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 pain73 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 restSxs continued with minimal exertion over subsequent daysMorning 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 CholesterolHTNBreast CA: s/p left breast lumpectomy 12/05, s/p XRT, ER+ on tamoxifenPsoriasisMeds on admission:ASA 81mg PO QDTamoxifen 20mg PO QDIrbisartan 150mg PO QDPravastatin 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%, T97.6NADJVP 6 cm H20, nl contoursNo carotid bruitsCV: non-displaced discrete PMIExt: warm, no edema or tenderness bilaterally2+ DP bilat10.432838.7Troponin I = 0.12 (ULN = 0.04)CK = 105, CK-MB = 5.2 (ULN =5)
8 ACUTE CORONARY SYNDROMES Spectrum of CADNo ST elevationST elevationStableanginaUnstableanginaNSTEMISTEMIACUTE CORONARY SYNDROMESThis 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.1The 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 MillionDischarges Per Year~0.33 MillionDischarges Per YearCAD = 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 RevisionRisk Assessment Dependent on Contingent ProbabilitiesDoes this patient have symptoms due to acute ischemia from obstructive CAD?Likelihood of obstructive CAD as cause of symptomsDominated by acute findingsExaminationSymptomsMarkersTraditional risk factors are of limited utilityWhat is the likelihood of death, MI, heart failure?Risk of bad outcomeDominated by acute findingsOlder age very importantHemodynamic abnormalities criticalECG, markersAssessment 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 hST-segment deviationElevated cardiac markers (CK-MB or troponin)Number of Predictors510152025303540450/12346/7% Death / MI / RevascA 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.1This 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).2,3Seven 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.1To calculate the risk score, simply add the number of risk factors that are present. The score will therefore range from 0 to 7.1A 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 MonthsNSTEMI 6-Month Postdischarge MortalityRisk GRACE Probability Category Score of DeathLow <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).1258%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/UOdds RatioDeath or MITrialInvConsTIMI 3B5.1%8.1%VANQWISH27.2%28.0%MATE12.0%8.9%FRISC II4.3%11.4%TACTICSA 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%VINO4.8%14.8%RITA 37.4%10.9%TOTAL7.4%11.0%OR 0.82, P=.0010.20.5125FavorsInvasiveFavorsConservativeMehta 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 StrategyPatient CharacteristicsInvasiveRecurrent angina or ischemia at rest or with low-level activities despite intensive medical therapyElevated cardiac biomarkers (TnT or TnI)New or presumably new ST-segment depressionSigns or symptoms of HF or new or worsening mitral regurgitationHigh-risk findings from noninvasive testingHemodynamic instabilitySustained ventricular tachycardiaPCI within 6 monthsPrior CABGHigh-risk score (eg, TIMI, GRACE)Reduced left ventricular function (LVEF of <40%)ConservativeLow-risk score (eg, TIMI, GRACE)Patient or physician preference in the absence of high-risk featuresACC/AHA 2002 UA/NSTEMI guidelines: High-risk indicators for early invasive strategyPatients 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 hoursACC = 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 TAnderson 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_021710TIMACS: GRACE Score and Primary End PointMehta/p 2170/col 2/para 2; p 2171/Figure 2HR=0.65( )P=0.006HR=1.12( )P=0.48DelayedEarlyDeath, MI, or Stroke at 6 MonthsLow/Intermediate RiskScore ≤140N=2,070High RiskScore >140N=961GRACE=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 UpdatesTiming of Angiography in UA/NSTEMINew RecommendationBIt 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 reasonableKushner 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 StrategyASA (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE: A)AProceed with an Initial Conservative StrategySelect Management StrategyBInvasive StrategyInit ACT (Class I, LOE: A)Acceptable options: enoxaparin or UFH (Class I, LOE: A)bivalirudin or fondaparinux (Class I, LOE: B)B1Prior to AngiographyInit at least one (Class I, LOE: A) orboth (Class IIa, LOE: B) of the following:ClopidogrelIV GP IIb/IIIa inhibitorB2Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include:Delay to AngiographyHigh Risk FeaturesEarly recurrent ischemic discomfortProceed to Diagnostic AngiographyAnderson 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 RevisionInitial Invasive Strategy: Antiplatelet, Anticoagulant TherapyAspirinInitiate 