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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

2 Disclosures CME 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: Meds on admission: ASA 81mg PO QD
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 Data 10.4 328 38.7 Troponin I = 0.12 (ULN = 0.04)
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 10.4 328 38.7 Troponin I = 0.12 (ULN = 0.04) CK = 105, CK-MB = 5.2 (ULN =5)

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8 ACUTE CORONARY SYNDROMES
Spectrum of CAD No ST elevation ST elevation Stable angina Unstable angina NSTEMI STEMI ACUTE CORONARY SYNDROMES This slide illustrates the spectrum of coronary artery disease and distinguishes ST-segment elevation myocardial infarction (STEMI) from unstable angina and non-ST-segment elevation MI by illustrating occlusive and non-occlusive thrombi. Acute coronary syndromes represent a spectrum of diseases with underlying coronary plaque rupture and thrombosis. The severity of the syndrome depends on the degree of occlusion. Classic ST-segment elevation myocardial infarction (STEMI) is characterized by virtually total thrombotic occlusion, while unstable angina/non–ST-segment elevation myocardial infarction (UA/NSTEMI) is characterized by subtotal, but nevertheless severe, occlusion. Stable angina is associated with occlusion without thrombus formation. Perhaps 99% of all plaque ruptures are clinically silent. A minor rupture may produce a small thrombus that heals, but contributes to a cumulative plaque buildup that is analogous to the rings on a tree. This atherothrombotic progression should emphasize the key role of antithrombotic therapy in both acute and chronic management of patients with ACS.1 The number of unique hospital discharges for ACS in 2004 was estimated at 1.57 million. Approximately 0.33 million of these were for STEMI and about 1.24 million per year were for UA/NSTEMI.2 ~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. Cannon CP. Optimizing the treatment of unstable angina. J Thromb Thrombolysis. 1995;2: American Heart Association. Heart Disease and Stroke Statistics—2007 Update. Circulation. 2007; 115: Photos courtesy of Davies MJ. The pathophysiology of acute coronary syndromes. Heart. 2000;83: Reprinted with permission from Davies MJ. Heart. 2000;83: American Heart Association. Heart Disease and Stroke Statistics—2007 Update. Circulation. 2007; 115:

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

10 Risk Assessment Dependent on Contingent Probabilities
2007 ACC/AHA UA/NSTEMI Guideline Revision 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 Assessment of a patient’s risk begins at the initial evaluation, which should provide information about the diagnosis and prognosis. The attempt should be made to answer two questions. First, what is the likelihood that the signs and symptoms represent ACS secondary to obstructive CAD? In patients with ACS, traditional risk factors are less important than are symptoms, ECG findings, and cardiac biomarkers. The 2007 ACC/AHA UA/NSTEMI Guideline Revision recommends that the presence or absence of traditional risk factors ordinarily not be heavily weighed in determining whether a patient should be admitted or treated for ACS. Second, what is the likelihood of an adverse clinical outcome? Outcomes of concern include death, MI or recurrent MI, stroke, heart failure, recurrent symptomatic ischemia, and serious arrhythmia. Factors that predict the risk of a bad outcome are older age, hemodynamic abnormalities, ECG findings, and biomarkers. Anderson JL, et al. Accessed August 8, Reproduced by STRIVE with permission from Cardiosource.com. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2007;50(7):e1-e157.

11 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) Number of Predictors 5 10 15 20 25 30 35 40 45 0/1 2 3 4 6/7 % Death / MI / Revasc A simplified TIMI 11B risk score has been developed to predict the risk of death and cardiac ischemic events in patients with unstable angina or non–ST-segment elevation myocardial infarction (UA/NSTEMI) and to provide a basis for individualized therapeutic decisions.1 This scoring system is based on an analysis of more than 7000 patients from two randomized, double-blind international trials: the Thrombolysis In Myocardial Infarction (TIMI) 11B study (N=3910) and the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave MI (ESSENCE) study (N=3171).2,3 Seven easily evaluable risk variables were chosen: age 65 years; at least 3 risk factors for CAD; ST-segment deviation at presentation; at least 2 anginal events in the past 24 hours; prior coronary stenosis 50%; use of aspirin in the preceding 7 days; and elevated serum cardiac markers.1 To calculate the risk score, simply add the number of risk factors that are present. The score will therefore range from 0 to 7.1 A pattern of increasing events with risk score was observed in all cohorts. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non–ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284: Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation. 1999;100: Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337: Antman EM, et al. JAMA. 2000;284:

12 NSTEMI 6-Month Postdischarge Mortality
Our Patient’s GRACE Prediction Score for All-Cause Mortality From Discharge to 6 Months NSTEMI 6-Month Postdischarge Mortality Risk GRACE Probability Category Score of Death Low <3% Medium % High >8% table.cfm. The Global Registry of Acute Coronary Events (GRACE) risk model, which predicts in-hospital mortality (and death or MI), can be useful in guiding treatment type and intensity. The sum of the individual scores for each of 9 variables is applied to a reference monogram to determine the corresponding all-cause mortality from hospital discharge to 6 months. As shown on the slide, the patient’s total risk score is 150 points, based on his scores for the 9 variables: Age of 76 years (73 points) History of congestive heart failure (24 points) No history of MI (0 points) Resting heart rate of 90 bpm (14 points) Systolic blood pressure of 162 mm Hg (4 points) ST-segment depression (11 points) Initial serum creatinine level of 1.7 mg/dL (9 points) Elevated cardiac enzymes (15 points) No in-hospital PCI (0 points) His mortality risk is 10% (high risk). 125 8% Reprinted with permission from Eagle KA, et al. JAMA. 2004;291(22): Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291(22):

