1. Initiating Antiplatelet Therapy in Patients with Atherothrombosis
Sunil V. Rao MD
Durham VA Medical Center
Duke Clinical Research Institute
Duke University Medical Center

2. Notes:
Includes the American Heart Association’s Heart Disease and Stroke Statistics—2006 Update.
The 2006 statistical update on heart disease and stroke from the American Heart Association estimated that 1,550,000 unique hospitalizations (including primary and secondary discharge diagnoses) for ACS occurred in the United States in This figure includes 946,000 hospitalizations for MI and 650,000 for unstable angina (UA) (31,000 patients had a diagnosis of both UA and MI).
The National Registry of Myocardial Infarction (NRMI) databases have shown that 30%–45% of MI is STEMI by classification. Thus, one third (33%) of the 946,000 patients with MI is approximately 312,000 and 66% (approximately 634,000) are estimated to have NSTEMI.
Thus, UA/NSTEMI is a major public health problem and represents the most common reason for hospital admission for coronary heart disease.
References:
American Heart Association. Heart Disease and Stroke Statistics—2006 Update: A report from the American Heart Association Statistics committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85-e151.
NSTE ACS

3. Notes:
A large proportion of deaths among patients with MI occurs within the first 24 hours after presentation. It is not clear whether this phenomenon is also true of patients without ST elevation who may or may not have infarction at the time of presentation. The Global Utilization of Strategies for Total Occlusion (GUSTO-IIb) trial was designed to examine the pattern of early ischemic events among patients with ACS and to determine whether the direct thrombin inhibitor desirudin (r-hirudin) would be most effective during this period. The trial compared the early, 30-day occurrence of death and reinfarction in patients with STEMI versus patients with NSTEMI.
Death or (re)infarction occurred within 24 hours in 113 patients (2.7%) with ST elevation and in 97 patients without ST elevation (1.2%, P<0.001), representing 26% and 14% of the 30-day event rates, respectively, for the two enrollment strata. Among patients with ST elevation, most of these events were deaths, whereas among patients without ST elevation, most events were (re)infarctions.
Kleiman NS, Granger CB, White HD, et al, for the GUSTO-llb Investigators. Death and nonfatal reinfarction within the first 24 hours after presentation with an acute coronary syndrome: experience from GUSTO-IIb. Am Heart J. 1999;137:12-23.

4. Plasma Clotting cascade
Thrombus formation
Thrombin and platelets play a central role
Thrombin
Platelet activation
Prothrombin
Fibrinogen
Fibrin
Platelet aggregation
ADP
TXA2
Plasma Clotting cascade
Collagen
Tissue Factor
THROMBUS
Thrombin is a procoagulant that plays a critical, if under-appreciated role in thrombosis through its actions in the coagulation process and as a platelet activator.
Thrombin plays a critical and central role in thrombogenesis through:
Converting fibrinogen to fibrin strands that hold the clot together,
Regulating its own production via positive and negative feedback loops to further promote thrombin generation,
Stabilizing the fibrin clot through activation of factor XIII and inhibiting fibrinolytic pathways.
Thrombin is the link between tissue injury and cellular response. Thrombin:
Is the most effective agonist for platelet activation
Elicits multiple responses in platelets, endothelial, and other cells
Because of the central role that thrombin plays, and effective thrombin-specific inhibitor is important in thrombosis.

5. Clopidogrel Indications
Clopidogrel is indicated for the reduction of atherothrombotic events
Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined end point of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
Acute Coronary Syndrome
For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, clopidogrel has been shown to decrease the rate of a combined end point of cardiovascular death, MI, or stroke as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischemia.
For patients with ST-segment elevation acute myocardial infarction, clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined end point of death, reinfarction, or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.
Notes:
Indications[1]:
clopidogrel® (clopidogrel bisulfate) is indicated for the reduction of atherothrombotic events
For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel® (clopidogrel bisulfate) has been shown to reduce the rate of a combined end point of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
For patients with non–ST-segment elevation acute coronary syndrome (unstable angina/ non–Q-wave MI*), including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, clopidogrel has been shown to decrease the rate of a combined end point of cardiovascular death, MI, or stroke as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischemia.
For patients with ST-segment elevation acute myocardial infarction, clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined end point of death, reinfarction, or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.
References:
Please see Important Risk Information and Full Prescribing Information.
*Also known as non–ST-segment elevation MI.
1. clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.
Clopidogrel prescribing information, sanofi-aventis US, LLC

