1. health and fitness
2. therapy

4/13/15 UW MEDICINE │ TITLE OR EVENT
UW MEDICINE | DIVISION OF CARDIOLOGY
CURRENT ANTIPLATELET AGENTS:
PLACE IN THERAPY AND ROLE OF
GENETIC TESTING
DISCLOSURES
•  Consultant: CTI, Fletcher Spaght, Pfizer,
RubiconMD
•  Data Safety Committee: Gilead
•  Research Funding: Amgen, NHLBI
EUGENE YANG, MD, FACC
CLINICAL ASSOCIATE PROFESSOR OF MEDICINE
DIVISION OF CARDIOLOGY
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
AC FORUM
APRIL 2015, WASHINGTON, DC
•  This presentation will not include any
discussion of off-label or investigational
uses of a medical therapy or device.
THIS IS NOT ME!
THIS IS ME
OBJECTIVES
CASE #1: TO TREAT OR NOT TO TREAT
•  To treat or not to treat- evaluate role of aspirin
for primary prevention of CVD
•  68 year old white man with history of
hypertension and hyperlipidemia but no overt
atherosclerotic cardiovascular disease
•  How long is too long- discuss recent data
regarding duration of dual antiplatelet therapy
following PCI
•  What’s new in the anti-platelet world- examine
the role of new anti-platelet agents and review
updated clinical guidelines
•  To test or not to test- review current state of
genetic and platelet function testing
•  Current medications:
• 
Hydrochlorothiazide 25 mg daily
• 
Simvastatin 20 mg daily
•  Vital signs: BP 134/88 mm Hg
•  Labs: TC 210, HDL 42
1 4/13/15 WOULD YOU PRESCRIBE ASPIRIN TO THIS PATIENT
FOR PRIMARY PREVENTION OF CV DISEASE?
ASPIRIN CONTROVERSY
•  First anti-platelet agent to reduce risk of
CV events
•  Yes
•  No
•  Well established benefit for secondary
prevention- 20% risk reduction (6.7%
aspirin versus 8.2% control, per year)
•  Primary prevention benefit is small (12%)
and driven by non-fatal MI (0.51% aspirin
versus 0.57% control, per year)
Antithrombotic Trialists’ (ATT) Collaboration. Lancet 2009; 373: 1849–60
LACK OF GUIDELINE CONSENSUS
• 
American College of Chest Physicians (2012)
• 
• 
• 
American Heart Association (2011)
• 
Not recommended for women <65 years old
• 
Consider in women ≥65 years old if benefit for ischemic
stroke and MI prevention outweigh risk of bleeding
Canadian Cardiovascular Society (2011)
• 
• 
Consider for people ≥50 years old without symptomatic CVD
•  Japanese Primary Prevention Project (JPPP)
evaluated the role of aspirin in primary prevention
of CV events in Japanese patients 60-85 years
old with atherosclerotic risk factors
•  14,464 patients randomized to aspirin 100 mg
daily versus placebo
•  Average age ~71 years old, 58% women
Not recommended for routine use
European Society of Cardiology (2012)
• 
RECENT STUDY: JPPP
No recommended in patients without overt CVD
•  Patients had risk factors including hypertension
(84%), hyperlipidemia (72%), and diabetes (34%)20% had all 3
Ikeda Y et al. JAMA. doi:10.1001/jama.2014.15690.
RESULTS: JPPP
WHERE ARE WE HEADED?
•  Study prematurely terminated due to futility
•  No difference in primary outcomes- CV death,
nonfatal stroke, and nonfatal MI
•  Aspirin significantly reduced incidence of
nonfatal MI (HR,0.53, P=.02) and transient
ischemic attack (HR,0.57, P =.04)
•  Aspirin significantly increased the risk of
extracranial hemorrhage requiring transfusion
or hospitalization (HR,1.85, P =.004).
Ikeda Y et al. JAMA. doi:10.1001/jama.2014.15690.
2 4/13/15 CASE #1: TO TREAT OR NOT TO TREAT
•  68 year old white man with history of
hypertension and hyperlipidemia but no overt
atherosclerotic cardiovascular disease
•  Current medications:
• 
Hydrochlorothiazide 25 mg daily
• 
Simvastatin 20 mg daily
CV RISK ASSESSMENT
•  10 year Framingham risk score: 20%
•  ACC/AHA ASCVD 10 year risk
calculator: 21.6%
•  Vital signs: BP 134/88 mm Hg
•  Labs: TC 210, HDL 42
WHY TREAT?
