1. Acute Coronary Syndrome: In Hospital Antiplatelet Management

2. Disclosures

3. Learning Objectives
At the completion of this program participants will be better able to:
Apply the Canadian Cardiovascular Society antiplatelet guideline recommendations to hospitalized patients with acute coronary syndrome
Recognize how patient characteristics impact the choice of antiplatelet therapy
Recognize how the approach to revascularization impacts the choice of antiplatelet therapy

4. Case: Mr. TC
67 yr old sedentary male with history of DM, HTN, dyslipidemia
Medication: ramipril 10 mg OD, ASA 81 mg OD, simvastatin 40 mg OD, metformin 500 mg BID
Presentation:
new onset crescendo angina x 3 days culminating in rest pain for the past 1h
No bleeding diathesis
No history of TIA or stroke
Weight: 80kg
Exam: BP 150/85, HR 80 (sinus). No CHF; +S4 otherwise normal

5. Mr. TC Labs: Normal CBC, electrolytes Creatinine: 112 umol/L
Troponin: positive
ECG:1-2 mm horizontal ST depression infero-lateral leads
CXR: normal (no signs of volume overload)

6. Mr. TC’s EKG

7. What is the CCS guideline recommended initial antiplatelet treatment?
Mr. TC
Diagnosis: NSTEACS
What is the CCS guideline recommended initial antiplatelet treatment?

8. Metabolism of P2Y12 Receptor Antagonists
May 5th TTT vs
Metabolism of P2Y12 Receptor Antagonists
It is important to note that ticagrelor is orally active without metabolic transformation whereas clopidogrel and prasugrel require metabolic activation to exert their pharmacologic effect on inhibition of platelet activation and aggregation. CYP3A4/5 is the major drug metabolizing enzyme(s) for ticagrelor; CYP enzymes 1A2, 2C19, and 2E1 do not contribute meaningfully to metabolism of ticagrelor in vitro. Therefore drug- drug interactions with drugs that either inhibit or induce CYP3A4/5 can be expected to have an effect on ticagrelor plasma concentrations and hence clinical effect. The concomitant use of ticagrelor with strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, nefazadone, ritonavir, and atazanavir is not recommended.
Absorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR- C124910XX (also active) from ticagrelor is rapid with a median tmax of approximately 2.5 hours. The Cmax and AUC of ticagrelor and the active metabolite increased in an approximately proportional manner with dose over the dose range studied ( mg). The mean absolute bioavailability of ticagrelor was estimated to be 36%, (range 25.4%-64.0%). In a study of healthy subjects, ingestion of a high-fat meal had no effect on ticagrelor Cmax or the AUC of the active metabolite, but resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax. These changes are considered of minimal clinical significance. Ticagrelor was administered without regard to food in PLATO. Therefore, ticagrelor may be given with or without food.
The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (> 99%).
The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor. CYP3A is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. Ticagrelor and the active metabolite are weak p-glycoprotein inhibitors.
 The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in feces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is most likely via biliary secretion. The mean t1/2 was approximately 6.9 hours (range hours) for ticagrelor and 8.6 hours (range hours) for the active metabolite.
Clopidogrel, a thienopyridine, is a prodrug. After intestinal absorption, it undergoes two steps of cytochrome P450 (CYP)-dependent oxidation to generate its active drug. After absorption clopidogrel is rapidly metabolized by two metabolic pathways in the liver one of which is hydrolysis by esterases leading to inactive metabolites (approx 85% of circulating metabolite) and the other by multiple CYP450 enzymes leading to a two-step formulation of the active thiol metabolite.
Prasugrel is rapidly metabolized in the intestine to a thiolactone, which is then converted to its active metabolite by a single step of cytochrome P450 metabolism primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19.
References: 1. Brilinta (ticagrelor) Product Monograph; May 26, Plavix (clopidogrel) Product Monograph; May 9, Effient (Prasugrel) Product Monograph; March 11, Schomig A. NEJM. 2009; 361(11):
Adapted from: Schomig A. NEJM. 2009;361(11): Effient (Prasugrel) Product Monograph March 11, 2011 version Brilinta (Ticagrelor) Product Monograph May 26, 2011 version. Plavix (Clopidogrel) Product Monograph May 9, 2011 version.