6. Clopidogrel Clinical Trials Overview
Clopidogrel vs aspirin
Clopidogrel + aspirin
vs placebo + aspirin
Notes:
clopidogrel has been studied in more than 81,000 patients across a broad range of atherothrombotic patient types at risk for MI, ischemic stroke, and death.
The CAPRIE trial included recent MI, recent ischemic stroke, or established PAD patients, comparing clopidogrel vs aspirin with a combined end point of MI, ischemic stroke, or vascular death.[1]
The CURE trial included ACS (UA/NSTEMI) patients comparing clopidogrel plus aspirin vs placebo plus aspirin with primary composite end points of MI, stroke, or CV death and a composite end point of MI, stroke, CV death or refractory ischemia.[2]
The COMMIT trial included ACS (STEMI) patients comparing clopidogrel plus aspirin vs placebo plus aspirin and with primary end points of all-cause mortality, and a composite end point of death, reinfarction, or stroke.[3]
The CLARITY trial included ACS (STEMI) patients comparing clopidogrel plus aspirin vs placebo plus aspirin with trial end points of occluded infarct-related artery (TIMI flow grade 0 or 1) on predischarge angiogram, or death, or recurrent MI by the time of the start of coronary angiography.[4]
References:
clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.
1. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:
2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (CURE). Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:
3. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction) Collaborative Group. Addition of clopidogrel to aspirin in patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:
4. Sabatine MS, Cannon CP, Gibson CM, et al, for the CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:

7. ID:1133
Notes: Patients were eligible for CURE if they were admitted to the hospital within 24 hours of an episode of chest pain suggestive of unstable angina or non–Q-wave MI.* The average time between onset of pain and admission was 14 hours.
Patients were randomized to one of two treatment arms: clopidogrel (300-mg loading dose followed by 75 mg/d) or placebo, both in addition to aspirin (75–325 mg/d) and other standard therapies.
Medications at time of randomization included heparin or low–molecular-weight heparin, beta-blockers, ACE inhibitors, lipid-lowering agents, calcium-channel blockers, and/or intravenous nitrates.
Treatment duration was for up to 1 year. The average duration of treatment was 9 months.
Follow-up assessments were conducted at 1 and 3 months for all patients and at 6, 9, and 12 months for patients randomly assigned early in the study.
*Also known as non–ST-segment elevation MI (NSTEMI).
References:
CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:

8. ID:519
Notes: Clopidogrel, in addition to aspirin (ASA) and other standard therapy, provided a 20% relative risk reduction in the combined co-primary end point of MI, stroke, or CV death (95% CI, 0.72–0.90, P= ).[1,2] Overall there were 719 (11.4%) first events in the placebo plus ASA group and 582 (9.3%) in the clopidogrel plus ASA group. The hazard rate curves began to separate within the first few hours after therapy initiation and remained separated over the course of the trial.
The addition of clopidogrel to ASA and other standard therapy significantly reduced the rate of the co-primary end point of MI, stroke, cardiovascular death, or refractory ischemia (16.5% vs 18.8%, RRR=14%, 95% CI, 6.2 to 20.6, P=0.0005).[2]
The CURE trial was not specifically powered to detect differences at the 24-hour time point. However, in a post hoc analysis, the rate of death from cardiovascular causes, nonfatal MI, stroke, or refractory or severe ischemia was significantly lower in the clopidogrel plus ASA group by 24 hours after randomization (1.4% vs 2.1% in the placebo plus ASA group; RRR=34%, 95% CI, 0.51–0.86).
Figure adapted with permission (2002). Copyright © 2001 Massachusetts Medical Society. All rights reserved.
References:
The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:
clopidogrel® (clopidogrel bisulfate) Prescribing Information.