13 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% VANQWISH 27.2% 28.0% MATE 12.0% 8.9% FRISC II 4.3% 11.4% TACTICS A search of the MEDLINE and Cochrane databases from 1970 through June 2004 found 7 randomized, controlled trials that evaluated early invasive or early conservative treatment for UA or NSTEMI. A total of 9212 patients were treated in these trials. A meta-analysis of these trials revealed that rates of death or MI were reduced in patients receiving early invasive treatment (OR 0.82, P=.001). However, during early hospitalization the early invasive strategy was associated with a significantly higher rate of death (1.8% vs 1.1%, P=.007). Lower rates after discharrge (mean follow up: 17 months) led to the lower overall incidence. This analysis shows that while an early invasive strategy is superior overall to an early conservative strategy, better strategies are needed to minimize early mortality. 4.0% 5.3% 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 Invasive Favors Conservative Mehta SR, Cannon C, Fox KAA,, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes. JAMA. 2005;293: Adapted with permission from Mehta S, et al. JAMA. 2005;293:

14 ACC/AHA UA/NSTEMI Guidelines: High-risk Indicators for Early Invasive Strategy
Preferred Strategy Patient Characteristics Invasive Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy Elevated cardiac biomarkers (TnT or TnI) New or presumably new ST-segment depression Signs or symptoms of HF or new or worsening mitral regurgitation High-risk findings from noninvasive testing Hemodynamic instability Sustained ventricular tachycardia PCI within 6 months Prior CABG High-risk score (eg, TIMI, GRACE) Reduced left ventricular function (LVEF of <40%) Conservative Low-risk score (eg, TIMI, GRACE) Patient or physician preference in the absence of high-risk features ACC/AHA 2002 UA/NSTEMI guidelines: High-risk indicators for early invasive strategy Patients with UA/NSTEMI, recurrent symptoms suggestive of ACS and/or ECG ST-segment deviations, or positive cardiac biomarkers who are stable hemodynamically should be admitted to an inpatient unit for bed rest with continuous rhythm monitoring and careful observation for recurrent ischemia (a step-down unit) and managed witheither an invasive or conservative strategy. Patients with continuing discomfort and/or hemodynamic instability should be hospitalized for at least 24 h in a coronary care unit characterized by a nursing-to-patient ratio sufficient to provide: 1) continuous rhythm monitoring, 2) frequent assessment of vital signs and mental status, 3) documented ability to perform defibrillation quickly after the onset of ventricular fibrillation, 4) adequate staff to perform these functions. Patients should be maintained at that level of care until they have been observed for an adequate period of time, generally at least 24 h, without any of the following major complications: sustained ventricular tachycardia or fibrillation, sinus tachycardia, high-degree atrioventricular (AV) block, sustained hypotension, recurrent ischemia documented by symptoms or ST-segment change, new mechanical defect (ventricular septal defect or mitral regurgitation), or HF. Shorter periods of monitoring might be appropriate for selected patients who are successfully reperfused and who have normal LV function and minimal or no necrosis. 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

15 TIMACS: GRACE Score and Primary End Point
ACC 2010 Dr BhattSymo\posium to GA_021710 TIMACS: GRACE Score and Primary End Point Mehta/p 2170/col 2/para 2; p 2171/Figure 2 HR=0.65 ( ) P=0.006 HR=1.12 ( ) 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):

16 Timing of Angiography in UA/NSTEMI
2009 ACC/AHA STEMI/PCI Guidelines Focused Updates Timing of Angiography in UA/NSTEMI New Recommendation B 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 Kushner FG, Hand M, Smith SC Jr, et al focused updates: ACC/AHA guidelines for the management of patients With ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54(23): Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):

17 Diagnosis of UA/NSTEMI is Likely or Definite
Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy 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.

18 Initial Invasive Strategy: Antiplatelet, Anticoagulant Therapy
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 According to the ACC/AHA 2007 guidelines for the management of patients with UA/NSTEMI, anticoagulant therapy with enoxaparin or UFH (class I, level of evidence: A) or bivalirudin or fondaparinux (class I, level of evidence: B) should be initiated as soon as possible after presentation. Prior to angiography, initiate clopidogrel or an IV GP IIb/IIIa inhibitor (class I, level of evidence: A) or both (class IIa, level of evidence: B). Use both if there is delay to angiography, high-risk features, or early recurrent ischemic syndromes. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2007;50(7):e1-e157. Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

19 CURE: Primary Outcome by Type of Intervention
Cumulative Hazard Rates 0.20 0.15 0.10 0.05 0.00 Any Revascularization Group 100 200 300 Placebo Clopidogrel RR:0.82 ( ) Cumulative Hazard Rates 0.20 0.15 0.10 0.05 0.00 Medical Rx Group Days of Follow-up 100 200 300 Placebo Clopidogrel RR:0.80 ( ) Days of Follow-up Among the 12,562 ACS patients in the CURE study, 9.3% of those randomized to clopidogrel experienced the primary end point of cardiovascular death, MI, or stroke compared with 11.4% of those taking placebo (RR 0.80, 95% CI, ; P<.001). All patients received aspirin (75 mg to 325 mg daily). 2072 patients underwent CABG and 2658 underwent PCI, for a total revascularization rate of 36.4%. For any revascularization, 11.5% of patients in the clopidogrel group and 13.9% in the placebo group sustained the primary end point (RR 0.82, 95% CI, ). The benefits were consistent among those undergoing PCI (9.6% for clopidogrel vs 13.2% for placebo; RR 0.72, 95% CI, ) and CABG (14.5% for clopidogrel vs 16.2% for placebo; RR 0.89, 95% CI, ), and among those receiving medical therapy only (8.1% for clopidogrel vs 10.0% for placebo; RR 0.80, 95% CI, ; test for interaction among strata not significant). Comparable benefits were seen among the 1015 patients who underwent surgical revascularization during their initial hospitalization (RR 0.81; 95% CI, ). 0.20 0.20 PCI Group CABG Group 0.15 0.15 Placebo Placebo Cumulative Hazard Rates 0.10 Cumulative Hazard Rates 0.10 Clopidogrel Clopidogrel 0.05 0.05 RR:0.72 ( ) RR:0.89 ( ) 0.00 0.00 100 200 300 100 200 300 Days of Follow-up Days of Follow-up Adapted with permission from Fox KAA, et al. Circulation. 2004;110: Fox KAA, Mehta SR, Zhao F, Gersh B, Yusuf S. The risks versus benefits of clopidogrel treatment in acute coronary syndrome patients overall, and those undergoing CABG: the CURE trial. Circulation. 2004;110:

20 Timing of Antiplatelet Therapy in UA/NSTEMI
2009 ACC/AHA STEMI/PCI Guidelines Focused Updates Timing of Antiplatelet Therapy in UA/NSTEMI New Recommendation A 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 A A B Kushner FG, Hand M, Smith SC Jr, et al focused updates: ACC/AHA guidelines for the management of patients With ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54(23): Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):

21 Initial Medical Treatment: Anticoagulant Dosing
2007 ACC/AHA UA/NSTEMI Guideline Revision Initial Medical Treatment: Anticoagulant Dosing Bivalirudin 0.1 mg/kg bolus, 0.25 mg/kg/h infusiona Enoxaparin 30 mg IV bolus may be givena 1 mg/kg SC every 12 h; extend dosing interval to 1 mg/kg every 24 h if estimated creatinine clearance <30 mL/min Fondaparinux 2.5 mg SC once dailya Avoid for creatinine clearance <30 mL/min Unfractionated heparin 60 U/kg (max 4000 U) as IV bolus IV infusion of 12 U/kg/h (max 1000 U/h) to maintain aPTT at times control (approx s) Antithrombotic therapy is essential to modify the disease process and its progression to death, MI, or recurrent MI in the majority of patients who have ACS due to thrombosis or plaque. A combination of aspirin, an anticoagulant, and additional antiplatelet therapy represents the most effective therapy. The intensity of treatment is tailored to individual risk, and triple-antithrombotic treatment is used in patients with continuing ischemia or with other high-risk features and in patients oriented to an early invasive strategy. Anticoagulant therapy should be added to antiplatelet therapy in UA/NSTEMI patients as soon as possible after presentation. The slide shows the recommended doses of the various anticoagulant agents. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2007;50(7):e1-e157. a Use in UA/NSTEMI is off-label. Adapted from Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157. 21

22 ACUITY Study: 30-Day Results
Moderate- to high-risk patients with UA or NSTEMI undergoing an invasive strategy (N=13,819) UFH or enox + GP IIb/IIIa n=4603 Ischemic Composite Bleeding Net Clinical Outcome 7.3% 5.7% 11.7% 7.7% 5.3% 11.8% 7.8% 3.0% 10.1% Moderate- to high- risk ACS Bivalirudin + GP IIb/IIIa n=4604 R* The ACUITY trial used a 2  2 factorial design to compare a heparin (UFH or enoxaparin) with or without upstream GP IIb/IIIa inhibition versus bivalirudin with or without upstream GP IIb/IIIa inhibition; a third arm tested bivalirudin alone and provisional BP IIb/IIIa inhibition. Bivalirudin plus a GP IIb/IIIa inhibitor compared with UFH/enoxaparin and a GP IIb/IIIa inhibitor was associated with noninferior 30-day rates of the composite ischemia end point (7.7% for bivalirudin/GP IIb/IIa inhibitor vs 7.3% for UFH/enoxaparin/GP IIb/IIIa inhibitor), major bleeding (5.3% vs 5.7%) and the net clinical outcome end point (11.8% vs 11.7%). Bivalirudin alone compared with UFH/enoxaparin and a GP IIb/IIIa inhibitor was associated with noninferior 30-day rates of the composite ischemia end point (7.8% vs 7.3%, P=.32), significantly reduced rates of major bleeding (3.0% vs 5.7%, P<.001), and superior 30-day net clinical outcomes (10.1% vs 11.7%, P=.02). Bivalirudin alone n=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): Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J. 2004;148: Stone GW, McLaurin BT, Cox DA, et al for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355(21):

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

24 Excess Dosing of Antithrombotic Agents
Dose and Major Bleeding 35 30 25 20 15 10 5 Underdosed Recommended Mild Excess Major Excess Major Bleeding, % Investigators undertook a prospective observational analysis that included 30,136 CRUSADE patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS) to determine the frequency with which UFH, LMWH, and GP IIb/IIIa inhibitors were administered in doses exceeding recommendations; patient and hospital factors associated with the delivery of excess doses; and the association between dosing and major outcomes after adjustment. A total of 3354 patients (42%) with NSTE ACS who were administered antithrombotic agents received at least 1 initial dose outside the recommended range. An excess dose was administered to 2934 patients (32.8%) treated with UFH, 1378 (13.8%) treated with LMWH, and 2784 (26.8%) treated with GP IIb/IIIa inhibitors. As shown on the slide, a dose-response relationship was seen between the magnitude of excess dose and bleeding for all 3 agents (P<.001 for both UFH and GP IIb/IIIa inhibitors; P=.25 for LMWH). Factors associated with excess dosing included older age, as well as female sex, renal insufficiency, low body weight, diabetes mellitus, and congestive heart failure. Relative to patients not administered excess dosages, patients with excess dosages of UFH, LMWH, and GP IIb/IIIa inhibitors either tended toward or had higher risks for major bleeding (adjusted odds ratio [OR], 1.08; 95% CI, ; OR, 1.39; 95% CI, ; and OR, 1.36; 95% CI, , respectively). The study showed that dosing errors are common in community practice, particularly among vulnerable populations, and are associated with an increased risk of major bleeding. (n=2074) (n=2063) (n=2073) (n=714) (n=2327) (n=3998) (n=922) (n=237) (n=5879) (n=1955) (n=178) Unfractionated Heparin Low-Molecular-Weight Heparin Glycoprotein IIb/IIIa Inhibitors Treatment Group Reproduced with permission from Alexander KP, et al. JAMA. 2005;294(24): Alexander KP, Chen AY, Roe MT, et al; CRUSADE Investigators. Excess dosing of antiplatelet and antithrombin agents in the treatment of non–ST-segment elevation acute coronary syndromes. JAMA. 2005;294(24):