9. Properties of P2Y12 Receptor Antagonists
Clopidogrel
Prasugrel
Ticagrelor
Requires Metabolic Activation through CYP2C19
Yes sensitive to polymorphisms and drug interactions
Yes but less sensitive to polymorphisms and drug interactions No
Indications
ACS, PCI, PAD, CVD
PCI
ACS, PCI
Loading/Maintenance Dosing
300 mg /75 mg OD
60 mg/10 mg OD
180 mg/90 mg BID
Inhibition
Irreversible
Reversible
Efficacy ++
Further 2% ARR over ASA monotherapy
+++
Further 2% ARR over clopidogrel + ASA
Bleeding risk +
Issues
Rash
4.2% observed in clinical trials leading to 0.5% drug discontinuation
Further increased bleeding risk in:
Prior Stroke / TIA
< 60 Kg
>75 yrs
Increased fatal bleeding
Dyspnea
Ventricular pause
Hyperuricemia
Slight increased Cr
ARR – Absolute Risk Reduction. Note: No head to head comparisons of these agents have been done

10. CURE: Clopidogrel + ASA vs ASA (2001)
Study design:
Patients with NSTEACS with ECG changes or positive cardiac biomarkers
All patients received standard therapy, including ASA
Randomized to clopidogrel 300 mg load followed by 75 mg daily or placebo
n=12,562
References:
Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):
Yusuf S, et al. N Engl J Med. 2001;345(7):

11. Established DAPT, with clopidogrel + ASA as the standard of care
CURE (2001)
Nonfatal MI, stroke or CV death
Major bleeding:
3.7 vs 2.7%
NNH 100
No difference in fatal bleeding
ARR 2.1%
NNT 48
Established DAPT, with clopidogrel + ASA as the standard of care
References:
Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):
ABSTRACT
Background Despite current treatments, patients
who have acute coronary syndromes without ST-segment
elevation have high rates of major vascular
events. We evaluated the efficacy and safety of the
antiplatelet agent clopidogrel when given with aspirin
in such patients.
Methods We randomly assigned 12,562 patients
who had presented within 24 hours after the onset of
symptoms to receive clopidogrel (300 mg immediately,
followed by 75 mg once daily) (6259 patients) or placebo
(6303 patients) in addition to aspirin for 3 to 12
months.
Results The first primary outcome — a composite
of death from cardiovascular causes, nonfatal myocardial
infarction, or stroke — occurred in 9.3 percent of
the patients in the clopidogrel group and 11.4 percent
of the patients in the placebo group (relative risk with
clopidogrel as compared with placebo, 0.80; 95 percent
confidence interval, 0.72 to 0.90; P<0.001). The
second primary outcome — the first primary outcome
or refractory ischemia — occurred in 16.5 percent of
the patients in the clopidogrel group and 18.8 percent
of the patients in the placebo group (relative risk, 0.86,
P<0.001). The percentages of patients with in-hospital
refractory or severe ischemia, heart failure, and revascularization
procedures were also significantly lower
with clopidogrel. There were significantly more patients
with major bleeding in the clopidogrel group
than in the placebo group (3.7 percent vs. 2.7 percent;
relative risk, 1.38; P=0.001), but there were not significantly
more patients with episodes of life-threatening
bleeding (2.1 percent vs. 1.8 percent, P=0.13) or hemorrhagic
strokes.
Conclusions The antiplatelet agent clopidogrel has
beneficial effects in patients with acute coronary syndromes
without ST-segment elevation. However, the
risk of major bleeding is increased among patients
treated with clopidogrel. (N Engl J Med 2001;345: )
Yusuf S, et al. N Engl J Med. 2001;345(7):

12. TRITON: Prasugrel vs. Clopidogrel (2007)
Study design:
Patients with ACS with planned PCI
Coronary anatomy defined prior to P2Y12 antagonist administration
All patients received standard therapy, including ASA
Randomized to prasugrel 60 mg load followed by 10 mg daily or clopidogrel 300 mg load followed by 75 mg daily
n=13,608
References:
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):
Background
Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment
to prevent thrombotic complications of acute coronary syndromes and percutaneous
coronary intervention.
Methods
To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned
13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled
percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose
and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a
75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point
was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal
stroke. The key safety end point was major bleeding.
Results
The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel
and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel,
0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant
reductions in the prasugrel group in the rates of myocardial infarction (9.7% for
clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization
(3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding
was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients
receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater
in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%;
P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23)
and fatal bleeding (0.4% vs. 0.1%; P=0.002).
Conclusions
In patients with acute coronary syndromes with scheduled percutaneous coronary
intervention, prasugrel therapy was associated with significantly reduced rates of
ischemic events, including stent thrombosis, but with an increased risk of major
bleeding, including fatal bleeding. Overall mortality did not differ significantly
between treatment groups. (ClinicalTrials.gov number, NCT )
Wiviott SD, et al. N Engl J Med. 2007;357(20):

