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Dr. Taylor Chuich
Dr. Chuich is a PGY2 cardiology resident at Vanderbilt University Medical Center in Nashville, TN. She graduated from Purdue University and completed her PGY1 Pharmacy Practice Residency at Northwestern Memorial Hospital in Chicago, IL. Dr. Chuich’sprofessional interests within cardiology include advanced heart failure, cardiac critical care, mechanical circulatory support, and clinical research. She has accepted a position at Northwestern in the CCU and advanced heart failure unit upon completion of her PGY2.
Dr. Kelly Rogers
Dr. Rogers completed her Doctorate of Pharmacy at the University of Tennessee and went on to complete her Pharmacy Practice Residency at the University of Virginia Health Sciences Center. She is currently a Professor of Clinical Pharmacy at the University of Tennessee, where she teaches cardiology and precepts residents and students on cardiology rotations at the Memphis VA Medical Center.
Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease
(EUCLID Trial)Taylor Chuich, PharmD
PGY 2 Cardiology ResidentVanderbilt University Medical Center
Nashville, TN
Kelly Rogers, PharmD, FCCP, AACCProfessor of Clinical Pharmacy
The University of Tennessee College of Pharmacy and VAMCMemphis, TN
Disclosure Statement
• The speaker has nothing to disclose concerning possible financial or personal relationships with commercial entities that my have direct or indirect interest in the subject matter of this presentation.
Definitions of PAD Key TermsTerm Definition
Claudication Fatigue, discomfort, cramping, or pain of vascular origin in the muscles of the lower extremities that is consistently induced by exercise and consistently relieved by rest
Acute LimbIschemia (ALI)
Acute ( < 2 week), severe hypoperfusion of the limb characterized by: pain, pallor, pulselessness, paresthesias, paralysis, and poikilothermia
Critical LimbIschemia (CLI)
Condition characterized by chronic (>/= 2 week) ischemic rest pain, non-healing wound/ulcers, or gangrene in 1 or both legs
Nonviable limb Condition of extremity (or portion of extremity) in which loss of motor function, neurological function, and tissue integrity cannot be restored with treatment
SalvageableLimb
Condition of the extremity with potential to secure viability and preserve motor function to the weight bearing portion of the foot if treated
Gerherd-Herman et al. 2016 AHA/ACC PAD Guideline
Peripheral Artery DiseaseIncreased Risk of PAD Age >/= 65 years Age 50-64 years with risk
factors (RF) for atherosclerosis Diabetes mellitus, Smoking,
Hyperlipidemia, HTN, or family history
Age <50 with DM and 1 RF Known atherosclerotic disease
Examination Findings• Abnormal lower extremity
pulse examination• Vascular bruit• Non-healing lower
extremity wound• Lower extremity gangrene
Gerherd-Herman et al. 2016 AHA/ACC PAD Guideline
Diagnosis of PADAnkle Brachial Index (ABI) Equation
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑝𝑝𝑝𝑝𝑝𝑝𝐷𝐷𝐷𝐷 𝐷𝐷𝐷𝐷 𝑝𝑝𝐷𝐷𝐷𝐷𝑝𝑝𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑝𝑝𝐷𝐷𝑡𝑡𝐷𝐷𝐷𝐷𝐷𝐷 𝐷𝐷𝑠𝑠𝐷𝐷𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝑠𝑠 𝑝𝑝𝐷𝐷𝑝𝑝𝐷𝐷𝐷𝐷𝑝𝑝𝐷𝐷𝑝𝑝𝐻𝐻𝐷𝐷𝐻𝐻𝐻𝑝𝑝𝐷𝐷𝑝𝑝 𝐷𝐷𝐷𝐷𝐻𝐻𝐻𝑝𝑝 𝐷𝐷𝐷𝐷 𝐷𝐷𝑝𝑝𝑙𝑙𝑝𝑝 𝐷𝐷𝐷𝐷𝑎𝑎 𝑡𝑡𝐷𝐷𝐷𝐷𝐷𝐷𝑝𝑝 𝐷𝐷𝑠𝑠𝐷𝐷𝑝𝑝𝐷𝐷𝐷𝐷𝐷𝐷𝑠𝑠 𝑝𝑝𝐷𝐷𝑝𝑝𝐷𝐷𝐷𝐷𝑝𝑝𝐷𝐷𝑝𝑝
ABI </= 0.90 = AbnormalABI 0.91-0.99 = Borderline
ABI 1.00-1.40 = NormalABI > 1.40 = Non-compressible
Gerherd-Herman et al. 2016 AHA/ACC PAD Guideline
