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The Primary Care-Cardiology Partnership to Ensure Optimal
Patient Outcomes in Acute Coronary Syndromes
Pri-Med Update – Melville November 20, 2008
Education Partner
7:45AM-9:00AM
Session 6: The Primary Care-Cardiology Partnership to Ensure Optimal Patient Outcomes in Acute Coronary Syndromes Learning Objectives
• Outline the concept of thienopyridine resistance and explain its potential implications for secondary prevention in patients post-ACS.
• Compare and contrast emerging treatment options for antiplatelet therapy post-ACS. Faculty
Dean J. Kereiakes, MD, FACC Medical Director The Christ Hospital Heart & Vascular Center and the Lindner Research Center Chairman, Executive Committee Ohio Heart and Vascular Center, Inc. Professor of Clinical Medicine Ohio State University Cincinnati, Ohio
Dean J. Kereiakes, MD, is medical director of The Christ Hospital Heart and Vascular Center and the Lindner Center for Research and Education; and professor of clinical medicine at Ohio State University in Cincinnati. Dr Kereiakes received his medical degree at the University of Cincinnati. Postgraduate training included residencies at the University of California, San Francisco and Massachusetts General Hospital in Boston, and fellowships in adult cardiology and coronary angioplasty. Dr Kereiakes is very active as an investigator, participating in over 800 clinical trials and authoring over 500 publications. He serves on the editorial boards of several journals, including The Journal of the American College of Cardiology, American Heart Journal, American Journal of Cardiology and Journal of Interventional Cardiology, and as a section editor for MedReviews. Dr Kereiakes is a fellow of the American College of Cardiology. He has been a member of the joint ACC/AHA Task Force committees to write four separate guidelines for both coronary angioplasty and unstable angina, and has received many awards for his research and innovation in cardiovascular therapy.
Peter P. Toth, MD, PhD, FAAFP, FICA, FAHA, FCCP, FACC Director of Preventive Cardiology Sterling Rock Falls Clinic, Ltd.
Chief of Medicine CGH Medical Center
Clinical Associate Professor University of Illinois School of Medicine
Editor-in-Chief, Journal of Applied Research in Clinical and Experimental Therapeutics Dr Peter P. Toth earned his doctorate from Michigan State University and his medical degree from Wayne State University School of Medicine in Detroit, Michigan. He completed residency training at the University of Iowa Hospitals and Clinics. Dr Toth is a fellow of the American Academy of Family Physicians, the International College of Angiology, and the American College of Cardiology. He is also a member of the American Heart Association and the American Medical Association. He is a visiting clinical associate professor at the University of Illinois School of Medicine and practices at Sterling Rock Falls Clinic in Sterling, Illinois, where he is director of preventive cardiology. He is also chief of medicine at the CGH Medical Center in Sterling, Illinois. Dr Toth has authored more than 80 publications in peer-reviewed journals and textbooks, including Circulation, Current Opinion in Cardiology, and The Journal of Biological Chemistry. He is a section editor for Current
Session 6
Session 6
Atherosclerosis Reports and a member of the editorial boards for Lipids Online, Mosby's Drug Consult, and Practical Lipid Management. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Kereiakes receives grant/research support from Abbott Bioabsorbable Vascular Solutions; Amylin Pharmaceuticals, Inc.; Cordis/Johnson & Johnson; Boston Scientific; Medtronic; and Daiichi Sankyo, Inc. He receives consulting fees from Devax, Eli Lilly and Company, Boston Scientific, Abbott Vascular Solutions, and Medpace and participates in speakers bureau with Eli Lilly and Company. Dr Toth receives honoraria for presenting from Abbott Laboratories; AstraZeneca LP; Merck & Co., Inc.; Pfizer Inc.; Schering-Plough Corporation; GlaxoSmithKline, and Takeda Pharmaceuticals North America, Inc. Education Partner Financial Disclosure Statements The content collaborators at ACCELMED® have reported the following: Tony Limbil, MD, MPH, has no relationship(s) to disclose. Stephanie Breslan, MS, has no relationship(s) to disclose. Drug List Generic Trade Generic Trade clopidogrel Plavix ticlopidine Ticlid cilostazol Pletal bivalirudin Angiomax Investigational Generic Trade prasugrel Effient Suggested Reading List 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) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):e1-e157.
Wiviott SD, Braunwald E, McCabe CH, TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.
Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006;27:1166-1173. Pfisterer M, Brunner-La Rocca HP, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006;48:2584-2591. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA. 2008;299:532-539.