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)ClopidogrelIV GP IIb/IIIa inhibitorUse both if:Delay to angiographyHigh-risk featuresEarly recurrent ischemic syndromesAccording 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 Rates0.200.150.100.050.00Any Revascularization Group100200300PlaceboClopidogrelRR:0.82 ( )Cumulative Hazard Rates0.200.150.100.050.00Medical Rx GroupDays of Follow-up100200300PlaceboClopidogrelRR:0.80 ( )Days of Follow-upAmong 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, ).0.200.20PCI GroupCABG Group0.150.15PlaceboPlaceboCumulative Hazard Rates0.10Cumulative Hazard Rates0.10ClopidogrelClopidogrel0.050.05RR:0.72 ( )RR:0.89 ( )0.000.00100200300100200300Days of Follow-upDays of Follow-upAdapted 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 UpdatesTiming of Antiplatelet Therapy in UA/NSTEMINew RecommendationAPatients 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)orprasugrel (at the time of PCI) is recommended as a second antiplatelet agentAABKushner 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 RevisionInitial Medical Treatment: Anticoagulant DosingBivalirudin0.1 mg/kg bolus, 0.25 mg/kg/h infusionaEnoxaparin30 mg IV bolus may be givena1 mg/kg SC every 12 h; extend dosing interval to 1 mg/kg every 24 h if estimated creatinine clearance <30 mL/minFondaparinux2.5 mg SC once dailyaAvoid for creatinine clearance <30 mL/minUnfractionated heparin60 U/kg (max 4000 U) as IV bolusIV 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=4603Ischemic CompositeBleedingNet Clinical Outcome7.3%5.7%11.7%7.7%5.3%11.8%7.8%3.0%10.1%Moderate- to high- riskACSBivalirudin+ GP IIb/IIIa n=4604R*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).Bivalirudinalone n=4612Aspirin in all;clopidogrel dosing and timingper local practiceEnd 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 18.104.22.168.87.09.13.012345678910ACUITY Composite ischemiaendpoint at 30 daysIschemia endpoint bythienopyridine loading before angiography or PCI YESthienopyridine loading beforeangiography or PCI NoACUITY Major bleeding at 30daysUFH + GP IIb/IIIaBivalirudin aloneAbsolute Risk ReductionHazard Ratio95% CI 0.93– – – –0.65p (for interaction) < 0.001Stone GW, et al. N Engl J Med 2006;355:2203–16.
24 Excess Dosing of Antithrombotic Agents Dose and Major Bleeding3530252015105UnderdosedRecommendedMild ExcessMajor ExcessMajor 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 HeparinLow-Molecular-Weight HeparinGlycoproteinIIb/IIIa InhibitorsTreatment GroupReproduced 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 doseAnticoagulant dosing protocolAnticoagulant error tracking systemClopidogrel prescribed at discharge for medically treated AMI patientsFor 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 MIGP IIb/IIIaInhibitorTrialnRisk Ratio and 95% CIPlaceboPRISM3,2327.1%5.8%PRISM-PLUS1,91511.9%10.2%PARAGON A2,28211.7%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.PURSUIT9,46115.7%14.2%PARAGON B5,16511.4%10.5%GUSTO-IVACS7,8008.0%8.7%0.92 (0.86, 0.995)P=.03711.5%10.7%Pooled29,8550.5GP IIb/IIIa Inhibitor Better1.0Placebo Better1.5CI = 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-PositiveTnT-NegativePARAGON-BPRISMTreatment 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, ).CAPTURECombined0.1250.5120.1250.512GP IIb/IIIaBetterGP IIb/IIIaWorseGP IIb/IIIaBetterGP IIb/IIIaWorseNewby 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)2015105Troponin >0.03 µg/LLog-Rank P=.02Cumulative Rate ofPrimary 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/LLog-Rank P=.9851015202530Days After RandomizationISAR-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 Design2 of 3 high-risk criteria:1. Age > 60 years2. + CKMB or TnT/I3. ST or transient ST (Or age 50-59, h/o CVDand + CKMB or TnT/I)High-risk NSTE ACS n = 10,500Routine, early eptifibatide (180/2/180)Placebo / delayed provisional eptifibatide pre-PCIRandomize within 12 hours of presentationInvasive strategy: 12 to 96 hours after randomizationSafety Endpoints at 120 hrs: Bleeding (GUSTO and TIMI scales), Transfusions, Stroke, Non-hemorrhagic SAEsPrimary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailoutKey Secondary Endpoint: 30-d Death or MI
30 Kaplan-Meier Curves for Primary Endpoint 1510.0%10Delayed provisional eptifibatide9.3%Death, MI, RIUR or TBO (%)P = 0.235(stratified for intended early clopidogrel use)Routine early eptifibatide81624324048566472808896Time Since Randomization (Hours)
31 In ED, patient received: Initial TherapiesIn ED, patient received:ASA 325mg PO x15mg IV metoprolol x1IV unfractionated heparin w/ bolus and infusion (weight based)Clopidogrel 300 mgReferred for cardiac catheterization