•  May be other benefits to aspirin
CASE #2: HOW LONG IS TOO LONG?
• 
57 year old woman with history of CAD s/p inferior
STEMI with PCI to the LAD with everolimus eluting stent
3/2014, diabetes, hypertension, and hyperlipidemia who
presents to clinic for routine follow up. No history of GI
or other pathological bleeding.
• 
Current medications:
•  Reduce risk of colorectal cancer
•  If bleeding risk is small, may reduce
risk of non-fatal MI or TIA
•  Individualize decision based on net
clinical benefit
WOULD YOU CONTINUE DAPT?
•  Yes
•  No
• 
Aspirin 81 mg
• 
Atorvastatin 40 mg
• 
Clopidogrel 75 mg
• 
Losartan 25 mg
• 
Metformin 850 mg twice daily
• 
Metoprolol succinate 25 mg
CURRENT DAPT GUIDELINES FOR PCI
•  ACCF/AHA guidelines for STEMI (2013)
and NSTE-ACS (2014) recommend at
least one year of dual antiplatelet therapy
(DAPT) with aspirin and P2Y12 inhibitor
for patients undergoing primary PCI
•  2011 ACCF/AHA/SCAI Guidelines for PCI
recommend one year of DAPT with
aspirin and clopidogrel for patients
undergoing elective PCI with DES
3 4/13/15 HOW LONG IS TOO LONG?
• 
Drug eluting stent (DES) for PCI may be associated with
increased risk of stent thrombosis beyond 1 year after
treatment with DAPT
• 
Stent thrombosis is rare but often associated with fatal MI
• 
Extending DAPT beyond 1 year may reduce risk of MI after
DES placement
• 
• 
DAPT TRIAL
• 
• 
• 
Prolonged DAPT may increase risk of bleeding without
reduction in MI
Unknown if DAPT beyond 1 year reduces rate of stent
thrombosis or ischemic events occurring in an area remote
from the stent
Enrolled 9961 patients to 18 additional months of DAPT with
aspirin and P2Y12 inhibitor (30 months) versus aspirin alone
(12 months) following DES implantation
• 
65% clopidogrel, 35% prasugrel
Continued treatment with DAPT reduced the rates of stent
thrombosis and major adverse CV events
• 
Stent thrombosis (0.4 vs.1.4 %; HR, 0.29; p<0.001)
• 
Major adverse cardiovascular and cerebrovascular events
(4.3 vs. 5.9 %; HR 0.71; p<0.001)
• 
Death from any cause (2.0 vs. 1.5 % HR, 1.36; p = 0.05)
Moderate or severe bleeding rates and death from any cause
were higher with continued DAPT (2.5 vs. 1.6 %, p = 0.001)
Eisenstein EL et al. JAMA 2007;297:159-68.
Valgimigli M et al. Circulation 2012;125:2015-26.
Park S-J et al. N Engl J Med 2010;362:1374-82.
Feres F et al. JAMA 2013;310:2510-22.
Collet JP et al. Lancet 2014 July 15 (Epub ahead of
print).
Mauri L et al. N Engl J Med. 2014 Dec 4;371(23):2155-66.
ITALIC TRIAL
•  Randomized, multicenter, double-blind, placebo
controlled study of ~2000 everolimus DES
patients treated with 6- or 24-months of DAPT
with confirmed non-resistance to aspirin
• 
98.5% clopidogrel, 1.5% prasugrel, 1 patient
received ticagrelor
Composite of death, MI, repeat emergency TVR,
stroke or TIMI major bleeding within 12 months of
stenting
•  Safety endpoint
• 
•  Study terminated early due to slow recruitment
•  No difference in primary end point between 6
month and 24 month DAPT treatment groups
(1.6% versus 1.5%, p=0.85)
•  TIMI major bleeding rates, 6 months versus 24
months (0% versus 0.3%)
•  Primary endpoint
• 
ITALIC TRIAL RESULTS
TIMI major bleeding
•  Significance of findings questioned:
• 
Lack of power
• 
Lower-than-expected event rates
• 
Imbalanced study medication compliance
Gilard M et al. J Am Coll Cardiol. 2015;65(8):777-786.
ISAR-SAFE STUDY
• 
Randomized, multi-center, double-blind, placebo
controlled study of ~4000 DES patients who received 6
months of open-label DAPT with aspirin and clopidogrel.
• 
• 
ISAR-SAFE STUDY: RESULTS
•  Trial terminated early due to slow recruitment
•  Primary endpoint occurred in 29 patients
(1.5%) assigned to 6 months of clopidogrel
and 32 patients (1.6%) treated for 12 months
Primary endpoint:
• 
• 
At 6 months, randomized 1:1 to receive an additional 6
months of DAPT
Gilard M et al. J Am Coll Cardiol. 2015;65(8):777-786.
