was open-label
Primary outcome: Composite of death, myocardial infarction, definite stent thrombosis, stroke, or TIMI major bleeding at 9 months after randomization
Results

Duration: 9 months
Outcome 6 weeks 6 months Comparisons
Primary outcome 9.8% 8.8% HR 1.14 [0.68 - 1.91] p=0.63
Composite of cardiac death, heart attack, stent thrombosis, and stroke 4% 4.3% HR 0.93 [0.43 - 2.05], p=0.87
TIMI major bleeding 5.3% 4.0% HR 1.35 [0.64 - 2.84], p=0.44
All-cause mortality 4% 5.2% HR 0.75 [0.35 - 1.59], p=0.45
  • At 9 months, 96% of patients were still taking aspirin and 88.5% of patients were still taking anticoagulants
  • In a prespecified landmark analysis, outcomes were compared from Week 6 to 9 months. No significant difference was seen for the primary outcome, TIMI major bleeding, or other cardiovascular outcomes.

Findings: Six weeks of triple therapy was not superior to 6 months with respect to net clinical outcomes. These results suggest that physicians should weigh the trade-off between ischemic and bleeding risk when choosing the shorter or longer duration of triple therapy.



  • Reference [1]
Factors associated with increased bleeding risk
History of prior bleeding
Oral anticoagulant therapy
(See triple therapy above)
Female sex
Advanced age (> 65 years)
Low body weight
Chronic kidney disease
Diabetes
Anemia
Chronic steroid or NSAID therapy




  • Reference [1]
Factors associated with increased ischemic risk
Advanced age
Acute coronary syndrome presentation
Multiple prior myocardial infarctions
Extensive coronary artery disease
Chronic kidney disease
Diabetes
Factors associated with increased risk of stent thrombosis
Acute coronary syndrome presentation
Diabetes
Left ventricular ejection fraction < 40%
First-generation DES
Stent undersizing
Stent underdeployment
Small stent diameter
Greater stent length
Bifurcation stents
In-stent restenosis



ACCOAST study - Prasugrel before or at the time of PCI, NEJM (2013) [PubMed abstract]
  • The ACCOAST study enrolled 4033 patients with NSTEMI
Main inclusion criteria
  • NSTEMI
  • Scheduled to undergo coronary angiography and PCI, if indicated, within 2 to 48 hours
Main exclusion criteria
  • STEMI
  • Prior history of stroke or TIA
  • Fibrinolytic therapy
Baseline characteristics
  • Average age 64 years
Randomized treatment groups
  • Group 1 (2037 patients) - Prasugrel 30 mg before coronary angiography, then prasugrel 30 mg at the time of PCI if angiography confirmed the need for PCI
  • Group 2 (1996 patients) - Placebo before coronary angiography, then prasugrel 60 mg at the time of PCI if angiography confirmed the need for PCI
  • Almost all patients (98%) received aspirin
  • Treatment of patients who received medical therapy alone or CABG was left to the discretion of the treating physician
Primary outcome: Composite of death from cardiovascular causes, heart attack, stroke, urgent revascularization, or GP IIb/IIIa rescue therapy through day 7
Results

Duration: 7 days
Outcome Before PCI At time of PCI Comparisons
Primary outcome 10% 9.8% HR 1.02, 95%CI [0.84 - 1.25], p=0.81
Major bleeding 2.6% 1.4% HR 1.90, 95%CI [1.19 - 3.02], p=0.006
  • PCI was performed in 69% of patients, medical therapy was used in 25% of patients, and CABG was performed in 6.2% of patients
  • Among the subgroup of patients who underwent PCI, there was no significant difference between the two groups for the primary outcome (HR 1.01, 95%CI [0.82 - 1.24], p=0.93). Group 2 had a higher rate of major bleeding (HR 2.69, 95%CI [1.13 - 6.40], p=0.02)

Findings: Among patients with NSTE acute coronary syndromes who were scheduled to undergo catheterization, pretreatment with prasugrel did not reduce the rate of major ischemic events up to 30 days but increased the rate of major bleeding complications