9. Hours after randomization
Early Benefit of Dual Antiplatelet Therapy in ACS: Death/MI/Ischemia < 24 Hrs in CURE
0.025
RR=0.67
P=0.002
Placebo
0.020
0.015
Cumulative hazard rates
0.010
Clopidogrel
0.005
Hours after randomization
—Berger P, Steinhubl S. Circ 2002

10. Effects of Clopidogrel on Combined End Point (Death, Reinfarction, or Stroke) by Treatment Interval
better
Clopidogrel
Notes:
The efficacy of clopidogrel on the combined end point of death, reinfarction, or stroke was evaluated according to treatment interval.[1] During the first time interval (0–24 hours) 38 (0.6%) patients on clopidogrel experienced a combined end point event compared with 53 (0.8%) patients on placebo.[1] The other two time intervals (0–30 days and 0–365 days) had similar results.[1] During the 0 to 30 days interval, 272 (4.3%) patients experienced a combined end point compared with 349 (5.5%) patients on placebo, and during the 0 to 365 days interval, 582 (9.3%) patients experienced a combined end point compared with 719 (11.4%) patients on placebo.[1] In CURE, the RRR in the combined end point of MI, stroke, or CV death was 20% (P= ) at 9 months.[2,3]
1. Data on file. sanofi-aventis U.S. LLC.
2. clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.
3. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:

11. Effects of Clopidogrel on Bleeding Rate by Treatment Interval
The overall incidence of major bleeding (including life-threatening and other major bleeding) was:
Clopidogrel + ASA = 3.7%
Clopidogrel + ASA = 2.7%
P=0.001
Placebo + ASA
Clopidogrel + ASA
Placebo + ASA
Clopidogrel + ASA
Notes:
The safety of clopidogrel was evaluated according to two prespecified time intervals (Days 0–30 and Days 31–365). During the first time interval (Days 0–30), 1% of patients on placebo plus ASA experienced a life-threatening bleed,* compared with 1.3% of patients on clopidogrel plus ASA. During the second time interval (Days 31–365), 0.8% of patients on placebo plus ASA experienced a life-threatening bleed, compared with 0.9% of patients on clopidogrel plus ASA.
The investigators also evaluated other major bleeding† during these time intervals. During Days 0 to 30, 0.6% of patients on placebo plus ASA experienced major bleeding, compared to 0.8% of patients on placebo plus clopidogrel. During Days 31 to 365, 0.4% of patients on placebo plus ASA experienced major bleeding, compared with 0.8% of patients on clopidogrel plus ASA.
The overall incidence of major bleeding (including life-threatening and other major bleeding) was:
clopidogrel + ASA = 3.7%
Placebo + ASA = 2.7% (P=0.001)
* Life-threatening bleeding: defined as fatal or leading to a drop in hemoglobin ≥5 g/dL, significant hypotension with need for inotropes, requiring surgery (other than vascular site repair), symptomatic intracranial hemorrhage, or requiring transfusion of ≥4 units of red blood cells or equivalent whole blood.
† Major bleeding: defined as significantly disabling intraocular bleeding leading to significant loss of vision, or bleeding requiring transfusion of 2 or 3 units of red blood cells or equivalent whole blood.
Data on file. sanofi-aventis U.S. LLC.

12. 2007 ACC/AHA Guidelines for UA/NSTEMI
Aspirin should be administered to UA/NSTEMI patients as soon as possible after hospital presentation and continued indefinitely in patients not known to be intolerant of that medication. (Level of Evidence: A)
Clopidogrel (loading dose followed by daily maintenance dose)* should be administered to UA/NSTEMI patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A)
Anderson JL et al. ACC/AHA Guideline Update Available at: Accessed August 7, 2007.

13. 2007 ACC/AHA Guidelines for UA/NSTEMI
For UA/NSTEMI patients in whom an initial invasive strategy is selected:
Either clopidogrel (loading dose followed by daily maintenance dose)*or an intravenous GP IIb/IIIa inhibitor should be initiated before diagnostic angiography (upstream) (Level of Evidence: A)
For UA/NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected:
Clopidogrel (loading dose followed by daily maintenance dose) should be added to ASA and anticoagulant therapy as soon as possible after admission and administered for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B)
Anderson JL et al. ACC/AHA Guideline Update Available at: Accessed August 7, 2007.

