Transcript Document
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Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.
Learning Objectives
• Identify high-risk ACS patients (high-risk NSTEMI, STEMI) and promptly initiate suitable risk stratification and patient management strategies • Adopt and adhere to guidelines-based treatment strategies for use of appropriate antiplatelet options to reduce the risk of recurrent events • Identify inefficiencies in discharge planning and patient education on the necessity of drug adherence to improve quality of care and long-term outcomes of high-risk ACS patients
Pre-activity Survey
• Please take out the Pre-activity Survey from your packet • Your answers are important to us and will be used to help shape future CME activities • It is important that you fill out the information at the top of the form: – Please select the best answer(s) for the questions below: – Degree: _ MD/DO _ Nursing Professional _ PharmD _Other:_____________________________ – Specialty: _ Cardiologist _ Emergency Room Physician _ Internal Medicine _Other:______________________
Pre-activity Survey Question 1
How confident are you in your ability to adopt evidence based care for high-risk NSTEMI patients to reduce the need for rehospitalization?
1 Not at all confident 2 3 4 5 Expert
Pre-activity Survey Question 2
How confident are you in your ability to adopt evidence based care for STEMI patients to reduce the need for rehospitalization?
1 Not at all confident 2 3 4 5 Expert
Pre-activity Survey Question 3
The choice between an initial conservative strategy or an initial invasive strategy in patients diagnosed with NSTE ACS is made largely on the basis of: A.
Risk of ischemic complications B.
Whether symptoms are typical or atypical C.
D.
E.
Whether the ECG is interpretable Whether the patient can take a stress exercise test All of the above
Pre-activity Survey Question 4
Compared to ACS patients who do not have diabetes, those who have diabetes mellitus are at: A.
B.
C.
D.
Greater risk of major cardiovascular events and similar risk of major bleeding events Greater risk of major cardiovascular events and greater risk of major bleeding events Similar risk of major cardiovascular events and greater risk of major bleeding events Similar risk of major cardiovascular events and similar risk of major bleeding events
Pre-activity Survey Question 5
In STEMI patients, primary PCI is superior to fibrinolytic therapy to reduce in-hospital mortality if PCI can be performed within ___ hours after the onset time of infarction: A.
<1.5 hours B.
3 hours C.
D.
E.
6 hours 12 hours 24 hours
Pre-activity Survey Question 6
According to the GRACE registry, use of 5 or more medications for secondary prevention of ACS can reduce 6-month mortality by: A.
Less than 20% B.
20%-30% C.
D.
E.
30%-40% 40%-50% More than 50%
HIGH-RISK ACS Overview
ACS Classification and Hospitalizations
Acute Coronary Syndromes TIMI flow grade 2/3 in culprit artery TIMI flow grade 0/1 in culprit artery - Troponin + Troponin + Troponin Unstable angina NSTEMI STEMI 0.81 million admissions per year 0.33 million admissions per year Shared pathophysiology; Shared core treatment targets
Gibson CM et al. Presented at: 2008 AHA Scientific Sessions. New Orleans, LA.
Go AS et al. Heart Disease and Stroke Statistics – 2013 update. Circulation. 2013;1127:e6-e245
Acute Coronary Syndromes
•
Common Features of ACS
–
Similar pathophysiology
–
Similar presentation and early management rules
•
Differentiating Features of ACS
– –
Unstable Angina Non-occlusive thrombus No diagnostic ECG changes, but ischemic ST-T changes confer higher risk Normal cardiac enzymes NSTEMI Occluding thrombus sufficient to cause myocardial damage No diagnostic ECG changes, but ischemic ST-T changes: higher risk Elevated cardiac enzymes
–
STEMI
Complete thrombus occlusion ST elevation or new LBBB Elevated cardiac enzymes More severe symptoms
Age- and Sex-adjusted Incidence Rates Of Acute MI, 1999 to 2008.
O’Gara PT et al. Circulation 2013;127:e362-e425 Copyright © American Heart Association
Mortality in Acute Coronary Syndromes
Death from Hospital Admission to 6 Months
16 12 8 STEMI NSTEMI UA 4 0 0 30 60 90 120 150 180
Days Fox KAA et al. BMJ. 2006;333:1091.
GRACE n=43,810
“Dynamic Risk Stratification” Tools
• • • • • •
History and physical Standard ECG and non-standard ECG leads
–
15-lead ECGs should perhaps become “standard” in all but very-low-risk patients Biomarkers
–
CK-MB, troponins I and T, myoglobin
– –
High-sensitivity troponin Brain natriuretic peptide (BNP) Non-invasive imaging
–
Echocardiogram
– –
Stress testing Technetium-99m-sestamibi Invasive imaging
–
Cardiac computed tomography angiography (CCTA) Predictive indices/schemes
–
Better as research tools than for real-time clinical decision-mak ing
Risk Scores
TIMI Age Hypertension Diabetes Smoking ↑ Cholesterol Family history History of CAD Severe angina Aspirin within 7 days Elevated markers ST-segment deviation GRACE Age Heart rate Systolic BP Elevated creatinine Heart failure Cardiac arrest Elevated markers ST-segment deviation GRACE = Global Registry of Acute Coronary Events; TIMI = Thrombolysis in Myocardial Infarction Antman EM et al. JAMA. 2000;284:835-842. Eagle KA et al. JAMA. 2004;291:2727-2733.
