1. Becoming apt at DAPT: incorporating new dual antiplatelet therapy guidelines into clinical practice
_________________
Caitlin M. Gibson, PharmD, BCPS
Assistant Professor, Department of Pharmacotherapy
University of North Texas System College of Pharmacy

2. Learning objectives Pharmacists
Given a patient case, calculate a DAPT score and formulate a treatment recommendation for a patient receiving DAPT
Technicians
Identify standard treatment durations for patients receiving DAPT

3. Abbreviations ACS = acute coronary syndromes
NNH = number needed to harm
ARR = absolute risk reduction
NNT = number needed to treat
ASA = aspirin
NSTE = non-ST elevation
BMS = bare metal stent
PCI = percutaneous coronary intervention
CABG = coronary artery bypass grafting
SIHD = stable ischemic heart disease
DAPT = dual antiplatelet therapy
STEMI = ST-elevation MI
DES = drug-eluting stent
TIA = transient ischemic attack
MACE = major adverse cardiovascular events
TIMI = thrombolysis in myocardial infarction
MI = myocardial infarction
USA = unstable angina

4. Drug and dose selection
Outline
Background
Duration of DAPT
Drug and dose selection
Special populations

5. What is Dual Antiplatelet Therapy? (DAPT)
P2Y12 Receptor Antagonist
Clopidogrel
Aspirin
Prasugrel
Ticagrelor

6. CURE trial Design Double-blind, placebo-controlled RCT Patients
12,562 NSTE-ACS patients
Interventions
ASA 325 mg daily + clopidogrel 75 mg daily or ASA 325 mg daily + PBO
Primary outcomes
Composite of death from CV
causes, nonfatal MI, or stroke
Composite of above or
refractory ischemia
DAPT
Aspirin
p value
NNT
9.3%
11.4%
<0.001 47
DAPT
Aspirin
p value
NNT
16.5%
18.8%
<0.001 43
NEJM 2001;345:

7. Review of P2Y12 Antagonists
Clopidogrel (Plavix®)
Prasugrel (Effient®)
Ticagrelor (Brilinta®)
Loading dose
300 or 600mg PO
60mg PO
180mg PO
Maintenance dose
75mg PO daily
10mg PO daily
60 or 90mg PO BID
Dose adjustments --
Weight <60kg, consider 5mg daily
Degree of platelet inhibition + ++
Adverse events
+ Bleeding
++ Bleeding
Time to peak effect
~6 hours
~30 minutes
~90 minutes
Metabolism
Prodrug (CYP 2C19)
Prodrug
Active drug
Drug interactions
Inhibitors of CYP 2C19 may prevent activation of drug (omeprazole, esomeprazole, fluoxetine)

8. Review of P2Y12 Antagonists
Clopidogrel (Plavix®)
Prasugrel (Effient®)
Ticagrelor (Brilinta®)
Contraindications
Active bleeding
History of CVA or TIA (stroke or mini-stroke)
Pearls
25-30% of patients have genetic polymorphism reducing efficacy of clopidogrel  genetic or platelet reactivity testing
 Not for medical management
Aspirin must be dosed <100 mg daily
Can cause dyspnea
Generic available?
Yes No

9. Where do these guidelines fit?
Updates to recommendations in various American Heart Association collaborative guidelines:
SIHD
NSTE-ACS
STEMI
PCI
CABG
Non-cardiac surgery

10. Drug and dose selection
Outline
Background
Duration of DAPT
Drug and dose selection
Special populations

11. Ischemic Events Bleeding
Balancing risks
Prolonged DAPT
Shortened DAPT
Anticoagulants
Clopidogrel
Prior MI
Ticagrelor
Prasugrel
Ischemic Events Bleeding

12. Duration of DAPT Medical Management PCI with BMS PCI with DES CABG
Medical Management
PCI with BMS
PCI with DES
CABG
Fibrinolysis
SIHD
N/A
> 1 month
> 6 months
12 months
ACS
> 12 months
Total of 12 months*
14 days – 12 months
*If the patient received DAPT as part of recent (<12 months ago) PCI, the total DAPT duration should equal 12 months
Class I recommendation
Class IIa recommendation
JACC 2016;68(10):

13. CABG recommendations
Mixed results in studies; most do not show benefit for DAPT
Largest meta-analysis showed DAPT vs. ASA alone resulted in:
Reduced early saphenous vein graft occlusion
RR=0.59, 95% CI , p=0.002
Reduced incidence of 30-day/in-hospital mortality
Incidence 0.8% vs. 1.9%, p<0.001
Trend toward increase bleeding risk
RR=1.17, 95% CI , p=0.05
J Card Surg. 2013;28:

14. Duration of DAPT: Longer may be reasonable
Medical Management
PCI with BMS
PCI with DES+
CABG
Fibrinolysis
SIHD
N/A
> 1 month
> 6 months
12 months
ACS
> 12 months
Total of 12 months*
14 days – 12 months
*If the patient received DAPT as part of recent (<12 months ago) PCI, the total DAPT duration should equal 12 months
+Second-generation drug-eluting stents
JACC 2016;68(10):

15. Duration of DAPT: Longer may be reasonable
Trial
Patients
Intervention
Drugs
Endpoints
Results: long vs. standard
NNT/NNH
DAPT
NEJM 2014; 371(23):
N = 9961
Any IHD with stent placed
30 vs. 12 mo DAPT after DES
ASA mg
Clopidogrel
Prasugrel
Stent thrombosis
0.4% vs. 1.4% (p<0.001)
100
Major adverse cardiovascular and cerebrovascular events
4.3% vs. 5.9% (p<0.001) 63
Moderate-severe bleeding
2.5% vs 1.6% (p=0.001)
111

16. Duration of DAPT: Shorter may be reasonable
Medical Management
PCI with BMS
PCI with DES
CABG
Fibrinolysis
SIHD
N/A
> 1 month
> 6 months
12 months
ACS
> 12 months
Total of 12 months*
14 days – 12 months
*If the patient received DAPT as part of recent (<12 months ago) PCI, the total DAPT duration should equal 12 months
JACC 2016;68(10):

17. Results*: short vs. standard
Trial
Patients
Intervention
Drugs
Primary endpoint
Results*: short vs. standard
SECURITY
JACC 2014;64(20):
N = 1399
SIHD, USA
6 vs. 12 mo DAPT after DES
ASA - ? Dose
Clopidogrel
Ischemic event or bleeding
4.5% vs 3.7% (p<0.05)
EXCELLENT
Circulation 2012;125:
N = 1443
Any IHD
ASA mg
Target vessel failure
4.8% vs. 4.3% (p=0.001)
RESET
JACC 2012;60(15):
N = 2117
3 vs. 12 mo DAPT after DES
ASA 100 mg
Ischemic event, revascularization, or bleeding
4.7% vs. 4.7% (p<0.001)
OPTIMIZE
JAMA 2013:310(33):
N = 3211
SIHD or low-risk ACS
6.0% vs. 5.8% (p=0.002)
*All p-values are for non-inferiority

18. Risk vs. benefit of DAPT duration
Generally, extending duration of DAPT >12 months results in a 1-2% decrease in late stent thrombosis & ischemic complications, but a 1% increase in risk of bleeding
For every 1000 patients, prolonged DAPT after DES implantation results in 6 fewer MIs and 3 fewer stent thomboses, but also 5 major bleeds
Prolonged DAPT is most likely to benefit patients with a history of MI
JACC 2016;68(10):

19. DAPT Score Variable Points Age >75 years -2 Age 65 – 74 -1
Current smoker 1
Diabetes mellitus
MI at presentation
Prior PCI or MI
Stent diameter <3mm
Paclitaxel-eluting stent
CHF or LVEF <30% 2
Saphenous vein graft PCI
A score of >2 is associated with a favorable benefit/risk ratio for prolonged DAPT; <2 is associated with an unfavorable ratio
JACC 2016;68(10):

20. Drug and dose selection
Outline
Background
Duration of DAPT
Drug and dose selection
Special populations

21. Aspirin dosing in DAPT I
A daily aspirin dose of 81 mg (range: mg) is recommended
Daily ASA doses as low as mg inactivate COX-1 and inhibit thromboxane production
Studies comparing low-dose to standard dose aspirin have consistently found comparable rates of ischemic events but higher bleeding rates with high dose aspirin:
TRANSLATE-ACS: NNT for 1 major bleed = 67
PCI-CURE: NNT for 1 major bleed = 50
Serenbrauny, et al: NNT for any bleed = 16
JACC 2016;68(10):
Circulation. 2015: 132(3):
Eur Heart J. 2009; 30(8):900-7.
Am J Cardiol. 2005; 95(10):

22. P2Y12 selection Medical Management PCI with BMS PCI with DES CABG
Medical Management
PCI with BMS
PCI with DES
CABG
Fibrinolysis
SIHD
Clopidogrel
NSTEMI/USA or STEMI
Ticagrelor > clopidogrel
Ticagrelor or prasugrel > clopidogrel
Clopidogrel, prasugrel, ticagrelor
JACC 2016;68(10):

23. Prasugrel – TRITON-TIMI 38
Randomized, double-blind, multinational trial
Patients: ACS undergoing PCI (n=13,608)
Median age = 61 years; 74% male; 92% white race
74% NSTE-ACS; 26% STEMI
99% PCI (94% stented); 1% CABG
Prasugrel 60mg  10mg PO daily
Clopidogrel 300mg  75mg PO daily
vs.
New Eng J Med 2007;357(20):