Overall Treatment Plan for PAD• Antiplatelet Agent • Statin • Antihypertensive therapy • ACE Inhibitor or ARB • Smoking cessation• Management of diabetes • Cilostazol for claudication• Flu vaccination
Medical Therapy for PADRecommendation
Antiplatelet therapy with aspirin alone (range 75-325 mg per day) or clopidogrel along (75 mg) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD. (COR I LOE A)
In asymptomatic patients with PAD, antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death. (COR IIa LOE C)
The effectiveness of DAPT (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established. (COR IIb LOE B)
DAPT may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization (COR IIb LOE C)
Gerherd-Herman et al. 2016 AHA/ACC PAD Guideline
Title Inclusion Intervention Outcome
CAPRIE (n= 19,185)
Recent ischemic stroke, MI, or PAD
ASA vs. Clopidogrel
Ischemic stroke, MI, or vascular death: 5.83% vs. 5.32% (p= 0.043)• Subgroup analysis: PAD (p= 0.0028)
CHARISMA (n= 15,603)
Multiple atherothrombotic risk factors, CAD, CVA, symptomatic PAD
Aspirin vs.Clopidogrel + ASA
MI, Stroke, Death from CV causes: 7.3% vs. 6.8%, 0.93 (0.83-1.05), p = 0.22• PAD: 7.6 vs. 8.9, p = 0.183 (Significantly
decreased MI and Hospitalization)
PLATO(n= 18,624)
ACS with or without ST-segment elevation
Ticagrelor vs.Clopidogrel (+ ASA)
Death from vascular causes, MI, or stroke: 9.8 vs. 11.7, 0.84 (0.77-0.92), p < 0.001• PAD: 18 vs. 20.6, 0.85, p= 0.99Death from any cause: p < 0.001• PAD: 8.7 vs. 11.9, p= 0.73
PEGASUS-TIMI 54(n= 21,162)
MI 1-3 years prior to enrollment, >/= 50 yo, + High risk feature
Ticagrelor 60 mg BID, 90 mg BID, Placebo
CV Death, MI, or Stroke 7.77 vs. 7.85 vs. 9.04 • 60 mg vs. Placebo (p = 0.004)
• PAD: 14.1 vs. 19.3, p = 0.045• 90 mg vs. Placebo (p = 0.008)
• PAD: 16.3 vs. 19.3, p= 0.24Wallentin L, et al. NEJM 2009Bonaca MP, et al. NEJM 2015
Gent M, et al. Lancet 1996.Bhatt DL, et al. NEJM 2006.
Study Design and Population• International, multicenter, randomized, double blind, parallel
group, end point driven phase IIIb study (n=13,885) conducted between December 2012 through March 2014
• Inclusion Criteria:– ≥50 years of age with symptomatic PAD defined by one of the
following:• ABI ≤ 0.80• Prior lower extremity revascularization >30 days prior
• Exclusion Criteria: – Planned use of dual antiplatelet therapy, requirement of aspirin,
increased risk of bleeding, treatment with anticoagulation, or poor metabolizer status for CYP2C19
Hiatt WR, et al. NEJM 2017.
Intervention and Outcomes• Ticagrelor 90 mg twice daily vs. clopidogrel 75 mg once daily • Primary End Point: Composite of CV death, MI, or ischemic stroke• Primary Safety End Point: Major bleeding using TIMI definition • Secondary End Points
– Composite of CV death, MI, ischemic stroke, and ALI requiring hospitalization– Death from any cause– Cardiovascular death, MI, or ischemic or hemorrhagic stroke– Hospitalization for ALI– Lower extremity revascularization– Coronary or peripheral revascularization, including limb, mesenteric, renal,
carotid or other type
Hiatt WR, et al. NEJM 2017.
Statistics• Superiority Trial
– Intention to treat principle – Cox proportional hazards model for time-to-event
analyses– Kaplan-Meier estimates of the cumulative proportion
of patients with events– P-values were not adjusted– Subgroup analyses performed to evaluate variation of
treatment effect
Hiatt WR, et al. NEJM 2017.
