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Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies

Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies. Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Investigator, TIMI Study Group.

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Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies

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  1. Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies Stephen D Wiviott MDCardiovascular DivisionBrigham and Women’s HospitalAssistant Professor of MedicineHarvard Medical School Investigator, TIMI Study Group

  2. DisclosuresCME Honoraria: Eli Lilly, Daiichi Sankyo; Accumetrics, Astra-Zeneca, Pfizer, Merck. Consultancies: Sanofi-Aventis, BMS, Portola, Astra-Zeneca TIMI Study Group Receives Research Funding From: Eli Lilly, Daiichi Sankyo, Merck, Schering Plough, Sanofi-Aventis, AstraZeneca, Accumetrics

  3. History of Present Illness CC: Chest pain 73 yo F with a h/o HTN, HL, strong FH of CAD admitted with new onset CP. • 4 days prior to admission: CP radiating to both arms while walking & relieved with rest • Sxs continued with minimal exertion over subsequent days • Morning of admission, pt developed CP radiating to both arms at rest. Recurred 3x during am. • Denied SOB, N/V, lightheadedness or diaphoresis

  4. Day of presentation • Seen in urgent care clinic at PCP’s office • Referred to ED. CP-free on arrival. • BP 123/68, P95 regular, O2 sat 99% RA

  5. Past Medical History: Cholesterol HTN Breast CA: s/p left breast lumpectomy 12/05, s/p XRT, ER+ on tamoxifen Psoriasis Meds on admission: ASA 81mg PO QD Tamoxifen 20mg PO QD Irbisartan 150mg PO QD Pravastatin 20mg PO QD

  6. BP 117/73 both arms, P68 reg, R 14, O2 97%, T97.6 NAD JVP 6 cm H20, nl contours No carotid bruits CV: non-displaced discrete PMI Ext: warm, no edema or tenderness bilaterally 2+ DP bilat Data 141 110 11 96 10.4 328 38.7 4.2 26 0.8 Troponin I = 0.12 (ULN = 0.04) CK = 105, CK-MB = 5.2 (ULN =5)

  7. ACUTE CORONARY SYNDROMES Spectrum of CAD No ST elevation ST elevation Stable angina Unstable angina NSTEMI STEMI ~1.24 Million Discharges Per Year ~0.33 Million Discharges Per Year CAD = coronary artery disease; NSTEMI = non–ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction. Reprinted with permission from Davies MJ. Heart. 2000;83:361-366. American Heart Association. Heart Disease and Stroke Statistics—2007 Update. Circulation. 2007; 115:69-171.

  8. Decision Making • Diagnosis • Risk Assessment • Early Invasive/Early Conservative Managment? • Antithrombin? • GP IIB/IIIA? • Oral Antiplatelets?

  9. Risk Assessment Dependent on Contingent Probabilities Does this patient have symptoms due to acute ischemia from obstructive CAD? Likelihood of obstructive CAD as cause of symptoms Dominated by acute findings Examination Symptoms Markers Traditional risk factors are of limited utility What is the likelihood of death, MI, heart failure? Risk of bad outcome Dominated by acute findings Older age very important Hemodynamic abnormalities critical ECG, markers 2007 ACC/AHA UA/NSTEMI Guideline Revision Anderson JL, et al. http://cardiosource.com/guidelinefocus/gfc_acs.asp. Accessed August 8, 2007. Reproduced by STRIVE with permission from Cardiosource.com.

  10. 45 40 35 30 25 % Death / MI / Revasc 20 15 10 5 0 0/1 2 3 4 5 6/7 Number of Predictors TIMI Risk Score for UA/NSTEMI:7 Independent Predictors • Aged ≥65 y • ≥3 CAD risk factors (high cholesterol, family history, hypertension, diabetes, smoking) • Prior coronary stenosis ≥50% • Aspirin in last 7 days • ≥2 anginal events ≤24 h • ST-segment deviation • Elevated cardiac markers (CK-MB or troponin) Antman EM, et al. JAMA. 2000;284:835-842.

