Adjunctive Antithrombotic for PCI SCAI Fellows Course December 8, 2014 Theodore A Bass, MD FSCAI Immediate Past-President SCAI Professor of Medicine, University of Florida Medical Director UF Health CV Center, Jacksonville
Disclosures Adjunctive Antithrombotic Therapy for PCI: Theodore A. Bass MD, FSCAI The following relationships exist related to this presentation n Consulting: Merck
Thrombus Formation Two key elements: cellular (platelets) and plasmatic (coagulation factors) ADP Platelet activation Platelet aggregation Collagen TXA2 Thrombin Plasma Tissue Clotting Prothrombin Factor cascade Fibrinogen Fibrin THROMBUS
ANTITHROMBOTIC DRUGS USED IN ACS/PCI I. ANTIPLATELET DRUGS COX-1 inhibitor (aspirin) P2Y12 inhibitors (ticlopidine; clopidogrel; prasugrel; ticagrelor) Glycoprotein IIb/IIIa inhibitors (abciximab; eptifibatide; tirofiban) PAR-1 receptor inhibitor (vorapaxar secondary prevention) II. ANTICOAGULANT DRUGS Anti-Factor II (anti-thrombins) - Indirect Thrombin Inhibitors (UFH & LMWH) - Direct Thrombin Inhibitors (Bivalirudin) Anti-Factor X - Fondaparinux - Rivaroxiban (not in the US)
ANTITHROMBOTIC DRUGS USED IN PCI Many options! Who wins?
Optimal Antithrombotic PCI Cocktail Stable CAD UA/NSTEMI STEMI
What s MY Antithrombotic Cocktail Stable CAD elective PCI Aspirin 325mg LD / 81mg maintenance + Clopidogrel 600mg LD / 75mg maintenance + UFH (70-100 IU/kg)
TRIALS OF TAILORED ANTIPLATELET THERAPY USING PLATELET FUNCTION TESTING GRAVITAS TRIGGER-PCI ARCTIC
Primary Endpoint: CV Death, MI, Stent Thrombosis High Platelet Reactivity Observed event rates are listed; P value by log rank test.
Early termination of TRIGGER-PCI at March 18, 2011 236 patients completed 6 months follow-up Only 1 clinical endpoint (peri-procedural MI) observed Event rate, % rate 0.4% 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Non-CABG TIMI major, minor or minimal bleeding Prasugrel Clopidogrel Hazard Ratio 1.517 (95% CI, 0.428-5.376) p=0.516 0 30 60 90 120 150 180 210 240 Days from randomization Trenk D. JACC 2012
Optimal Antithrombotic Cocktail Stable CAD UA/NSTEMI STEMI
Optimal Antithrombotic Cocktail When to consider: 1.GP IIb/IIIa inhibitors 2. Bivalirudin 3. New P2Y12 receptor antagonists
NSTEMI: The Role of GP IIb/IIIa inhibitors in the era of clopidogrel and direct thrombin inhibitors Shifting the paradigm!! IIb or not IIb? Major Considerations: 1) Trials performed in the good old days - Less experience; not all with stents; devices 2) Antiplatelet therapy - 1st generation thienopyridine (ticlopidine) - 300mg LD clopidogrel 3) Anticoagulant therapy - indirect thrombin inhibitors William Shakespeare (1564-1616)
ISAR-REACT 2: Abciximab vs. Placebo in ACS All patients pretreated with 600mg clopidogrel at least 2 hrs prior to PCI. 20 Death/MI/UTVR, % Troponin-Positive: RR=0.71 [0.54-0.95] 15 10 Abciximab vs. Placebo 5 Troponin-Negative: RR=0.99 [0.56-1.76] 0 0 5 10 15 20 25 30 Days after randomization Kastrati et al. JAMA. 2006;295:1531-8.