14. 86% received heparin (LMW+UFH) 45% received GP IIb-IIIa inhibitors
Notes:
Within the first 24 hours after presentation, patients in the CRUSADE study without contraindications (n=6,080) received the following therapies:
97% received ASA
93% received β-blockers
86% received heparin (LMW+UFH)
45% received GP IIb-IIIa inhibitors
60% received clopidogrel
Duke Clinical Research Institute. CRUSADE data Q Available at Accessed August 29, 2007.

15. Notes:
Tricoci and colleagues evaluated the temporal trends of clopidogrel use at discharge in 61,052 patients with high risk NSTEMI participating in the CRUSADE Quality Improvement Initiative.
Clopidogrel discharges had increased by the last quarter of However, by the end of the study period, fewer than 25% of patients who underwent CABG and fewer than 50% of patients who did not undergo catheterization received clopidogrel at discharge.
Clopidogrel use at discharge has increased since the release of the ACC/AHA guideline recommendations for treatment of NSTEMI in patients treated with medical therapy alone and those who undergo CABG; however, the authors conclude that the majority of these patients still do not receive clopidogrel at discharge.
Please see Important Risk Information and Full Prescribing Information.
Tricoci P, Roe MT, Mulgund J, et al. Clopidogrel to treat patients with non–ST-segment elevation acute coronary syndromes after hospital discharge. Arch Intern Med ;166:
CRUSADE is a national quality improvement initiative of the Duke Clinical Research Institute. Partial funding for CRUSADE is provided by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.

16. Notes:
The 2006 fourth-quarter update of the CRUSADE Quality Improvement Initiative presented the most recent data on the prevalence of various invasive cardiac procedures of UA/NSTEMI patients in the CRUSADE registry (among patients without contraindications to catheterization). The data shown are for Q4 of 2006 (n=6,080).
According to the study sponsors, patients described as medically managed received catheterization but no revascularization, while patients described as truly medically managed received neither catheterization nor revascularization.
Duke Clinical Research Institute. CRUSADE data Q Available at: Accessed August 29, 2007.
CRUSADE is a national quality improvement initiative of the Duke Clinical Research Institute. Partial funding for CRUSADE is provided by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.

17. The Major Bleeding Rate Was Increased When Clopidogrel Was Administered <5 Days Before CABG in CURE
Major bleeding rate in patients undergoing CABG according to whether therapy is stopped or continued 5 days before CABG1
Placebo + ASA
Clopidogrel + ASA
Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued five days prior to surgery.
Notes:
The major bleeding rate was increased when clopidogrel was administered within 5 days of CABG in CURE. This slide reviews the major bleeding rate in patients undergoing CABG according to whether therapy is stopped or continued 5 days before CABG (n=1,822). In patients who stopped therapy greater than 5 days before CABG and received placebo plus ASA, the major bleeding rate was 5.3%. The major bleeding rate in patients who received clopidogrel plus ASA was 4.4%. In patients who stopped therapy in 5 days or less before CABG and received placebo plus ASA, the major bleeding rate was 6.3%. The major bleeding rate in patients who received clopidogrel plus ASA was 9.6%. Thus, based on the data presented in this slide, in patients who stopped taking clopidogrel more than 5 days before undergoing CABG, there was no increase in major bleeding; but an increase in major bleeding was observed in patients who continued taking clopidogrel within 5 days of the CABG procedure.
It should be noted that clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 days prior to surgery.
Please see Important Risk Information and Full Prescribing Information.
1. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:
2. clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.

