ANTIPLATELET THERAPY IN CAD















AHA 2016 periprocedural recommendations for dual antiplatelet therapy
Elective, noncardiac surgery
  • Drug-eluting stents (DES)
    • < 3 months since DES implantation
      • Delay surgery
    • 3 - 6 months since DES implantation
      • Proceeding with surgery may be considered
      • If having surgery, discontinue DAPT before surgery (aspirin should be continued if possible)
      • After surgery, restart DAPT as soon as possible if still indicated
      • There is no convincing evidence that "bridging therapy" with parenteral antiplatelet/anticoagulant agents is beneficial
    • ≥ 6 months since DES implantation
      • Proceed with surgery
      • Discontinue DAPT before surgery (aspirin should be continued if possible)
      • After surgery, restart DAPT as soon as possible if still indicated
      • There is no convincing evidence that "bridging therapy" with parenteral antiplatelet/anticoagulant agents is beneficial [1]

  • Bare metal stents (BMS)
    • < 30 days since BMS implantation
      • Delay surgery
    • ≥ 30 days since BMS implantation
      • Proceed with surgery
      • If having surgery, discontinue DAPT before surgery (aspirin should be continued if possible)
      • After surgery, restart DAPT as soon as possible if still indicated
      • There is no convincing evidence that "bridging therapy" with parenteral antiplatelet/anticoagulant agents is beneficial [1]
Coronary artery bypass graft surgery (CABG)
  • Urgent on-pump CABG
    • Aspirin - do not stop aspirin before surgery
    • P2Y12 inhibitor:
      • Clopidogrel - stop clopidogrel 24 hours before surgery if possible
      • Ticagrelor - stop ticagrelor 24 hours before surgery if possible [7]

  • Elective CABG
    • Aspirin
      • Do not stop aspirin before surgery
    • P2Y12 inhibitor:
      • Clopidogrel - stop clopidogrel 5 days before surgery
      • Ticagrelor - stop ticagrelor 5 days before surgery
      • Prasugrel - stop prasugrel 7 days before surgery [8]




PCI or VTE + A fib (triple therapy)

Overview
  • In some cases, indications may arise in the same patient for dual antiplatelet therapy (P2Y12 inhibitors + aspirin) and anticoagulation (dabigatran, Factor Xa inhibitors, etc.)
  • A common scenario would be PCI with heart stent placement in someone with atrial fibrillation. The stent placement is an indication for dual antiplatelet therapy, and the atrial fibrillation is an indication for anticoagulation. In this example, an anticoagulant, aspirin, and a P2Y12 inhibitor would all be indicated based on the separate diagnoses. Taking all three medications together greatly increases a person's risk of bleeding.
  • A handful of studies have looked at bleeding and CV outcomes with different combinations or anticoagulant and antiplatelet therapy. Those studies are detailed below (see triple therapy studies below.
  • Recommendations on triple therapy from the AHA and ACCP are presented below (see triple therapy recommendations below)
  • Guidelines on VTE do not make recommendations for triple therapy so the atrial fibrillation guidelines may be helpful in these patients