Web Resources American Heart Association. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents. http://www.americanheart.org/presenter.jhtml?identifier=3045241 Angioplasty.org. Drug-eluting stent overview. http://www.ptca.org/stent
The TIMI Study Group. http://www.timi.org/
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1
Pic here
The Primary Care–Cardiology Partnership to Ensure Optimal Patient Outcomes in Acute Coronary Syndrome
Dean J. Kereiakes, MDPeter P. Toth, MD, PhD
Pic here
Peter P. Toth, MD, PhD
33
Case Study: Mr. Johnson
• Initial presentation– Mr. Johnson, a 65-year-old male, presents to
his primary care physician for: • Exertional chest pain for 4 days• Spontaneous and persistent chest pain at rest
for the last 30 minutes
– History of type 2 diabetes for 6 years, HBP for 15 years, and smoking
– Family history of fatal MI (father)– Normal physical exam– Current medications: metformin, ACE inhibitor,
aspirin, pravastatin– ECG performed in the office is normal
What is the best next step in management?
ACE = angiotensin-converting enzyme; ECG = electrocardiogram; HBP = high blood pressure; MI = myocardial infarction 44
Question 1: What Is the Best Next Step in Management?
1. Ask him to take nitroglycerin every time he has chest pain and to come back in 2 weeks
2. Start him on lifestyle management that includes exercise and healthy diet
3. Give him aspirin and call EMS to take him to the ER
4. Ask him to go to the ER
5. Obtain an appointment for a stress test
55
Case Study: Mr. Johnson
• Mr. Johnson was sent by ambulance to the emergency department
– Cardiac enzymes were elevated– ECG showed ST-segment
depression
66
Question 2: What Is the Most Likely Diagnosis?
1. Acute coronary syndrome (ACS) 2. Pulmonary embolism3. Muscle strain4. Aortic dissection5. Pericarditis
2
77
Acute Coronary Syndrome (ACS)
ACS(cardinal sign: chest pain)
Unstable angina (UA) Myocardial infarction (MI)
NSTEMI STEMI
Cardiac enzymes elevated?
No Yes
ST-elevation?
No Yes
STEMI = ST-elevation MI; NSTEMI = non–ST-elevation MI1. Antman EM, et al. Circulation. 2004;110:e82-e293; 2. Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374. 88
Hospital Discharges in the United States: UA/NSTEMI and STEMI
1.4 million hospital dischargesa
STEMI
1.1 million discharges per year
268,000b
discharges per year
ACS
UA/NSTEMI
1. Rosamond W, et al. Circulation. 2008;117:e25-e146.
aEstimate for secondary discharges in 2005bBased on the “Get With the Guidelines” project by the American Heart Association (AHA)
99
Risk Factors for ACS
CVD = cardiovascular disease1. Antman EM. Circulation. 2004;110:e82-e293.
• Diabetes• Smoking• Hypertension• High cholesterol• Family history of CVD• Age• Obesity• Socioeconomic status• Gender (more men with the disease but more women dying)
1010
Baseline Characteristics Contribute to TIMI Risk Score for UA/NSTEMI1
aRisk factors included family history of CAD, hypertension, hypercholesterolemia, diabetes, and current smokingbCreatine kinase MB fraction and/or cardiac-specific troponin level
1. Antman EM, et al. JAMA. 2000;284:835-842.
CAD = coronary artery disease; CI = confidence interval; OR = odds ratio; TIMI = thrombolysis in MI
Multivariate Analysis
Characteristics β Coefficient P Value OR (95% CI)
Age, >65 years 0.5575 < .001 1.75 (1.35-2.25)
At least 3 risk factors for CADa 04336 .003 1.54 (1.16-2.06)
Significant coronary stenosis (eg, prior coronary stenosis >50%) 0.5284 < .001 1.70 (1.30-2.21)
ST deviation 0.4125 .005 1.51 (1.13-2.02)
Severe anginal symptoms (eg, >2 anginalevents in last 24 hours 0.4279 .001 1.53 (1.20-1.96)
Use of aspirin in last 7 days 0.5534 .006 1.74 (1.17-2.59)
Elevated serum cardiac markersb 0.4420 < .001 1.56 (1.21-1.99)
1111
Question 3: What Is Mr. Johnson’s TIMI Risk Score?