Impact of MI and Major Bleeding (Non-CABG) in the First 30 Days on Risk of Death Over 1 Year ACUITY 1 Year Estimate Both MI and Major Bleed (N=94) Major Bleed Only (Without MI) (N=551) MI Only (Without Major Bleed) (N=611) No MI or Major Bleed (N=12,557) Mortality (%) 30 28.9% 12.5% 8.6% 3.4% 25 20 15 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Days From Randomization Mehran R, et al. Eur Heart J. 2009;30(12):1457-1466. 390
ACUITY: Primary Results UFH/Enox + GP IIb/IIIa Observed Bivalirudin + GP IIb/IIIa Bivalirudin alone Rate Rate P Value Rate P Value Net clinical outcome 11.7% 11.8% <0.001 NI 10.1% 0.015 Sup Ischemic events 7.3% 7.7% 0.007 NI 7.8% 0.011 NI Major bleeding 5.7% 5.3% 0.001 NI 3.0% <0.001 Sup Endpoint NI = non-inferiority; Sup = superiority
ACUITY: Limitations Complex trial design Non-uniform use of clopidogrel regimens (timing and dosing varied) Different GPI s use Sensitive definition of bleeding (ACUITY)
ISAR-REACT 4 Trial 1721 Pts with elevated troponin (NSTEMI) Pre-treated with 600 mg of clopidogrel Double-blind Bivalirudin UFH+Abciximab PCI 30-day Quadruple End Point
Primary endpoint ISAR-REACT 4 Death, large MI, utvr, major bleeding Cumulative Incidence (%) 20 Relative risk, 0.99 (95% CI, 0.74 1.32) P=0.94 Abciximab 10.9% Bivalirudin 11.0% 15 10 5 0 0 5 10 15 20 Days since Randomization 25 30 Kastrati et al. NEJM 2011
What s MY Antithrombotic Cocktail UA/NSTEMI PCI Bivalirudin: - High bleeding risk (elderly, CKD, diabetes) - Pre-treated w/clopidogrel - Unclear prior anticoagulation (safe to switch) GPI: - Already on upstream GPI - Not pre-treated w/clopidogrel (especially if high thrombotic burden) - ACS while on DAPT
What s MY Antithrombotic Cocktail UA/NSTEMI PCI New P2Y12 Receptor Antagonists?
TRITON TIMI 38 (prasugrel vs clopidogrel) PLATO (ticagrelor vs clopidogrel)
TRITON vs PLATO: Is there a winner? Prasugrel and ticagrelor both showed favorable efficacy and safety profiles in their respective trials and only a head-to-head comparison will be able to define the winner. Subgroup analysis will allow to define their best niche. Prasugrel. Particularly efficacious in reducing stent thrombosis, MI, utvr and great benefit in diabetics and STEMI. Contraindicated: high-risk bleeding; prior TIA/stroke Considerations: elderly, low-weight; CABG/surgery (7days). Ticagrelor. Particularly efficacious in reducing mortality (offtarget effects), OK for patients with prior TIA/ ischemic stroke. Contraindicated: high-risk bleeding; prior hemorrhagic stroke Considerations: COPD/asthma, bradyarrythmia, gout syndromes, advanced CKD, compliance (b.i.d. administration), regional differences (North America?/ASA dose), CABG/surgery (5-7days).
Optimal Antithrombotic PCI Cocktail Stable CAD UA/NSTEMI STEMI
All-cause mortality or reinfarction (%) 3-Year All-Cause Mortality or Reinfarction Landmark analysis Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 3-year HR (95% CI) 30-day HR (95% CI) 0.72 (0.58 0.91) 0.84 (0.61 1.16) p=0.005 10.6% p=0.30 5 4 3 7.8% 2 4.5% 3.8% 1 0 0 3 6 9 12 15 18 21 24 Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2 27 30 33 36
Def/Prob Stent Thrombosis (%) Stent Thrombosis 1-Day Landmark Analysis: Impact of Antithrombin 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Considerations: 1.MagnitudeBivalirudin of early ST diminished with upstream monotherapy heparin bolus and 600mg clopidogrel pre-treatment. Heparin + GPIIb/IIIa inhibitor 2.Consider prolonging bivalirudin infusion post-pci HR [95%CI] = 3.0% 5.93 [2.06-17.04] at PCI dose (EUROMAX trial). P = 0.0002 3.Prasugrel/ticagrelor reduce ST compared with 2.2% clopidogrel. 1.5 4.HEAT PPCI does not support superiority of % HR [95%CI] = bivalirudin over UFH, but then refuted1.73 by[0.47-1.13] the BRIGHT trial. P = 0.06 0.3% 0.0 0 Number at risk Bivalirudin UFH+GPIIb/IIIa 1 30 90 180 270 365 1485 1457 1355 1315 Time in Days 1611 1600 1562 1591 1587 1521 1525 1495 1506 1476
Death, MI or Stroke in STEMI-PCI P=0.02 % P=0.07 P=0.11 Drug Follow-up N=6364 N=7544 N=3534 Double dose clopidogrel Ticagrelor Prasugrel 1 month 6-12 months 15 months
INFUSE-AMI: Infarct size at 30 days* - Primary endpoint - Median [IQR] Median [IQR] 15.1% 17.9% Infarct size, %LV [6.8, 22.7] [10.3, 25.4] P=0.03 IC abciximab No abciximab N=229 N=223 JAMA 2012 *Core laboratory assessed
What s MY Antithrombotic Primary PCI Cocktail STEMI (# 1) Aspirin 325mg LD + Prasugrel 60mg LD (unless contraindicated then I use ticagrelor) + UFH (4000 IU)
What s MY Antithrombotic Cocktail STEMI Bivalirudin in all my Primary PCI patients. Consider GPI: - Bail-out - STEMI while on DAPT - Already on upstream GPI - Sometimes (selected cases) intracoronary bolus
NOT in my Antithrombotic Cocktail what s not good for me, may be good for others.it s a matter of taste! LMWH (enoxaparin) STEEPLE, ATOLL High maintenance dose clopidogrel - OASIS-7 Fondaparinux - OASIS-5, OASIS-6, OASIS-8
Current Controversies on DAPT in PCI Which drug? When to start? Which dose? How long? Testing?