13. TRITON (2007) Nonfatal MI, stroke or CV death ARR 2.2% NNT 45
Major bleeding:
ARI 0.6
NNH: 166
Increase in fatal bleeding
References:
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):
Wiviott SD, et al. N Engl J Med. 2007;357(20):

14. PLATO: Ticagrelor vs. Clopidogrel (2009)
Study design:
Patients with high risk ACS
All patients received standard therapy, including ASA
Excluded patients receiving lytics
Randomized to ticagrelor 180 mg load followed by 90 mg bid or clopidogrel 300 mg load followed by 75 mg daily
34% in ticagrelor arm had already received clopidogrel load
n=18,624
References:
Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):
Background
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate
receptor P2Y12 that has a more rapid onset and more pronounced platelet
inhibition than clopidogrel.
Methods
In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg
loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading
dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624
patients admitted to the hospital with an acute coronary syndrome, with or without
ST-segment elevation.
Results
At 12 months, the primary end point — a composite of death from vascular causes,
myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ticagrelor
as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84;
95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing
of secondary end points showed significant differences in the rates of other composite
end points, as well as myocardial infarction alone (5.8% in the ticagrelor
group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes
(4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of
death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel;
P<0.001). No significant difference in the rates of major bleeding was found
between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively;
P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related
to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more
instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.
Conclusions
In patients who have an acute coronary syndrome with or without ST-segment elevation,
treatment with ticagrelor as compared with clopidogrel significantly reduced
the rate of death from vascular causes, myocardial infarction, or stroke without an
increase in the rate of overall major bleeding but with an increase in the rate of non–
procedure-related bleeding. (ClinicalTrials.gov number, NCT )
Wallentin L, et al. N Engl J Med. 2009;361(11):

15. PLATO (2009) Nonfatal MI, stroke or CV death
ARR 1.9%
NNT 53
cumulative incidence of primary endpoint %
Non CABG major bleeding:
4.5 vs 3.8%
NNH 143
No difference in fatal bleeding
References:
Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):
Months
Wallentin L, et al. N Engl J Med. 2009;361(11):

16. CCS NSTEACS Antiplatelet Guideline Recommendations
References:
Tanguay J-F, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol. 2013;29(11):
* Prasugrel should be avoided in patients with previous TIA or stroke. A 5-mg maintenance dose of prasugrel should be considered in patients aged 75 years or older or weight < 60 kg. **Patients eligible for ticagrelor include those with at least 2 high risk criteria including: (1) ischemic ST changes on electrocardiogram; (2) positive cardiac biomarkers and (3) 1 of the following: 60 years of age or greater, previous MI or CABG, CAD > 50% stenosis in 2 vessels, previous ischemic stroke, diabetes, peripheral arterial disease, or chronic renal dysfunction. ***A 600 mg loading dose and a 150 mg daily maintenance dose of clopidogrel may be considered for the first 6 days.
Tanguay J-F, et al. Can J Cardiol. 2013;29(11):

17. CCS Antiplatelet NSTEACS Guideline Text
We recommend ASA 81 mg daily indefinitely in all patients with NSTEACS. (Strong Recommendation, High-Quality Evidence)
We recommend ticagrelor 90 mg twice daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily in patients with moderate to high risk NSTEACS managed with either PCI, CABG surgery or medical therapy alone (Strong Recommendation, High-Quality Evidence)
We recommend prasugrel 10 mg daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily in P2Y12 inhibitor-naïve patients with NSTEACS after their coronary anatomy has been defined and PCI planned(Strong Recommendation, High-Quality Evidence)
References:
Tanguay J-F, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol. 2013;29(11):
Tanguay J-F, et al. Can J Cardiol. 2013;29(11):

18. Mr. TC Diagnosis: NSTEACS Treatment:
Receives ASA 160 mg chew, clopidogrel 300 mg, enoxaparin 1 mg/kg, metoprolol 25 mg, atorvastatin 80 mg
Admitted to CCU for cardiac catheterization in morning

19. Would you make any changes to his antiplatelet therapy?
Mr. TC
Would you make any changes to his antiplatelet therapy?
More clopidogrel?
Different P2Y12?
More ASA?
If clopidogrel is to be continued and the patient undergoes PCI, a 150 mg daily maintenance dose of clopidogrel may be considered for the first 6 days.
Ticagrelor and prasugrel are preferred ADP receptor antagonists by CCS guidelines. A switch from clopidogrel prior to discharge should be considered
As the attending cardiologist or internist you may consider switching from clopidogrel to ticagrelor. About 1/2 of patients in PLATO were clopidogrel loaded prior to randomization, then switched to ticagrelor.
References:
Tanguay J-F, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol. 2013;29(11):
After an initial 160 mg load the optimal dose of ASA is 81 mg daily. No dose increase should be considered
Tanguay J-F, et al. Can J Cardiol. 2013;29(11):