• Summary of case study:– 65-year-old male– Chief complaint:
• Exertional chest pain for 4 days• Persistent chest pain at rest for the past 30
minutes– History of type 2 diabetes, hypertension,
smoking– Current medications: metformin, ACE
inhibitor, daily aspirin, pravastatin– Family history of fatal MI (father)– Normal physical exam– Normal ECG performed in the office– ECG: ST-depression in ER– Cardiac enzymes elevated
His total TIMI risk score is:1. ≤22. 33. 44. 55. ≥6
1212
TIMI Risk Score Correlates With Outcomes1
1. Antman EM, et al. JAMA. 2000;284:835-842.*All-cause death, MI, and recurrent ischemia prompting revascularization (<14 days)
Rat
e of
Com
posi
te E
nd P
oint
(%*)
Test CohortNo. 85 339 627 573 267 66% (4.3) (17.3) (32.0) (29.3) (13.6) (3.4)
No. of Risk Factors
4.78.3
13.2
19.9
26.2
40.9
05
1015202530354045
0/1 2 3 4 5 6/7
P < .001 by X2 for trend
3
1313
Question 4: Cardiac Enzymes Elevated and ST-segment Depression; What Is the Best Next Step?
1. Discharge Mr. Johnson with a follow-up appointment with a cardiologist
2. Watchful waiting
3. Angiography
4. Non-invasive imaging and evaluation
5. None of the above
1414Anderson JL, et al. J Am Coll Cardiol. 2007;50:1-157.
ACC/AHA UA/NSTEMI Guidelines: High-risk Indicators for Early Invasive Strategy
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 T
Preferred Strategy Patient CharacteristicsInvasive • 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
1515
Therapeutic Approaches
• Pre-hospital care by EMS: oxygen, aspirin, nitroglycerin, telemetry,morphine?
• In-hospital care:– Revascularization in STEMI or in high-risk UA/NSTEMI – Antithrombin therapy and antiplatelet therapy: aspirin, clopidogrel, GPIIb/IIIa
inhibitors– Anti-ischemics: nitrates, beta-blocker– Anticoagulants: UFH, LMWH, bivalirudin– Lipid-lowering therapy: statins
• Post-hospital care:– Continue antiplatelets, beta-blocker, and statins– Smoking cessation– Cardiac rehabilitation
Cardiac catheterization reveals a thrombotic lesion in Mr. Johnson’s proximal left anterior descending (LAD) artery
1. Braunwald E et al. J Am Coll Cardiol. 2002;40:1366-1374. 2. Antman E, et al. Circulation. 2004;110:588-636.GPIIb/IIIa = glycoprotein llb/llla; LMWH = low molecular weight heparin; UFH = unfractioned heparin
1616
Question 5: What Is the Most Appropriate Revascularization Strategy for Mr. Johnson?
1. Fibrinolysis2. PCI3. CABG4. Fibrinolysis followed by PCI5. He does not need revascularization
Drug-eluting stent (DES) was placed and antiplatelettherapy with clopidogrel was started
1717
Case Study: Mr. Johnson
Mr. Johnson was discharged on day 2 post-PCI with a prescription for clopidogrel and aspirin added to his usual medication
1818
Question 6: How Long Will Mr. Johnson Have to Take the Dual Antiplatelet Therapy?
1. Mr. Johnson does not need dual antiplatelet therapy 2. 2 weeks for both drugs3. 4 weeks for clopidogrel and 1 year for aspirin4. 6 months for both drugs5. At least 1 year for clopidogrel and aspirin for lifetime
4
1919
Antiplatelet Therapy: ACC/AHA Guidelines
UA/NSTEMI Patients at Discharge
Bare-Metal Stent (BMS) Group
DES Group
ASA 162-325 mg/day for at least 1 month,then 75-162 mg/day indefinitely;
andClopidogrel 75 mg/day for at least 1 month
(ideally up to 1 year)
ASA 162-325 mg/day for at least 3-6 months,then 162 mg/day indefinitely;
andClopidogrel 75 mg/day for at least 1 year
Anderson JL, et al. J Am Coll Cardiol. 2007;50:1-157. 2020
Discharge Strategies for Patients in Post-ACS
Patient education
Long-term dual antiplatelet therapy
Lifestyle modification (smoking cessation, nutrition, and exercise)
Continuity of care: Cardiac rehabilitation(PCP + cardiologist + other team members)
PCP = primary care physician
2121
Cardiac Rehabilitation in Post-ACS: A Multidisciplinary Approach
• Primary care physician will ensure1:– Management of common risk factors for CHD (eg, hypertension
and diabetes)– Patient education on:
• Clinical signs of heart attack• The importance of early care when symptoms arise• Possibility of future ACS event after discharge• Possibility of antiplatelet resistance
– Management of long-term antiplatelet therapy– Follow-up on the referral to the cardiac rehabilitation center– Effective communication within the multidisciplinary team that
includes the cardiologist and other specialty clinicians
1. Resar JR. Johns Hopkins Advanced Studies in Medicine. 2007;17:538-539.
CHD = coronary heart disease
2222
Case Study: Mr. Johnson
• 6 months later• Returns to ER with chest discomfort • Patient claims that he followed the treatment
correctly• ECG shows STEMI• Urgent coronary angiography reveals stent
thrombosis
• Repeat PCI is performed
Courtesy of Dean Jenkins and Stephen Gerred.