Early Invasive vs Initial Conservative Strategy
General Considerations in UA/NSTEMI
• • • • • • • • • • • •
EARLY INVASIVE STRATEGY GENERALLY PREFERRED Recurrent angina at rest or with low level activities despite intensive medical therapy Elevated cardiac biomarkers (TnT or TnI) New or presumably new ST-depression Signs or symptoms of heart failure or new or worsening mitral regurgitation High-risk findings from noninvasive testing Hemodynamic instability Sustained ventricular tachycardia PCI within 6 mo; prior CABG High risk score (e.g. GRACE, TIMI) Mild to moderate renal dysfunction Diabetes mellitus Reduced left ventricular function (LVEF <40%)
• •
INITIAL CONSERVATIVE STRATEGY GENERALLY PREFERRED OR REASONABLE Low risk score (e.g. GRACE, TIMI) Patient or physician preference in the absence of high-risk features
CABG = coronary artery bypass graft surgery; GRACE = Global Registry of Acute Coronary Events; LV = left ventricular; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = Thrombolysis in Myocardial Infarction; TnI = troponin I; TnT = troponin T
Anderson et al. J Am Coll Cardiol 2012;61:e1-e171
ACCF/AHA Guidelines 2011 Focused Update
Early Invasive Strategies for High-Risk ACS Patients
I II a II b I I I
High-risk patients with: -
Refractory ischemia Recurrent angina/ischemia Elevated cardiac biomarkers (T) New ST-segment depression New CHF or worsening MR High-risk on non-invasive testing LV dysfunction (EF <40%) Hemodynamic instability Sustained VT Diabetics with single-vessel disease Mild to moderate kidney disease PCI within 6 months, prior CABG high-risk score Not in low-risk women Wright RS et al. Circulation. 2011;123:2022-2060.
TACTICS: Primary Endpoint
Death, MI, Rehospitalized for ACS at 6 Months
20 16 19.4% 15.9% 12 8 O.R. 0.78
95% CI (0.62, 0.97) P=0.025
4 0 0 1
Cannon CP et al. N Engl J Med. 2001;344:1879-1887.
2 3 4
Time (months)
Conservative : Invasive: 5 6
ANTIPLATELET THERAPY IN ACS
Platelet Aggregation and Mechanisms of Action of Antiplatelet Therapies
clopidogrel prasugrel ticagrelor ADP ADP Glycoprotein IIb/IIIa inhibitors abciximab eptifibatide tirofiban Gp IIb/IIIa (Aggregation) aspirin COX TXA 2 ADP cAMP Activation ADP = adenosine diphosphate; TXA 2 = thromboxane A 2 ; COX = cyclooxygenase Adapted from Schafer AI. Am J Med. 1996;101:199-209.
Collagen Thrombin TXA 2 Heparins
CURE Study
Primary End Point: MI/Stroke/CV Death
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0 Placebo + Aspirin (n=6303)
Yusuf S et al. N Engl J Med. 2001;345:494-502.
Clopidogrel + Aspirin (n=6259) 3 6 9
Months of Follow-up
12 20% Relative Risk Reduction P<0.001
n=12,562
ADP P2Y
12
Receptor Blockers
Class Reversibility Activation Onset of Effect^ Duration of Effect Withdrawal before major surgery Clopidogrel
Thienopyridine
Prasugrel
Thienopyridine Irreversible Irreversible Prodrug, limited by metabolism Prodrug, not limited by metabolism
Ticagrelor
Triazolopyrimidine Reversible Active drug 2-4 hours 30 minutes 30 minutes 3-10 days 5 days 5-10 days 7 days 3-4 days 5 days ^ 50% inhibition of platelet aggregation
Hamm CW et al. Eur Heart J. 2011;32:2999-3054
Metabolism of Novel P2Y
12
Receptor Blockers
P-Glycoprotein Prasugrel Ticagrelor Intestinal Absorption Intestinal Esterases 85% Intestinal Absorption Hepatic CYP3A4 30% 1 Step Intestinal/hepatic CYP-Conversion 55% 3A4 2B6 2C9 2C19 Efficient active metabolite generation Rapid Consistent /Greater IPA Rapid Consistent /Greater IPA
IPA = individual platelet adhesion assay
Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-2259
CURRENT: Clopidogrel Double vs Standard Dose
Primary Outcome: PCI Patients
0.04
CV Death, MI or Stroke
Clopidogrel Standard 15% RRR Clopidogrel Double 0.03
0.02
HR 0.85
95% CI 0.74-0.99
P=0.036
0.0
0 3 6 9 12 15 18 21
Days Mehta SR et al. Presented at: European Society of Cardiology, September, 2009.
