Download Becoming apt at DAPT

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
Learning objectives
Pharmacists
• Compare and contrast P2Y12 receptor
antagonists which may be used as part
of a dual antiplatelet therapy (DAPT)
regimen
• Describe changes in recommended
agents and duration of treatment for
patients receiving DAPT for ischemic
heart disease
• Given a patient case, calculate a DAPT
score and formulate a treatment
recommendation for a patient receiving
DAPT
Technicians
• Recognize the appropriate drugs and
dosage forms to be used as part of a dual
antiplatelet (DAPT) regimen
• Identify appropriate DAPT regimens for
patients with differing ischemic heart
disease diagnoses and treatments
• Identify standard treatment durations for
patients receiving DAPT
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
Outline
Background
Duration of
DAPT
Drug and
dose
selection
Special
populations
What is Dual Antiplatelet Therapy?
(DAPT)
P2Y12 Receptor Antagonist
Clopidogrel
Aspirin
Prasugrel
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
Composite of death from CV
causes, nonfatal MI, or stroke
DAPT Aspirin p value
9.3%
Primary
outcomes
Composite of above or
refractory ischemia
11.4%
<0.001
DAPT Aspirin p value
16.5%
18.8%
<0.001
NNT
47
NNT
43
NEJM 2001;345:494-502.
Review of P2Y12 Antagonists
Loading dose
Maintenance dose
Clopidogrel (Plavix®)
300 or 600mg PO
75mg PO daily
Dose adjustments
--
Degree of platelet
inhibition
+
++
++
Adverse events
+ Bleeding
++ Bleeding
++ Bleeding
Time to peak
effect
~6 hours
~30 minutes
~90 minutes
Metabolism
Prodrug (CYP 2C19)
Prodrug
Active drug
--
--
Inhibitors of CYP 2C19 may
prevent activation of drug
Drug interactions
(omeprazole, esomeprazole,
fluoxetine)
Prasugrel (Effient®)
60mg PO
10mg PO daily
Weight <60kg, consider
5mg daily
Ticagrelor (Brilinta®)
180mg PO
60 or 90mg PO BID
--
Review of P2Y12 Antagonists
Clopidogrel (Plavix®)
Prasugrel (Effient®)
Ticagrelor (Brilinta®)
Contraindications
Active bleeding
Active bleeding
History of CVA or TIA (stroke
or mini-stroke)
Active bleeding
Pearls
25-30% of patients have
genetic polymorphism
reducing efficacy of
clopidogrel  genetic or
platelet reactivity testing
Not for medical
management
Yes
No
Generic available?
Aspirin must be dosed
<100 mg daily
Can cause dyspnea
No
Where do these guidelines fit?
• Updates to recommendations in various American Heart Association
collaborative guidelines:
SIHD
PCI
NSTE-ACS
STEMI
CABG
Non-cardiac
surgery
Outline
Background
Duration of
DAPT
Drug and
dose
selection
Special
populations
Balancing risks
Prolonged
DAPT
Shortened
DAPT
Clopidogrel
Prior MI
Ischemic Events
Anticoagulants
Ticagrelor
Prasugrel
Bleeding
Duration of DAPT
Medical
PCI with BMS PCI with DES
Management
SIHD
N/A
> 1 month
> 6 months
CABG
Fibrinolysis
12 months
N/A
Total of 12
14 days – 12
months*
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
ACS
> 12 months
> 12 months
> 12 months
JACC 2016;68(10):1082-115
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 0.43-0.82, p=0.002
Reduced incidence of 30-day/inhospital mortality
Incidence 0.8% vs. 1.9%, p<0.001
Trend toward increase bleeding risk
RR=1.17, 95% CI 1.00-1.37, p=0.05
J Card Surg. 2013;28:109-16.
Duration of DAPT: Longer may be
reasonable
Medical
PCI with BMS
Management
SIHD
N/A
> 1 month
PCI with
DES+
CABG
Fibrinolysis
> 6 months
12 months
N/A
Total of 12
14 days – 12
months*
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
ACS
> 12 months
> 12 months
> 12 months
JACC 2016;68(10):1082-115
Duration of DAPT: Longer may be
reasonable
Trial
DAPT
NEJM 2014;
371(23):
2155-66.
Patients
Intervention
N = 9961
Any IHD
with stent
placed
30 vs. 12 mo
DAPT after
DES
Drugs
ASA 75162mg
Clopidogrel
Endpoints
Results: long vs.
standard
NNT/NNH
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
Prasugrel
Duration of DAPT: Shorter may be
reasonable
Medical
PCI with BMS PCI with DES
Management
SIHD
N/A
> 1 month
> 6 months
CABG
Fibrinolysis
12 months
N/A
Total of 12
14 days – 12
months*
months
*If the patient received DAPT as part of recent (<12 months ago) PCI, the total DAPT duration
should equal 12 months
ACS
> 12 months
> 12 months
> 12 months
JACC 2016;68(10):1082-115
Trial
Patients
Intervention
Drugs
Primary
endpoint
Results*: short
vs. standard
SECURITY
N = 1399
JACC 2014;64(20):
2086-97.
