Optimal Duration of Dual Antiplatelet Therapy Luis A Guzman, MD, FACC, FSCAI Associate Professor of Medicine Director, Cardiac and Vascular Cath Lab University of Florida College of Medicine - Jacksonville
Current Controversies on DAPT in PCI Which drug? When to start? Which dose? How long?
Is shorter DAPT better? Less bleeding Less cost Current DES are safer than I generation DES Many patients do fine with short DAPT duration
2011 ACCF/AHA/SCAI Guideline for PCI Postprocedural Antiplatelet Therapy I IIa IIb III After PCI, aspirin should be continued indefinitely. I IIa IIb III The duration of P2Y 12 inhibitor therapy after stent implantation should generally be as follows: a) In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y 12 inhibitor therapy should be given for at least 12 months (clopidogrel 75 mg daily); prasugrel 10 mg daily; and ticagrelor 90 mg twice daily. b) In patients receiving a DES for a non ACS indication, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. c) In patients receiving a BMS for a non-acs indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks).
DES and Prolonged DAPT What are we treating? The patient or the stent?
Death, MI, or Stroke (%) NSTE-ACS: Evidence for Clopidogrel Use 14 12 10 CURE Primary Results (N=12,562) Placebo + ASA 11.4% 9.3% 8 6 4 2 Clopidogrel + ASA 20% RRR P<0.001 0 0 3 6 9 12 Months of Follow Up NSTE-ACS = non-st segment elevation-acute coronary syndrome. RRR = relative risk ratio. Yusuf S, et al. N Engl J Med. 2001;345:494-502.
TRITON TIMI 38 (prasugrel vs clopidogrel) PLATO (ticagrelor vs clopidogrel)
DES and Prolonged DAPT In the setting of ACS (across the spectrum: UA, NSTEMI, STEMI) dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is the standard of care irrespective of management (medical therapy, percutaneous revascularization with POBA/BMS/DES, surgical revascularization) Guideline recommendations since 2002 based on robust large scale clinical trial data. Little room to debate shorter duration of DAPT in DES treated patients with ACS.
DES and Prolonged DAPT What are we treating? The patient or the stent?
Incidence, Predictors, and Outcome of Thrombosis After Successful Implantation of Drug-Eluding Stents Univariate Predictors of Cumulative Stent Thrombosis Premature Antiplatelet Therapy Discontinuation Prior Brachytherapy Renal Failure Bifurcation with 2 Stents Bifurcation Lesion Unprotected Left Main Artery Diabetes 0 10 20 30 40 Incidence of Stent Thrombosis Hazard Ratio for ATP Discontinuation = 89 Iakovou, I, et al. JAMA. 2005;293:2126-30.
Basket Late Pfisterer et al. JACC 2006
Duke registry Eisenstein et al. JAMA 2007
Challenging the guidelines Duration of dual antiplatelet therapy is: Too long! Not long enough!
DES and Prolonged DAPT Are we overreacting to ST data from first generation DES? Does DES type make a difference on duration on DAPT?
1 st vs 2 nd DES
Relative ex vivo Thrombogenicity between Different Stent Designs Thin strut BMS, thick BMS, and drug-eluting stent (XIENCE V) Single Stent Overlapping Stent Kolandaivelu K et al. Circulation 2011;123:1400-1409
Stent Thrombosis Network Metaanalysis Palmerini et al. Lancet 2012;379:1393-402
Stent Thrombosis Network Metaanalysis Palmerini et al. Lancet 2012;379:1393-402
Stent Thrombosis Network Metaanalysis Palmerini et al. Lancet 2012;379:1393-402
PRODIGY Study Design 6 months vs 24 months 1,970 patients with BMS, ZES, PES, EES (1:1:1:1) 30 days of DAPT R Short-term of DAPT 6 months* Long-term of DAPT 24 months 24 months of follow up after randomization Primary Endpoint: Composite of death, myocardial infarction, cerebrovascular accidents *<6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI Valgimigli M et al, Circulation. 2012;125:2015-26
OPTIMIZE Study Design 3 months vs 12 months 3.119 patients with, ZES R Short-term of DAPT 3 months* Long-term of DAPT 12 months 12 months of follow up after randomization Primary Endpoint: Composite of death, myocardial infarction, cerebrovascular accidents *<6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI Feres F et al, JAMA. 2013;
SECURITY Study Design 6 months vs 12 months 1,399 patients with 2 nd generation DES R Short-term of DAPT 6 months Long-term of DAPT 12 months 24 months of follow up after randomization Primary Endpoint: Composite of death, myocardial infarction, cerebrovascular accidents Colombo A et al, TCT 2014
Courtesy Dr Tullio Palmereni
Can we consider these data conclusive? Open label trials but they point all to the Underpowered for ischemic events same direction! Randomization performed at the time of PCI and not at the time of platelet discontinuation With Second Generation DES 3-6 months appears to be sufficient Inclusion of discordant endpoint in the PE May apply to low risk patients
Challenging the guidelines Duration of dual antiplatelet therapy is: Too long! Not long enough!
