Acute Coronary Syndrome & The

PLATO Trial: Ticagrelor vs. Clopidogrel

Joshua Rutland M.D, M.SJuly 18, 2014

Acute Coronary Syndrome• Third Universal Definition of MI –

Circulation 2012– 5 Types

• I – Spontaneous MI = atherosclerotic plaque rupture

• II – MI due to Ischemic Imbalance = vasospasm or fixed CAD concomitant w/ supply-demand imbalance

• III – Cardiac death due to MI before biomarkers can be drawn or identified

• IV – MI a/w PCI – procedural (4a) vs. in-stent restenosis (4b)

• V – MI a/w CABG

Acute Coronary Syndrome• AHA ECG Criteria for Acute Myocardial

Ischemia that may/may not lead to infarction– ST Elevation

• ≥ 0.1mV (1mm) in 2 contiguous leads (other than V2-V3)

• V2-V3 require ≥ 0.2mV (2mm) in M ≥ 40yo, ≥ 0.25mV (2.5mm) in M ≤ 40yo, and ≥ 0.15mV in W

– ST depression and T wave changes• New horizontal or down-sloping STD ≥

0.05mV in two contiguous leads • And/or TWI ≥ 0.1mV in two contiguous leads

w/ prominent R waves or R/S ratio > 1

Acute Coronary Syndrome

Acute Coronary Syndrome• Contiguous Leads

– Anterior Leads (V2-V4)– Inferior Leads (II, III, aVF) – Lateral Leads (I, aVL, V5, V6)– Septal Leads (V1, V2)– R-sided Leads (V3R, V4R) – RV free

wall– Far Lateral Leads (V7-V9) – LV Infero-

basilar wall

Acute Coronary Syndrome• AHA ECG Criteria for Acute

Myocardial Ischemia that may/may not lead to infarction– Cardiac Arrhythmias (i.e. VT, VF)– Intraventricular and Atrioventricular

Conduction Delays (i.e. new BBB or AV Block)

– Loss of precordial R wave Amplitude

Acute Coronary Syndrome• Other Factors Causing ST

deviation– Acute Pericarditis– Left Ventricular Hypertrophy– Left Bundle Branch Block– Brugada Syndrome– Stress Cardiomyopathy– Early Repolarization

Acute Coronary Syndrome• ECG Changes associated with Prior MI

–Q waves• ≥ 0.03sec and ≥ 0.1mV deep or a QS complex in the following leads:

– I, II (a Q in III is free!)– aVL, aVF– V4-V6

–R waves• ≥ 0.04 sec (1 small box) in V1-V2 and R/S ≥ 1 w/ a concordant positive T wave in the absence of a conduction defect (i.e. LBBB/RBBB)

Acute Coronary Syndrome• Imaging Techniques

– Echocardiography– Radionuclide Ventriculography– Myocardial Perfusion Scintigraphy

(MPS) using Single Photon Emission Computed Tomography (SPECT)

– MRI– PET– CT Angiogram

Acute Coronary Syndrome• Diagnosis of ACS

– STEMI, NSTEMI, or UA– STEMI = ischemic symptoms + STE

+ troponins– NSTEMI = ischemic symptoms +

ECG changes (STD or TWI) + troponins

– UA = ischemic symptoms +/- ECG changes +/- troponins

Acute Coronary Syndrome• Criteria for the diagnosis of Acute MI

– Evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia

– Under the above conditions, any of the following criteria meets the diagnosis of acute MI:

– Rise or fall of cardiac biomarker w/ at least one value above the 99th percentile URL in conjunction w/ any one of the following:

• symptoms of ischemia• new ST/TW changes or LBBB• new Q waves• imaging evidence of loss of viable myocardium or

regional wall motion abnormality• Identification of intracoronary thrombus by

angiography or autopsy

Acute Coronary Syndrome• Criteria for the diagnosis of Acute MI

– Cardiac death with symptoms and presumed new ECG changes but death occurred before biomarkers were obtained or likely to have increased