  11. Our Patient’s GRACE Prediction Score for All-Cause Mortality From Discharge to6 Months NSTEMI 6-Month Postdischarge Mortality Risk GRACE ProbabilityCategory Score of Death Low 1-88 <3%Medium 89-118 3-8%High 119-263 >8%http://www.outcomes-umassmed.org/grace/grace_risk_table.cfm. 125 8% Reprinted with permission from Eagle KA, et al. JAMA. 2004;291(22):2727-2733.

  12. Invasive Management of UA/NSTEMI Meta-analysis:  Death/MI at 17-Month F/U Odds Ratio Death or MI Trial Inv Cons TIMI 3B 5.1% 8.1% 27.2% VANQWISH 28.0% MATE 12.0% 8.9% 4.3% 11.4% FRISC II 4.0% 5.3% TACTICS VINO 4.8% 14.8% RITA 3 7.4% 10.9% TOTAL 7.4% 11.0% OR 0.82, P=.001 0.2 0.5 1 2 5 Favors Conservative Favors Invasive Adapted with permission from Mehta S, et al. JAMA. 2005;293:2908-2917.

  13. ACC/AHA UA/NSTEMI Guidelines: High-risk Indicators for Early Invasive Strategy Coronary angiography needs to be performed within 48 hours ACC = American College of Cardiology; AHA = American Heart Association; CABG = coronary artery bypass graft surgery; GRACE = Global Registry of Acute Coronary Events; HF = heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TnI = troponin I; TnT = troponin T Anderson JL, et al. J Am Coll Cardiol. 2007;50:1-157.

  14. TIMACS: GRACE Score and Primary End Point HR=0.65 (0.48-0.89) P=0.006 HR=1.12 (0.81-1.56) P=0.48 Delayed Early Death, MI, or Stroke at 6 Months Low/Intermediate Risk Score ≤140 N=2,070 High Risk Score >140 N=961 GRACE=Global Registry of Acute Coronary Events; HR=hazard ratio; MI=myocardial infarction.Mehta SR, et al. N Engl J Med. 2009;360(21):2165-2175.

  15. It is reasonable for initially stabilized high-risk patients with UA/NSTEMI (GRACE risk score >140) to undergo an early invasive strategy within 12 to 24 hours of admission. For patients not at high risk, an early invasive approach is also reasonable Timing of Angiography in UA/NSTEMI 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates New Recommendation B Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):2205-2241.

  16. Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) A Proceed with an Initial Conservative Strategy Select Management Strategy B Invasive Strategy Init ACT (Class I, LOE: A) Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B) B1 Prior to Angiography Init at least one (Class I, LOE: A) or both (Class IIa, LOE: B) of the following: Clopidogrel IV GP IIb/IIIa inhibitor B2 Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include: Delay to Angiography High Risk Features Early recurrent ischemic discomfort Proceed to Diagnostic Angiography Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.

  17. 2007 ACC/AHA UA/NSTEMI Guideline Revision Initial Invasive Strategy: Antiplatelet, Anticoagulant Therapy • Aspirin • Initiate anticoagulant therapy as soon as possible after presentation (I, A). Regimens with established efficacy: • Enoxaparin or UFH (I, A) • Bivalirudin or fondaparinux (I, B) • Prior to angiography, initiate one (I, A) or both (IIa, B) • Clopidogrel • IV GP IIb/IIIa inhibitor Use both if: • Delay to angiography • High-risk features • Early recurrent ischemic syndromes Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

  18. 0.20 0.20 Medical Rx Group Any Revascularization Group Placebo 0.15 0.15 Placebo 0.10 0.10 Clopidogrel Cumulative Hazard Rates Cumulative Hazard Rates Clopidogrel 0.05 0.05 RR:0.80 (0.69-0.92) RR:0.82 (0.69-0.96) 0.00 0.00 0 100 200 300 0 100 200 300 Days of Follow-up CURE: Primary Outcome by Type of Intervention Days of Follow-up 0.20 0.20 PCI Group CABG Group Placebo 0.15 0.15 Placebo 0.10 0.10 Clopidogrel Cumulative Hazard Rates Cumulative Hazard Rates Clopidogrel 0.05 0.05 RR:0.72 (0.57-0.90) RR:0.89 (0.71-1.11) 0.00 0.00 0 100 200 300 0 100 200 300 Days of Follow-up Days of Follow-up Adapted with permission from Fox KAA, et al. Circulation. 2004;110:1202-1208.