32 Cardiac Catheterization Single Vessel CAD95% Proximal Hazy LAD lesion consistent with acute plaque rupture with thromboisisTIMI 3 (Normal) Flow
33 Revascularization Strategy in UA/NSTEMI Cardiac cathDischarge from protocolCADNoYesLeft main diseaseYesCABGNo1- or 2- Vessel Disease3- or 2-vessel disease with proximal LAD involvementLV dysfunction or treated diabetes*YesCABGMedial Therapy, PCI or CABGNo*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 LADDrug Eluting Stent (2.25 x 12) to mid LADBoth stents post-dilated and fully deployedHeparin discontinued
35 Duration of Thienopyridine Therapy 2009 ACC/AHA STEMI/PCI Guidelines Focused UpdatesDuration of Thienopyridine TherapyModified RecommendationsIn 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 monthsIf the risk of morbidity from bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be consideredBCKushner 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 UpdatesDuration of Thienopyridine TherapyModified RecommendationContinuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing drug-eluting stent placementCKushner 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 RevisionSecondary Prevention: Additional Recommendations (cont)Cardiac rehabBP control<140/90 mm Hg<130/80 mm Hg with diabetes or CKDDiabetes management: HbA1c <7%Smoking cessation/no environmental smoke exposureEducation, referral programs, drug therapyPhysical activity (30-60 min, 7 d/wk; min 5 d/wk)Weight managementBMI kg/m2Waist circumference: men, <40 in; women, <35 inDischarge education/referralStepped-care approach to musculoskeletal pain managementAnnual influenza immunizationHRT, antioxidant vitamin supplements (C, E, beta carotene) and folic acid not recommendedPatients 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)120100Pravastatin 40mg21%80LDL-C(mg/dL)60Atorvastatin 80mg49% 40P<0.00120<24hRand.30 Days4 Mos.8 Mos.16 Mos.FinalNote: Changes in LDL-C may differ from prior trials:25% of patients on statins prior to ACS eventACS response lowers LDL-C from true baseline
39 All-Cause Death or Major CV Events in All Randomized Subjects 30Pravastatin 40mg(26.3%)2520% with EventAtorvastatin 80mg(22.4%)151016% RR (P = 0.005)531821242730691215Months of Follow-up
40 HD # 3 - DischargePatient discharged to home to f/u in cardiology clinic in 2 weeksDischarge regimen including:ASA 162 mg POClopidogrel 75mg PO QDMetoprolol XL 50 mg/dLisinopril 10 mg/dAtorvastatin 80 mg
41 Secondary Prevention: Additional Recommendations 2007 ACC/AHA UA/NSTEMI Guideline RevisionSecondary Prevention: Additional Recommendationsβ-blockersACE inhibitors/ARBsAldosterone blockade (low EF)Lipid managementStatin regardless of baseline LDL-C initiated prior to dischargeGoal LDL-C <100 mg/dLLDL <70 mg/dL reasonableTreatment of triglycerides and non–HDL-C usefulIf TG mg/dL, non–HDL-C should be <130 mg/dLTG 500 mg/dL, fibrate or niacin before LDL-C lowering to prevent pancreatitisEncouraging consumption of omega-3 fatty acids for risk reduction reasonableFor 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 basementReturned to ED with 8/10 crushing SSCPPatient reported compliance with her medicationsIV UFH started in ED
44 Cardiac Catheterization Total Occlusion of LAD in previously stented segment consistent with STENT THROMBOSIS
45 Hospital Course2 additional stents deployed bridging gap between prior stentsIVUS showed no evidence of edge dissection, stents fully deployedReloaded with clopidogrel 600mg x1Peak CK 2100, CK-MB 150TTE: LVEF 40%, HK antero-septal wall
46 Stent Thrombosis: A Multifactorial Problem LesionLong lesionsSmall diameterMultivesselAcute myocardial infarction (AMI)DiabetesBifurcationsTechnicalUnderexpansionIncomplete wall appositionCrush techniqueOverlappingStentThrombosisStent 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.StentMaterialPolymer matrixAntithrombotic agentPatientAntiplatelet noncomplianceResponse variabilityAdapted 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)3029.020The 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 (%)22.214.171.124.126.96.36.199UAThrombusDiabetesUnprotected left main arteryBifurcation lesionRenal failurePrior brachytherapyPremature antiplatelet therapy discontinuationIakovou 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)33300 mg Clopidogrel30600 mg Clopidogrel2724Resistance = 28% (300 mg)Resistance = 8% (600 mg)2118Patients (%)1512963≤-30(-20,-10](0,10](20,30](40,50](60,70](-30,-20](-10,0](10,20](30,40](50,60]> 70D Aggregation (5 µM ADP-induced Aggregation) at 24 HrGurbel 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 ReactivityNon-responders defined as >70% aggregation by LTA 12 hours after 600 mg clopidogrel loadP < 0.001P < 0.001P < 0.001Antoniucci D et al. Presented at ACC 2007.