– PCI-related MI (Type IV) • > 5x URL of troponin elevation in patients

with normal baseline values or • a rise of > 20% if the baseline values are

elevated and stable or if they are falling

– CABG-related MI (Type V) • > 10x URL of troponin elevations in patients

w/ normal baseline values

Acute Coronary Syndrome• What is the URL (upper reference limit) for

troponin?– It depends on the assay!– There are 3 different types of troponin and the

assay uses a monoclonal Ab to each• Troponin C (not cardiac-specific, found on slow-

twitch skeletal muscle)• Troponin T (cardiac-specific isoform, but can cross-

react)• Troponin I

– TnT has only one known assay and thus the 99% URL is defined at 0.01ng/mL

– TnI has several different commercially available assays therefore the URL is different for each institution (ranges from 0.01 – 0.40)

Acute Coronary Syndrome• What is the URL for troponin at

UAMS?• What is the URL for troponin at

the VA?

Acute Coronary Syndrome• We have made the diagnosis of AMI,

now what?• Risk Stratification

– TIMI score (JAMA 2000) based on TIMI 11b and ESSENCE trial data (1957 patients)

– to asses short-term risk (14 days) for mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization

– TIMI score guides you to the recommended therapy!

Acute Coronary Syndrome• TIMI score for NSTEMI/UA

– 7 variables (mnemonic = AMERICA)• Age > 65• Markers (elevated CK-MB or Troponin)• EKG changes (STD or TWI)• Risk factors (3+ CAD risk factors: age > 45 for

M or 55 for F, famhx of 1st deg relative w/ CAD before 55 in M or 65 in F, HPLD, HTN, Smoking, T2DM, Obesity, Sedentary Lifestyle, Metabolic Syndrome)

• Ischemia (2 or more anginal events in 24hrs)• CAD (prior known stenosis > 50%; this did not

include CAD risk equivalents in this study)• ASA use in the past 7 days

Acute Coronary Syndrome• TIMI score for NSTEMI/UA

– 1 point for each variable– 0-2 pts = Low Risk– 3-4 pts = Intermediate Risk– 5-7 pts = High Risk

• Intermediate and High Risk benefit from early invasive strategy coronary angiography

• Low Risk medical therapy and CONSIDER predischarge stress test (if abnormal LHC)

Acute Coronary Syndrome• Medical Therapy

– Anti-Anginal therapy = BB, CCB, or Nitrates

– Anticoagulants = LMWH or UFH– Antiplatelets = ASA + P2Y12 inhibitor

• P2Y12 inhibitors– Clopidogrel (Plavix)– Prasugrel (Effient)– Ticagrelor (Brilinta)

• Does it matter which P2Y12 inhibitor you use?

P2Y12 Inhibitors• STEMI (2013 AHA Guidelines)

• Clopidogrel (Plavix)• Prasugrel (Effient)• Ticagrelor (Brilinta)

• NSTEMI/UA (2012 AHA Guidelines)

• Clopidogrel (Plavix) – Class IA• Prasugrel (Effient) – Class IB, only for

PCI-treated pts• Ticagrelor (Brilinta) – Class IB

P2Y12 Inhibitors

• P2Y12 Inhibitors– Thienopyridines (bind to the ADP

receptor P2Y12)• Ticlopidine• Clopidogrel• Prasugrel

– Cyclo-pentyl-triazolo-pyrimidines (CPTP; thought to be an allosteric inhibitor of ADP receptor P2Y12)

• Ticagrelor

ASA

AbciximabTirofibanEptifibatide

TiclopidineClopidogrelPrasugrelTicagrelor©

Medscape

Cattaneo M Circulation. 2010;121:171-179 Copyright © American Heart Association, Inc. All rights reserved.