Composite of death, MI, stent thrombosis, stroke, or
TIMI major bleeding at 9 months after randomization
(15 months after index DES implantation)
•  Validity of study results questioned:
Safety endpoint:
• 
•  No difference in TIMI major bleeding, 0.2% (6
months) versus 0.3% (12 months), p=0.74
TIMI major bleeding at 9 months (15 months after
index DES implantation)
Schulz-Schüpke S et al. European Heart Journal Jan 2015.
• 
• 
Lack of power
Low recruitment
Schulz-Schüpke S et al. European Heart Journal Jan 2015.
4 4/13/15 PEGASUS TIMI 54 STUDY
•  Double-blind, randomized control trial of
21,162 patients who had history of MI 1 to 3
years earlier to ticagrelor 90 mg twice daily,
ticagrelor 60 mg twice daily, or placebo
•  All patients received low-dose aspirin and
were followed for a median of 33 months
PEGASUS TIMI 54 STUDY: RESULTS
• 
• 
•  Primary efficacy end point was composite of
CV death, MI, or stroke
•  Primary safety end point was TIMI major
bleeding
Bonaca MP et al. N Engl J Med. DOI: 10.1056/NEJMoa1500857.
CASE #2: HOW LONG IS TOO LONG?
• 
• 
57 year old woman with history of CAD s/p inferior
STEMI with PCI to the LAD with everolimus eluting stent
3/2014, diabetes, hypertension, and hyperlipidemia who
presents to clinic for routine follow up. No history of GI
or other pathological bleeding.
Current medications:
• 
Aspirin 81 mg
• 
Atorvastatin 40 mg
• 
Clopidogrel 75 mg
• 
Losartan 25 mg
• 
Metformin 850 mg twice daily
• 
Metoprolol succinate 25 mg
• 
Primary efficacy end point at 3 years was lower in
ticagrelor groups:
• 
90 mg ticagrelor twice daily, 7.85%; HR 0.85, p=0.008)
• 
60 mg ticagrelor twice daily, 7.77%; HR 0.84, p=0.004)
• 
Placebo, 9.04%
Rates of TIMI major bleeding were higher with ticagrelor:
• 
90 mg ticagrelor twice daily, 2.60%; HR 2.69, p<0.001)
• 
60 mg ticagrelor twice daily, 2.30%; HR 2.32, p<0.001)
• 
Placebo, 1.06%
No differences in intracranial hemorrhage rates
Bonaca MP et al. N Engl J Med. DOI: 10.1056/NEJMoa1500857.
DAPT CONTROVERSY CONTINUES
•  Consider longer duration therapy in high risk
patients with low bleeding risk
•  Need randomized trials powered to detect
difference in hard CV outcomes and bleeding
risk
•  Heterogeneity in trial design (differences in
DES type, patient population, P2Y12
inhibitors)
WHAT’S NEW IN ANTIPLATELET THERAPIES?
•  Vorapaxar was the first FDA-approved
protease-activated receptor-1 (PAR-1)
antagonist to reduce CV events in
patients with history of MI or PAD
•  The Trial to Assess the Effects of
Vorapaxar in Preventing Heart Attack and
Stroke in Patients With Atherosclerosis
(TRA 2°P-TIMI 50) examined if vorapaxar
provides additional CV benefits over SOC
therapies alone among patients with
history of MI, stroke, or PAD
Morrow DA et al. N Engl J Med 2012;366:1404-13.
•  Individualize decisions based on net clinical
benefit
VORAPAXAR: TRA 2°P-TIMI 50 STUDY
•  Randomized, double-blind placebo
controlled trial of >26,000 patients
•  Primary outcome was composite of
death from CV causes, MI, or stroke
•  Safety outcome was GUSTO moderate
or severe bleeding
Morrow DA et al. N Engl J Med 2012;366:1404-13.