24 27 30
PRINCIPLE TIMI 44:
Comparison of Prasugrel with Higher Dose Clopidogrel
100 80 60
IPA (%; 20 mM ADP) N=201 P<0.0001 for each
64,5 74,8
Prasugrel 60 mg
69,3 40 20 30,8 4,9 20,3 31,8
Clopidogrel 600 mg
32,6 100
IPA (%; 20 mM ADP) P<0.0001
80
61,9
60
45,4
40 20 0 0 4 8 12 16
Hours Wiviott SD et al. Circulation. 2007;116:2923-2932.
20 24 28 0
Clopidogrel 150 mg Prasugrel 10 mg 14 Days
TRITON-TIMI 38 Efficacy and Safety
Prasugrel vs Clopidogrel
16 14 12 10 8
CV Death/MI/Stroke Clopidogrel Prasugrel 138 events 12.1
9.9
HR 0.81
(0.73-0.90) P < 0.001
NNT = 46
6 4
TIMI Major Non-CABG Bleeds Prasugrel
2
Clopidogrel
0 0 30 60 90 180 270
Days After Randomization
360 450
2.4
1.8
HR 1.32
(1.03-1.68) P = 0.03
NNH = 167 35 events CABG = coronary-artery bypass surgery; NNH = number needed to harm; NNT = number needed to treat; TIMI = Thrombolysis in Myocardial Infarction.
All Cause Mortality: Clopidogrel 3.2%, Prasugrel 3.0%, P = 0.64.
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Clopidogrel vs. Ticagrelor
ONSET/OFFSET Study
100 80 60 * 40 * * 20 0
0 .5
4
* Loading Ticagrelor 180mg * Clopidogrel 600 mg
8 12
Hours
16 20 24
Maintenance and Offset *P<0.0001; †P<0.005; ‡, P<0.05, ticagrelor vs clopidogrel.
Gurbel PA et al. Circulation. 2009;120:2577-2585.
PLATO:
Kaplan-Meier Estimate of Time to First Primary Efficacy Event (Composite of CV Death, MI, or Stroke)
1 0 4 3 2 13 12 11 10 9 8 7 6 5
Clopidogrel
HR = hazard ratio CI = confidence interval
Ticagrelor HR 0.84 (95% CI 0.77–0.92), P=0.0003
0
No. at risk
Ticagrelor Clopidogrel 9,333 9,291
Wallentin L et al. N Engl J Med. 2009;361:1045 1057.
60 120 180 240 8,628 8,521
Days after randomisation
8,460 8,362 8,219 8,124 6,743 6,743 300 5,161 5,096 360
11.7
9.8
4,147 4,047
Time to Major Bleeding:
Primary Safety Event
15 10
Ticagrelor Clopidogrel 11.58
11.20
5 0 0 60
HR 1.04 (95% CI 0.95–1.13), P=0.434
120 180 240 300 360 No. at risk Ticagrelor Clopidogrel 9,235 9,186 7,246 7,305
Days from first IP dose
6,826 6,930 6,545 6,670 5,129 5,209 3,783 3,841 3,433 3,479
Wallentin L et al. N Engl J Med. 2009;361:1045-1057.
Ticagrelor Interaction with Aspirin Dose
Hazard Ratio (CV Death, MI, Stroke) Compared With Clopidogrel
Region
US Non-US
Aspirin (mg/day)
≥300 >100 – <300 ≤100 ≥300 >100 – <300 ≤100
Ticagrelor N / Events
324 / 40 22 / 2 284 / 19 140 / 28 503 / 62 7449 / 546
Clopidogrel N / Events
352 / 27 16 / 2 263 / 24 140 / 23 511 / 63 7443 / 699
Hazard Ratio
1.62
0.73
1.23
1.00
0.78
95% CI
0.99 – 2.64
0.40 – 1.33
0.71 – 2.14
0.71 – 1.42
0.69 – 0.87
• •
Warning: Aspirin Dose and Ticagrelor Effectiveness
Maintenance doses of aspirin > 100 mg reduce effectiveness of ticagrelor; should be avoided. After any initial dose, use with aspirin 75-100 mg per day.
Mahaffey KW et al. Circulation. 2011;124:544-554.