P2Y12 Inhibitors• Clopidogrel & Prasugrel

– Prodrugs that require CYP450 2C19 for conversion to active metabolite

– Potential for drug interaction (i.e. PPIs) or poor responders due to genetic variants

– Irreversible inhibition by forming disulfide bond in the active site of the P2Y12 receptor

• Ticagrelor– Active drug, no conversion needed– Reversible allosteric inhibitor of P2Y12

receptor

Acute Coronary Syndrome• How should I decide which P2Y12 Inhibitor to use?–Head to head trials comparing

Clopidogrel vs. Prasugrel (TRITON-TIMI 38, NEJM 2007) or Clopidogrel vs. Ticagrelor (PLATO, NEJM 2009)

–Ticlopidine use is discourage due to slow onset action and risk of neutropenia, aplastic anemia, and TTP

PLATO• NEJM 2009• Purpose – compare clopidogrel vs. ticagrelor for

prevention of CV events in ACS• Multi-centered

– 862 centers in 43 Countries on 6 continents– North America – US, Canada, Mexico– South America – Brazil– Europe – Argentina, Austria, Belgium, Bulgaria, Czech

Republic, Denmark, Finland, Georgia, Israel, Italy, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Spain, Sweden, Switzerland, Turkey, Ukraine, United Kingdom

– Asia – China, Malaysia, Philippines, Singapore, South Korea, Taiwan, Thailand

– Africa – South Africa– Australia

• Sponsored by Astra-Zeneca

PLATO – Study Design• Phase III, Multi-centered, double-blinded,

randomized controlled trial• Astra-Zeneca designed and oversaw the trial, but an

independent data & safety monitoring board also was used

• 18,624 patients admitted to the hospital for any ACS (UA, NSTEMI, STEMI) regardless of planned therapy

• Patients were randomized to receive Ticagrelor or Clopidogrel– Ticagrelor – 180mg loading dose followed by 90mg bid– Clopidogrel – 300mg loading dose followed by 75mg qd

• Minimum treatment length – 6 months• Maximum treatment length – 12 months• Follow-up with outpatient visits at 1, 3, 6, 9, & 12

months

PLATO – Study Design• Inclusion Criteria

– ACS w/ symptoms within the last 24hr– All STEMI included (if intention to perform

PCI)– If NSTEMI/UA pt had to have 2 of the

following 3:• ST segment changes on ECG• Positive Biomarkers• One of several risk factors (age 60+, previous MI or CABG, CAD w/ > 50% stenosis of 2+ vessels, previous ischemic CVA, TIA, carotid a. stenosis > 50% or prior revascularization, DM, PAD, CKD-III or worse)

PLATO – Study Design• Exclusion Criteria

–Any contraindication to Clopidogrel–Previous fibrinolytic therapy within 24hr before randomization

–Oral anticoagulant use–Increased Risk of Bradycardia (not defined)

–Concomitant therapy w/ a strong cytochrome P-450 3A inhibitor or inducer (not defined)

PLATO – End Points• Therapeutic End Points

– Primary End Point was the time to first occurrence of a composite of death from vascular causes or no death w/ MI or stroke

– Death from vascular causes = death from any CV cause or CVA or death w/o another known cause

– Secondary End Point was the primary endpoint alone in a subgroup undergoing invasive management

– Additional Endpoints• Composite of death from any cause or no death w/ MI or

stroke• Composite of death from vascular causes or no death w/ MI,

CVA, or arterial thrombotic events (recurrent ischemia, TIA, etc)

• MI alone• Death from CV causes alone• Stroke alone• Death from any cause alone

PLATO – End Points• Safety End Points

– Primary Safety Endpoint was the first occurrence of any major bleeding

– Major Life-threatening Bleeding • fatal bleeding, ICH, or intrapericardial bleed w/

tamponade• Hypovolemic shock or severe HOTN due to bleeding that

required pressors or surgery• Decline in Hgb of ≥ 5g/dL • Need for transfusion of ≥ 4 units PRBC

– Major Bleeding• Any of the above plus leading to significant disability (i.e.

intraocular bleeding w/ permanent vision loss, requiring at least 2 units transfusion or Hgb drop > 3g/dL