2323
Short-term* Outcomes by Treatment Strategy in AMI: Meta-analysis of 23 Randomized Trials
1. Keeley EC, et al. Lancet. 2003;361:13-20; 2. Hochman JS, et al. N Engl J Med. 1999;341:625-634.
*4-6 weeks; N=7739
AMI = acute myocardial infarction; SHOCK = SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK?
Per
cent
age
AngioplastyThrombolysis
P < .0001
P < .0001P < .0004
P < .0001P = .0003
Death Death(excludes
SHOCK trial)
Non-fatalreinfarction
Stroke HemorrhagicStroke
Death,reinfarction,
stroke
75
31 .05
89
7 7
21
14
0
5
10
15
20
P = .0002
2424
PCI-related Time Delay and Survival Benefit vs Fibrinolysis From Randomized Trials*
Betriu A, et al. Am J Cardiol. 2005;95:100-101. DTB = door-to-balloon; DTN = door-to-needle
*21 trials/7350 patients
Abs
olut
e R
isk
Diff
eren
ce in
Dea
th (%
)
0 20 40 60 80 100 120PCI-related Time Delay [DTB-DTN] (minutes)
110 minutes
0.24% survival benefit decrease/10-minute delay
-5
0
5
10
15
5
2525
Question 7: What Could Cause Mr. Johnson’s New ACS Event?
1. Old age2. Diabetes3. Antiplatelet discontinuation4. Antiplatelet resistance5. Stent thrombosis6. All of the above
0
5
10
15
0 1 2 3 4 5 6 7 8 9 10 11 12
2626
Early Thienopyridine Discontinuation* After DES for STEMI: PREMIER Registry
PREMIER: The Prospective Registry Evaluating Myocardial Infarction: Event and RecoverySpertus JA, et al. Circulation. 2006;113;2803-2809.
• Discontinuation Factors– Patient factors:
• Older age• Less education (not high-
school graduate) • Unmarried • Cost of healthcare• Pre-existing CVD• Anemia
– Institutional factors: • Less likely to receive
discharge instructions • Less likely to receive referral
to cardiac rehabilitation
P < .001
Mor
talit
y (%
)
Months
ContinuedDiscontinued
*Within 30 days
2727
Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients with Coronary
Artery StentsA Science Advisory From the American Heart Association, AmericanCollege of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental
Association, With Representation from the American College of Physicians
Grines C, et al. Circulation. 2007;115:813-818.
AHA/ACC/SCAI/ACS/ADA Science Advisory
• Discuss dual antiplatelet therapy with the patient prior to stent implantation
• Consider BMS or balloon angioplasty if discontinuation will be needed (eg, surgery)
• Educate patients on the need to comply with the therapy
• Get clearance from the cardiologist prior to any surgical procedure
Pic here
Dean J. Kereiakes, MD
2929
Antiplatelet Therapy: Rationale for Use
• Platelets are involved in plaque inflammation as well as thrombosis and atherosclerosis
• Patients with NSTE ACS show abnormalities in platelet size and function1,2
• ISIS-2 study demonstrated aspirin to safely reduce vascular mortality by about 25% and recurrent non-fatal infarction by about 50%3
• There remains substantial risk of death from cardiovascular events, reinfarction, and ischemia in patients with ACS who are routinely treated with aspirin in both short- and long-term follow-up
• There is a need for more potent antiplatelet therapies
1. Pizulli L. Eur Heart J. 1998;19:80-84; 2. Khandekar MM. J Clin Pathol. 2006;59(2):146-149; 3. Baigent C, et al. Br Med J. 1998;316:1337-1343.
ISIS-2 = Second International Study of Infarct Survival; NSTE ACS = non–ST-elevation acute coronary syndrome(s)
3030
Mechanism of Action of Aspirin
Papathanasiou A, et al. Hellenic J Cardiol. 2007;48:352-363.