  19. Patients with definite or likely UA/NSTEMI selected for an invasive approach should receive dual antiplatelet therapy. Aspirin should be initiated on presentation. Clopidogrel (before or at the time of PCI) or prasugrel (at the time of PCI) is recommended as a second antiplatelet agent Timing of Antiplatelet Therapy in UA/NSTEMI 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates New Recommendation A A A B Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):2205-2241.

  20. 2007 ACC/AHA UA/NSTEMI Guideline Revision Initial Medical Treatment: Anticoagulant Dosing a Use in UA/NSTEMI is off-label. Adapted from Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

  21. ACUITY Study: 30-Day Results Moderate- to high-risk patients with UA or NSTEMIundergoing an invasive strategy (N=13,819) UFH or enox+ GP IIb/IIIan=4603 Moderate-to high- risk ACS Bivalirudin + GP IIb/IIIan=4604 R* Bivalirudin alonen=4612 Aspirin in all; clopidogrel dosing and timing per local practice End points: death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30 days); composite of the above (30 days) *Stratified by preangiography thienopyridine use or administration. Stone GW, et al. N Engl J Med. 2006;355(21):2203-2216.

  22. 10 9.1 9 7.8 8 7.3 7.3 7.1 7.0 7 UFH + GP IIb/IIIa 5.7 6 5 4 3.0 3 2 1 0 ACUITY Composite ischemia Ischemia endpoint by Ischemia endpoint by ACUITY Major bleeding at 30 endpoint at 30 days thienopyridine loading before angiography or PCI YES thienopyridine loading before days angiography or PCI No ACUITY Composite Ischemia & Bleeding Outcomes Bivalirudin alone Absolute Risk Reduction -0.5 0.3 -2.0 2.7 Hazard Ratio 1.08 0.97 1.29 0.53 95% CI 0.93–1.24 0.80–1.17 1.03–1.63 0.43–0.65 p 0.32 0.054 (for interaction) < 0.001 Stone GW, et al. N Engl J Med 2006;355:2203–16.

  23. Excess Dosing of Antithrombotic Agents Dose and Major Bleeding 35 30 25 20 15 10 5 0 Underdosed Recommended Mild Excess Major Excess Major Bleeding, % (n=2063) (n=3998) (n=5879) (n=1955) (n=178) (n=2074) (n=2327) (n=2073) (n=714) (n=922) (n=237) Unfractionated Heparin Low-Molecular-WeightHeparin Glycoprotein IIb/IIIa Inhibitors Treatment Group Reproduced with permission from Alexander KP, et al. JAMA. 2005;294(24):3108-3116.

  24. New ACC/AHA 2008 Test Measures for STEMI and NSTEMIa LDL assessment (formerly a performance measure) Excessive initial UFH, enoxaparin, eptifibatide, tirofiban, or abciximab dose Anticoagulant dosing protocol Anticoagulant error tracking system Clopidogrel prescribed at discharge for medically treated AMI patients a For use in internal quality improvement programs only. Krumholz HM, et al. J Am Coll Cardiol. 2008;52(24):2046-2099.

  25. GP IIb/IIIa Inhibition for Non–ST-Elevation ACS 30-Day Death or Nonfatal MI GP IIb/IIIa Inhibitor n Trial Risk Ratio and 95% CI Placebo 7.1% 5.8% PRISM 3,232 PRISM-PLUS 11.9% 10.2% 1,915 PARAGON A 11.7% 11.3% 2,282 PURSUIT 15.7% 14.2% 9,461 PARAGON B 11.4% 10.5% 5,165 GUSTO-IV ACS 8.0% 8.7% 7,800 0.92 (0.86, 0.995) P=.037 11.5% 10.7% Pooled 29,855 Placebo Better 0.5 1.0 1.5 GP IIb/IIIa Inhibitor Better CI = confidence interval. Boersma E, et al. Lancet. 2002;359:189-198.