Current Controversies on DAPT in PCI Which drug? When to start? Which dose? How long? Testing?
2011 ACCF/AHA/SCAI Guideline for PCI Postprocedural Antiplatelet Therapy I IIa IIb III After PCI, aspirin should be continued indefinitely. The duration of P2Y12 inhibitor therapy after stent implantation should generally be as follows: I IIa IIb III a) In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y12 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).
2011 ACCF/AHA/SCAI Guideline for PCI Postprocedural Antiplatelet Therapy (cont.) I IIa IIb III Continuation of clopidogrel, prasugrel or ticagrelor beyond 12 months may be considered in patients undergoing DES placement.
Trials of DAPT duration support short length after elective PCI, particularly if 2nd gen DES are used 3 months 48 months R OP ES TI ET M IZ E OPTID U 6 months SECURITY EXCELLENT ITALIC ISAR SAFE AL 30 months Completed AHA 2014 Ongoing DAPT ARCTIC Y PR O G DI 12 months E LAT S DE RE SCO 24 months Capodanno C, Angiolillo DJ. Circulation. 2013;128:2785-98
ACC/AHA/SCAI 2007 Focused Update for PCI Oral Antiplatelet Adjunctive Therapies (New Recommendation) I IIa IIb III B C Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely. In patients requiring warfarin, clopidogrel, and aspirin therapy after PCI, an INR of 2.0 to 2.5 is recommended with low dose aspirin (75 mg to 81 mg) and a 75-mg dose of clopidogrel.
The WOEST Trial: First randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting treated with clopidogrel Dewilde WJ et al. Lancet. 2013;381(9872):1107-15
Clopidogrel Genetic Testing I IIa IIb III Genetic testing might be considered to identify whether a patient at high risk for poor clinical outcomes is predisposed to inadequate platelet inhibition with clopidogrel. I IIa IIb III When a patient predisposed to inadequate platelet inhibition with clopidogrel is identified by genetic testing, treatment with an alternate P2Y12 inhibitor (e.g., prasugrel or ticagrelor) might be considered. I IIa IIb III No Benefit The routine clinical use of genetic testing to screen clopidogrel-treated patients undergoing PCI is not recommended.
Platelet FunctionTesting I IIa IIb III Platelet function testing may be considered in patients at high risk for poor clinical outcomes. I IIa IIb III In clopidogrel-treated patients with high platelet reactivity, alternative agents, such as prasugrel or ticagrelor, might be considered. I IIa IIb III No Benefit The routine clinical use of platelet function testing to screen clopidogrel-treated patients undergoing PCI is not recommended.
PPIs and Antiplatelet Therapy I IIa IIb III PPI should be used in patients with history of prior GI bleed who require DAPT (In patients in whom there is a clear indication for PPI therapy, some clinicians may choose to use a PPI other than omeprazole). I IIa IIb III PPI use is reasonable in patients with increased risk of gastrointestinal bleeding (advanced age, concomitant use of warfarin, steroids, NSAIDS, H pylori infection, etc.) who require DAPT. I IIa IIb III No Benefit Routine use of a PPI is not recommended for patients at low risk of gastrointestinal bleeding, who have much less potential to benefit from prophylactic therapy.
Thank You