Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation George D. Dangas MD, PhD Professor of Medicine Icahn School of Medicine at Mount Sinai
Summary Predictors of restenosis such diabetes, small vessel size, long lesions, treatment of multiple lesions are still significant in the era of DES. The rate DES-ISR increases when complex lesions are treated. The mechanism of restenosis after DES should be clarified (imaging or functional measurements) to determine the optimal treatment for each individual patient.
Why DAPT after Stenting? Restenosis Vs. Thrombosis Smooth Muscular Cell Proliferation Platelet and Coagulation Pathways Activation
Why DAPT after Stenting? The role of platelets in thrombosis Nat. Rev. Cardiol. 8, 547 559 (2011)
Rationale for DAPT Among Patients Undergoing PCI With Stents Death, MI, or Revascularization at 30 Days ASA+coumarin ASA+ticlopidine % 12 10 8 6 4 2 0 6.2 P=0.01 8.6 3.6 1.6 2.4 0.6 ISAR FANTASTIC MATTIS STARS 11 P=0.02 P=0.07 P=0.37 P=0.004 5.7 5.6 NEJM 1996 Circulation 1998 Circulation 1998 NEJM 1998
DAPT options 2015
CV death, MI, or stroke (%) TRITON-TIMI-38 Timing of benefit (landmark analysis) 8 CLOPIDOGREL PRASUGREL CLOPIDOGREL PRASUGREL 6.9% 6 5.6% 5.6% 4 4.7% 2 HR 0.82 P=0.01 HR 0.80 P=0.003 1 0 0 1 2 3 Days 3 30 60 90 180 270 360 450 Days Wiviott SD et al. NEJM 2007;357:2001-15
Primary Efficacy Endpoint (Composite of CV Death, MI or Stroke) 8 8 6 4 Clopidogrel Ticagrelor 5.4% 4.8% 6 4 Clopidogrel 6.6% 5.3% Ticagrelor 2 HR 0.88 (95% CI 0.77 1.00) 2 HR 0.80 (95% CI 0.70 0.91) 0 P=0.045 0 P<0.001 No. at risk Ticagrelor 0 10 20 30 Days after randomization 9,333 8,942 8,827 8,763 31 90 150 210 270 330 Days after randomization * 8,673 8,543 8,397 7,028 6,480 4,822 Clopidogrel 9,291 8,875 8,763 8,688 8,688 8,437 8,286 6,945 6,379 4,751 * Excludes patients with any primary event during the first 30 days Wallentin L et al. NEJM 2009;361:1045-57
Clinical Trials of Newer Antiplatelet Agents or Regimens Agent Prasugrel Ticagrelor Double-Dose Clopidogrel Trial Name TRITON PLATO CURRENT OASIS 7 Patient Population PCI only Invasive/Conservative Invasive Regimen Once daily Twice daily Once daily Comparator Clop 300/75 Clop 300 or 600/75 Clop 300/75 Timing of Rx After coronary anatomy defined Emergency room Emergency room Sample Size 14000 18000 25000 Duration of Rx 1 year 1 year 7 days Aspirin dose 75-160 mg 75-325 mg Randomized <100 mg or >300 mg Wiviott et al. N Engl J Med. 2007;357:2001-2015. Wallentin et al. N Engl J Med. 2009;361:1045-57. CURRENT Investigators. N Engl J Med. 2010;363:930-42.
So why are we Interested in Pre-Loading? Up in the Air!
Clopidogrel Metabolism P-Glycoprotein Intestinal Absorption 15% Inactive metabolite 2 Step Hepatic CYP Conversion 2C19 1A2 2B6 2C19 2C9 3A4 2B6 Variable and inefficient active metabolite generation Slow, Variable IPA Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-9.