TRITON vs PLATO
Proof of concept: Higher Inhibition of Platelet Activityi to Support ACS
Differences between trials 1. Patient Population
TRITON: ACS undergoing PCI (indication only for ACS undergoing PCI) PLATO: Full spectrum ACS (indication for ACS irrespective of management)
2. Pretreatment
TRITON: No pretreatment (except STEMI) PLATO: Pretreatment
3. Clopidogrel Loading Dose
TRITON: 300mg PLATO: 300-600mg
4. Duration of trial (median)
TRITON: 14.5 months PLATO: 9 months
Novel P2Y12 Receptor Antagonists
Prasugrel
•
Contraindicated:
high-risk bleeding; prior TIA/stroke; hypersensitivity
•
Precautions:
elderly (>75y), low-weight (<60kg); CABG/surgery (7days).
Ticagrelor
•
Contraindicated:
high-risk bleeding; prior hemorrhagic stroke; severe hepatic dysfunction; hypersensitivity
•
Precautions:
compliance (b.i.d. administration), drug interactions (CYP 3A4 interfering agents); regional differences (North America/ASA dose <100mg), COPD/asthma, bradyarythmia, gout syndromes, CABG/surgery (5 days).
What are We Treating with Extended Dual Antiplatelet Therapy?
Long-Term Treatment (Stable Atherosclerosis)
“Vulnerable” Stent “Vulnerable” Patient
OR
Curfman GD, et al. N Engl J Med. 2007;356:1059-1060 Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
CHARISMA Prior MI Cohort
Management of STEMI
A Focus On Antiplatelet Therapy
Time and Myocardial Salvage
An Essential Fact Regardless of Mode of Reperfusion
100 80
E
60
D C Potential outcomes A – A – B – E – B — no benefit C — benefit C — benefit D — harm
40 20
B A
0 1 3 6
Time to treatment is critical Gersh BJ, et al. JAMA. 2005;293:979-986.
Extent of salvage (% of area at risk)
12 24
Hours Opening the artery is the primary goal (PCI > lysis)
STEMI: Relationship Between PCI–Related Delay and In-Hospital Mortality
(NRMI 2,3,4,5) NRMI 2,3,4,5 = National Registry of Myocardial Infarction, registries 2, 3, 4, 5 X-PCI = transfer PCI O-FT = onsite fibrinolytic therapy XDB-DN = transfer door to balloon time Pinto D S et al. Circulation 2011;124:2512-2521
Regional Systems of STEMI Care, Reperfusion Therapy, and Time-to-Treatment Goals
I IIaIIb III
Reperfusion therapy should be administered to all eligible patients with STEMI with symptom onset within the prior 12 hours.
I IIaIIb III
Primary PCI is the recommended method of reperfusion when it can be performed in a timely fashion by experienced operators.
I IIaIIb III
EMS transport directly to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI with an ideal FMC-to-device time system goal of 90 minutes or less.* *The proposed time windows are system goals. For any individual patient, every effort should be made to provide reperfusion therapy as rapidly as possible.
O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-e140
Streptokinase, Aspirin, or Both in Patients with Acute MI
ASA Improves Outcomes in STEMI – We Haven’t Looked Back
17187 Patients 2 x 2 Randomization SK vs Placebo ASA (162. 5 mg) vs Placebo ISIS-2 Collaborative Group. Lancet 1988;2(8607):349-360
Acute MI
Immediate Angioplasty Versus Thrombolytic Therapy
14 12 10 2 0 8 6 4 6,5
P=0.06
P=0.06
P=0.05
12 2,6 6,5 2,6 Death MI 5,1 Death/MI
P=0.02
2 ICH 0 Lytic PCI
N = 395
The Primary Angioplasty in Myocardial Infarction Study Group Grines CL et al. N Engl J Med. 1993;328:673-679
TRITON TIMI 38: STEMI Cohort
N=3534
15 10 5
CV Death / MI / Stroke Clopidogrel 12.4% 9.5% 6.5% Prasugrel HR 0.68
(0.54-0.87) P=0.002
TIMI Major NonCABG Bleeds Prasugrel 10.0% HR 0.79
(0.65-0.97) P=0.02
NNT = 42 2.4
Clopidogrel 2.1
0 0 30 60 90 180 270 360
Days From Randomization
450
Montalescot g. et al Lancet 2009; 373:723-731
Stent Thrombosis
(ARC Definite + Probable)
3
Any Stent at Index PCI N = 12,844
2 Clopidogrel 2.4
(142) 1 0 0 30 60 90
Wiviott SD et al N Engl J Med. 2007;357:2001-2015
180
Days
270 Prasugrel 360 1.1 (68) HR 0.48
P <0.0001
NNT= 77 450
PLATO STE-ACS
Primary Composite Endpoint
10.8% 9.4% STE-ACS Ticagrelor (n=3752) Clopidogrel (n=3792) HR (95% CI) = 0.87(0.75–1.01) p=0.07
Months after randomisation Primary endpoint benefit with ticagrelor was consistent with the overall PLATO trial results
ACS, acute coronary syndromes; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; STE, ST-segment elevation.
Steg PG, et al. Circulation 2010;122:2131–2141; Wallentin L, et al. N Engl J Med 2009;361:1045–1057.