18. Clopidogrel + Aspirin Placebo + Aspirin
Aspirin Dose (+ standard therapy*) (+ standard therapy*)
*Other standard therapies were given at physician’s discretion.
Clopidogrel prescribing information. sanofi-aventis U.S. LLC
CURE Trial Investigators. N Engl J Med. 2001;345:
Notes:
Definition of major bleeding[1]:
Life-threatening bleeding, which was defined as fatal or leading to one of the following: intracranial hemorrhage, drop in hemoglobin of 5 g/dL, substantial hypotension requiring inotropic therapy, surgical intervention, or transfusion of four or more units of blood.
Other major bleeding was defined as substantially disabling bleeding, intraocular bleeding leading to the loss of vision, or bleeding necessitating the transfusion of two to three units of blood.
Major bleeding episodes were primarily gastrointestinal hemorrhages or bleeding at site of arterial puncture.[2] The incidence of major bleeding increased with aspirin (ASA) dose in both treatment groups, with the highest incidence among patients receiving more than 200 mg of ASA.[1]
References:
1. clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.
2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (CURE). Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:
* Other standard therapies were given at the physician’s discretion
Clopidogrel prescribing information. sanofi-aventis US, LLC
CURE Trial Investigators. N Engl J Med. 2001;345;

19. 2007 ACC/AHA Guidelines for UA/NSTEMI
For UA/NSTEMI patients in whom CABG is selected as a postangiography management strategy:
Continue ASA. (Level of Evidence: A)
Discontinue clopidogrel 5 to 7 d before elective CABG. (Level of Evidence: B)
More urgent surgery, if necessary, may be performed by experienced surgeons if the incremental bleeding risk is considered acceptable. (Level of Evidence: C)
Anderson JL et al. ACC/AHA Guideline Update Available at: Accessed August 7, 2007.

20. Fox KAA, et. al. Circulation 2004

21. Notes:
In the past decade, PCI has undergone extensive changes in techniques used to achieve revascularization. Using the Society of Thoracic Surgeons National Cardiac Surgery Database, Haan and colleagues examined trends in emergent CABG procedures within 6 hours after PCI or stenting.
The investigators observed that the proportion of isolated CABG procedures done emergently after PCI decreased from 2.9% (3,357 of 115,679) in 1994 to 0.8% (1,227 of 155,831) in 1999 and remained stable through The proportions of these procedures for patients having an MI within the previous 24 hours followed a similar trend, which is approximately 1/3 of all emergent CABG/PCI cases, 3,352 of 1,042,864 (0.3%). Data were not available from the database regarding the timing of the MI relative to PCI, ie, whether the MI preceded the PCI or occurred secondary to the attempted or failed procedure. This lack of data on the timing of MI relative to PCI is because the STS database is a cardiac surgery procedural database.
Haan CK, O’Brien S, Edwards FH, Peterson ED, Ferguson TB. Trends in emergency coronary artery bypass grafting after percutaneous coronary intervention, Ann Thorac Surg. 2006;81:

22. Notes:
Acute treatment (therapy given within the first 24 hours) is associated with improved outcomes for patients with NSTEMI. Gibler and colleagues hypothesized that patients receiving appropriate, aggressive therapy within the first 24 hours of hospitalization are more likely to receive guideline-indicated therapy on hospital discharge.
The investigators compared the relationship between acute therapies (ASA, -blockers, clopidogrel) given in the ED in eligible high-risk patients from the CRUSADE Quality Improvement initiative. They observed that early treatment for NSTEMI within the first 24 hours in-hospital is associated with appropriate treatment on hospital discharge. Conversely, patients who did not receive appropriate early therapy were less likely to receive guidelines-indicated medication when discharged from the hospital. This was statistically significant (P<0.001).
Gibler WB, Peterson ED, Roe MT, et al. Early treatment for non–ST-segment elevation acute coronary syndromes is associated with appropriate discharge care: the CRUSADE experience. Presented at: American College of Cardiology Congress. March 6, Orlando, FL.

23. Notes:
Includes the American Heart Association’s Heart Disease and Stroke Statistics—2006 Update.
The 2006 statistical update on heart disease and stroke from the American Heart Association estimated that 1,550,000 unique hospitalizations (including primary and secondary discharge diagnoses) for ACS occurred in the United States in This figure includes 946,000 hospitalizations for MI and 650,000 for unstable angina (UA) (31,000 patients had a diagnosis of both UA and MI).
The National Registry of Myocardial Infarction (NRMI) databases have shown that 30%–45% of MI is STEMI by classification. Thus, one third (33%) of the 946,000 patients with MI is approximately 312,000 and 66% (approximately 634,000) are estimated to have NSTEMI.
Thus, UA/NSTEMI is a major public health problem and represents the most common reason for hospital admission for coronary heart disease.
References:
American Heart Association. Heart Disease and Stroke Statistics—2006 Update: A report from the American Heart Association Statistics committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85-e151.

