A patient with an acute coronary syndrome one year ago. Options for antiplatelet treatment
Ronen Durst, MD Cardiology Department Hadassah, Hebrew University Medical Center.
Chairman, Israeli society for treatment and prevention of atherosclerosis.
Case presentation
• 67 year old man.
• PMH: – PUD at 40 treated with PPI and antibiotics
– DM HbA1c 7.5,
– HTN
– Smoking
• 12 months ago had MI. Primary PCI on the LAD with DES. NOA of the RCA and M2
• Treatment: – Atorvastain 80mg
– Aspirin 100mg
– Prasugrel 10mg
– Ramipril 10mg
– Januet (sitagliptin and metformin 50/1000)*2
Wants to stop some of the medication
Should we stop Prasugrel?
Sangkuhl Katrin, Shuldiner Alan R, Klein Teri E, Altman Russ B. "Platelet aggregation pathway" Pharmacogenetics and genomics (2010).
Platelet activation pathways
Coronary stents: historical development
Time Person(s) Landmark events
1964 Dotter and Judkins Conceptual description of coronary angioplasty using an implantable prosthetic device
May 1977 Gruntzig and Myler First coronary angioplasty during coronary artery bypass graft surgery
September 1977
Andreas Gruntzig First coronary angioplasty in an awake patient; a revolution in interventional cardiology
1979 Geoffrey Hartzler First balloon angioplasty to treat AMI
1986 Sigwart and Puel The first implantation of a stent in human coronary arteries; second revolution in interventional cardiology
1991 Cannon and Roubin First coronary stenting to treat AMI
1994 Serruys et al. and Fischman et al.
Publication of first two landmark (Benestent and STRESS) trials
1994 FDA FDA-approved use of stents to treat acute and threatened vessel closure after failed balloon angioplasty
1999 Eduardo Sousa The first drug (sirolimus) eluting stent implanted in human coronary artery; third revolution in interventional cardiology
2002–04 EME and FDA Approvals of Cypher and Taxus stents in Europe and USA
2011 EME Approval of Absorb BVS (bioresorbable vascular scaffold) in Europe; fourth revolution in interventional cardiology
British Medical Bulletin Volume 106, Pp. 193-211
Stent complications
• These initial stents had high metallic density: sub-acute stent thrombosis Intimal proliferation and restenosis
• Exposed metal struts acts as a nidus for platelet aggregation and thrombosis
• This potentially devastating complication is associated with a 50% incidence of AMI and a 20% mortality rate
Stent antiplatelets
• Initially, stent thrombosis was tackled by the use of complex anticoagulation regimens using aspirin, heparin and warfarin
• Combination led to high rates of major bleeding, vascular complications and prolonged hospital stays.
• The development of new anti-platelet agents led to a breakthrough with the adoption of a dual anti-platelet treatment (DAPT) combining aspirin with a thienopyridine – Aspirin and ticlopidine
– Aspirin and clopidogrel
Figure 3. Kaplan-Meler cumulative hazard rates for cardiovascular death or myocardial infarction from randomisation to end of
follow-upA=median time from randomisation to percutaneous coronary intervention. B=30 days after median time of PCI.
Shamir R Mehta, Salim Yusuf, Ron JG Peters, Michel E Bertrand, Basil S Lewis, Madhu K Natarajan, Klas Malmberg, Hans-
Jürgen Rupprecht, Feng Zhao, Susan Chrolavicius, Ingrid Copland, Keith AA Fox
Effects of pretreatment with clopidogrel and aspirin followed by long-term
therapy in patients undergoing percutaneous coronary intervention: the PCI-
CURE study
null, Volume 358, Issue 9281, 2001, 527–533
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. N Engl J Med 2001;345:494-502.
Cumulative Hazard Rates for the First Primary Outcome (Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, or Stroke) during the 12 Months of the Study.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. N Engl J Med 2001;345:494-502.
The Rates and Relative Risks of the First Primary Outcome (Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, or Stroke) in Various Subgroups.
Clopidogrel Pathway
Sangkuhl Katrin, Klein Teri E, Altman Russ B. "Clopidogrel pathway" Pharmacogenetics and genomics (2010).
Date of download: 6/12/2016 Copyright © 2016 American Medical
Association. All rights reserved.
From: Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of
Clopidogrel Therapy
JAMA. 2009;302(8):849-857. doi:10.1001/jama.2009.1232
Simon T et al. N Engl J Med 2009;360:363-375.
Estimated Rates of Death from Any Cause, Nonfatal Myocardial Infarction, or Stroke, According to
Characteristics of Variant-Allele Polymorphisms.
Mega JL et al. N Engl J Med 2009;360:354-362.
Association between Status as a Carrier of a CYP2C19 Reduced-Function Allele and the Primary Efficacy Outcome or Stent
Thrombosis in Subjects Receiving Clopidogrel.
Schömig A. N Engl J Med 2009;361:1108-1111.
Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and Ticagrelor.
ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat
10
15
Days
0
5
0 30 60 90 180 270 360 450
Prasugrel
Clopidogrel
Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%)
HR 0.81
(0.73-0.90)
P<0.001
ARR=2.2
NNT=46
12.1
(n=781) 9.9
(n=643)
HR 0.77
(0.67-0.88)
P<0.001
HR 0.80
(0.71-0.90)
P<0.001
CV
De
ath
/MI/S
tro
ke (%
)
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON-TIMI 38: Primary End Point All ACS Population
8,688
8,763
0 10 20 30
8
6
4
2
0
Cu
mu
lati
ve i
ncid
en
ce
(%)
Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
Cu
mu
lati
ve i
ncid
en
ce
(%)
Primary efficacy endpoint over time
(composite of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days
Non-CABG and CABG-related major bleeding
p=0.026
p=0.025
NS
NS
9 K
-M e
sti
mate
d r
ate
(%
per
year)
Non-CABG
PLATO major
bleeding
8
7
6
5
4
3
2
1
0 Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
Ticagrelor
Clopidogrel
Mauri L et al. N Engl J Med 2014;371:2155-2166.
DAPT trial Enrollment, Randomization, and Follow-up.
• Multicenter, randomized, placebo-controlled trial
• Continued therapy (prsugrel clopidogrel) (n=5,020)
Aspirin (n=4,941)
Inclusion Criteria
• At time of PCI: Age >18 years
• Undergoing PCI with stent, or had PCI with stent in
prior 3 days
• No contraindications for DAPT for the next 30 months
• At month 12 randomization: Event free in prior 12
months (death, MI, stroke, repeat coronary
revascularization, stent thrombosis, or moderate
or severe GUSTO bleeding)
• Compliant with medical therapy in prior 12 months
Mauri L et al. N Engl J Med 2014;371:2155-2166.
Cumulative Incidence of Major Adverse Cardiovascular and Cerebrovascular Events, According to Study Group.
0
5
10
CV death, MI, or stroke
PEGASUS-TIMI 54
• CV death, MI, or stroke: 7.8% of the ticagrelor
90 mg bid group (hazard ratio [HR] vs. placebo
= 0.85, p = 0.008), 7.8% of the ticagrelor 60 mg
bid group (HR vs. placebo = 0.84, p = 0.004),
and 9.0% of the placebo group
• TIMI major bleeding: 2.6% with ticagrelor 90 mg
(HR vs. placebo = 2.7, p < 0.001), 2.3% with
ticagrelor 60 mg (HR vs. placebo = 2.3, p <
0.001), and 1.1% with placebo
Trial design: Subjects with a history of MI (1-3 years prior) on aspirin therapy were
randomized to ticagrelor 90 mg bid (n = 7,050) or ticagrelor 60 mg bid (n = 7,045) vs.
placebo (n = 7,067).
Results
Conclusions
• Among patients with prior MI on aspirin therapy,
the addition of ticagrelor was beneficial
• Ticagrelor compared with placebo reduced the
risk of cardiovascular death, MI, or stroke, but
was associated with increased major bleeding
Bonaca MP, et al. N Engl J Med 2015;Mar 14:[Epub]
(ticagrelor 90 mg vs. placebo p = 0.008;
ticagrelor 60 mg vs. placebo p = 0.004)
ticagrelor 90 mg bid
%
7.8 7.8
Placebo
ticagrelor 60 mg bid
9.0
Case presentation
• 67 year old man.
• PMH: – PUD at 40 treated with PPI and antibiotics
– DM HbA1c 7.5,
– HTN
– Smoking
• 12 months ago had MI. Primary PCI on the LAD with DES. NOA of the RCA and M2
• Treatment: – Atorvastain 80mg
– Aspirin 100mg
– Prasugrel 10mg
– Ramipril 10mg
– Januet (sitagliptin and metformin 50/1000)*2
Wants to stop some of the medication
Should we stop Prasugrel?
Pro and cons
• Pros
– Significant residual risk
• Cons
– History of peptic disease
– Reduces compliance
Would you continue DAPT treatment?
1. Yes
2. No
Figure 2. Treatment Algorithm for Duration of P2Y12 Inhibitor Therapy in Patients Treated With PCI
DAPT score
• http://www.daptstudy.org/for-clinicians/score_calculator.htm
• A new risk score (the “DAPT score”), derived from the Dual Antiplatelet Therapy study
• Analysis of study data suggest that in patients treated for 1 year with DAPT without significant bleeding or ischemic events, the benefit/risk ratio with prolonged DAPT may be favorable for those with a high DAPT score (≥2)
Factors Used to Calculate a “DAPT Score”
Points Variable
-2 Age ≥75 y
1- Age 65 to <75 y
0 Age <65 y
1 Current cigarette smoker
1 Diabetes mellitus
1 MI at presentation
1 Prior PCI or prior MI
1 Stent diameter <3 mm
1 Paclitaxel-eluting stent
2 CHF or LVEF <30%
2 Saphenous vein graft PCI
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