Metabolism of P2Y 12 Receptor Blockers Prasugrel Intestinal Esterases 85% Intestinal Absorption P-Glycoprotein Intestinal Absorption 30% Hepatic CYP3A4 Ticagrelor 1 Step Intestinal/hepatic CYP-Conversion 55% 3A4 2B6 2C9 2C19 Efficient active metabolite generation Rapid Consistent /Greater IPA Rapid Consistent /Greater IPA Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-9
Clopidogrel Pretreatment in Patients Undergoing PCI: a Meta-analysis MI before PCI (%) Clopidogrel No Trial Pretreatment Pretreatment PCI-CURE 3.6 5.1 CREDO n/a n/a PCI-CLARITY 4.0 6.1 Overall 3.7 5.5 CV Death or MI after PCI (%) Clopidogrel No Trial Pretreatment Pretreatment PCI-CURE 2.9 4.4 CREDO 6.0 7.1 PCI-CLARITY 3.3 5.4 Overall 3.9 5.5 Favors Pretreatment 0.25 0.5 1.0 2.0 OR (95% CI) 0.25 0.5 1.0 2.0 OR (95% CI) Sabatine MS, et al. JAMA. 2005;294:1224-1232. Favors No Pretreatment OR: 0.67 P=.005 OR: 0.71 P=.004
ACCOAST design NSTEMI + Troponin 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg Randomize 1:1 Double-blind n~4100 (event driven) Prasugrel 30 mg Placebo CABG or Medical Management (no more prasugrel) Coronary Angiography Prasugrel 30 mg Coronary Angiography Prasugrel 60 mg CABG or Medical Management (no prasugrel) PCI PCI Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days 1 Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa inh. Bailout, at 7 days Montalescot G et al. Am Heart J 2011;161:650-656
Pharmacodynamic Sub-Study 350 300 Placebo LD1 60 mg LD2 Pre-treatment (30/30) No Pre-treatment (0/60) *P<0.05 P2Y 12 Reaction Units 250 200 150 100 50 30 mg LD1 Approximate time of PCI * * 0 30 mg LD2 Pre LD1 (baseline) Pre LD2 0.5 1 2 3 4 24 Hours (post LD2) Data presented as median ± SEM. * p<0.05 relative to the No pre-treatment group. LD = loading dose. Pretreatment=Prasugrel 30 mg/prasugrel 30 mg; No Pre-treatment=Placebo/Prasugrel 60 mg
Endpoint (%) 1 Efficacy End Point @ 7 + 30 days (All Patients) 15 Pre-treatment 10.0 CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout Pre-treatment 10.8 10 No Pre-treatment 10.8 No Pre-treatment 9.8 5 Hazard Ratio, 1.02 (95% 0.84, 1.25) P=0.81 Hazard Ratio, 0.997 (95% 0.83, 1.20) P=0.98 No. at Risk, Primary Efficacy End Point: No pre-treatment Pre-treatment 0 0 5 10 15 20 25 30 1996 2037 1788 1821 Days From First Dose 1775 1809 1769 1802 1762 1797 1752 1791 1621 1616
All TIMI (CABG or Non-CABG) Major Bleeding (PCI Patients) 5 4 Endpoint (%) 3 2 HR, 2.69 (95% 1.13, 6.40) P=0.02 Pre-treatment 1.4 All TIMI Major Bleeding PCI Cohort HR, 2.65 (95% 1.23, 5.70) P=0.010 Pre-treatment 1.7 1 No Pre-treatment 0.5 No Pre-treatment 0.7 0 0 5 10 15 20 25 30 No. at Risk, All TIMI Major Bleeding: No pre-treatment Pre-treatment 1372 1389 1356 1364 1302 1314 Days From First Dose 1280 1293 1272 1282 1268 1280 1249 1269
Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery G. Montalescot, A.W. van t Hof, F. Lapostolle, J Silvain, J.F. Lassen, L. Bolognese, W.J. Cantor, A. Cequier, M. Chettibi, S.G. Goodman, C.J. Hammett, K. Huber, M. Janzon, B. Merkely, R.F. Storey, U. Zeymer, O. Stibbe, P. Ecollan, W.M.J.M. Heutz, E. Swahn, J.P. Collet, F.F. Willems, C. Baradat, M. Licour, A. Tsatsaris, E. Vicaut, C.W. Hamm, for the ATLANTIC investigators G. Montalescot, COI are available at www.action-coeur.org
Study population and design
1 st Co-primary endpoint No ST-segment resolution ( 70%)
2 nd Co-primary endpoint No TIMI 3 flow in infarct-related artery
Crushed ticagrelor tablet administration in STEMI patients is feasible and provides earlier platelet inhibition compared with standard integral tablets - The MOJITO Study - Parodi et al - JACC 2015
AD-HOC PCI Study Design Prospective, open-label, randomized, multicenter, US, Phase IV study to evaluate the effect of ticagrelor versus clopidogrel loading dose (LD) after diagnostic angiography on platelet reactivity in troponin-negative ACS patients undergoing ad-hoc PCI Up to 7 days Visit 1 Screening period Visit 2 Randomization 1:1, pre-ld platelet function testing,* first dose 1 day Ticagrelor 180 mg LD after diagnostic angiography, then 90 mg 12 h later + aspirin 160 500 mg LD, then 75 100 mg daily Clopidogrel 600 mg LD after diagnostic angiography + aspirin 160 500 mg LD, then 75 100 mg daily 1 day Visit 3 Platelet function testing* (0.5, 2, and 8 h post-ld, and end of PCI) *Measurement of P2Y 12 reaction units (PRU) with VerifyNow NCT01603082 23