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
N = 1443
Circulation
2012;125:505-13.
Any IHD
6 vs. 12 mo
DAPT after
DES
ASA 100-200
mg
Clopidogrel
Target vessel
failure
4.8% vs. 4.3%
(p=0.001)
RESET
N = 2117
JACC 2012;60(15):
1340-48.
Any IHD
3 vs. 12 mo
DAPT after
DES
ASA 100 mg
Clopidogrel
Ischemic event,
revascularization,
or bleeding
4.7% vs. 4.7%
(p<0.001)
OPTIMIZE
N = 3211
JAMA
2013:310(33):
2510-22.
SIHD or lowrisk ACS
3 vs. 12 mo
DAPT after
DES
ASA 100-200
mg
Clopidogrel
Ischemic event or
bleeding
6.0% vs. 5.8%
(p=0.002)
*All p-values are for non-inferiority
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):1082-115
DAPT Score
Variable
Points
Age >75 years
-2
Age 65 – 74
-1
Age <65
0
Current smoker
1
Diabetes mellitus
1
MI at presentation
1
Prior PCI or MI
1
Stent diameter <3mm
1
Paclitaxel-eluting stent
1
CHF or LVEF <30%
2
Saphenous vein graft PCI
2
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):1082-115
Outline
Background
Duration of
DAPT
Drug and
dose
selection
Special
populations
Aspirin dosing in DAPT
I
A daily aspirin dose of 81 mg (range: 75-100 mg)
is recommended
• Daily ASA doses as low as 30-50 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):1082-115.
Circulation. 2015: 132(3):174-81.
Eur Heart J. 2009; 30(8):900-7.
Am J Cardiol. 2005; 95(10):1218-22.
P2Y12 selection
Medical
PCI with BMS PCI with DES
Management
CABG
Clopidogrel
Clopidogrel
Clopidogrel
Ticagrelor or
prasugrel >
clopidogrel
Ticagrelor or
prasugrel >
clopidogrel
Clopidogrel,
prasugrel,
ticagrelor
SIHD
NSTEMI/USA
or STEMI
Ticagrelor >
clopidogrel
Fibrinolysis
Clopidogrel
JACC 2016;68(10):1082-115
Prasugrel – TRITON-TIMI 38
• Randomized, double-blind, multinational trial
Prasugrel 60mg 
10mg PO daily
vs.
Clopidogrel 300mg
 75mg PO daily
• 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
New Eng J Med 2007;357(20): 2001-15.
Prasugrel – TRITON-TIMI 38
Endpoint
Outcome in prasugrel group
ARR
NNT
Primary
endpoint
Reduction CV death, MI, or
stroke
2.2%
45
Nonfatal MIs
2.2%
45
Stent thrombosis
1.3%
77
Cardiovascular mortality
NS
NS
Incidence of TIMI major
bleeding
0.6%
167
Secondary
endpoints
Safety
New Eng J Med 2007;357(20): 2001-15.
- Patients with
diabetes (HR 0.70,
95% CI 0.58-0.85)
- History of stroke
or transient
ischemic attack
(HR 1.54, 95% CI
1.02-2.32)
- > 75 years
- <60 kg
No net benefit / net harm
Net benefit
Prasugrel – TRITON-TIMI 38
Ticagrelor - PLATO
• Randomized, double-blind, multinational trial
Ticagrelor 180mg
 90mg PO BID
vs.
Clopidogrel 300600mg  75mg PO
daily
• 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
Lancet 2010;375: 283-93.
Ticagrelor - PLATO
Endpoint
Outcome in Ticagrelor Group
ARR
NNT
Primary
endpoint
Reduction CV death, MI, or
stroke
1.9%
53
Nonfatal MIs
1.1%
91
Stent thrombosis
0.7%
143
Cardiovascular mortality
1.4%
71
Incidence of TIMI major
bleeding
NS
NS
Secondary
endpoints
Safety
Lancet 2010;375: 283-93.
Net benefit
Prasugrel – TRITON-TIMI 38
- Enrolled in North
America (ASA
dosing?)
- Not taking lipidlowering drugs
No net benefit
- Less than median
weight for sex
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?
Ticagrelor 90mg PO
BID + ASA
vs.
Ticagrelor 60mg PO
BID + ASA
vs.
Placebo + ASA
• 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
N Eng J Med 2015;372(19):1791-1800.
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
NS
Safety
Incidence of TIMI major bleeding
1.5%
1.3%
N Eng J Med 2015;372(19):1791-1800.
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
Outline
Background
Duration of
DAPT
Drug and
dose
selection
Special
populations
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 2.0-2.5
Clopidogrel is preferred P2Y12 inhibitor
JACC 2016;68(10):1082-115
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):1082-115
DAPT and elective non-cardiac surgery
I
Delay surgery 30 days after BMS implantation
I
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):1082-115
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
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