  26. Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials TnT-Positive TnT-Negative PARAGON-B PRISM CAPTURE Combined 0.125 0.5 1 2 0.125 0.5 1 2 GP IIb/IIIa Better GP IIb/IIIa Worse GP IIb/IIIa Better GP IIb/IIIa Worse Newby KL, et al. Circulation. 2001;103:2891-2896.

  27. 20 15 10 5 0 ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in SubsetsWith and Without Elevated Troponin levels (>0.03 µg/L) Placebo Group (n=1010) Abciximab Group (n=1012) Troponin >0.03 µg/L Log-Rank P=.02 Cumulative Rate of Primary End Point, % Troponin ≤0.03 µg/L Log-Rank P=.98 0 5 10 15 20 25 30 Days After Randomization ISAR-REACT 2 = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2. Adapted with permission from Kastrati A, et al. JAMA. 2006;295:1531-1538.

  28. Study Design High-risk NSTE ACSn = 10,500 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) Routine, early eptifibatide(180/2/180) Placebo / delayed provisional eptifibatide pre-PCI Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization Safety Endpoints at 120 hrs: Bleeding (GUSTO and TIMI scales), Transfusions, Stroke, Non-hemorrhagic SAEs Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout Key Secondary Endpoint: 30-d Death or MI

  29. Kaplan-Meier Curves for Primary Endpoint 15 10.0% 10 Delayed provisional eptifibatide 9.3% Death, MI, RIUR or TBO (%) P = 0.23 (stratified for intended early clopidogrel use) 5 Routine early eptifibatide 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time Since Randomization (Hours)

  30. Initial Therapies • In ED, patient received: • ASA 325mg PO x1 • 5mg IV metoprolol x1 • IV unfractionated heparin w/ bolus and infusion (weight based) • Clopidogrel 300 mg • Referred for cardiac catheterization

  31. Cardiac Catheterization • Single Vessel CAD • 95% Proximal Hazy LAD lesion consistent with acute plaque rupture with thromboisis • TIMI 3 (Normal) Flow

  32. Revascularization Strategy in UA/NSTEMI Cardiac cath Discharge from protocol CAD No Yes Yes Left main disease CABG No 1- or 2- Vessel Disease 3- or 2-vessel disease with proximal LAD involvement LV dysfunction or treated diabetes* Yes CABG Medial Therapy, PCI or CABG No *There is conflicting information about these patients. Most consider CABG to be preferable to PCI. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 20. PCI or CABG

  33. Cardiac Catheterization • Drug Eluting Stent (2.5 x 15) to proximal LAD • Drug Eluting Stent (2.25 x 12) to mid LAD • Both stents post-dilated and fully deployed • Heparin discontinued

  34. 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates Duration of Thienopyridine Therapy Modified Recommendations • In patients receiving a stent (BMS or DES) during PCI for ACS, clopidogrel 75 mg daily or prasugrel 10 mg daily should be given for at least 12 months • If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered B C Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):2205-2241.

  35. 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates Duration of Thienopyridine Therapy Modified Recommendation • Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing drug-eluting stent placement C Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):2205-2241.

  36. Secondary Prevention: Additional Recommendations (cont) Cardiac rehab BP control <140/90 mm Hg <130/80 mm Hg with diabetes or CKD Diabetes management: HbA1c <7% Smoking cessation/no environmental smoke exposure Education, referral programs, drug therapy Physical activity (30-60 min, 7 d/wk; min 5 d/wk) Weight management BMI 18.5-24.9 kg/m2 Waist circumference: men, <40 in; women, <35 in Discharge education/referral Stepped-care approach to musculoskeletal pain management Annual influenza immunization HRT, antioxidant vitamin supplements (C, E, beta carotene) and folic acid not recommended 2007 ACC/AHA UA/NSTEMI Guideline Revision Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

  37. Changes from (Post-ACS) Baseline in Median LDL-C Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) 120 100 Pravastatin 40mg 21% 80 LDL-C (mg/dL) 60 Atorvastatin 80mg 49%  40 P<0.001 20 <24h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final • Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event • ACS response lowers LDL-C from true baseline