Enrollment
16,237 Patients assessed for
eligibility
2352 Were Excluded
489 Did not meet inclusion criteria for symptomatic
PAD616 Were
homozygous for cytochrome P450
2C191335 Had other
reasons
13,885 Underwent
Randomization
6930 Received Ticagrelor
123 Withdrew consent
2083 Discontinued
study drug
6955 Received Clopidogrel
113 Withdrew consent
1803 Discontinued
study drug
Hiatt WR, et al. NEJM 2017.
Baseline CharacteristicsCharacteristic Ticagrelor (N=6930) Clopidogrel (N=6955)
Median Age (years, IQR) 66 (60-72) 66 (60-73)
Female Sex- no. (%) 1908(27.5) 1980 (28.5)
Inclusion Criteria• Revascularization- no. (%)
• ABI value• ABI or TBI criteria- no. (%)
• ABI value• TBI value
3923 (56.6)0.78 +/- 0.233007 (43.4)
0.63 +/- 0.150.49 +/- 0.14
3952 (56.8)0.78 +/- 0.233003 (43.2)
0.63 +/- 0.150.55 +/- 0.27
Limb Symptoms- no. (%)AsymptomaticMild or moderate claudicationSevere claudication
1309 (18.9)3674 (53)
1620 (23.4)
1292 (18.6)3736 (53.7)1608 (23.1)
Baseline CharacteristicsCharacteristic Ticagrelor Clopidogrel
Past Medical History- no. (%)StrokeTransient ischemic attackCoronary artery diseaseMyocardial infarctionDiabetes (Type I or II)HypertensionHyperlipidemia
576 (8.3)279 (4.0)
2019 (29.1)1242 (17.9)2639 (38.1)5437 (78.5)5229 (75.5)
567 (8.2)228 (3.3)
2013 (28.9)1280 (18.4)2706 (38.9)5420 (77.9)5251 (75.5)
Tobacco Use - Never smoked (%) 21.4 21.6
Medications before randomization- no (%)AspirinClopidogrelStatinACE InhibitorARB
4667 (67.3)2193 (31.6)5058 (73.0)2826 (40.8)1741 (25.1)
4604 (66.2)2280 (32.8)5123 (73.7)2809 (40.4)1747 (25.1)
Results: Primary Outcome
Results: Primary Outcome
Hiatt WR, et al. NEJM 2017.
Results: Secondary Outcomes
Hiatt WR, et al. NEJM 2017.
Primary Efficacy Endpoint by Patient Subgroup
Results: Safety Outcomes
Hiatt WR, et al. NEJM 2017.
Author’s Conclusion“In patients with symptomatic peripheral artery disease, ticagrelor was not superior to clopidogrel for the reduction of cardiovascular events, and each drug was associated with similar rates of major bleeding. However, ticagrelor was discontinued more frequently than clopidogrel because of the occurrence of side effects (mainly dyspnea and minor bleeding).”
Hiatt WR, et al. NEJM 2017.
Study Analysis: Positive Critique
• Intent to treat analysis enhanced external validity (would like to see per protocol analysis)
• Analysis focused on symptomatic PAD patients only
Study Analysis: Negative Critique• Study population reflects patients in community, excludes
patients on DAPT or anticoagulation– Although excluded DAPT patients, ~66-67% were on aspirin at
baseline. From protocol, these patients were stopped on aspirin. If they developed an indication during the study they could add low dose aspirin to regimen.
– This would exclude patients with advanced disease • No mention of exact statin and anti-hypertensive regimens• Excluded patients that had poor metabolizer status for
CYP2C19 (616 patients)
Conclusions• Need to have better understanding of pathophysiology of
peripheral vascular disease– Use caution in extrapolating evidence from coronary artery
disease patients to PAD• EUCLID is a stepping stone to understanding multiple
subsets of patients with PAD– Symptomatic PAD with and without high risk features– PAD with revascularization < 30 days
• Ticagrelor was shown to be as effective as clopidogrel for patients with peripheral arterial disease
Acknowledgments• Kelly Rogers, PharmD, FCCP
• ACCP Cardiology PRN Journal Club Coordinators– Ted Berei, PharmD, MBA– Monique Conway, PharmD– Genevieve Hale, PharmD, BCPS– Zachary Noel, PharmD, BCPS– Thomas Szymanski, PharmD
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