6
3131
Mechanism of Action of Clopidogrel
Papathanasiou A, et al. Hellenic J Cardiol. 2007;48:352-363.
AC = adenyl cyclase; PKA = protein kinase A; PLC = phospholipase C; VASP = vasodilator-stimulated phosphoprotein
A
3232
Clinical Angiographic
Advanced age Impaired renal function Long stents
ACS Comorbidities Multiple lesions
Diabetes Concomitant medications: drug-drug interactions Overlapping stents
Low ejection fraction (EF) Medication compliance Ostial or bifurcation lesions
Prior brachytherapy Access to medications Small reference vessel
Bleeding risk Inability to manage multiple medications
Suboptimal stent deployment
Ischemic risk
Grines CL. Circulation. 2007:115;813-818.
Factors That Increase Risk of ST in PCI
ST = stent thrombosis
3333
Early Discontinuation of Antiplatelet Therapy Is an Important Risk Factor for ST
Iakovou I, et al. JAMA. 2005;293:2126-2130.
UA Thrombus Diabetes Unprotected left main
artery
Bifurcation lesion
Renal failure
Prior brachytherapy
Premature antiplatelet
therapy discontinuation
Inci
denc
e (%
)
Overall ST-elevation = 1.3% (P = .09, N=2229)
1.4 2.0 2.5 3.3 3.66.2
8.7
29.0
0
10
20
30
68.4
84.6
0
20
40
60
80
100
3434
Percent of ST Risk Not Attributable to Clopidogrel Discontinuation
ST N
ot A
ttrib
utab
le to
C
lopi
dogr
el C
ompl
ianc
e (%
)
Kuchulakanti1 Iakovou2
1. Kuchulakanti PK, et al. Circulation. 2006;113:1108-1113; 2. Iakovou I, et al. JAMA. 2005;293:2126-2130; 3. Tsai TT, et al. Circulation. 2006;114:e362.
PAR = population attributable riskPAR% = [prevalence clopid discont] X [relative risk -1] / [prev clopid discont] X [relative risk-1] + 13
3535
The First Clopidogrel Resistance Study:A “Fingerprint” of Clopidogrel Response Variability
2 Hours 24 Hours
5 Days 30 Days
Gurbel PA, et al. Circulation. 2003;107:2908-2913.
Resistance = 31%
10
20
≤ -30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
>60
Resistance
Resistance
Resistance = 15%
Δ Aggregation (%)
14
28
≤ -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance = 31%
Δ Aggregation (%)
Resistance
Pat
ient
s (%
)
11
22
≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60
Resistance = 63%Resistance
Pat
ient
s (%
)
12
24
≤ -30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
>60
3636
Clopidogrel Response Variability
O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.
GP GP IIb/IIIaIIb/IIIa receptor receptor expressionexpression
Hepatic metabolismHepatic metabolismCytochromeCytochrome P450 pathwayP450 pathway
Poor complianceInadequate administration
Variable absorptionDrug-drug interactions
Genetic polymorphisms CYP enzymes Drug-drug interactions (3A4/5; 2C19)
Genetic polymorphisms P2Y12 receptorAlternate pathways of platelet activation
• Release of circulating ADPHigher baseline platelet reactivity
Genetic polymorphisms
Intestinal absorptionIntestinal absorption
P2YP2Y1212 receptorreceptor(irreversible inhibition)(irreversible inhibition)
Active MetaboliteActive Metabolite
ADP = adenosine diphosphate; CYP = cytochrome P450
7
3737
High Residual Platelet Reactivity* Correlates With Ischemic Events
Post
-trea
tmen
t Agg
rega
tion
(LTA
; %)
Without Ischemic Events With Ischemic Events
P P = .02= .02
0
10
20
30
40
50
60
70
80
90
100
Gurbel PA, et al. J Am Coll Cardiol. 2005;46:1820-1826.
*20 μmol ADP post-stent/post-clopidogrel residual platelet reactivityLTA = light transmission aggregometry; ADP = adenosine diphosphate
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
3838
Clopidogrel, Platelet Reactivity, and SAT
20 μM ADP-induced Platelet Aggregation5 μM ADP-induced Platelet Aggregation
7575thth percentilepercentile
N=13N=13 7575thth percentilepercentile
N=12N=12
No SAT SAT(N=100) (N=20)
No SAT SAT(N=100) (N=20)
Agg
rega
tion
(%)
P < .001
P < .001
Gurbel PA, et al. J Am Coll Cardiol. 2005;46:1827-1832. ADP = adenosine diphosphate; SAT = subacute stent thrombosis.
