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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

Presenter

Presentation Notes

ALI: Viable: Limb is not immediately threatened; no sensory loss; no muslce weakness; auditory arterial and venous Doppler Threatened Mild to moderate sensory or motor loss; inaudible arterial doppler; audible venous Doppler; may be further divided into IIa (marginally threatened) or Iib (immediately threatened) Irreversible: Major tissue loss or permanent nerve damage inevitable, profound sensory loss; profound muscle weakness or paralysis; inaudible arterial and venous doppler

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


Presenter

Presentation Notes

Lower extremity PAD is a common cardiovascular disease that is estimated to affect approximately 8.5 million Americans above the age of 40. It has been estimated that 202 million people worldwide have PAD. Individuals with known atherosclerotic disease in another vascular bed (coronary, carotid, subclavian, renal, mesenteric artery stenosis, or AAA)

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


Presenter

Presentation Notes

If the value is > 1.40, this indicates that the arteries were not able to be compressed, which is common among individuals with diabetes mellitus and/or advanced chronic kidney disease. Toe-brachial index should be measured to diagnose patients with suspected PAD when the ABI is great than > 1.40. A TBI </= 0.70 is abnormal and diagnostic of PAD because the digital arteries are rarely non-compressible.

Overall Treatment Plan for PAD• Antiplatelet Agent • Statin • Antihypertensive therapy • ACE Inhibitor or ARB • Smoking cessation• Management of diabetes • Cilostazol for claudication• Flu vaccination

Presenter

Presentation Notes

Overall treatment decisions: Treatment with a statin medication is indicated for all patients with PAD. Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death. The use of ACE inhibitors or ARBs can be effective to reduce the risk of CV ischemic events in patients with PAD. (HOPE study) Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit. Management of diabetes in the patient with PAD should be coordinated between members of the healthcare team. The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain. Anticoagulation should NOT be used to reduce the risk of CV ischemic events in patients with PAD. (III: HARM) (WAVE trial) Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication. (Contraindicated in CHF) Pentoxifylline is not effective for treatment of claudication. (III: No benefit) Influenza vaccine

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)


Presenter

Presentation Notes

Overall treatment decisions: Treatment with a statin medication is indicated for all patients with PAD. Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death. The use of ACE inhibitors or ARBs can be effective to reduce the risk of CV ischemic events in patients with PAD. (HOPE study) Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit. Management of diabetes in the patient with PAD should be coordinated between members of the healthcare team. The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain. Anticoagulation should NOT be used to reduce the risk of CV ischemic events in patients with PAD. (III: HARM) (WAVE trial) Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication. (Contraindicated in CHF) Pentoxifylline is not effective for treatment of claudication. (III: No benefit) Influenza vaccine

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.

Presenter

Presentation Notes

CAPRIE: A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. (CAPRIE). Lancet 1996. Aspirin 325 mg daily vs. Clopidogrel 75 mg daily Atherosclerotic PA: intermittent claudication of presumed atherosclerotic origin; and ankle/arm systolic BP ratio </= 0.85 in either leg at rest (two assessments on separate days) or history of intermittent claudication with previous leg amputation, reconstructive surgery or angioplasty with no persisting complications from intervention When each endpoint was individualized, none were significnat CHARISMA: Clopidogrel and aspirin versus aspirin alone for the presentation of atherothombotic events. NEJM 2006. Aspirin 75-162 mg daily vs. Clopidogrel 75 mg daily + Asa 75-162 mg daily Exclusion: Established indications for clopidogrel therapy Patients who were scheduled to undergo a revascularization were not allowed to enroll until the procedure had been completed; such patients were excluded if they were considered to require clopidogrel after revascularization Safety endpoint: Severe bleeding, GUSTO definition; No difference in severe bleeding, fatal bleeding, primary ICH, but moderate bleeding was increased 2.1 vs. 1.3, p < 0.001 Stroke (nonfatal) 1.9 in DAPT group vs. 2.4 in aspirin group, p 0.03 Secondary efficacy endpoint 16.7 vs. 17.9, p =0.04 (first occurrence of MI, stroke, death from CV causes, hospitalization for unstable angina, TIA, or a revascularization procedure PLATO: Ticagrelor versus clopidogrel in patients with acute coronary syndromes. NEJM 2009.

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.

Presenter

Presentation Notes

Guidelines recommendation: Revascularization is a reasonable treatment option for the patient with lifestyle-limiting claudication with an inadequate response to GDMT (12,37,38,232,233). For patients qualifying by ABI criteria, 2 distinct measurements are require. The ABI measurement must be < 0.80; and at the subsequent randomization visit, < 0.85. This was done to ensure that all patients enrolled have substantial hemodynamic evidence of PA and ensures the upper bound would be < 0.90. If the ABI > 1.40, a TBI < 0.60 at visit 1 and 0.65at visit 2 is alternatively accepted. Symptomatic PAD: Classic cluadication, other exertional leg discomfort associated with physical limitiations from PAD, ishemic rest pain, ischemic ulcers, or gangrene For patients with prior lower extremity revascularization for symptomatic PAD qualify for enrollment if revascularization was > 30 days before randomization, irrespective of present leg symptoms and hemodynamics at the time of study screening. Concomitant therapy: Additional antithrombotic therapy was prohibied including other P2Y12 antagonists, long term anticoagulants, and other platelet inhibitors. DAPT therapy at the start of the study was prohibited but allowed if a clinical indication (MI) occurred during the course of folllow up with the allowance of the addition of open-label aspirin.

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


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


Presenter

Presentation Notes

Sample Size (amended in Dec. 2013): Increased sample size from 11,500 to 13,500 patients with the targeted number of primary events reduced from 1,596 to 1,364 with a decrease in power from 90% to 85% at 4.94% significance level Original Assumptions: Primary end point would occur in 7% of the patients in the clopidogrel group and patients in the ticagrelor group would have a 15% lower relative risk than those in the clopidogrel group The initail sample was calculated based on the assumptom of a 6-6.5% per year aggregate rate of CV death, MI, or ischemic stroke.Because of the lower than expected event rate, the EUCLID committtee modified the trial to preserve adequate power to test the primary study hypothesis.

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


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: Secondary Outcomes


Primary Efficacy Endpoint by Patient Subgroup

Presenter

Presentation Notes

No difference between groups in regards to the following: Geographic region, age group, sex, history of diabetes mellitus, smoking status Prior antiplatelet therapy, metabolizer status of CYP2C19, statin at baseline and ongoing during treatment, or PPI use Rutherford classification, inclusion criteria met, number of prior vascular beds,

Results: Safety Outcomes


Presenter

Presentation Notes

Any bleeding: Documented in case-report form; these events included unadjudicated minimal bleeding

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).”


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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