25 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 For 2008, the ACC/AHA writing committee to develop performance measures for STEMI and NSTEMI changed LDL-cholesterol testing during inpatient hospitalization for AMI from a performance measure to a test measure. The committee felt that as a performance measure, LDL assessment generates substantial data collection burden, may be difficult to ascertain from chart review, and may not necessarily improve quality regarding the ultimate goal of ensuring that patients appropriate for lipid-lowering therapy receive a discharge prescription. Five test measures relate to excessive initial dosing of UFH, enoxaparin, eptifibatide, tirofiban, and abciximab, the most commonly used agents. Excess dosing of anticoagulant therapy and IV GP IIb/IIIa inhibitors in patients with UA/NSTEMI is a common occurrence, particularly in vulnerable populations such as the elderly and patients with impaired renal function. Recommended doses for parenteral anticoagulant therapy and IV GP IIb/IIIa inhibitors are well established but may require knowledge of patient weight and/or glomerular filtration rate to guide dosing. An anticoagulant dosing protocol is recommended to avoid excess dosing; an anticoagulant error tracking system is recommended for the same reason. Consistent with current ACC/HA clinical practice guidelines for STEMI and UA/NSTEMI, the writing committee also agreed to adopt prescription of clopidogrel at hospital discharge for medically treated AMI patients as a test performance measure. Krumholz HM, Anderson JL, Bachelder BL, et al. ACC/AHA 2008 performance measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures for ST-Elevation and Non-ST-Elevation Myocardial Infarction) Developed in Collaboration With the American Academy of Family Physicians and American College of Emergency Physicians Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, Society for Cardiovascular Angiography and Interventions, and Society of Hospital Medicine. J Am Coll Cardiol. 2008;52(24): a For use in internal quality improvement programs only. Krumholz HM, et al. J Am Coll Cardiol. 2008;52(24):

26 GP IIb/IIIa Inhibition for Non–ST-Elevation ACS
30-Day Death or Nonfatal MI GP IIb/IIIa Inhibitor Trial n Risk Ratio and 95% CI Placebo PRISM 3,232 7.1% 5.8% PRISM-PLUS 1,915 11.9% 10.2% PARAGON A 2,282 11.7% 11.3% The utility of glycoprotein IIb/IIIa inhibitors is illustrated in this meta-analysis by Boersma, et al. Overall, there was an approximately 8% reduction in the risk of death or nonfatal MI across six ACS trials — statistically significant although relatively modest in its overall size. The findings with abciximab in GUSTO-IV ACS were not consistent with findings from studies of eptifibatide, tirofiban, or lamifiban in UA/NSTEMI patients. In the PRISM, PRISM PLUS, PARAGON A, PARAGON B, and PURSUIT studies, the benefits of these agents were consistently significant. Potential explanations for GUSTO-IV ACS findings include: The extremely conservative management strategy employed in this study, especially in such a high risk population; and the use of a dosing regimen that did not maintain adequate inhibition of platelet aggregation (> 80%) over for the full duration of treatment. PURSUIT 9,461 15.7% 14.2% PARAGON B 5,165 11.4% 10.5% GUSTO-IV ACS 7,800 8.0% 8.7% 0.92 (0.86, 0.995) P=.037 11.5% 10.7% Pooled 29,855 0.5 GP IIb/IIIa Inhibitor Better 1.0 Placebo Better 1.5 CI = confidence interval. Boersma E, et al. Lancet. 2002;359: Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:

27 Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials
TnT-Positive TnT-Negative PARAGON-B PRISM Treatment benefit of GP IIb/IIIa therapy is limited almost exclusively to troponin-positive patients. Both the individual and the combined odds ratios of the PARAGON-B, PRISM, and CAPTURE trials support the value of GP IIb/IIIa inhibitor therapy in reducing the increased risk of death or nonfatal MI in patients with acute coronary syndromes and elevated troponin levels. By contrast, there was no significant treatment effect in patients in troponin-negative patients (combined OR, 1.06; 95% CI, ). 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: Newby LK, Ohman EM, Christenson RH, et al; for the PARAGON-B Investigators. The PARAGON-B Troponin T Substudy. Circulation. 2001;030:

28 Days After Randomization
ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets With and Without Elevated Troponin levels (>0.03 µg/L) Placebo Group (n=1010) Abciximab Group (n=1012) 20 15 10 5 Troponin >0.03 µg/L Log-Rank P=.02 Cumulative Rate of Primary End Point, % The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) trial, included ACS patients undergoing PCI that were pretreated with 600 mg of clopidogrel at least two hours before the procedure. In this trial, there was no benefit of adding a GP IIb/IIIa inhibitor, in this case abciximab, to the troponin-negative patients. On the other hand, there was a significant 30% reduction in events — death, MI or urgent target vessel revascularization, in the troponin positive group. Thus, there is now very current data confirming that in an ACS patient who is non-STEMI with a positive troponin, the addition of a GP IIb/IIIa inhibitor, even on top of clopidogrel, is of benefit. Troponin ≤0.03 µg/L Log-Rank P=.98 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: Kastrati A, Mehilli J, Neumann F-J, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA. 2006;295:

29 Placebo / delayed provisional eptifibatide pre-PCI
Study Design 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) High-risk NSTE ACS n = 10,500 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

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

31 In ED, patient received:
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

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

33 Revascularization Strategy in UA/NSTEMI
Cardiac cath Discharge from protocol CAD No Yes Left main disease Yes 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

34 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

35 Duration of Thienopyridine Therapy
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, Hand M, Smith SC Jr, et al focused updates: ACC/AHA guidelines for the management of patients With ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54(23): Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):

36 Duration of Thienopyridine Therapy
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, Hand M, Smith SC Jr, et al focused updates: ACC/AHA guidelines for the management of patients With ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54(23): Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):

37 Secondary Prevention: Additional Recommendations (cont)
2007 ACC/AHA UA/NSTEMI Guideline Revision 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 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 Patients with blood pressure ≥140/90 mm Hg (or ≥130/80 mm Hg for patients with diabetes or chronic kidney disease), should initiate or maintain lifestyle modification—weight control, increased physical activity, alcohol moderation, sodium reduction, and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products. For such patients, it is useful as tolerated to add blood pressure medication, treating initially with -blockers and/or ACE inhibitors, with the addition of other drugs such as thiazides as needed to achieve goal blood pressure. Patients with diabetes should initiate lifestyle changes or take medication to achieve near-normal HbA1c. The 2007 goal for smoking is complete cessation and no exposure to environmental tobacco smoke. All patients should be encouraged to achieve 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking on most—preferably all—days of the week, supplemented by an increase in daily lifestyle activities (eg, walking breaks at work, gardening, and household work). It is recommended that patients maintain/achieve a BMI between 18.5 and 24.9 kg/m2. If waist circumference is ≥40 inches (102 cm) in men and ≥35 inches (89 cm) in women, it is useful to initiate lifestyle changes and consider treatment strategies for metabolic syndrome as indicated. Detailed discharge instructions should include education on medications, diet, exercise, and smoking cessation counseling (if appropriate), referral to a cardiac rehabilitation/secondary prevention program (when appropriate), and the scheduling of a timely follow-up appointment. Low-risk medically treated patients and revascularized patients should return in 2 to 6 weeks, and higher risk patients should return within 14 days. NSAIDs should be discontinued at the time of presentation and avoided during hospitalization. A stepped-care approach to treatment, beginning with acetaminophen, small doses of narcotics, or nonacetylated salicylates, should be used. Patients with cardiovascular disease should have an annual influenza vaccination. Menopausal hormone therapy (estrogen plus progestin or estrogen alone) should not be given de novo for secondary prevention of coronary events. Antioxidant vitamin supplements (C, E, or beta carotene) and folic acid (with or without B6 and B12) should not be used for secondary prevention. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2007;50(7):e1-e157. Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157. 37

38 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

39 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 3 18 21 24 27 30 6 9 12 15 Months of Follow-up

40 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

41 Secondary Prevention: Additional Recommendations
2007 ACC/AHA UA/NSTEMI Guideline Revision Secondary Prevention: Additional Recommendations 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 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 -blockers are indicated for all patients recovering from UA/NSTEMI unless contraindicated. Treatment should begin within a few days of the event, if not initiated acutely, and should be continued indefinitely. ACE inhibitors should be started and continued indefinitely in all patients with LVEF ≤40% and for those with hypertension, diabetes, or chronic kidney disease, unless contraindicated. Use of angiotensin receptor blockers (ARBs) is recommended in patients who are intolerant of ACE inhibitors and have heart failure or have had an MI with LVEF ≤40%. Use of aldosterone blockade in post-MI patients without significant renal dysfunction or hyperkalemia is recommended in patients who are already receiving therapeutic doses of an ACE inhibitor and -blocker, have an LVEF ≤40%, and have either diabetes or heart failure. A fasting lipid panel should be assessed in all patients and within 24 hours of hospitalization for those with an acute cardiovascular or coronary event. For hospitalized patients, initiation of lipid-lowering medication is indicated before discharge (LDL-C should be <100 mg per dL; further reduction of LDL-C to <70 mg per dL is reasonable). Adding plant stanol/sterols (2 g per day) and/or viscous fiber (>10 g per day) is reasonable to further lower LDL-C. If triglycerides are 200 to 499 mg/dL, further reduction of non–HDL-C to less than 100 mg per dL is reasonable. Encouraging consumption of omega-3 fatty acids in the form of fish or in capsule form (1 g per d) for risk reduction may be reasonable. For treatment of elevated triglycerides, higher doses (2 to 4 g per d) may be used for risk reduction (class IIb, level of evidence: B). For patients with blood pressure ≥140/90 mm Hg (or ≥130/80 mm Hg for patients with diabetes or chronic kidney disease), it is recommended to initiate or maintain lifestyle modification—weight control, increased physical activity, alcohol moderation, sodium reduction, and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products. For such patients, it is useful as tolerated to add blood pressure medication, treating initially with -blockers and/or ACE inhibitors, with the addition of other drugs such as thiazides as needed to achieve goal blood pressure. Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2007;50(7):e1-e157.

42 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

43

44 Cardiac Catheterization
Total Occlusion of LAD in previously stented segment consistent with STENT THROMBOSIS

45 Hospital Course 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

46 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 Thrombosis is a local problem, like restenosis. We can try to passivate every platelet, but at a high risk to the patient, OR we can make stents less thrombogenic with a passivating strategy. Stent Material Polymer matrix Antithrombotic agent Patient Antiplatelet noncompliance Response variability Adapted from Kereiakes DJ et al. Rev Cardiovasc Med. 2004;5:9-15.