3939
Question 8: After the Repeat PCI Is Performed on Mr. Johnson, What Do We Do Next?
1. Consider increasing the dosage for antiplatelet therapy
2. Stop antiplatelet therapy since it is non-efficacious
3. Consider switching antiplatelet therapies
4. Consider adding a third antiplatelet agent
5. Prescribe coumadin
6. A combination of 1, 3, and 4
4040
Potential Solution: Give More Clopidogrel*
Montalescot G, et al. J Am Coll Cardiol. 2006;48:931-938.
Clopidogrel dose 300 mg 600 mg 900 mg
The Albion Trial
*FDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dose
0.0
5.0
10.0
15.0
20.0
41
600 mg 300 mg(N=126) (N=129)
Com
posi
te 1
End
Poi
nt (%
)*
ARMYDA-2 Trial
41
ARMYDA = Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty; TVR = target vessel revascularizationFDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dose
Proposed Solution: Give Clopidogrel Loading Dose Prior to PCI
Patti G, et al. Circulation. 2005;111:2099-2106.
*Death and MI; TVR to 30 days; P =.041
4242
Clopidogrel 600 mg Loading DoseTime Course of Effect
Max
imal
Agg
rega
tion
5 µm
ol/L
AD
P (%
)
0
100
80
60
40
20
02 4 6 108
Time From Loading Dose to Catheterization (hours)
Hochholzer W, et al. Circulation. 2005;111:2560-2654.
FDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dose
8
4343
Explore New Compounds
• New compounds have been shown to be more active and effective1:
– Prasugrel– Cangrelor– AZD6140
1. Cattaneo M. Eur Heart J. 2006;27:110-112.
-10
0
10
20
30
40
50
60
70
80
90
100
1/.25 1/.5 1/1 1/2 1/4 1/6 2/0 3/0 4/0 5/0 6/0 7/0 8/0 9/0
4444
Prasugrel: More Effective Platelet Inhibition
Prasugrel vs Clopidogrel1• More potent • More rapid in onset • More consistent inhibition of
platelet aggregation (IPA) • Less frequent poor IPA
response• More efficient generation of
its active metabolite
Time Post-dose (Day/Hour)
IPA in healthy subjects2
Inhi
bitio
n of
Pla
tele
t Agg
rega
tion
(%)
Pras 60/10Clop 300/75Clop 600/75
Pras = prasugrel (loading dose/maintenance dose [mg]); Clop = clopidogrel1. Wiviott SD, et al. Am Heart J. 2006;152:627-635. 2. Payne CD, et al. Am J Cardiol. 2006;98:S8.
Prasugrel is not yet approved by the FDA for use.
4545
Use an Agent That Is Effective for Clopidogrel Non-responders
Brandt JT, et al. Am Heart J. 2007;153:e9-e16.
Prasugrel is not yet approved by the FDA for use.
4646
TRITON TIMI-38 Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) and Planned PCIASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
First-degree end point: CV death, MI, strokeSecond-degree end points: CV death, MI, stroke, rehospitalization,
recurrent ischemia, UTVR
Median duration of therapy: 12 months
N=13,600
Wiviott SD, et al. Am Heart J. 2006;152:627-635.
UTVR = urgent target vessel revascularization; TRITON TIMI = TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel Thrombolysis In Myocardial InfarctionFDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dose
Prasugrel is not yet approved by the FDA for use.
4747
Days
35events
TRITON TIMI-38: Balance of Efficacy and Safety
HR 0.81(0.73-0.90)P = .0004
HR 1.32(1.03-1.68)
P = .03
138events
NNT = 46
NNH = 167
HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm1. Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
End
Poin
t (%
)
12.1
9.9
1.82.4
0
5
10
15
0 30 60 90 180 270 360 450
CV Death/MI/Stroke
TIMI Major Non-CABG Bleeds
Clopidogrel
Prasugrel
Prasugrel
Clopidogrel
Prasugrel is not yet approved by the FDA for use.
4848
TRITON TIMI-38: Bleeding Events*
1. Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
ARD 0.5%HR 1.52P = .01
ARD 0.6%HR 1.32P = .03
NNH = 167
ARD 0.2%P = .23
ARD 0%P = .74
ARD 0.3%P = .002
Perc
enta
ge o
f Eve
nts Clopidogrel
Prasugrel
1.8
0.9 0.9
0.1 0.3
2.4
1.41.1
0.4 0.3
0
2
4
TIMI MajorBleeds
Life-threatening Nonfatal Fatal ICH
ICH in Patients with Prior Stroke/TIA
(N = 518)
Pras 6 (2.3)%(P = .02)
Clop 0 (0)%
*N = 13,457TIA = transient ischemic attack; ICH = intracranial hemorrhage; ARD = absolute risk difference
Prasugrel is not yet approved by the FDA for use.