Patient Disposition Screened (n=343) Met inclusion/exclusion criteria (n=102) Randomized (n=100) Incorrectly randomized (n=4) Did not meet inclusion/ exclusion criteria (n=241) Not randomized (n=2) Progressive disease (n=1) PI s decision (n=1) Ticagrelor (n=51) Safety population (n=51) PD population (n=46) Missing analyzable data (n=1) Protocol deviation (n=4) Clopidogrel (n=49) Safety population (n=49) PD population (n=47) Missing analyzable data (n=0) Protocol deviation (n=2) Completed study (n=49) Completed treatment (n=47) No PCI, patient had received 2 doses prior, discontinued, unable to place stent/wire (n=1 each) Completed study (n=48) Withdrawn due to AE (n=1) Completed treatment (n=49) One patient with pre-dose PRU <150 was excluded from primary and secondary endpoint analyses (n=45) 24
Mean (SD) PRU at 2 h after LD PRU at 2 h after LD PD Population Treatment difference (95% CI): -159.1 (-194.7, -123.5); p<0.001 350 300 Ticagrelor (n=45) Clopidogrel (n=47) 250 257.5 200 150 100 50 98.4 0 25
Mean PRU (95% CI) Time Course of PRU PD Population 350 300 250 p<0.05 Ticagrelor (n=45) Clopidogrel (n=47) 200 150 100 p<0.001 50 p<0.001 0 Baseline 0.5 End of PCI 2 Mean time to end of PCI 0.6 h Post LD (h) 8 26
Optimal Duration of Anti-platelet Therapy Post DES.. Still Unclear? CURE (PCI-CURE) 2001 1 1 year Cypher Stent Launch 2003 ESC PCI Guidelines 2010 (6-12 months post PCI) ESC Revasc. Updated Guidelines 2014 6-mo post DES, 3- mo in high bleeding risk BMS Era DES Era AHA/ACC Guidelines 2001 (9-12 months post PCI) TAXUS Express 2TM Stent Launch 2004 AHA/ACC/SCAI Updated Guidelines 2005 (TAXUS stent 6 months post PCI) (Cypher stent 3 months post PCI) FDA, ACC/AHA/SCAI Recommendations 2011 (1 year post PCI in pts at low risk of bleeding)
2014 ESC Revasc Guidelines Stable CAD DAPT for at least 1 month after BMS DAPT for 6 Months after DES Shorter DAPT duration (< 6 mos) may be considered after DES in patients at high bleeding risk NSTEACS DAPT to 12 mos unless excessive bleeding risk STEMI DAPT After Stenting Bleeding risk- An important driver! DAPT to 12 mos unless excessive bleeding risk IA/B IA IB IIb A IA/B ISAR SARS PRODIGY PRODIGY EXCELLENT Metaanalysis RESET OPTIMIZE PLATO TRITON PCI CURE PLATO TRITON Windecker et al. EHJ 2014
10 Trials of DAPT Duration after DES RESET (n=2117) OPTIMIZE (n=3119) SECURITY (n=1399) EXCELLENT (n=1443) ISAR-SAFE (n=4000) Timing of aspirin only vs. DAPT ITALIC (n=1850) * ARCTIC-Interruption (n=1259) PRODIGY (n=2014) DAPT DES (n=9961) DES Late (n=5045) 31,666 randomized patients 0 3 6 9 12 15 18 21 24 27 30 33 36 Months after PCI *Primary endpoint at 12 months
32,135 patients 10 trials Mean weighted follow-up time among all 10 RCTs was 19.6 months. Mean weighted exposure time to antiplatelet therapy within the S-DAPT and L-DAPT groups was 8.5 and 23.2 months, respectively. Giustino,.. Dangas; JACC 2015
Longer DAPT is associated with lower risk of Stent Thrombosis and Myocardial Infarction Giustino,.. Dangas; JACC 2015
Shorter DAPT is associated with lower risk of Clinically Significant Bleeding and All-Cause Mortality *CSB defined as a BARC 3 or 5, TIMI major or minor, GUSTO moderate or severe or STEEPLE major Giustino, Dangas; JACC 2015
First- Versus Second-Generation DES and risk for Stent Thrombosis.. Where is the difference? 1 st -generation DES 2 nd -generation DES SES 13 months PES 11 months ZES 3 months EES 6 months Representative Images of 2 nd - vs. 1 st -generation DES in Human Coronary Arteries
Risk of ST with 1 st - and 2 nd -Generation Drug-Eluting Stents According to Duration of Dual Antiplatelet Therapy Giustino, Dangas; JACC 2015
Who may benefit of prolonged DAPT?
Overlap Between Bleeding and Ischemic Risk Clinical Factors Bleeding Risk Factors Lower PRU PRU Higher PRU Ischemic Risk Factors Chronic AC or NSAID therapy Previous Bleeding Liver Disease Hemorrhagic Diathesis Prior Major Bleeding PUD Older Age Low BMI Female Gender CKD Anemia ACS Atherothrombotic Risk Factors Cardiogenic Shock CHF Lesion Complexity Thrombus Burden Multivessel CAD Incomplete Apposition Thrombotic Diathesis DAPT Disruption Diabetes Mellitus Stent Length / Diameter Type of Stent
Charisma Substudy Subgroup analysis in patients at high atherothrombotic risk (prior MI, stroke or peripheral arterial disease) from the CHARISMA trial (DAPT versus aspirin for 28 months in 15,603 patients with CAD or multiple risk factors) Lower risk of cardiac death / MI / stroke in patients on DAPT! Bhatt et al - JACC Vol. 49, No. 19, 2007
Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction Median follow-up 33 months CV death, MI, or stroke Bonaca et al NEJM 2015
Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction However Higher risk of major and minor bleeding And no differences in all-cause mortality
Optimal DAPT duration after DES Implantation: What does it really mean? 3/6 Months 12 Months Required DAPT Possible DAPT PCI Ischemic Benefit Effectiveness / Safety Uncertain Increased risk for Bleeding!
Thank you for your attention!