50 Platelet Function Test Platelet response assessed on ASA 162mg QD and clopidogrel 75mg BID using Accumetrics™ deviceAppropriate 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/dClopidogrel 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 PCIIschemic 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 3,616CABG 1,809CAD 2,430Compliance:Clop in 1st 7d (median) 7d d d dEfficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCIComplete Followup 99.8%
53 Clopidogrel: Double vs Standard Dose Primary Outcome and Components HR95% CIPIntn PCV Death/MI/StrokePCI (2N=17,232)188.8.131.520.0360.016No PCI (2N=7855)184.108.40.206.14Overall (2N=25,087)4.40.950.370MI2.62.00.780.0120.0251.41.71.250.220.127.116.110.097CV Death0.960.681.02.82.70.772.10.628Stroke0.40.880.590.500.80.91.110.670.50.990.950
54 Clopidogrel Double vs Standard Dose Bleeding Overall Population HazardRatio95% CIPTIMI Major10.951.041.090.50CURRENT Major22.02.51.250.01CURRENT Severe18.104.22.168.03Fatal0.110.131.150.71ICH0.050.670.53RBC transfusion ≥ 2U1.762.211.26CABG-related Major0.91.01.100.481ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal 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 Dose0.01242%RRR0.008Cumulative HazardClopidogrel Double Dose0.004HR 0.5895% CIP=0.0010.036912151821242730Days
56 85% Inactive Metabolites Esterases Change the Agent?PrasugrelPro-drugOxidation(Cytochrome P450)HOOC* HSNOFActive MetaboliteSHydrolysis(Esterases)CH3ClCH3Clopidogrel85% Inactive Metabolites EsterasesOCH3Herbert JM, Savi P. Sem Vasc Med. 2003;3:
57 Inhibition of Platelet Aggregation (IPA) at 24 Hours (Healthy Volunteers) 100.080.0Interpatient Variability60.040.0Inhibition of Platelet Aggregation (%)Interpatient Variability20.0Clopidogrel Responder0.0Clopidogrel Non-responder*Responder = 25% IPA at 4 and 24 h-20.0Response to ClopidogrelResponse to PrasugrelBrandt JT et al. Am Heart J. 2007;153:66.e9-e16.