24. Clopidogrel Clinical Trials Overview
Clopidogrel vs aspirin
Clopidogrel + aspirin
vs placebo + aspirin
Clopidogrel Clinical Trials Overview
Notes:
clopidogrel has been studied in more than 81,000 patients across a broad range of atherothrombotic patient types at risk for MI, ischemic stroke, and death.
The CAPRIE trial included recent MI, recent ischemic stroke, or established PAD patients, comparing clopidogrel vs aspirin with a combined end point of MI, ischemic stroke, or vascular death.[1]
The CURE trial included ACS (UA/NSTEMI) patients comparing clopidogrel plus aspirin vs placebo plus aspirin with primary composite end points of MI, stroke, or CV death and a composite end point of MI, stroke, CV death or refractory ischemia.[2]
The COMMIT trial included ACS (STEMI) patients comparing clopidogrel plus aspirin vs placebo plus aspirin and with primary end points of all-cause mortality, and a composite end point of death, reinfarction, or stroke.[3]
The CLARITY trial included ACS (STEMI) patients comparing clopidogrel plus aspirin vs placebo plus aspirin with trial end points of occluded infarct-related artery (TIMI flow grade 0 or 1) on predischarge angiogram, or death, or recurrent MI by the time of the start of coronary angiography.[4]
References:
clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.
1. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:
2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (CURE). Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:
3. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction) Collaborative Group. Addition of clopidogrel to aspirin in patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:
4. Sabatine MS, Cannon CP, Gibson CM, et al, for the CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:

25. Acute MI Platelet Activation by Fibrinolytics
Normalized Maximal Aggregation Rate
t-PA SK
1.5
1.0
0.5 50
100
150
200
250
Time (min)
Rabbit model, .05mM ADP as agonist
Rudd and Loscalzo, CircRes ‘90
SGE; , 22

26. Notes:
COMMIT: Study Design
COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) included a 2x2 factorial design with independent comparisons of clopidogrel vs placebo (plus usual care) and metoprolol vs placebo (plus usual care). For the clopidogrel part of the trial, the primary purpose was to evaluate the efficacy and safety of clopidogrel as part of standard therapy (including ASA) in patients (N=45,852) presenting within 24 hours of the onset of the symptoms of suspected MI with suspected ECG abnormalities (ST elevation, ST depression, or left bundle-branch block). The two co-primary end points for the COMMIT trial are death and the composite of the first occurrence of death, MI, or stroke during initial hospitalization (28 days or hospital discharge, whichever came first). A total of 55% of patients in COMMIT received thrombolytics.
References:
Please see Important Risk Information and Full Prescribing Information.
COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:

27. * All treated patients received aspirin.
Clopidogrel prescribing information. sanofi-aventis US, LLC
Notes:
COMMIT: Effects of Clopidogrel on Composite End Point
Clopidogrel significantly reduced the relative risk of the combination of re-infarction, stroke, or death by 9% (P=0.002).
References:
clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.

28. Notes:
In COMMIT, an 11% (99% CI, 0 to 20; P=0.014) proportional reduction was observed during the prespecified period of Days 0–1. This included a 12% (SE 6, P=0.05) reduction on Day 0 (which lasted for an average of only about 12 hours after initiation of treatment).
COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:

29. Clopidogrel prescribing information. sanofi-aventis US, LLC
Notes:
COMMIT: Major and Minor Bleed in Hospital
The rates for major noncerebral or cerebral bleeding are listed in the slide above. A greater number of patients in the clopidogrel group experienced major noncerebral or cerebral bleeding (134 vs 125, respectively).
Rates for any major noncerebral or cerebral bleeding were not significant. However, clopidogrel was associated with a small but significant rate of other noncerebral bleeding (non-major) and any noncerebral bleeding. Major bleeds are cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion.
References:
clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.