– Minor Bleeding• Any bleeding requiring medical intervention not meeting

the above criteria

PLATO – End Points• Additional Safety End Points–Dyspnea–Bradyarrhythmia–Any other clinical adverse event–Results of laboratory safety tests

PLATO - Results• Premature d/c in 23.4% vs. 21.5%, median

exposure 277 days• 1° Endpoint (composite of death from vascular

causes or no death w/ MI or CVA) occurred in 9.8% vs. 11.7% at 12 mo (HR 0.84, p < 0.001)

• 2° Endpoint analysis showed significant reductions:– 1° Endpoint w/ invasive therapy (8.9% vs. 10.6%, p

= 0.003). If PCI then significantly less restenosis (1.3% vs. 1.9%, p = 0.009)

– Composite death from any cause or no death w/ MI or CVA (10.2% vs. 12.3%, p < 0.001)

– Composite death from vascular cause or no death w/ MI, CVA, or arterial thrombotic event (14.6% vs. 16.7%, p < 0.001)

– MI alone (5.8% vs. 6.9%, p = 0.005)– Death due to vascular causes (4.0% vs. 5.1%, p =

0.001)– Death from any cause (4.5% vs. 5.9%, p < 0.001)– CVA alone (no difference – 0.2% vs. 0.1%) –

although more hemorrhagic CVA in the Ticagrelor group

PLATO - Results• Analysis for Heterogeneity of Data

(33 subgroups)– New STE/LBBB– First troponin positive– Invasive vs. Medical Management– TIMI Risk Score (Low, Intermediate, High)– History of MI, PCI, CABG, DM, TIA, or CVA (each

individually)– Age < 65, 65-75, > 75– Sex– Race– Weight <60kg, 60-80kg, >80kg– Region by continent– Anti-platelet therapy prior– Final diagnosis– Use of Heparin, Lipid-lowering agent, BB, ACEI,

ARB, CCB, PPI (each individually)

PLATO - Results• No statistical significant difference

except in 3 classes in which the benefit of Ticagrelor was attenuated

• Pts weighing less than the median weight for their sex (p = 0.04)

• Pts not taking lipid-lowering drugs (p = 0.04)

• Pts in North America (p = 0.045)

PLATO - Results• No significant life-threatening bleeding

(5.8% vs. 5.8%, p = 0.70)• There was a nearly significant increase in

ICH (0.3% vs. 0.2%, p = 0.06) and when this occurred it was more significantly associated w/ mortality (0.1% vs. 0.01%); however, there were fewer episodes of other types of fatal bleeding (0.1% vs. 0.3%)

• No significant major bleeding via study criteria (11.6 vs. 11.2%, p = 0.43) or by TIMI (7.9% vs. 7.7%, p = 0.57)

• Significant difference in the composite of major & minor bleeding (16.1 vs. 14.6%, p = 0.008) but they did not report minor bleeding alone

PLATO - Results• Other Adverse Events

– Dyspnea was more common (13.8% vs. 7.8%, p < 0.001) w/ only a few discontinuing the drug b/c of it (0.9% vs. 0.1%, p < 0.001)

– No significant difference in bradycardia although there was a trend toward increased syncope (1.1% vs. 0.8%, p = 0.08)

– Initially some patients (2866 pts) underwent Holter monitoring (avg. length 6 days) during the first week which was repeated at 30 days and showed a significant increase in ventricular pauses > 3 sec (rarely symptomatic but not reported) within the first week but which resolved by 30 days

– Any other adverse events leading to d/c of the study drug occurred more frequently w/ ticagrelor (7.4% vs. 6.0%, p < 0.001)

PLATO - Discussion• Advantages

– Lower mortality– Comparable major bleeding risk– Faster and more intense platelet

inhibition– Reversible

• Disadvantages– Expense, familiarity– BID dosing vs. daily for Plavix– ? Efficacy in North America– Increased non-major bleeding

PLATO - Discussion• Pitfalls