47 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 The premature discontinuation of thienopyridine therapy is associated with a marked increase in the risk of stent thrombosis and is the leading independent predictor for stent thrombosis in multivariate analyses. Although the number of actual stent thromboses reported in individual studies is modest, the findings are noteworthy. The figure is from a prospective observational cohort study conducted at 1 academic hospital and 2 community hospitals in Germany and Italy. A total of 2229 consecutive patients underwent successful implantation of sirolimus-eluting (1062 patients, 1996 lesions, 2272 stents) or paclitaxel-eluting (1167 patients, 1801 lesions, 2223 stents) stents between April 2002 and January 2004. Premature discontinuation of antiplatelet therapy was found to be a major significant univariate predictor of stent thrombosis. The cumulative incidence of thrombosis was 29% (5 of 17 patients), with a hazard ratio of 152 (95% Confidence interval; 52 to 442; P<0.001); clopidogrel was discontinued in one patient. Other significant univariate predictors included prior brachytherapy, renal failure, bifurcation with 2 stents, bifurcation lesions, and diabetes, with respective cumulative thrombosis rates of 8.7%, 6.2%, 3.9%, 3.6%, and 2.5% (P<0.05). Unstable angina, thrombus, and unprotected left main artery were not significant univariate predictors of thrombosis. Incidence (%) 10 8.7 6.2 3.3 3.6 2.5 1.4 2.0 UA Thrombus Diabetes Unprotected left main artery Bifurcation lesion Renal failure Prior brachytherapy Premature antiplatelet therapy discontinuation Iakovou I, et al. JAMA. 2005;293: 47

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

49 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.

50 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)

51 Clinical Management No guideline recommendations
Aspirin increased to 325/d Clopidogrel increased to 150 mg/d (today may switch to prasugrel)

52 Study Design, Flow and Compliance
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose ( mg/d) vs Low dose ( mg/d) Angio 24,769 (99%) PCI 17,232 (70%) No PCI 7,855 (30%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Compliance: Clop in 1st 7d (median) 7d d d d Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Complete Followup 99.8%

53 Clopidogrel: Double vs Standard Dose Primary Outcome and Components
HR 95% CI P Intn P CV Death/MI/Stroke PCI (2N=17,232) 4.5 3.9 0.85 0.036 0.016 No PCI (2N=7855) 4.2 4.9 1.17 0.14 Overall (2N=25,087) 4.4 0.95 0.370 MI 2.6 2.0 0.78 0.012 0.025 1.4 1.7 1.25 0.23 2.2 1.9 0.86 0.097 CV Death 0.96 0.68 1.0 2.8 2.7 0.77 2.1 0.628 Stroke 0.4 0.88 0.59 0.50 0.8 0.9 1.11 0.67 0.5 0.99 0.950

54 Clopidogrel Double vs Standard Dose Bleeding Overall Population
Hazard Ratio 95% CI P TIMI Major1 0.95 1.04 1.09 0.50 CURRENT Major2 2.0 2.5 1.25 0.01 CURRENT Severe3 1.5 1.9 1.23 0.03 Fatal 0.11 0.13 1.15 0.71 ICH 0.05 0.67 0.53 RBC transfusion ≥ 2U 1.76 2.21 1.26 CABG-related Major 0.9 1.0 1.10 0.48 1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

55 Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio confirmed) Clopidogrel Standard Dose 0.012 42% RRR 0.008 Cumulative Hazard Clopidogrel Double Dose 0.004 HR 0.58 95% CI P=0.001 0.0 3 6 9 12 15 18 21 24 27 30 Days

56 85% Inactive Metabolites Esterases
Change the Agent? Prasugrel Pro-drug Oxidation (Cytochrome P450) HOOC * HS N O F Active Metabolite S Hydrolysis (Esterases) C H 3 Cl CH3 Clopidogrel 85% Inactive Metabolites Esterases OCH3 Herbert JM, Savi P. Sem Vasc Med. 2003;3:

57 Inhibition of Platelet Aggregation (IPA) at 24 Hours (Healthy Volunteers)
100.0 80.0 Interpatient Variability 60.0 40.0 Inhibition of Platelet Aggregation (%) Interpatient Variability 20.0 Clopidogrel Responder 0.0 Clopidogrel Non-responder *Responder = 25% IPA at 4 and 24 h -20.0 Response to Clopidogrel Response to Prasugrel Brandt JT et al. Am Heart J. 2007;153:66.e9-e16.

58 Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600
Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, Stroke 2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Wiviott SD, AHJ 2006

59 Balance of Efficacy and Safety
15 138 events Clopidogrel 12.1 HR 0.81 ( ) P=0.0004 CV Death / MI / Stroke 9.9 10 NNT = 46 Prasugrel Endpoint (%) This slide depicts the balance of efficacy and safety observed in the trial. At the top is shown the significant reduction in the primary endpoint as presented a few moments ago. The number needed to treat to prevent one event was 46 At the bottom is the rate of TIMI major non CABG bleeds--a key safety endpoint-- which was 2.4% with prasugrel and 1.8% with clopidogrel—a 0.6% Absolute risk increase. The excess of 35 major bleeds with prasugrel corresponded to an HR of 1.32 and P value of The number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167. 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32 ( ) P=0.03 1.8 Clopidogrel NNH = 167 30 60 90 180 270 360 450 Days Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

60 Stent Thrombosis (ARC Definite + Probable)
3 Any Stent at Index PCI N= 12,844 2.4 (142) Clopidogrel 2 Endpoint (%) 1.1 (68) 1 Prasugrel HR 0.48 P <0.0001 NNT= 77 30 60 90 180 270 360 450 Days Wiviott SD, Braunwald E, McCabe CH et al NEJM2007 Antman EM, AHA2007