9
4949
TRITON TIMI-38: Stent Thrombosis (ARC Definite + Probable)
Days
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48P < .0001
Prasugrel
Clopidogrel 2.4(142)
74 events
NNT = 77
1.1 (68)En
d Po
int (
%)
Any Stent at Index PCIN = 12,844
ARC = Academic Research Consortium; PCI = percutaneous coronary intervention1. Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Prasugrel is not yet approved by the FDA for use.
5050
TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups
Post-hoc analysis1. Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Overall
≥60 kg<60 kg
<75
NoYes
0.5 1 2
PriorStroke / TIA
Age
Weight
Risk (%)
+ 37-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
≥75
Prasugrel is not yet approved by the FDA for use.
5151
IPA
Mea
n ±
SEM
(%)
Time (hours)
0
25
50
75
100
0 2 4 8 12
IPA Maximal Extent
P < .0002 for all AZD6140 vs clopidogrel at 4 hours
• AZD61401
– Class: CPTP (non-thienopyridine)– Reversible platelet P2Y12 receptor
antagonist– Orally active– Rapid onset of action (2 hours)
± loading dose– Acts directly (no metabolic
activation required)– Plasma t½ ~12 hours (BID drug)– Inhibitory even in non-metabolized form– Lessening of inhibition over the
24-hour post-dose period– Good tolerability2
Potential Solution: Use a Non-thienopyridineClass of Drug
1. Husted S. Eur Heart J. 2006:27;1038-1047.
BID = twice daily; CPTP = cyclo-pentyl-triazolo pyrimidineFDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading doseAZD6140 is not yet approved for use
AZD6140 90 mgAZD6140 180 mg
AZD6140 270 mgCLOP 300 mg
0
20
40
60
80
100
0 point 1 point 2 point 3 point 4 point 5 point 6 point
All patients Non-shock patients
5252
Pharmacotherapy Index in NSTE ACS: The More the Better?
1. Dziewierz A. Coronary Artery Disease. 2007;18:299-303.
Mortality Decreases With Higher Pharmacotherapy Index1M
orta
lity
(%)
Pharmacotherapy Indexa
aBased on number of drugs used: aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitor, LMWH, beta-blocker, ACE inhibitor/ARB
N = 807P < .0001
5353
Evidence-based Therapies Provide Incremental Survival Benefita
Appropriateness Level IV 0.10 0.03 – 0.42
OR 95% CI
Evidence Therapies: Antiplatelet, Beta-blocker, ACE-I, Lipid-lowering
a6 months follow-up; 1358 patients with ACS
0.0 0.5 1.0 1.5Lower Mortality Higher Mortality
MukherjeeMukherjee D, et al. D, et al. Circulation.Circulation. 2004,109:7452004,109:745--749.749.
Appropriateness Level III 0.17 0.04 – 0.75
Appropriateness Level II 0.18 0.04 – 0.77
Appropriateness Level I 0.36 0.08 – 1.75
54
Conclusions
• Patients with ACS have abnormalities in platelet size and function that predispose them to ischemic cardiovascular events
• The current ACC/AHA clinical practice guidelines recommend:– For patients who present with STEMI: immediate angiography and
PCI– For NSTEMI patients who present with high-risk indicators: early
(<48 hours) angiography and revascularization
• Wide interindividual variability exists in platelet inhibitory response to currently available oral antiplatelet therapies
10
5555
Conclusions
• Patients should be risk-stratified for both stentthrombosis as well as risk of bleeding before DES deployment
• Dual (aspirin plus thienopyridine) antiplatelet therapy should be continued for at least 1 year following DES deployment
• New platelet inhibition therapies currently in development appear to provide more rapid, intense, and uniform platelet inhibition and promise to overcome many of the limitations associated with current therapies
56
Agg
rega
tion
(Per
cent
age)
Platelet aggregation 4 hours post-clopidogrel*
*450 mg PO (P=.0002); **P=.15
14CO
2 Exhaled/Hour (Percentage)
Clopidogrel Nonresponsiveness: Correlation With CYP3A4 Enzyme Activity
Lau WC, et al. J Am Coll Cardiol. 2003;41:225A.