59 Balance of Efficacy and Safety 15138 eventsClopidogrel12.1HR 0.81 ( ) P=0.0004CV Death / MI / Stroke9.910NNT = 46PrasugrelEndpoint (%)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 46At 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 ofThe number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167.535 eventsTIMI Major NonCABG BleedsPrasugrel2.4HR 1.32 ( ) P=0.031.8ClopidogrelNNH = 167306090180270360450DaysWiviott SD, Braunwald E, McCabe CH et al NEJM2007
60 Stent Thrombosis (ARC Definite + Probable) 3Any Stent at Index PCI N= 12,8442.4 (142)Clopidogrel2Endpoint (%)1.1 (68)1PrasugrelHR 0.48 P <0.0001NNT= 77306090180270360450DaysWiviott SD, Braunwald E, McCabe CH et al NEJM2007Antman EM, AHA2007
61 Definite/Probable ST: Any Stent (N=12844) Wiviott SD, Braunwald E, McCabe CH, Lancet 2008Definite/Probable ST: Any Stent (N=12844)STENT ANALYSISEARLY STLATE STHR 0.41 [ ]P<0.0001HR 0.60 [ ]P=0.03CLOPIDOGREL1.56%PRASUGREL% of Subjects59%0.82%40%0.64%0.49%DAYSAntman EM, NYHA 2007
62 Bleeding Events Safety Cohort (N=13,457) ICH in Pts w Prior Stroke/TIA (N=518)ClopidogrelPrasugrelClop 0 (0)% Pras 6 (2.3)% (P=0.02)% EventsMore 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 prasugrelLife 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 0.01Subcategories 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 ofThere 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=167ARD 0.5% HR 1.52 P=0.01ARD 0.2% P=0.23ARD 0.3% P=0.002ARD 0% P=0.74Wiviott SD, Braunwald E, McCabe CH et al NEJM200762
63 TIMI Major NonCABG Bleeds Diabetic SubgroupN=314618Clopidogrel17.016CV Death / MI / Stroke1412.212HR 0.70 P<0.001Endpoint (%)Prasugrel10NNT = 4686TIMI Major NonCABG Bleeds4Clopidogrel2.62.52Prasugrel306090180270360450DaysWiviott SD, Circulation 2008
64 TIMI Major NonCABG Bleeds Days From Randomization STEMI Cohort N=353415CV Death / MI / StrokeClopidogrel12.4%9.5%10.0%10HR 0.79Percent (%)( )6.5%PrasugrelP=0.02NNT = 42HR 0.68( )5P=0.002TIMI Major NonCABG BleedsPrasugrel2.42.1Clopidogrel306090180270360450Days From RandomizationMontalescot et al Lancet 2008
65 LessonThe 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 HNFSTicagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)Direct actingNot a prodrug; does not require metabolic activationRapid onset of inhibitory effect on the P2Y12 receptorGreater inhibition of platelet aggregation than clopidogrelReversibly boundDegree of inhibition reflects plasma concentrationFaster offset of effect than clopidogrelFunctional recovery of all circulating platelets
68 PLATO study designNSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;randomised within 24 hours of index event(N=18,624)ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)Ticagrelor180 mg loading dose, then90 mg bid maintenance;(additional 90 mg pre-PCI)6–12-month exposurePrimary endpoint: CV death + MI + StrokePrimary safety endpint: Total major bleedingPCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
69 PLATO Primary End Point: CV Death, MI, or Stroke 121110987654321Clopidogrel11.09.3TicagrelorK-M Estimated Rate, % per YearHR: 0.85 (95% CI, ); P=.02MonthsSteg PG. Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida.6969
70 PLATO: All-Cause Mortality K-M Estimated Rate, % per Year 7654321Clopidogrel6.04.9TicagrelorK-M Estimated Rate, % per YearHR 0.82 (95% CI, ); P=.04MonthsSteg PG Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida.7070
71 Time to major bleeding – primary safety event 15Ticagrelor11.5811.2010ClopidogrelK-M estimated rate (% per year)5HR 1.04 (95% CI 0.95–1.13), p=0.43460120180240300360Days from first IP doseNo. at riskTicagrelor9,2357,2466,8266,5455,1293,7833,433Clopidogrel9,1867,3056,9306,6705,2093,8413,479Adapted 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-up4Ticagrelor33.062.312K-M estimated rate (% per year)Clopidogrel1HR 1.31 (95% CI 1.08–1.60), p=0.00660120180240300360Days from first IP doseNo. at riskTicagrelor9,2357,6417,2476,9795,4964,0673,698Clopidogrel9,1867,7187,3717,1345,5974,1473,764