Primary Efficacy Endpoint In Selected Pre-defined Subgroups
Characteristic Hazard Ratio (95% CI) Overall treatment effect Primary Endpoint Definition of STEMI* Persist. ST-segment elev.
LBBB Final diagnosis (only) Intended clop dose ≤24h post first dose 300 mg 600 mg Time from index event to therapy <12 hours ≥12 hours Total Patients 8,430 6,284 720 886 5,505 2,922 6,072 2,270 KM % at Month 12 Ti .
9.3
8.9
14.5
8.4
10.4
14.5
12.5
10.1
7.9
11.9
9.3
8.3
12.0
Cl.
11.0
9.5
14.2
HR (95% CI) 0.85 (0.74, 0.97) 0.87 (0.74, 1.02) 0.89 (0.59, 1.34) 0.67 (0.44, 1.02) 0.84 (0.71, 0.99) 0.86 (0.67, 1.11) 0.86 (0.73, 1.03) 0.85 (0.67, 1.07)
0.2
0.5
1.0
2.0
Ticagrelor better Clopidogrel better *Patients with LBBB and ST-elevation were classified as LBBB Steg PG, et al. Circulation 2010;122:2131–2141; Wallentin L, et al. N Engl J Med 2009;361:1045–1057.
p-value (Interaction) 0.49
0.90
0.89
PLATO STE-ACS: Stent Thrombosis
Stent thrombosis,* % [Steg 2010:K] Ticagrelor (n=3752) Clopidogrel (n=3792) Definite † 1.6
2.4
Probable or definite definite † † Possible, probable, or 2.6
3.3
3.4
4.3
HR (95% CI) p value 0.03
0.05
0.04
*As per Academic Research Consortium definitions.
[Cutlip 2007:A] † Denominator is number of patients receiving at least one stent.
ACS, acute coronary syndromes; CI, confidence interval; HR, hazard ratio; STE, ST-segment elevation.
Cutlip DE, et al. Circulation 2007;155:2344–2351; Steg PG, et al. Circulation 2010;122:2131–2141.
Ticagrelor better 1.0
Clopidogrel better
PLATO STE-ACS
Non-CABG- and CABG-related Major Bleeding
ACS, acute coronary syndromes; CABG, coronary artery bypass graft; NS, not significant; STE, ST-segment elevation; TIMI, thrombolysis in myocardial infarction.
Steg PG, et al. Circulation 2010;122:2131–2141.
ACS
High Bleeding Risk Or Other Concerns Yes
• • • • • • •
Bleeding Risks
Active Bleeding Major Surgery Thrombolytic Therapy Oral anticoagulants Prior ICH or Previous Severe Bleeding Severe Liver Disease Any history of STROKE/TIA for Prasugrel
Standard Clopidogrel Pathway
Other (Mostly Long Term)
• • •
Cost Coverage Compliance Concerns
STEMI
No DAPT Load Prasugrel or Ticagrelor if Rapidly Available High Bleeding Risk Or Other Concerns No Planned PPCI Yes Standard Clopidogrel Pathway Prior DAPT Load Ticagrelor If Rapidly Available Dx Catheterization
CABG
PCI
Med Rx CABG
Dx Catheterization PCI
Med Rx No DAPT early, clopidogrel/tic agrelor late Prasugrel* Ticagrelor Clopidogrel Ticagrelor
Stop DAPT early, clopidogrel/tic agrelor late Ticagrelor Clopidogrel Ticagrelor * Without Contraindication (STROKE/TIA)
2013 ACC/AHA STEMI Guidelines
Antithrombotic Therapy – Primary PCI
Class of Recommendation Level of Evidence O’Gara et al. J Am Coll Cardiol..2013;61:e78–e140
Guideline Recommendations for Duration of P2Y
12
Inhibitor Therapy
Society Management Recommended Duration Medical Ideally up to 12 months PCI (DES) At least 12 months ACCP All Medical PCI 12 months
“ Data suggest … SES or PES … may benefit from prolonged DAPT
beyond 1 year
.
” “ … data suggest that DAPT for
6 mos
might be sufficient because late and very late ST correlate poorly with d/c of DAPT.
”
12 months 12 months
(After 12 mos, recommend single antiplatelet therapy over continuation of DAPT)
2011 ACCF/AHA UA/NSTEMI; 2011 ACCF/AHA/SCAI PCI; 2010 ESC Myocardial Revascularization; 2011 ESC NSTEACS; 2012 ACCP Antithrombotic Therapy
Antiplatelet Therapy to Support Primary PCI for STEMI
I IIaIIb III
It is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses after primary PCI.
I IIaIIb III
P2Y 12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (BMS or DES) during primary PCI using the following maintenance doses: • Clopidogrel 75 mg daily; or • Prasugrel 10 mg daily; or • Ticagrelor 90 mg twice a day*
*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily. O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-e140
Periprocedural Anti Thrombotic Medication in Primary PCI
ADP = adenosine diphosphata.