CYP3A4** activity
0
20
40
60
80
100 80 ± 9
37 ± 201.9 ± 0.7
2.7 ± 1.0
Nonresponders (25%)Responders (75%)
0
1.0
3.0
4.0
5.0
2.0
80828486889092949698
100
0 30 60 90 120 150 180
57
DES Thrombosis and Residual Platelet Reactivity
Patie
nts
Free
Fro
m D
efin
ite o
r Pr
obab
le S
T (P
erce
ntag
e)
RespondersNonresponders*
*Residual platelet aggregation (10 µM ADP) ≥70%Buonamici P, et al. J Am Coll Cardiol. 2007;49:2312-2317.
Time (days)
98 ±1
91 ± 3
5858
Does More Clopidogrel Alter Resistance?
Gurbel PA, et al. J Am Coll Cardiol. 2005;45:1392-1396.
0369
1215182124273033
≤-30
(-30,-
20)
(-20,-
10)
(-10,0
)(0,
10)
(10,20
)
(20,30
)
(30,40
)
(40,50
)
(50,60
)
(60,70
)>7
0
300 mg Clopidogrel600 mg Clopidogrel
Platelet aggregation (5 µM ADP-induced aggregation) at 24 hours
Patie
nts
(Per
cent
age)
Resistance=28% (300 mg)
Resistance=8% (600 mg)
Absolute change in platelet aggregation (ΔA)
5959Kleiman NS. J Am Coll Cardiol. 2008;51:1412-1414.
P2Y12 Receptor Stimulation
0
20
40
60
80
100
6060
Omeprazole PlaceboGroup
PRI (
Perc
enta
ge)
NS
VASP PRI (%) on Day 1VASP PRI (%) on Day 7
P<.0001
Omeprazole and Clopidogrel Efficacy*
* CYP2C19; PRI = platelet reactivity index; VASP = vasodilator stimulated phosphoproteinGilard M, et at. J Am Coll Cardiol. 2008;51:256-260.
11
6161
Smokers Paradox* With Clopidogrel: CLARITY-TIMI 28
* CYP1A2D/MI = death/myocardial infarctionDesai, et al. J Am Coll Cardiol. 2008;51:A203.
Non-smokers(n=1783)
0-9 cigs/day(n=206)
10-19 cigs/day(n=354)
20-29 cigs/day(n=715)
30+ cigs/day(n=422)
Primary endpoint (TIMI flow grade 0/1 or D/MI)
0.2 1 2.5 0.2 1 2.5Clop Better Clop Worse Clop Better Clop Worse
Pint=0.039 Pint=0.006
Cardiovascular death, MI, or urgent revascularization by 30 days
63.0
21.0 19.0
3.5
44.0
34.0 33.0
11.4
0
15
30
45
60
75
62Campo G, et al. J Am Coll Cardiol. 2007;50:1132-1137.
Non-responders to Clopidogrel or Ticlopidine
Patie
nts
(%)
Definition 1: absolute difference between baseline & post-treatment Aggmax < 10%
Definition 2: % IPA < 20%, IPA = inhibition of platelet aggregation
Clop/Ticlo R
Clop NRTiclo NR
Clop/Ticlo NR
Clop/Ticlo R
Clop NRTiclo NR
Clop/Ticlo NR
6363
BMS = bare-metal stentsEisenstein EL, et al. JAMA. 2007;297:159-168.
The Duke Landmark 6-month Analysis
64
0
0.05
0.1
0.15
0.2
0 90 180 270 360 450 540 630 720
64
Follow-up Time (days)
Mortality Following PCI for ACS by Clopidogrel Use: Veterans Administration 2003-2004*
*N=1455 (66% BMS, 34% DES); HR (BMS=2.65, DES=2.0)Ho PM, et al. Am Heart J. 2007;154:846-851.
Cum
ulat
ive
Mor
talit
y R
ate
Off clopidogrelOn clopidogrel
0
10
20
30
40
50
60
70
80
90
100
6 hours post-load 14 days chronic treatment
PrasugrelClopidogrel
6565Adapted from: Wiviott SD, et al. Circulation. 2007;116:2923-2932.
Prasugrel vs High-dose Clopidogrel: PRINCIPLE-TIMI 44
60 Prasugrel 10 Prasugrel/day600 Clopidogrel 50 Clopidogrel/day
Perc
enta
ge o
f IP
A (2
0 μM
AD
P)
P<.0001 P<.0001
74.8 ± 13.0
31.8 ± 21.1
61.3 ± 17.8
46.1 ± 21.3
Prasugrel is not yet approved by the FDA for use.