20. CURRENT: Clopidogrel & ASA high vs standard dose (2010)
Study design:
Patients with ACS and ECG changes or positive cardiac biomarkers
2x2 design for dose investigation of clopidogrel & ASA
Clopidogrel 600 mg load, 150 mg daily x 7 days then 75 mg daily vs 300 mg load, then 75 mg daily
ASA mg daily vs mg daily
n=25,087
References:
Mehta SR, Tanguay J-F, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010;376(9748):
Summary
Background
Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI.
Methods
The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25 086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2–7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300–325 mg daily) versus low-dose (75–100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17 263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT
Findings
8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74–0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39–0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84–1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09–1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92–1·53, p=0·20).
Interpretation
In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI.
Mehta SR, et al. Lancet. 2010;376(9748):

21. CURRENT (2010) Conclusions Dose Comparison
Double-dose clopidogrel significantly reduced stent thrombosis, CV death, MI and stroke in PCI patients.
In patients not undergoing PCI, double dose clopidogrel was not significantly different.
There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.
No significant efficacy or bleeding difference with increased ASA dose.
References:
Mehta SR, Tanguay J-F, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010;376(9748):
How has this influenced clopidogrel dosing at your institution?
Mehta SR, et al. Lancet. 2010;376(9748):

22. P2Y12 Switching Regimens
The only evidence to support switching P2Y12 receptor antagonists is from the PLATO trial
In the PLATO trial 46% of ticagrelor subjects received clopidogrel, mainly at loading dose. They were subsequently randomized and received a loading dose of ticagrelor 180 mg within 24 hours of onset of chest pain regardless of the timing and dose of clopidogel
Based on that evidence, if a switch from clopidogrel to ticagrelor is planned we suggest:
Acute Phase (within 24 hours of onset of chest pain): administer loading dose of 180 mg (unless active bleeding) regardless of clopidogrel timing/dose

23. P2Y12 Switching Regimens
No evidence exists to guide loading dose when switching between P2Y12 inhibitors beyond 24 hours after onset of chest pain
If a switch is necessary the following are reasonable strategies, but are not evidence based
Within 24 hours of onset of chest pain administer loading dose
Beyond 24 hours of onset of chest pain the use of a loading dose should be determined by the ischemic and bleeding risk

24. Mr. TC What if he had a STEMI?
…and primary PCI?
…and thrombolysis?
What if he has coronary anatomy requiring CABG?
Clopidogrel is the only P2Y12 that has data for thrombolytics (CLARITY trial). There is concern for excess bleeding with thrombolytics & ticagrelor/prasugrel

25. CLARITY: Clopidogrel vs placebo in STEMI (2005)
Study design:
Patients with STEMI
All thrombolysed, 57% received secondary PCI
All patients received standard therapy, including ASA
Randomized to clopidogrel 300 mg load followed by 75 mg daily or placebo
n=3491
References:
Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):
background
A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction
with ST-segment elevation have inadequate reperfusion or reocclusion of the
infarct-related artery, leading to an increased risk of complications and death.
methods
We enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after
the onset of an ST-elevation myocardial infarction and randomly assigned them to receive
clopidogrel (300-mg loading dose, followed by 75 mg once daily) or placebo. Patients
received a fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed
according to body weight) and were scheduled to undergo angiography 48 to 192 hours
after the start of study medication. The primary efficacy end point was a composite of
an occluded infarct-related artery (defined by a Thrombolysis in Myocardial Infarction
flow grade of 0 or 1) on angiography or death or recurrent myocardial infarction before
angiography.
results
The rates of the primary efficacy end point were 21.7 percent in the placebo group and
15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage
points in the rate and a 36 percent reduction in the odds of the end point with
clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001). By 30
days, clopidogrel therapy reduced the odds of the composite end point of death from
cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading
to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent,
P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the
two groups.
conclusions
In patients 75 years of age or younger who have myocardial infarction with ST-segment
elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of
clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic
complications.
Sabatine MS, et al. N Engl J Med. 2005;352(12):

26. CLARITY (2005) ARR 6.7% NNT 15 No difference in major bleeding
References:
Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):
Sabatine MS, et al. N Engl J Med. 2005;352(12):