Steg PG et al. Eur Heart J. 2012;33:2569-2619 doi:1093/eurheatj/ehs215
Guideline for STEMI
Reperfusion at a Non–PCI-Capable Hospital
Secondary Protection Against Post-MI Mortality
• Beta blocker ISIS 1. Lancet. 1986;2(8498):57-66 • ACEI Pfeffer et al. N Engl J Med. 1992;327:669-677 • CAB Pfeffer et al. N Engl J Med. 2003;349:1893-1906 • • Aldosterone antagonist Pitt et al. N Engl J. Med. 2003;348:1309-1321 Lipid management 15% risk reduction 19% risk reduction comparable to ACEI 15% risk reduction
Secondary Prevention and Long Term Management
• • • • • Smoking cessation – complete Blood pressure control goal – – < 140/90 mm Hg <130/80 mm Hg if chronic kidney disease or diabetes Physical activity – – Minimum goal: 30 minutes 3 to 4 days per week Optimal goal: daily Diabetes management – Goal: HbA1c < 7% Weight management – – BMI Goal: 18.5 to 24.9 kg/m 2 Waist circumference goal • • Women: < 35 in.
Men: < 40 in.
Management of High-Risk NSTEMI
ACS with Diabetes Mellitus Comorbidity
Case Study: Presentation
• Caucasian male age 67 years presents to ED with increasing dyspnea associated with substernal chest pressure over the past 1-2 hours • Subtle increase in exertional dyspnea, fatigue, and chest pressure over past 2 weeks • ECG: ST segment depression (2 mm) in II, III, aVF • Physical exam: – Heart rate, 70 bpm; occasional PVCs; blood pressure, 125/80 mm Hg – Lungs: Soft bibasilar rales; heart: soft gallop, 1/6 SM
Case Study: Additional Medical History
• Known history of CAD – CABG X 4 performed ~ 8 years ago • Patient 15-year history of type 2 diabetes with variable control; currently on insulin therapy • History of hypertension, mixed dyslipidemia • Prior tobacco use • Peripheral artery disease, mild chronic kidney disease • Current medications: aspirin, insulin, lisinopril, metoprolol, simvastatin
Case Study: Additional Medical History
• No medical records available • He knows he had a CABG x 4 and last year underwent a LHC for “chest pain” and he states that “the doctor said
that everything looks great and that all my vessels are OK except for the one going to the back of my heart which has a small blockage, but does not need a stent because doesn’t look too bad”
Case Study: Test Results
• K+, 4.0; glucose, 165 mg/dL; creatinine, 1.2 • CBC: WBC, 10.1; Hct, 43; Plt, 320; Hb, 13.4
• Troponin T: 0.1 μg/L • Chest radiograph: Mild vascular congestion • Symptoms and ECG changes resolve with nitroglycerin sl • Patient is treated with aspirin 325mg loading dose and enoxaparin 1mg/kg in the ED • He is admitted to the CCU • EF: 55% • Sent for LHC
Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS
Diabetes Subgroup Analysis 11 TIMI Trials, >62,000 pts 10,613 diabetics (17.1%) 14 12 10 8 6 P<0.0001
4 2 P<0.0001
0 0 30 90
No. at Risk
STEMI Diabetes 7156 6508 2947 No diabetes 39421 37136 UA/NSTEMI Diabetes 3457 3313 No diabetes 12002 11658 16685 2923 10505
Donahoe SM et al. JAMA. 2007;298:765-775.
STEMI
Diabetes No Diabetes
UA/STEMI
Diabetes No Diabetes 180
Days after ACS
2653 15274 2339 8191 270 2118 12276 1317 5141 P<0.0001 STEMI P<0.0001 UA/NSTEMI 360 1610 9351 924 4008
Mechanisms Involved in Platelet Dysfunction in Diabetes Mellitus
H 2 O Hyperglycemia Increased P-selectin expression Osmotic effect Activation of PKC Decreased membrane fluidity by glycation of surface proteins Deficient Insulin Action Impaired response to NO and PGI 2 IRS-dependent factors: Increased intracellular Ca++ Degranulation Associated Metabolic Conditions Obesity Dyslipidemia Inflammation Other Cellular Abnormalities Platelet Endothelial Dysfunction Increased platelet turnover Increased intracellular Ca++ Upregulation of P2Y 12 signaling Oxidative stress Increased P-selectin and GP expression Increased production of TF Decreased NO and PGI 2 production
ACP=adenosine disphosphate; GP=glycoprotein; IRS-1=insulin receptor substrate-1; NO=nitric oxide; PGI 2 =prostacyclin; PKC= protein kinase C; TF=tissue factor.