61 Definite/Probable ST: Any Stent (N=12844)
Wiviott SD, Braunwald E, McCabe CH, Lancet 2008 Definite/Probable ST: Any Stent (N=12844) STENT ANALYSIS EARLY ST LATE ST HR 0.41 [ ] P<0.0001 HR 0.60 [ ] P=0.03 CLOPIDOGREL 1.56% PRASUGREL % of Subjects 59% 0.82% 40% 0.64% 0.49% DAYS Antman EM, NYHA 2007

62 Bleeding Events Safety Cohort (N=13,457)
ICH in Pts w Prior Stroke/TIA (N=518) Clopidogrel Prasugrel Clop 0 (0)% Pras 6 (2.3)% (P=0.02) % Events More details of the bleeding events are shown on this slide. The TIMI major non CABG bleed data are shown in the pair of bar graphs on the left, showing the increase in events with prasugrel Life threatening bleeding--another key safety EP ( defined as requiring a 4 unit txn, fluid or inotropic support, surgical intervention, or an ICH) occurred in 0.9 % of clopidogrel and 1.4% of prasugrel subjects—a 0.5% ARI with prasugrel, associated with a P value of 0.01 Subcategories of life threatening bleeding are shown to the right. Fatal bleeding occurred in 0.1% of pts with clopidogrel and was increased to 0.4% of patients with prasugrel—a 0.3% Absolute risk increase associated with a P value of There was no difference in ICH overall in the trial—occurring in 0.3% of pts in both groups. Of note, in the subgroup of 518 patients with a history of prior stroke or TIA, no ICH’s occurred with clopidogrel while 6 occurred with prasugrel—a significant difference at the 0.02 level. ARD 0.6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74 Wiviott SD, Braunwald E, McCabe CH et al NEJM2007 62

63 TIMI Major NonCABG Bleeds
Diabetic Subgroup N=3146 18 Clopidogrel 17.0 16 CV Death / MI / Stroke 14 12.2 12 HR 0.70 P<0.001 Endpoint (%) Prasugrel 10 NNT = 46 8 6 TIMI Major NonCABG Bleeds 4 Clopidogrel 2.6 2.5 2 Prasugrel 30 60 90 180 270 360 450 Days Wiviott SD, Circulation 2008

64 TIMI Major NonCABG Bleeds Days From Randomization
STEMI Cohort N=3534 15 CV Death / MI / Stroke Clopidogrel 12.4% 9.5% 10.0% 10 HR 0.79 Percent (%) ( ) 6.5% Prasugrel P=0.02 NNT = 42 HR 0.68 ( ) 5 P=0.002 TIMI Major NonCABG Bleeds Prasugrel 2.4 2.1 Clopidogrel 30 60 90 180 270 360 450 Days From Randomization Montalescot et al Lancet 2008

65 Lesson The first* adequately powered clinical trial to test and confirm the hypothesis: a drug with greater P2Y12 effect and less response variability reduces ischemic events compared to standard clopidogrel *Now corroborated by PLATO and OASIS 7- PCI

66 Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist
H N F S Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP) Direct acting Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y12 receptor Greater inhibition of platelet aggregation than clopidogrel Reversibly bound Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Functional recovery of all circulating platelets

67 20 µM ADP- Final Extent     * * IPA % † ‡ 100 Last
Maintenance Dose Loading Dose Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) * * 90 80  70 60 IPA %  50  40 30 20 10  weeks Onset Maintenance Offset Time (hours) 67

68 PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

69 PLATO Primary End Point: CV Death, MI, or Stroke
12 11 10 9 8 7 6 5 4 3 2 1 Clopidogrel 11.0 9.3 Ticagrelor K-M Estimated Rate, % per Year HR: 0.85 (95% CI, ); P=.02 Months Steg PG. Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida. 69 69

70 PLATO: All-Cause Mortality K-M Estimated Rate, % per Year
7 6 5 4 3 2 1 Clopidogrel 6.0 4.9 Ticagrelor K-M Estimated Rate, % per Year HR 0.82 (95% CI, ); P=.04 Months Steg PG Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida. 70 70

71 Time to major bleeding – primary safety event
15 Ticagrelor 11.58 11.20 10 Clopidogrel K-M estimated rate (% per year) 5 HR 1.04 (95% CI 0.95–1.13), p=0.434 60 120 180 240 300 360 Days from first IP dose No. at risk Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479 Adapted from Wallentin L, et al. N Engl J Med. 2009;361:

72 Time to non-procedure-related PLATO major bleeding
Completeness of follow-up 99.97% = five patients lost to follow-up 4 Ticagrelor 3 3.06 2.31 2 K-M estimated rate (% per year) Clopidogrel 1 HR 1.31 (95% CI 1.08–1.60), p=0.006 60 120 180 240 300 360 Days from first IP dose No. at risk Ticagrelor 9,235 7,641 7,247 6,979 5,496 4,067 3,698 Clopidogrel 9,186 7,718 7,371 7,134 5,597 4,147 3,764

73 Potential Sites for Response Variability
Poor compliance Inadequate administration (dose, generics?) Intestinal absorption Variable absorption (Genetics – ABCB1) Drug-drug interactions Hepatic metabolism Cytochrome P450 pathway Genetic polymorphisms CYP enzymes (2C19) Drug-drug interactions (CYP 2C19) Active metabolite P2Y12 receptor (irreversible inhibition) Genetic polymorphisms P2Y12 receptor Alternate pathways of platelet activation ↑ release of circulating ADP Higher baseline platelet reactivity GP IIb/IIIa receptor expression Genetic polymorphisms Adapted from O’Donoghue M and Wiviott SD Circulation 2007