MACE (%) Arguments for DAPT prolongation: Benefits of prolonging DAPT could be other than stent related 25 20 All Culprit lesion (CL) related Non culprit lesion (NCL) related Indeterminate 20.4% 15 10 5 0 12.9% 11.6% 2.7% 0 1 2 3 Time in Years Stone et al. N Engl J Med. 2011;364:226-35
Dual Antiplatelet Therapy (DAPT) Study 12 mo 18 mo DES n=15,245 All patients on aspirin + open-label thienopyridine therapy for 12 months BMS n=5400 1:1 Randomization at month 12 50% of patients continue on dual antiplatelet therapy (clopidogrel or prasugrel) 50% of patients receive aspirin + placebo Total 33-month patient evaluation including additional 3-month follow-up
PCI and the Need for oral Anticoagulation The Triple Therapy Dilemma
The US perspective Low ST and Bleeding Risk High ST and low Bleeding Risk Any ST and High Bleeding Risk BMS Triple Tx for 1 months OAC + 1 AP for 12 months DES Triple Tx for 6 months OAC + 1 AP for 12 months BMS Triple Tx for 6 months OAC + 1 AP for 12 months DES Triple Tx for 12 months BMS Triple Tx for 1 months OAC + 1 AP for 12 months NO DES After 12 months. Single OAC Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534
The US perspective Low ST and Bleeding Risk High ST and low Bleeding Risk Any ST and High Bleeding Risk DES Triple Tx for 6 months OAC + 1 AP for 12 months DES Triple Tx for 12 months NO DES After 12 months. Single OAC Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534
North American Consensus Statement Regarding Antithrombotic Therapy in AF Requiring Stent (2011) Aspirin in a dose < 100 mg daily Clopidogrel is preferred in combination with aspirin and warfarin Prasugrel or Ticagrelor are not recommended Warfarin adjusted to 2.0-2.5 INR Not unreasonable to use Dabigatran in place of warfarin based on PETRO trial Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534
Bleeding event free survival Bleeding risk in PCI patients on dual antiplatelet therapy requiring oral anticoagulation % 100 95.1 % 90 95.1 % 80 70 60 50 Log Rank, p<0.0001 vs dual therapy Dual therapy Triple therapy (INR: 2.0-2.5) Triple therapy (INR > 2.5) 0 200 300 450 600 Log Rank, p<0.0001 vs triple therapy (INR: 2.0-2.5) Days 66.7 % Rossini & Angiolillo, Am J Cardiol. 2008;102:1618-23
Risk of Bleeding with Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrel in Patients With Atrial Fibrillation: Risk of nonfatal (n = 12 191) and fatal (n = 1381) bleeding Hansen et al. Arch Intern Med. 2010;170(16):1433-1441.
Risk of Stroke with Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrel in Patients With Atrial Fibrillation: Risk of nonfatal (n = 9785) and fatal (n = 3537) ischemic stroke Hansen et al. Arch Intern Med. 2010;170(16):1433-1441.
Major Bleeding in Patient with Oral Anticoagulation and Dual, Single or no Antiplatelet Treatment in RE-LY No APT SAPT DAPT No APT SAPT DAPT No APT SAPT DAPT Warfarin Dabigatran 150 mg Dabigatran 110 mg Similar trends were found for minor bleeding and no intracranial bleeding. No increase risk of intracranial bleeding was noted. Dans A, et al. Circulation 2013;127:634-40
Oral Anticoagulation and Antiplatelets in Atrial Fibrillation Patients After MI and PCI Denmark National Registry: 12,965 pts Triple therapy is used as reference (hazard ratio =1.00). Lambert M, et al JACC, Volume 62, Issue 11, 2013, 981-989
Triple Therapy With Aspirin, Prasugrel, and VKA s Kaplan-Meier analysis for the primary endpoint (TIMI major and minor bleeding) at 6 months. 377 DES treated pts of whom 21 switched to prasugrel because of HPR 6 [28.6%) vs. 24 [6.7%]; unadjusted HR: 4.6, CI: 1.9-11.4, p 0.001; adjusted HR: 3.2, CI: 1.1 to 9.1, p 0.03 Sarafoff N et al. J Am Coll Cardiol. 2013;61:2060-2066.