30. Notes:
CLARITY-TIMI 28: Study Design
CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy Thrombolysis in Myocardial Infarction-28) was a randomized, double-blind, placebo-controlled trial comparing clopidogrel plus acetylsalicylic acid (ASA) vs ASA alone in subjects with acute ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy. Patients with acute ST-elevation MI presenting within 12 hours of symptom onset received standard therapy that included aspirin, heparin (either unfractionated or low–molecular-weight heparin) and a fibrinolytic agent, being either TNK, rPA, TPA, or streptokinase.
Patients were then randomized to receive either clopidogrel or matching placebo at a dose of 300 mg as an initial loading dose, followed by 75 mg once daily. Patients also received aspirin (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent, and when appropriate, heparin for 48 hours. This was continued up through the time of angiography, hospital discharge, or Day 8.
The primary end point was a composite of an occluded infarct-related artery (TIMI flow grade 0 or 1) on the pre-discharge angiogram, or death or recurrent MI by the time of the start of coronary angiography. The patients were followed for 30 days.
References:
Sabatine MS, Cannon CP, Gibson CM, et al, for the CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:

31. * The total number of patients with a component event (occluded IRA, death, or recurrent MI) is greater than the number of patients with a composite event because some patients had more than a single type of component event.
Clopidogrel prescribing information. sanofi-aventis US, LLC
Notes:
CLARITY-TIMI 28: Primary Composite Endpoint
The patient population was mostly Caucasian (89.5%) and included 19.7% women and 29.2% patients ≥65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% β-blockers, 54.7% ACE inhibitors, and 63% statins.
The number of patients who reached the primary endpoint was 262 (15%) in the clopidogrel-treated group and 377 (21.7%) in the placebo group, but most of the events related to the surrogate endpoint of vessel patency.
Relative risk reduction and odds reduction are different and are not interchangeable. The CLARITY-TIMI 28 trial calculated odds reduction for all of the comparisons. Instead of saying “relative risk reduction” for comparisons, differences between groups should be described by using the odds ratio or by using terminology like “reduced the odds of xxx by x%.”
References:
clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.

32. Major bleeding defined as intracranial bleeding or bleeding associated with a fall in hemoglobin > 5 g/dL. Subgroups of patients defined by baseline characteristics, and type of fibrinolysis or heparin therapy.
Clopidogrel prescribing information, sanofi-aventis US, LLC
Notes:
In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin >5 g/dL) was similar between groups (1.3% vs 1.1% in the clopidogrel + aspirin and in the placebo + aspirin groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the clopidogrel + aspirin and in the placebo + aspirin groups, respectively) and intracranial hemorrhage (0.5% vs 0.7%, respectively) was low and similar in both groups.
The TIMI definition for major bleeding included either intracranial hemorrhage or any clinically overt sign of hemorrhage (including via an imaging study) that was associated with a fall in hemoglobin of >5 g/dL (or, when hemoglobin was not available, a fall in hematocrit of >15%). Bleeding episodes with clinically overt, nonintracranial signs of hemorrhage associated with smaller drops in hemoglobin were classified as TIMI minor (3–5 g/dL drop in hemoglobin) and minimal bleeding (<3 g/dL drop). Occurrence of primary intracranial hemorrhage was confirmed using CT, MRI, or autopsy.
References:
clopidogrel® (clopidogrel bisulfate) Prescribing Information. sanofi-aventis U.S. LLC.

