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 MONTH VS LONGER
Study Patient population DAPT comparisons Outcomes
MASTER-DAPT
NEJM (2021)
[PubMed]
High bleeding risk patients treated with DES
(N=4434)
  • Group 1: DAPT for 1 month
  • Group 2: DAPT for longer (median 193 days)
  • Death/MI/Stroke/Bleed: Group 1 - 7.5% | Group 2 - 7.7% (p>0.05)
  • Stent thrombosis: Group 1 - 0.5% | Group 2 - 0.3% (p>0.05)
  • Major bleed: Group 1 - 6.4% | Group 2 - 9.2% (p<0.05)
  • Overall mortality: Group 1 - 3.3% | Group 2 - 3.6% (p>0.05)
1 - 3 MONTH(S) VS 12 MONTHS OF DAPT
Study Patient population DAPT comparisons Outcomes
TICO
JAMA (2020)
[PubMed]
ACS patients treated with DES
(N=3056)
  • Group 1: T + ASA for 3 months then T only
  • Group 2: T + ASA for 12 months
  • Death/CVD event/Bleed: Group 1 - 3.9% | Group 2 - 5.9% (p=0.01)
  • Stent thrombosis: Group 1 - 0.4% | Group 2 - 0.3% (p=0.53)
  • Major bleed: Group 1 - 1.7% | Group 2 - 3% (p=0.02)
  • Overall mortality: Group 1 - 1.1% | Group 2 - 1.5% (p=0.27)
STOPDAPT-2
JAMA (2019)
[PubMed]
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
JAMA (2013)
[PubMed]
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
NEJM (2019)
[PubMed]
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
JAMA (2019)
[PubMed]
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
Lancet (2018)
[PubMed]
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
BMJ (2018)
[PubMed]
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
NEJM (2014)
[PubMed]
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)




PLATO Trial - Clopidogrel vs Ticagrelor in Patients with ACS, NEJM (2009) [PubMed abstract]
  • The PLATO trial enrolled 18,624 patients with an acute coronary syndrome
Main inclusion criteria
  • Acute coronary syndrome starting within past 24 hours
Main exclusion criteria
  • Fibrinolytic therapy within past 24 hours
  • Need for anticoagulation
  • Increased risk of bradycardia
  • Taking CYP3A4 strong inducer or inhibitor
Baseline characteristics
  • Median age 62 years
  • Qualifying event: STEMI - 38% | NSTEMI - 42% | Unstable angina - 17%
  • Index procedure: PCI - 64% | CABG - 10%
  • Stent type: BMS only - 42% | DES - 18%
Randomized treatment groups
  • Group 1 (9333 patients) - Ticagrelor 180 mg loading dose followed by 90 mg twice a day
  • Group 2 (9291 patients) - Clopidogrel 300 mg loading dose followed by 75 mg once daily
  • All patients also received aspirin 75 - 100 mg once daily throughout the study
Primary outcome: Composite of death from cardiovascular causes, heart attack, or stroke
Results

Duration: 12 months
Outcome Ticagrelor Clopidogrel Comparisons
Primary outcome 9.8% 11.7% HR 0.84, 95%CI [0.77 - 0.92], p<0.001
Death from cardiovascular causes 4.0% 5.1% HR 0.79, 95%CI [0.69 - 0.91], p=0.001
Myocardial infarction 5.8% 6.9% HR 0.84, 95%CI [0.75 - 0.95], p=0.005
Stroke 1.5% 1.3% HR 1.17, 95%CI [0.91 - 1.52], p=0.22
Overall mortality 4.5% 5.9% HR 0.78, 95%CI [0.69 - 0.89], p<0.001
Major bleeding 11.6% 11.2% HR 1.04, 95%CI [0.95 - 1.13], p=0.43
Bleeding requiring transfusion 8.9% 8.9% HR 1.00, 95%CI [0.91 - 1.11], p=0.96
Dyspnea 13.8% 7.8% HR 1.84, 95%CI [1.68 - 2.02], p<0.001
  • The median duration of study drug treatment was 277 days

Findings: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.



TRITON TIMI 38 Trial - Clopidogrel vs Prasugrel in Patients with ACS, NEJM (2007) [PubMed abstract]
  • The TRITON TIMI 38 trial enrolled 13,608 patients with an acute coronary syndrome who were scheduled for PCI
Main inclusion criteria
  • Acute coronary syndrome
  • Scheduled for PCI
Main exclusion criteria
  • Increased risk of bleeding
  • Anemia
  • Thrombocytopenia
  • History of pathologic intracranial findings
Baseline characteristics
  • Median age 61 years
  • Unstable angina or NSTEMI - 74% | STEMI - 26%
  • Index procedure: PCI - 99% | CABG - 1%
  • BMS only - 48%, DES - 47%
Randomized treatment groups
  • Group 1 (6813 patients) - Prasugrel 60 mg loading dose followed by 10 mg once daily
  • Group 2 (6795 patients) - Clopidogrel 300 mg loading dose followed by 75 mg once daily
  • All patients also received aspirin 75 - 162 mg once daily throughout the trial
  • Clopidogrel or prasugrel were given for 6 - 15 months
  • Loading dose was given anytime between randomization and 1 hour after PCI
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
Results

Duration: 15 months
Outcome Prasugrel Clopidogrel Comparisons
Primary outcome 9.9% 12.1% HR 0.81, 95%CI [0.73 - 0.90], p<0.001
Death from cardiovascular causes 2.1% 2.4% HR 0.89, 95%CI [0.70 - 1.12], p=0.31
Nonfatal MI 7.3% 9.5% HR 0.76, 95%CI [0.67 - 0.85], p<0.001
Nonfatal stroke 1.0% 1.0% HR 1.02, 95%CI [0.71 - 1.45], p=0.93
Overall mortality 3.0% 3.2% HR 0.95, 95%CI [0.78 - 1.16], p=0.64
Non-CABG TIMI major bleeding 2.4% 1.8% HR 1.32, 95%CI [1.03 - 1.68], p=0.03
Bleeding requiring transfusion 4.0% 3.0% HR 1.34, 95%CI [1.11 - 1.63], p<0.001
  • The median duration of study drug treatment was 14.5 months
  • In a post-hoc analysis, three subgroups of patients were identified that did not have a net clinical benefit with prasugrel - patients with a history of stroke or TIA, patients ≥ 75 years old, and patients weighing < 60 kg

Findings: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.








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.




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 [1,10]
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
Thrombocytopenia (< 100,000/mm3)
Known coagulation disorder
Chronic steroid or NSAID therapy
High bleeding risk malignancy
(gastrointestinal, genitourethral/renal and pulmonary)
Stroke at any time or TIA within 6 months




  • 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