5 4/13/15 TRA 2°P-TIMI 50 STUDY: RESULTS
•  After 2 years, DSMB recommended
discontinuation of the study treatment in
patients with a history of stroke due to
increased risk of intracranial hemorrhage
•  Primary end point occurred in 9.3% of patients
the vorapaxar group and 10.5% of patients in
the placebo group (HR 0.87; P<0.001) at 3
years
•  Moderate or severe bleeding occurred in 4.2%
of vorapaxar treated patients and 2.5% in
placebo group (HR 1.66; P<0.001)
TRA 2°P-TIMI 50 STUDY: RESULTS
•  Rate of intracranial hemorrhage in the
vorapaxar group was 1.0%, vs. 0.5% in
the placebo group (P<0.001)
•  No net clinical benefit was observed for
vorapaxar (11.7%) versus placebo
(12.1%), p=0.40
•  Defined as CV death, MI, stroke, or
GUSTO moderate or severe bleeding
Morrow DA et al. N Engl J Med 2012;366:1404-13.
ACCF/AHA NSTE-ACS GUIDELINES 2014:
HIGHLIGHTS
• 
For patients initially treated with either an early invasive or
initial ischemia-guided strategy, in addition to aspirin:
• 
Clopidogrel (300 or 600 mg loading dose) followed by 75 mg
daily for up to 12 months (Class I recommendation, LOE B)
• 
Ticagrelor (180 mg loading dose) followed by 90 mg twice
daily for up to 12 months- use 81 mg aspirin dose (Class I
recommendation, LOE B)
• 
P2Y12 inhibitor therapy (clopidogrel, prasugrel, or ticagrelor)
continued for at least 12 months in post–PCI patients treated
with coronary stents (Class I, LOE B)
• 
Ticagrelor preferred over clopidogrel for patients treated with
an early invasive or ischemia-guided strategy (Class 2a, LOE
B)
Morrow DA et al. N Engl J Med 2012;366:1404-13.
CASE #3: TO TEST OR NOT TO TEST
•  47 year old Microsoft engineer comes to
your office to discuss upcoming elective
PCI of his high-grade mid-LAD lesion for
persistent angina
•  Medications:
• 
• 
• 
• 
• 
Amlodipine 5 mg
Aspirin 81 mg
Atorvastatin 40 mg
Isosorbide mononitrate 60 mg
Metoprolol succinate 50 mg
Amsterdam EA et al. J Am Coll Cardiol. 2014 Sep 18. pii: S0735-1097(14)06279-2.
doi: 10.1016/j.jacc.2014.09.017. [Epub ahead of print]
CASE #3: TO TEST OR NOT TO TEST
•  Patient has been doing internet
searches on Bing (of course) about
genetic tests for clopidogrel and
platelet assays that can tell you how
“sticky my blood is”
WOULD YOU PERFORM ANY ADDITIONAL TESTS?
•  Yes
•  No
6 4/13/15 CLOPIDOGREL RESISTANCE
AVAILABLE TESTS: POINT OF CARE ASSAYS
•  CYP2C19 plays a key role in clopidogrel
metabolism and is highly polymorphic
• 
Traditional methods are time-consuming and cannot be
used routinely in clinical practice for patients presenting
with ACS
•  CYP2C19*2 (loss of function allele) is
common and occurs in 15% of
Caucasians and up to 30% of Asians
• 
Two point-of-care assays for CYP2C19*2 are
commercially available:
• 
• 
•  Carriers of CYP2C19*2 have a reduced
antiplatelet effect of clopidogrel
•  Some studies suggest an increased risk of
adverse CV events while others have not
reproduced these findings
• 
• 
• 
•  TRITON–TIMI 38 genetics substudy found
CYP2C19 polymorphisms had no significant effect
on prasugrel metabolism or clinical outcomes and
did not modify the benefit of prasugrel versus
clopidogrel
•  Genetics substudy from the PLATO trial did not
demonstrate any impact of CYP2C19 loss-offunction alleles
•  Other genes have been proposed to
independently predict clopidogrel response and
adverse clinical events including:
• 
ABCB1, PON-1, ITGB3, and P2Y12
PLATELET REACTIVITY AND CV OUTCOMES
•  ADP-induced platelet aggregation is a marker
for predicting ischemic events in clopidogrel
low responders or non-responders
•  Many assays commercially available to test
platelet reactivity
• 
• 
• 
• 
• 
• 
Double Randomization of a Monitoring Adjusted
Antiplatelet Treatment Versus a Common Antiplatelet
Treatment for DES Implantation, and Interruption
Versus Continuation of Double Antiplatelet Therapy
(ARTIC) N= 2,440
• 
Gauging Responsiveness With A VerifyNow AssayImpact On Thrombosis And Safety (GRAVITAS),
N=2,200
• 
Testing Platelet Reactivity In Patients Undergoing
Elective Stent Placement on Clopidogrel to Guide
Alternative Therapy With Prasugrel (TRIGGER-PCI),
N=423
Collet JP et al. N Engl J Med 2012;367: 2100–9.