74 GWAS of Platelet Aggregation in Response to Clopidogrel
14 CYP2C18-CYP2C19-CYP2C9-CYP2C8 -log10(P Value) 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Shuldiner A et al. JAMA 2009; 302:

75 Genetic Effects on PK/PD
Pharmacokinetics Pharmacodynamics CLOPIDOGREL Absolute Difference in DMPA % Difference in AUC0-t Gene P value P value CYP2C19 - 32.4 - 9.0 CYP2C9 - 6.8 0.59 - 0.6 0.86 CYP2B6 - 15.7 0.035 - 5.7 0.012 CYP3A5 5.6 0.59 7.5 0.012 CYP1A2 11.2 0.45 0.5 0.90 - 50 - 40 - 30 - 20 - 10 10 20 30 - 15 - 10 - 5 5 10 15 PRASUGREL Gene CYP2C19 - 6.1 0.061 - 1.3 0.63 CYP2C9 - 5.3 0.27 - 1.7 0.42 CYP2B6 - 0.4 0.90 - 0.6 0.65 CYP3A5 - 0.8 0.82 1.3 0.38 CYP1A2 - 3.5 0.47 - 1.6 0.37 - 50 - 40 - 30 - 20 - 10 10 20 30 - 15 - 10 - 5 5 10 15 Relative percent difference in AUC0-t (95%CI) in carriers vs non-carriers of a reduced-function allele Absolute difference in DMPA (95% CI) in carriers vs non-carriers of a reduced-function allele Mega JL et al. N Engl J Med. 2009;360: Mega JL et al. Circulation 2009

76 CYP2C19 Extended Classification
100 Clopidogrel 300mg 100 Clopidogrel 75mg 80 80 60 60 Reduction in MPA (%) at 24-hour Reduction in MPA (%) at 24-hour 40 40 20 20 UM EM IM PM n=47 n=43 n=27 n=3 UM EM IM PM n=22 n=31 n=29 n=8

77 CYP2C19 and Stent Thrombosis
Clopidogrel Prasugrel 4 4 Hazard Ratio 3.09 (95% CI ) P=0.015 n=1477 Hazard Ratio, 0.58 (95% CI ) P=0.48 n=1466 3 3 CYP2C19 Reduced-Function Allele Carriers 2.6 Definite or probable stent thrombosis (%) Definite or probable stent thrombosis (%) 2 2 Non-carriers 1.0 1 Non-carriers 0.8 1 Carriers 0.5 30 90 180 270 360 450 30 90 180 270 360 450 Days after randomization Days after randomization Number at Risk: Number at Risk: Non - Carrier 1014 1004 1001 989 885 765 547 Non - Carrier 1000 992 990 969 870 764 550 Carrier 375 368 366 359 316 279 186 Carrier 379 374 371 363 323 276 189 * Carriers ~30% of the population Mega JL et al. N Engl J Med. 2009;360:354-62/ Mega JL et al. Circulation 2009

78

79 CYP2C19 and Treatment with Clopidogrel
Risk Ratio (95% CI) P Value Major Adverse CV Events N=9,684 Carriers vs Non-Carriers 1.61 ( ) <0.001 Heterozygotes vs Wildtype 1.50 ( ) 0.016 Homozygotes vs Wildtype 1.81 ( ) 0.004 Stent Thrombosis Carriers vs Non-Carriers 2.76 ( ) <0.001 N=5,772 Heterozygotes vs Wildtype Homozygotes vs Wildtype 2.51 ( ) 4.78 ( ) <0.001 0.5 1.0 15.0 Risk Lower with CYP2C19 Variant Risk Higher with CYP2C19 Variant Mega, J et al AHA 2009

80 Clopidogrel and PPIs – The OCLA study
Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite Some PPIs are strong inhibitors of CYP2C19 activity PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP) Poor responders = 16 placebo and 39 in omeprazole PRI was measured at Day 1 and omeprazole vs. placebo was given for 7 days plus clopidogrel, PRI rechecked Graph represents change from baseline; omeprazole clearly attenuates the antiplatelet effect of clopidogrel, but is this significant clinically? p<0.0001 Gilard et al. J Am Coll Cardiol 2008;51:

81 Risk of Cardiovascular Events for Patients Taking Clopidogrel in Combination with a PPI
70 60 50 40 30 20 10 Clopidogrel + PPI Clopidogrel without PPI Adjusted OR 1.25 (95% CI ) Deaths or recurrent ACS (%) 90 180 270 360 450 540 630 720 810 900 990 1080 Days Since Discharge Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9): Ho PM, et al. JAMA. 2009;301:937

82 Results – 1 Year Endpoint from CREDO
Unadjusted Data Primary 1-Year Endpoint: Death, MI or Stroke 20 P=0.45 PPI at baseline (N=374) P=0.001 15 16.2 No PPI p-value is 0.035 No PPI at baseline (N=1742) 14.8 13.2 10 10.8 9.2 7.7 5 All N=2116 Placebo N=1063 Clopidogrel N=1053 Dunn S.P. et al AHA Slide courtesy of Steve Steinhubl MD 82

83 Observation from an RCT (TRITON-TIMI 38) Conducted for Another Purpose
Clopidogrel PPI use at randomization (n= 4529) Prasugrel CV death, MI or stroke CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI Days O’Donoghue M, et al Lancet 2009

84 COGENT STUDY P=0.001 CV Events Bhatt TCT 2009

85 Summary UA/NSTEMI is the most frequent manifestation of ACS
Early risk assessment guides angiography strategy and medication choices Dynamic evaluation based on angiogram and clinical course guides further therapy Robust evidence base allows for rational care. Future therapies in development may offer advantages over current standards


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