PCI and the Need for oral Anticoagulation The Triple Therapy Dilemma Bleeding Risk Atherothrombotic Events ST and Stroke
PCI and the Need for oral Anticoagulation The Triple Therapy Dilemma Oral Anticoagulants Bleeding Risk Atherothrombotic Events ST and Stroke Triple Therapy
PCI and the Need for oral Anticoagulation The Triple Therapy Dilemma How long Triple? (0 or 1 month) Double Therapy No Aspirin? No Clopidogrel? Either one? How long? (3, 6, 12 months) Role of New anticoagulants
The WOEST Trial: Randomised trial with or without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting Dewilde WJ et al. Lancet. 2013;381(9872):1107-15
ISAR-TRIPLE Study Randomized 600 patients Fiedler KA, et al. Presented at TCT September 2014.
XARELTO (rivaroxaban) Use in Patients With AF Undergoing PCI: PIONEER AF-PCI 2100 patients with NVAF No prior stroke/tia PCI with stent placement 72 hours After Sheath removal R A N D O M I Z E XARELTO 15 mg qd* Clopidogrel 75 mg qd 1,6, or 12 months XARELTO 2.5 mg bid Clopidogrel 75 mg qd Aspirin 75-100 mg qd 1,6, or 12 months VKA (target INR 2.0-3.0) Clopidogrel 75 mg qd Aspirin 75-100 mg qd XARELTO 15mg QD Aspirin 75-100 mg qd VKA (target INR 2.0-3.0) Aspirin 75-100 mg qd End of treatment at 12 months Primary endpoint: TIMI major, minor, and bleeding requiring medical attention Secondary endpoint: CV death, MI, stroke, and stent thrombosis *XARELTO dosed at 10 mg once daily in patients with CrCl of 30 to <50 ml/min. Alternative P2Y 12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor. Low-dose aspirin (75-100 mg/d). Data on File. Janssen Pharmaceuticals, Inc.
PCI and the Need for oral Anticoagulation ESC 2014 Guidelines
What do I do in my practice? 1) Which stent? - Define if PCI/stenting is appropriate - 2 nd generation DES is the prefer stent (no BMS) - Preferential use of radial approach during PCI 2) Which antiplatelet agent? - Clopidogrel (± low dose aspirin) - Avoid prasugrel/ticagrelor; avoind/limit NSAIDs - Add PPI (preferably non CYP2C19 interfering) 3) Always OAC. Which OAC? - I prefer VKA (more data; antidote), targeting an INR 2.0-2.5 - If already on NOAC, continue with same NOAC - Limited data on NOACs (no antidote; negative press; patients concerned) 4) For how long? - Triple Rx for 1 Month. May consider longer (6 months) if low bleeding risk - After: Dual Rx with OAC + clopidogrel (stop aspirin) up to 12 month - >1 year: Dual Rx with OAC ± aspirin (depending on patient risk)
MUCHAS GRACIAS
Antithrombotic strategies following coronary artery stenting in patients with AF at moderate to high thrombo-embolic risk (in whom oral anticoagulation therapy is required): HAS-BLED 0-2 Elective BMS 1 month: triple therapy of VKA (INR 2.0 2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Lifelong: VKA (INR 2.0 3.0) alone Elective DES 3 (-olimus group) to 6 (paclitaxel) months: triple therapy of VKA (INR 2.0 2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0 2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lifelong: VKA (INR 2.0 3.0) alone ACS BMS/DES 6 months: triple therapy of VKA (INR 2.0 2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0 2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lifelong: VKA (INR 2.0 3.0) alone Lip G, et al. Eur Heart J 2010; 31, 1311 1318 / ESC Guidelines for AF 2010
Antithrombotic strategies following coronary artery stenting in patients with AF at moderate to high thrombo-embolic risk (in whom oral anticoagulation therapy is required): HAS-BLED 3 Elective BMS 2 4 weeks: triple therapy of VKA (INR 2.0 2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Lifelong: VKA (INR 2.0 3.0) alone ACS BMS 4 weeks: triple therapy of VKA (INR 2.0 2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0 2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lifelong: VKA (INR 2.0 3.0) alone Lip G, et al. Eur Heart J 2010; 31, 1311 1318 / ESC Guidelines for AF 2010