  38. 0 30 3 6 9 12 15 18 21 24 27 All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 10 16% RR (P = 0.005) 5 0 Months of Follow-up

  39. HD # 3 - Discharge • Patient discharged to home to f/u in cardiology clinic in 2 weeks • Discharge regimen including: • ASA 162 mg PO • Clopidogrel 75mg PO QD • Metoprolol XL 50 mg/d • Lisinopril 10 mg/d • Atorvastatin 80 mg

  40. β-blockers ACE inhibitors/ARBs Aldosterone blockade (low EF) Lipid management Statin regardless of baseline LDL-C initiated prior to discharge Goal LDL-C <100 mg/dL LDL <70 mg/dL reasonable Treatment of triglycerides and non–HDL-C useful If TG 200-499 mg/dL, non–HDL-C should be <130 mg/dL TG 500 mg/dL, fibrate or niacin before LDL-C lowering to prevent pancreatitis Encouraging consumption of omega-3 fatty acids for risk reduction reasonable For treatment of elevated triglycerides, higher doses may be used for risk reduction 2007 ACC/AHA UA/NSTEMI Guideline Revision Secondary Prevention: Additional Recommendations Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

  41. Two days after discharge… • Recurrent CP while cleaning her basement • Returned to ED with 8/10 crushing SSCP • Patient reported compliance with her medications • IV UFH started in ED

  42. Cardiac Catheterization • Total Occlusion of LAD in previously stented segment consistent with STENT THROMBOSIS

  43. 2 additional stents deployed bridging gap between prior stents IVUS showed no evidence of edge dissection, stents fully deployed Reloaded with clopidogrel 600mg x1 Peak CK 2100, CK-MB 150 TTE: LVEF 40%, HK antero-septal wall Hospital Course

  44. Stent Thrombosis: A Multifactorial Problem Lesion • Long lesions • Small diameter • Multivessel • Acute myocardial infarction (AMI) • Diabetes • Bifurcations Technical • Underexpansion • Incomplete wall apposition • Crush technique • Overlapping Stent Thrombosis Stent • Material • Polymer matrix • Antithrombotic agent Patient • Antiplatelet noncompliance • Response variability Adapted from Kereiakes DJ et al. Rev Cardiovasc Med. 2004;5:9-15.

  45. Early Discontinuation of Antiplatelet Therapy Is an Important Risk Factor for ST Overall ST-elevation = 1.3% (P = .09, N=2229) 30 29.0 20 Incidence (%) 10 8.7 6.2 3.6 3.3 2.5 2.0 1.4 0 UA Thrombus Diabetes Unprotected left main artery Bifurcation lesion Renal failure Prior brachytherapy Premature antiplatelet therapy discontinuation Iakovou I, et al. JAMA. 2005;293:2126-2130.

  46. Clopidogrel Response Variability: Increase the Dose (300 mg vs. 600 mg) 33 300 mg Clopidogrel 30 600 mg Clopidogrel 27 Resistance = 28% (300 mg) 24 Resistance = 8% (600 mg) 21 18 Patients (%) 15 12 9 6 3 0 ≤-30 (-20,-10] (0,10] (20,30] (40,50] (60,70] (-30,-20] (-10,0] (10,20] (30,40] (50,60] > 70 DAggregation (5 µM ADP-induced Aggregation) at 24 Hr Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.

  47. The RECLOSE Study: 6-Month Outcomes After DES Implantation Stratified by Post-Clopidogrel ADP-mediated Platelet Reactivity Non-responders defined as >70% aggregation by LTA 12 hours after 600 mg clopidogrel load P < 0.001 P < 0.001 P < 0.001 Antoniucci D et al. Presented at ACC 2007.

  48. Platelet Function Test • Platelet response assessed on ASA 162mg QD and clopidogrel 75mg BID using Accumetrics™ device • Appropriate response to aspirin (ARU 410, non-responder >550) • HOWEVER, only 0-3% platelet inhibition to clopidogrel 75mg BID (PRU 253, baseline PRU 260)

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