AHA 2019 recommendations in patients with A fib and ACS
Acute treatment
  • Urgent direct-current cardioversion of new-onset AF in the setting of ACS is recommended for patients with hemodynamic ischemia, or inadequate rate control
  • Intravenous beta blockers are recommended to slow a rapid ventricular response to AF in patients with ACS who do not display HF, hemodynamic instability, or bronchospasm
  • Administration of amiodarone or digoxin may be considered to slow a rapid ventricular response in patients with ACS and AF associated with severe LV dysfunction and heart failure or hemodynamic instability
  • Administration of nondihydropyridine calcium antagonists may be considered to slow a rapid ventricular response in patients with ACS and A fib only in the absence of significant HF or hemodynamic instability
Drug regimens
  • For patients with ACS and A fib at increased risk of systemic thromboembolism (based on CHA₂DS₂-VASc risk score ≥ 2), anticoagulation is recommended unless the bleeding risk exceeds the expected benefit
  • If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed for patients with A fib at increased risk of stroke (based on CHA₂DS₂-VASc risk score of ≥ 2) who have undergone PCI with stenting for ACS, it is reasonable to choose clopidogrel in preference to prasugrel
  • In patients with A fib at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) who have undergone PCI with stenting for ACS, double therapy with a P2Y12 inhibitor (clopidogrel or ticagrelor) and dose-adjusted vitamin K antagonist is reasonable to reduce the risk of bleeding as compared with triple therapy (see WOEST study below)
  • In patients with A fib at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) who have undergone PCI with stenting for ACS, double therapy with P2Y12 inhibitors (clopidogrel) and low-dose rivaroxaban 15 mg daily is reasonable to reduce the risk of bleeding as compared with triple therapy (see PIONEER study below)
  • In patients with AF at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) who have undergone PCI with stenting for ACS, double therapy with a P2Y12 inhibitor (clopidogrel) and dabigatran 150 mg twice daily is reasonable to reduce the risk of bleeding as compared with triple therapy (see RE-DUAL PCI study below)
Triple therapy duration
  • If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed for patients with A fib who are at increased risk of stroke (based on CHA₂DS₂-VASc risk score ≥ 2) and who have undergone PCI with stenting (drug eluting or bare metal) for ACS, a transition to double therapy (oral anticoagulant and P2Y12 inhibitor) at 4 to 6 weeks may be considered [9]

ACCP 2012 triple therapy recommendations
  • Bare metal stent placed - P2Y12 inhibitor + aspirin + warfarin for 1 month, then 1 antiplatelet drug + warfarin up to 12 months post-stent, then warfarin alone
  • Drug-eluting stent placed - P2Y12 Inhibitor + aspirin + warfarin for 3 - 6 months, then 1 antiplatelet drug + warfarin up to 12 months post-stent, then warfarin alone
    • Patients undergoing Percutaneous Coronary Intervention (PCI) who have A fib with CHADS₂ score of 0 - 1
      • P2Y12 Inhibitor + aspirin for 12 months post-stent, then anticoagulation per recommendations [6]

Triple therapy studies

WOEST study - VKA + Plavix + ASA vs VKA + Plavix, 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: one 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

ISAR-TRIPLE trial - VKA + Plavix + ASA for 6 weeks vs 6 months 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 + clopidogrel (loading dose then 75 mg daily) + aspirin 75 - 200 mg once daily for 6 weeks
  • Group 2 (307 patients): Anticoagulation + clopidogrel (loading dose then 75 mg daily) + aspirin 75 - 200 mg once daily for 6 months
  • 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
  • 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.

RE-DUAL PCI - Dabigatran + P2Y12 inhibitor vs Triple Therapy in Atrial Fibrillation, 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% HR 0.52 [0.42 – 0.63], p<0.001
Primary outcome (Group 2 vs Group 3) 20.2% 25.7% HR 0.72 [0.58 – 0.88], p=0.002
Composite of thromboembolic events, death, or unplanned revascularization (Group 1 vs Group 3) 15.2% 13.4% HR 1.13 [0.90 – 1.43], p=0.30
Composite of thromboembolic events, death, or unplanned revascularization (Group 2 vs Group 3) 11.8% 12.8% HR 0.89 [0.67 – 1.19], p=0.44
Overall mortality (Group 1 vs Group 3) 5.6% 4.9% HR 1.12 [0.76 – 1.65], p=0.56
Overall mortality (Group 2 vs Group 3) 3.9% 4.6% HR 0.83 [0.51 – 1.34], 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 - P2Y12 inhibitor + Apixaban or VKA + Aspirin or Placebo [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: P2Y12 inhibitor (clopidogrel in 93%) + Apixaban 2.5 - 5 mg twice daily or VKA (INR 2 - 3) + ASA 81 mg daily or 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 - Rivaroxaban 15 mg once daily + P2Y12 inhibitor vs Rivaroxaban 2.5 mg twice daily + DAPT vs VKA + DAPT [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)
  • 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.





  • 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