Endothelial Cells Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011;123:798-813
Optimal Antithrombotic Management of the Patient With Diabetes and ACS/PCI
Acute and post-discharge phase (eg., oral agents)
Effect of Antiplatelet Therapy in Reducing Vascular Events in Diabetic Patients
30
Control Antiplatelet therapy
20 10 0
Benefit/1000 pts (SD): 2P: No Diabetes 36 (3) <0.00001
Antiplatelet Trialists Collaboration BMJ 1994;308:81-106 Diabetes 38 (12) <0.002
Platelet Function (COX-1 Independent) In DM Vs Non-DM On Aspirin
LTA
100 80
p<0.05
60 40 20 0
DM Non-DM
LTA = Light Transmission Aggregation
Angiolillo DJ et al. Diabetes 2005; 54:2430-2435
100 80 60 40 20 0
PFA-100
p<0.01
DM Non-DM
Angiolillo DJ et al. Am J Cardiol 2006; 97:38-43
Schematic of Circadian Release of Platelets into Bloodstream from Bone Marrow and Impact of a Single Daily Dose of Aspirin in Newly Generated Platelets in Type 2 DM
Twice daily aspirin is associated with better platelet inhibition than increasing once daily dosing in DM patients.
Capodanno D et al. Circ Cardiovasc Interv. 2011;4:180-187.
CURE: Outcomes With Clopidogrel in Various Subgroups
Characteristic
Overall Associated MI No associated MI Male sex Female sex old 65 yr > 65 yr old ST-segment deviation o ST-segment deviation Enzymes elevated at entry Enzymes not elevated at entry Diabetes No diabetes Low risk Intermediate risk High risk History of revascularization No history of revascularization Revascularization after randomization No revascularization after randomization
Percentage of Patients with Event No. of Patients
12562 3283 9279 7726 4836
Clopidogr el + ASA
9.3
11.3
8.6
9.1
9.5
Placebo + ASA
11.4
13.7
10.6
11.9
10.7
6354 6208 6275 6287 3176 9386 2840 9722 4187 4185 4184 2246 10316 4577 7985 5.4
13.3
11.5
7.0
10.7
8.8
14.2
7.9
5.1
6.5
16.3
8.4
9.5
11.5
8.1
7.6
15.3
Yusf S et al. N Engl J Med. 2001;345:494-502.
14.3 N 8.6
13.0
10.9
16.7
9.9
6.7
9.4
18.0
14.4
10.7
13.9
10.0
0.4
0.6
0.8
1.0
Relative Risk (95% CI) 1.2
Clopidogrel Better Placebo Better
Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Acute Phase of Treatment
38% DM 56% No-DM P=0.04
14% 8% 6% 78%
24 hrs post 300 mg LD
Non-responders (Platelet inhibition <10%) Low responders (Platelet inhibition 10-29%) Responders (Platelet inhibition >30%) Angiolillo DJ et al. Diabetes. 2005;54:2430-2435. 80
Long-term Phase of Treatment
P=0.002
P<0.0001
60 40 20 0
DM No DM
ADP 20 M
DM No DM
ADP 6 M Angiolillo DJ et al. J Am Coll Cardiol. 2006;48:298-304.
Diabetes as Predictor of Stent Thrombosis at 1 Year in the Era of DES
5 4 OR=2.0
(0.8-4.9) 3 OR=2.8
(1.7-4.3) HR=3.7
(1.7-7.9) HR=2.03
(1.07-3.83) 2 1 0
IDDM IDDM Diabetes
Kuchulakanti PK et al.
Circulation
2006;113:1108-1113 Urban P et al.
Circulation
2006;113:1434-1441 Iakovou I et al.
JAMA
2005;293:2126-2130
Diabetes
Daemen J et al.
Lancet
2007;116:961-968
Strategies to Enhance P2Y
12
Inhibition in Patients With Diabetes
• Increase clopidogrel dosing (eg, 150 mg maintenance dosing) • Adding agents that modulate
intraplatelet cAMP
(eg, triple therapy: ASA + clopidogrel + cilostazol) • Using novel potent P2Y
12
(eg, prasugrel, ticagrelor)
inhibitors
Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials
Study
TRITON-TIMI 38 PLATO CURRENT OASIS 7 (PCI Cohort)
% of Events Standard Hazard Ratio (95% confidence interval) New Drug/Approach
17.0
12.2
0.70 (0.58 – 0.85) 16.2
5.6
14.1
4.9
0.88 (0.76 – 1.03) 0.87 (0.66 – 1.15) 0 0.5
New Drug/Approach Better
1 1.5
Standard Clopidogrel Better CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Platelet Inhibition and Patient Outcomes; TRITON-TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction.
Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011;123:798-813
TRITON TIMI-38: Diabetic Subgroup
(n=3146)
18 16 14 12 10 8 6 4 2 CV Death/MI/Stroke 0 0 30 60 90 TIMI Major Non-CABG Bleeds 180
Days
270 Clopidogrel Prasugrel Clopidogrel Prasugrel 360
Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-1636.