73 Potential Sites for Response Variability Poor complianceInadequate administration (dose, generics?)Intestinal absorptionVariable absorption (Genetics – ABCB1)Drug-drug interactionsHepatic metabolism Cytochrome P450 pathwayGenetic polymorphisms CYP enzymes (2C19)Drug-drug interactions (CYP 2C19)Active metaboliteP2Y12 receptor(irreversible inhibition)Genetic polymorphisms P2Y12 receptorAlternate pathways of platelet activation↑ release of circulating ADPHigher baseline platelet reactivityGP IIb/IIIa receptor expressionGenetic polymorphismsAdapted from O’Donoghue M and Wiviott SD Circulation 2007
74 GWAS of Platelet Aggregation in Response to Clopidogrel 14CYP2C18-CYP2C19-CYP2C9-CYP2C8-log10(P Value)712345678910111213141516171819202122Shuldiner A et al. JAMA 2009; 302:
75 Genetic Effects on PK/PD PharmacokineticsPharmacodynamicsCLOPIDOGRELAbsolute Difference in DMPA% Difference in AUC0-tGeneP valueP valueCYP2C19-32.4-9.0CYP2C9-6.80.59-0.60.86CYP2B6-15.70.035-5.70.012CYP3A55.60.597.50.012CYP1A211.20.450.50.90-50-40-30-20-10102030-15-10-551015PRASUGRELGeneCYP2C19-6.10.061-1.30.63CYP2C9-5.30.27-1.70.42CYP2B6-0.40.90-0.60.65CYP3A5-0.80.821.30.38CYP1A2-3.50.47-1.60.37-50-40-30-20-10102030-15-10-551015Relative percent difference in AUC0-t (95%CI) in carriers vs non-carriers of a reduced-function alleleAbsolute difference in DMPA (95% CI)in carriers vs non-carriers of a reduced-function alleleMega JL et al. N Engl J Med. 2009;360:Mega JL et al. Circulation 2009
76 CYP2C19 Extended Classification 100Clopidogrel 300mg100Clopidogrel 75mg80806060Reduction in MPA (%) at 24-hourReduction in MPA (%) at 24-hour40402020UMEMIMPMn=47n=43n=27n=3UMEMIMPMn=22n=31n=29n=8
77 CYP2C19 and Stent Thrombosis ClopidogrelPrasugrel44Hazard Ratio 3.09(95% CI )P=0.015n=1477Hazard Ratio, 0.58(95% CI )P=0.48n=146633CYP2C19 Reduced-Function Allele Carriers2.6Definite or probable stent thrombosis (%)Definite or probable stent thrombosis (%)22Non-carriers1.01Non-carriers0.81Carriers0.530901802703604503090180270360450Days after randomizationDays after randomizationNumber at Risk:Number at Risk:Non-Carrier101410041001989885765547Non-Carrier1000992990969870764550Carrier375368366359316279186Carrier379374371363323276189* Carriers ~30% of the populationMega JL et al. N Engl J Med. 2009;360:354-62/Mega JL et al. Circulation 2009
79 CYP2C19 and Treatment with Clopidogrel Risk Ratio (95% CI)P ValueMajor Adverse CV EventsN=9,684Carriers vs Non-Carriers1.61 ( )<0.001Heterozygotes vs Wildtype1.50 ( )0.016Homozygotes vs Wildtype1.81 ( )0.004Stent ThrombosisCarriers vs Non-Carriers2.76 ( )<0.001N=5,772Heterozygotes vs WildtypeHomozygotes vs Wildtype2.51 ( )4.78 ( )<0.0010.51.015.0Risk Lower withCYP2C19 VariantRisk Higher withCYP2C19 VariantMega, 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 metaboliteSome PPIs are strong inhibitors of CYP2C19 activityPRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)Poor responders = 16 placebo and 39 in omeprazolePRI was measured at Day 1 and omeprazole vs. placebo was given for 7 days plus clopidogrel, PRI recheckedGraph represents change from baseline; omeprazole clearly attenuates the antiplatelet effect of clopidogrel, but is this significant clinically?p<0.0001Gilard et al. J Am Coll Cardiol 2008;51:
81 Risk of Cardiovascular Events for Patients Taking Clopidogrel in Combination with a PPI 70605040302010Clopidogrel + PPIClopidogrel without PPIAdjusted OR 1.25 (95% CI )Deaths or recurrent ACS (%)901802703604505406307208109009901080Days Since DischargeHo 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 DataPrimary 1-Year Endpoint:Death, MI or Stroke20P=0.45PPI at baseline (N=374)P=0.0011516.2No PPI p-value is 0.035No PPI at baseline (N=1742)14.813.21010.89.27.75AllN=2116PlaceboN=1063ClopidogrelN=1053Dunn S.P. et al AHA Slide courtesy of Steve Steinhubl MD82
83 Observation from an RCT (TRITON-TIMI 38) Conducted for Another Purpose ClopidogrelPPI use at randomization (n= 4529)PrasugrelCV death, MI or strokeCLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CIPRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CIDaysO’Donoghue M, et al Lancet 2009
85 Summary UA/NSTEMI is the most frequent manifestation of ACS Early risk assessment guides angiography strategy and medication choicesDynamic evaluation based on angiogram and clinical course guides further therapyRobust evidence base allows for rational care.Future therapies in development may offer advantages over current standards
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