24. Prasugrel – TRITON-TIMI 38
Endpoint
Outcome in prasugrel group
ARR
NNT
Primary endpoint
Reduction CV death, MI, or stroke
2.2% 45
Secondary endpoints
Nonfatal MIs
Stent thrombosis
1.3% 77
Cardiovascular mortality NS
Safety
Incidence of TIMI major bleeding
0.6%
167
New Eng J Med 2007;357(20):

25. Prasugrel – TRITON-TIMI 38
Net benefit
- Patients with diabetes (HR 0.70, 95% CI )
No net benefit / net harm
- History of stroke or transient ischemic attack (HR 1.54, 95% CI )
- > 75 years
- <60 kg

26. Ticagrelor - PLATO Randomized, double-blind, multinational trial
Patients: ACS patients (n=18,624)
Median age = 62 years; 72% male; 92% white race
59% NSTE-ACS; 38% STEMI
64% PCI (61% stented); 10% CABG
Ticagrelor 180mg  90mg PO BID
Clopidogrel mg  75mg PO daily
vs.
Lancet 2010;375:

27. Ticagrelor - PLATO Endpoint Outcome in Ticagrelor Group ARR NNT
Primary endpoint
Reduction CV death, MI, or stroke
1.9% 53
Secondary endpoints
Nonfatal MIs
1.1% 91
Stent thrombosis
0.7%
143
Cardiovascular mortality
1.4% 71
Safety
Incidence of TIMI major bleeding NS
Lancet 2010;375:

28. Prasugrel – TRITON-TIMI 38
Net benefit
No net benefit
- Not taking lipid-lowering drugs
- Less than median weight for sex
- Enrolled in North America (ASA dosing?)

29. Ticagrelor – PEGASUS-TIMI 54
Randomized, double-blind, 33-months
Does long-term therapy with ticagrelor added to low-dose aspirin reduce the risk of major adverse cardiovascular events among stable patients with a history of myocardial infarction?
Patients: History of MI in prior 1-3 years (n=21,162)
Median age = 65 years; 76% male; 87% white race
41% NSTE-ACS; 53% STEMI
83% PCI (61% stented); 10% CABG
Ticagrelor 90mg PO BID + ASA
Ticagrelor 60mg PO BID + ASA
Placebo + ASA
vs.
vs.
N Eng J Med 2015;372(19):

30. Ticagrelor – PEGASUS-TIMI 54
Endpoint
Outcome in ticagrelor group
90mg v. PBO ARR
60mg v. PBO ARR
Primary endpoint
Reduction CV death, MI, or stroke
1.2%
1.3%
Secondary endpoints
Incidence of MIs
0.9%
0.7%
Cardiovascular mortality NS
Safety
Incidence of TIMI major bleeding
1.5%
N Eng J Med 2015;372(19):

31. Ticagrelor – PEGASUS-TIMI 54
Patients had already received a year of DAPT
No head-to-head data against other P2Y12 antagonists in this setting
FDA approved to reduce the rate of CV death, MI, and stroke in patients with a history of MI
Package insert: Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily

32. Drug and dose selection
Outline
Background
Duration of DAPT
Drug and dose selection
Special populations

33. Triple therapy Results in 2-3x increased bleeding risk
Recommendations:
Assess ischemic and bleeding risks
Keep duration as short as possible
With warfarin, target INR of
Clopidogrel is preferred P2Y12 inhibitor
JACC 2016;68(10):

34. Proton pump inhibitors
Controversial drug interaction
Place in DAPT therapy: I
History of prior gastrointestinal bleeding
IIa
Increased risk of gastrointestinal bleeding:
Advanced age
Concomitant warfarin, steroids, or nonsteroidal anti-inflammatory drugs
III
Routine use in low-risk patients
JACC 2016;68(10):

35. DAPT and elective non-cardiac surgery
Delay surgery 30 days after BMS implantation
Delay surgery optimally 6 months after DES implantation
IIb
Surgery may be considered after 3 months of DAPT
III
Surgery should not be performed within 30 days after BMS or 3 months of DES implantation
JACC 2016;68(10):

36. Take home points Customizing duration of a DAPT regimen is reasonable
Weigh risk vs. benefit
Consider limitations of trials
Drug selection
Aspirin should be dosed at <100mg in DAPT
Ticagrelor and prasugrel may be a reasonable preference over clopidogrel
Special populations
Use triple therapy sparingly
Reserve PPI use for high-risk patients

37. Becoming apt at DAPT: incorporating new dual antiplatelet therapy guidelines into clinical practice
_________________
Caitlin M. Gibson, PharmD, BCPS
Assistant Professor, Department of Pharmacotherapy
University of North Texas System College of Pharmacy