Price MJ et al. JAMA 2011;305:1097–105.
Trenk D et al. J Am Coll Cardiol 2012;59:2159–64.
Platelet, light transmission, impedance
aggregometry
VASP phosphorylation
Platelet function analyzer
Cone and platelet analyzer
Thromboelastography
Siller-Matula JM et al. JACC Cardiovasc Interv 2013;6:1111-28.
NO BENEFITS: BUT…
CLINICAL TRIALS WITH TAILORED THERAPY
Phenotypic assays have been used in three clinical trials
to determine if tailored therapy based on platelet
reactivity reduces ischemic event rates:
Turnaround time 3 hours but can detect several CYP2C19
alleles
Siller-Matula JM et al. JACC Cardiovasc Interv 2013;6:1111-28.
Mega JL et al. Circulation. 2009;119:2553–2560.
Wallentin L et al. Lancet. 2010;376(9749):1320-8.
Siller-Matula JM et al. JACC Cardiovasc Interv 2013;6:1111-28.
• 
Turnaround time 1 hour, only detects CYP2C19*2 allele
Verigene XP system (Nanosphere, Northbrook, Illinois)
No published studies using these assays demonstrating
clinical outcome benefit
Siller-Matula JM et al. JACC Cardiovasc Interv 2013;6:1111-28.
CYP2C19 POLYMORPHISMS:
NO EFFECT ON OUTCOMES
Spartan RX system (Spartan Bioscience, Ottawa,
Canada)
•  ARTIC and GRAVITAS did not demonstrate
decrease in ischemic events despite strategy
of personalized antiplatelet therapy based on
platelet reactivity
•  TRIGGER-PCI was terminated early due to
low event rates and futility
•  Critics argue flawed design of these studies:
• 
• 
• 
Exclusion of STEMI patients in ARTIC
Delayed randomization in GRAVITAS
Inadequate personalized therapy
Collet JP et al. N Engl J Med 2012;367: 2100–9.
Price MJ et al. JAMA 2011;305:1097–105.
Trenk D et al. J Am Coll Cardiol 2012;59:2159–64.
7 4/13/15 CASE #3: TO TEST OR NOT TO TEST
NEED BETTER STUDIES
•  47 year old Microsoft engineer comes to
your office to discuss upcoming elective
PCI of his high-grade mid-LAD lesion for
persistent angina
•  Need well designed studies to determine
if there is clinical value to genetic testing
or phenotypic assays
•  Medications:
•  Lack of standardization for platelet
reactivity tests
• 
• 
• 
• 
• 
Amlodipine 5 mg
Aspirin 81 mg
Atorvastatin 40 mg
Isosorbide mononitrate 60 mg
Metoprolol succinate 50 mg
SUMMARY
•  Benefit of aspirin for primary prevention is
uncertain
•  Appropriate duration of DAPT following PCI
remains controversial:
• 
Six months of DAPT is minimally acceptable
duration of treatment for DES patients following
elective PCI
• 
Continuation of DAPT beyond 12 months needs to
be individualized based on analysis of ischemic
versus bleeding risk
•  Personalized medicine at what cost?
•  Updated AHA/ACC NSTE-ACS guidelines
do not recommend routine genotypic
testing
SUMMARY
•  Oral P2Y12 receptor inhibitors
clopidogrel, prasugrel, and ticagrelor
reduce the risk of CV events in ACS
patients
•  Ticagrelor is preferred antiplatelet option
for patients with NSTE-ACS regardless of
initial treatment strategy
•  PAR-1 antagonist vorapaxar was FDA approved,
but does not have a clear role in current practice
•  Personalized antiplatelet therapy based
on genetic and platelet function testing is
appealing, but clinical trials have not
demonstrated significant benefit
THANKS!
REFERENCES
Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute
Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am
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Collet JP, Cuisset T, Rangé G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367: 2100–
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Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE
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8 4/13/15 REFERENCES
REFERENCES
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nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol. 2015;65:777-786.
Schulz-Schüpke S et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 versus 12 months of clopidogrel therapy after
drug-eluting stenting. European Heart Journal Jan 2015, DOI: 10.1093/eurheartj/ehu523
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Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS.
Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical
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Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med
2012;366:1404-13.
Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel
after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet
Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll
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Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized
multicenter trial. Circulation 2012;125:2015-26.
Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with
ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376(9749):1320-8.
Park S-J, Park D-W, Kim Y-H, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med
2010;362:1374-82.
Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary
intervention: the GRAVITAS randomized trial. JAMA 2011;305:1097–105.
9