450 17.0
12.2 HR 0.70
P<0.001 NNT = 21 2.6
2.5
TRITON TIMI-38:
CV Death/MI/Stroke by Diabetic Status
No DM Pras Clop Reduction in Risk 9.2% 10.6% 14% DM No Insulin 11.5% 15.3% 26% DM on Insulin 14.3% 22.2%
0.3
Prasugrel better
1 2
Clopidogrel better 37% Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-1636.
OPTIMUS-3: Optimizing Antiplatelet Therapy in Diabetes Mellitus
Prasugrel (standard dose) vs Clopidogrel (high dose) in DM patients
350
B
LD MD Washout 300 250 200 150 100 *** *** 50 0 *** Mean ± SE 0 4 Hours post LD 24 *** ***p<0.0001
7 days No study drug (7 days) prasugrel 60 mg LD/10 mg MD clopidogrel 600 mg LD/150 mg MD
Verify Now ® -P2Y 12 % Inhibition
Similar findings obtained with MPA to 5 and 20 µM ADP, VASP PRI, and Verify Now® PRU
Angiolillo DJ et al. Eur Heart J. 2011;32:838-846
PLATO: Diabetes
PLATO: Diabetes
PLATO: Diabetes
ABCs of Treatment of Diabetic Patients and Impact on Thrombosis
A HbA 1C (blood glucose): <7% B B lood pressure: <130/80 mm Hg C C holesterol-LDL: <70 mg/dl
Platelet Reactivity
Discharge Strategies for Patients Post-ACS
Long-term Dual Antiplatelet Therapy, ACEI or ARB, β-blocker, Statin Therapy + Lifestyle Modification
(Smoking cessation, nutrition, and exercise)
+ Cardiac Rehabilitation
(PCP + cardiologist + other team members)
+ Patient Education
(Disease state, medication use, side effects)
+ Medication Compliance
(Counseling, other strategies)
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; PCP = primary care physician.
Antman EM et al. J Am Coll Cardiol. 2008;51:210-247; Levine GN et al. Circulation. 2011;124:e547-e651.
Evidence-based Therapies on 6-month Survival GRACE Registry Cohort*
NUMBER OF THERAPIES
(vs 0 or 1 therapy)
2 therapies 3 therapies 4 therapies 5 therapies 6 therapies 7 therapies 8 therapies OR = odds ratio *Registry of patients with ACS Chew DP et al. Heart. 2010;96:1201-1206.
0 0.5
1 OR OR
(95% CI)
0.80 (0.52-1.26) 0.74 (0.48-1.13) 0.59 (0.39-0.90) 0.51 (0.33-0.78) 0.40 (0.26-0.62) 0.27 (0.16-0.44) 0.31 (0.17-0.57) 1.5
2
Participant CME Evaluation
• Please take out the Participant CME Post-survey and Evaluation from the back of your packet • If you are not seeking credit, we ask that you fill out the information pertaining to your degree and specialty, as well as the few questions we will read through now measuring the knowledge and competence you have garnered from this program. The post-survey is located on page 1 of the evaluation form.
Post-activity Survey Question 1
After participating in this activity, how confident are you in adopting evidence-based care for high-risk NSTEMI patients to reduce the need for rehospitalization?
1 Not at all confident 2 3 4 5 Expert
Post-activity Survey Question 2
After participating in this activity, how confident are you in adopting evidence-based care for STEMI patients to reduce the need for rehospitalization?
1 Not at all confident 2 3 4 5 Expert
Pre-activity Survey Question 3
The choice between an initial conservative strategy or an initial invasive strategy in patients diagnosed with NSTE ACS is made largely on the basis of: A.
Risk of ischemic complications B.
Whether symptoms are typical or atypical C.
D.
E.
Whether the ECG is interpretable Whether the patient can take a stress exercise test All of the above
Pre-activity Survey Question 4
Compared to ACS patients who do not have diabetes, those who have diabetes mellitus are at: A.
B.
C.
D.
Greater risk of major cardiovascular events and similar risk of major bleeding events Greater risk of major cardiovascular events and greater risk of major bleeding events Similar risk of major cardiovascular events and greater risk of major bleeding events Similar risk of major cardiovascular events and similar risk of major bleeding events
Pre-activity Survey Question 5
In STEMI patients, primary PCI is superior to fibrinolytic therapy to reduce in-hospital mortality if PCI can be performed within ___ hours after the onset time of infarction: A.
<1.5 hours B.
3 hours C.
D.
E.
6 hours 12 hours 24 hours
Pre-activity Survey Question 6
According to the GRACE registry, use of 5 or more medications for secondary prevention of ACS can reduce 6-month mortality by: A.
Less than 20% B.
20%-30% C.
D.
E.
30%-40% 40%-50% More than 50%
Thank you for joining us today!
Please remember to turn in your evaluation form.
Your participation will help shape future CME activities.