33. American Heart Association. Circulation. 2005;112:IV-89-IV-110. Notes:
Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 days prior to surgery.
LBB-left bundle branch block; UFH = unfractionated heparin; LMWH = low molecular weight heparin.
American Heart Association. Circulation. 2005;112:IV-89-IV-110.
Notes:
According to the ACS Algorithm in the 2005 AHA Guidelines for CPR and ECC, patients with chest pain suggestive of ischemia should undergo EMS assessment and care and hospital preparation. In the ED, patients should be immediately assessed and treated with oxygen, ASA, nitroglycerin SL or spray, and morphine IV (if the pain is not relieved with nitroglycerin) if they have not already received treatment from EMS. Following this, patients can be stratified by their 12-lead ECG findings. Adjunctive treatment for STEMI patients includes immediate reperfusion as well as the use of β-adrenergic receptor blockers, clopidogrel, and heparin (unfractionated heparin [UFH] or low molecular weight heparin [LMWH]). Adjunctive treatment for UA/NSTEMI patients includes the use of nitroglycerin, β-adrenergic receptor blockers, clopidogrel, heparin (UFH or LMWH), and a glycoprotein (GP) IIb/IIIa inhibitor. Intermediate- or low-risk UA patients who develop high- or intermediate-risk criteria or are troponin-positive should receive the same adjunctive treatment administered to UA/NSTEMI patients.
American Heart Association. ECC guidelines. Part 8: stabilization of the patient with acute coronary syndromes. Circulation. 2005;112:IV-89–IV-110.
clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 days prior to surgery.

34. Notes:
This slide consolidates the key treatment recommendations of the 2005 AHA Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC): Clopidogrel Treatment Recommendations. Clopidogrel (300-mg loading dose) received a Class I recommendation as therapy for emergency department patients with ACS, with elevated cardiac markers or new ECG changes consistent with ischemia (excluding STEMI) in whom a medical approach or PCI is planned, in addition to standard care (aspirin, UFH, or LMWH and GP IIb/IIIa inhibitors if indicated).
Clopidogrel (300-mg loading dose) is also recommended for emergency department patients with suspected ACS, without ECG or cardiac marker changes who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance.
Clopidogrel (300-mg loading dose) is also recommended for ED patients up to 75 years of age with STEMI who receive aspirin, heparin, and fibrinolysis.
Class I: high-level prospective studies support the action or therapy, and the risk substantially outweighs the potential for harm.
Class IIa: the weight of evidence supports the action or therapy, and the therapy is considered acceptable and useful.
References:
American Heart Association AHA guidelines for CPR and ECC. Part 8: stabilization of the patient with acute coronary syndromes. Circulation. 2005;112(24 suppl):IV-89-IV-110.

35. Notes:
The new 2007 ACC/AHA STEMI Guidelines contain recommendations for the use of clopidogrel in the management of patients presenting with ST-elevation myocardial infarction (STEMI).
Clopidogrel 75 mg per day orally should be added to ASA in patients with STEMI regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy (IA). Treatment with clopidogrel should continue for at least 14 days (IB). In COMMIT, clopidogrel plus ASA was studied for up to 4 weeks.
In patients taking clopidogrel in whom CABG is planned, the drug should be withheld for at least 5 days and preferably for 7 days (IB).
In patients less than 75 years of age who receive fibrinolytic therapy or who do not receive reperfusion therapy, it is reasonable to administer an oral loading dose of clopidogrel 300 mg (IIaC).
Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol. 2008;51:1-38. Epub ahead of print. Accessed December 10, 2007.

36. Notes:
CRUSADE is among the first studies to link hospital process performance, measured in terms of composite adherence to the 4 ACC/AHA guideline-recommended acute treatments for patients with ACS, with patient outcomes. Risk-adjusted likelihood of in-hospital mortality decreased 10% for every 10% increase in composite adherence (adjusted odds ratio, 0.90; 95% confidence interval, ; P<.001).
Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA. 2006;295;
CRUSADE is a national quality improvement initiative of the Duke Clinical Research Institute. Partial funding for CRUSADE is provided by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.

37. Evidence-based Antithrombotic Pharmacology: Conclusions
Therapy directed at the platelet is the cornerstone of Atherothrombosis management
ASA and Clopidogrel
CURE, COMMIT, & CLARITY Trials support their role across the spectrum of risk
Administer early and at discharge

38. Evidence-based Antithrombotic Pharmacology: Conclusions
Bleeding is an issue with dual antiplatelet therapy
CABG – wait 5-7 days; outcomes improved if on clopidogrel
Long-term – reduce ASA dose
Guidelines are important
Adherence improves survival
Don’t forget about the medically managed patients