27. CCS STEMI Antiplatelet Guideline Recommendations
References:
Tanguay J-F, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol. 2013;29(11):
* Prasugrel should be avoided in patients with previous TIA or stroke. A 5 mg maintenance dose of prasugrel should be considered in patients aged 75 years or older or weight < 60 kg. **In patients who are managed with PPCI, a 600 mg loading dose and a 150 mg daily maintenance dose of clopidogrel may be considered for the first 6 days.
Tanguay J-F, et al. Can J Cardiol. 2013;29(11):

28. CCS Antiplatelet STEMI Guidelines
We recommend clopidogrel 75 mg daily for at least 1 month in addition to ASA 81 mg daily in patients with STEMI who were managed with either fibrinolytic therapy or no reperfusion therapy (Strong Recommendation, High-Quality Evidence). We suggest that clopidogrel can be continued for 12 months (Conditional Recommendation, Low-Quality Evidence).
We recommend either prasugrel 10 mg daily or ticagrelor 90 mg twice daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily after primary PCI (Strong Recommendation, Moderate-Quality Evidence).
We recommend clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily after primary PCI in patients who are not eligible for prasugrel or ticagrelor (Strong Recommendation, Moderate-Quality Evidence).
References:
Tanguay J-F, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol. 2013;29(11):
Tanguay J-F, et al. Can J Cardiol. 2013;29(11):

29. CCS Antiplatelet CABG Guidelines
Typically dual antiplatelet therapy is started prior to coronary anatomy being defined
If the anatomy is not amenable to PCI (eg. three vessel disease), CABG may be indicated
ASA should be continued through surgery, however P2Y12 inhibition causes excess CABG bleeding and must be stopped prior to surgery
If possible, hold clopidogrel and ticagrelor 5 days, prasugrel 7 days prior to surgery
DAPT should be restarted within hours after surgery when deemed safe by the cardiac surgical team

30. CCS Antiplatelet CABG Guidelines

31. Summary
Dual antiplatelet therapy improves outcomes for patients with ACS
Replacing clopidogrel with either ticagrelor or prasugrel improves outcomes to similar magnitude at a cost of increased bleeding
Patient characteristics and revascularization method affect drug choice

32. Supplementary material

33. CCS Recommended Duration of DAPT
1 month
3 months
12 months
STEMI: ST elevation myocardial infarction, DES: drug eluting stent, BMS: bare metal stent, MM: medical management

34. CCS PPI Recommendation
If the patient is deemed to require a PPI in combination with clopidogrel, use one least likely to inhibit CYP2C19 – pantoprozole or lansoprazole

35. PPI CYP2C19 Inhibition Relative inhibition of CYP2C19
Ogilvie BW, Yerino P, et al. Drug Metab Dispos Nov;39(11):

36. PLATO Bleeding Definition
Major life-threatening bleeding:
fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery, a decline in the hemoglobin level of 5.0 g per deciliter or more, or the need for transfusion of at least 4 units of red cells.
Other major bleeding:
bleeding that led to clinically significant disability (e.g., intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in the hemoglobin level of at least 3.0 g per deciliter but less than 5.0 g per deciliter or requiring transfusion of 2 to 3 units of red cells.
Minor bleeding:
bleeding requiring medical intervention but not meeting the criteria for major bleeding

37. TRITON Bleeding Definition
TIMI major bleeding not related to coronary-artery bypass grafting (CABG), non–CABG-related TIMI life-threatening bleeding, and TIMI major or minor bleeding
Non-CABG Related Bleeding:
1. Major
Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI)
Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or a ≥15% absolute decrease in haematocrit
Fatal bleeding (bleeding that directly results in death within 7 d)
2. Minor
Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL or ≥10% decrease in haematocrit
No observed blood loss: ≥4 g/dL decrease in the haemoglobin concentration or ≥12% decrease in haematocrit
Any overt sign of hemorrhage that meets one of the following criteria and does not meet criteria for a major or minor bleeding event, as defined above
Requiring intervention (medical practitioner-guided medical or surgical treatment to stop or treat bleeding, including temporarily or permanently discontinuing or changing the dose of a medication or study drug)
Leading to or prolonging hospitalization
Prompting evaluation (leading to an unscheduled visit to a healthcare professional and diagnostic testing, either laboratory or imaging)
3. Minimal
Any overt bleeding event that does not meet the criteria above
Any clinically overt sign of haemorrhage (including imaging) associated with a <3 g/dL decrease in haemoglobin concentration or <9% decrease in haematocrit
See speakers notes for further definitions