Reducing Risk in the Acute Coronary Syndrome Patient:

Reducing Risk in the Acute Coronary
Syndrome Patient:
Insights for Primary Care Clinicians
September 19, 2013
Boston, Massachusetts
9:30–11am
Roger Blumenthal, MD
Professor of Medicine
Johns Hopkins University School of Medicine
Baltimore, Maryland
Gregg Stone, MD
Professor of Medicine
Columbia University College of Physicians and Surgeons
New York, New York
Educational Partner:
Voxmedia, LLC
Session 2: Reducing Risk in the Acute Coronary Syndrome Patient:
Insights for Primary Care Clinicians
Learning Objectives
1.
2.
3.
Describe fundamental pharmacokinetics, pharmacodynamics, and pharmacogenetics of oral antiplatelet therapies.
Discuss efficacy and safety data with oral antiplatelet therapies from ACS outcomes trials.
Identify therapies to reduce risk and recognize goals to achieve in the management of patients who have experienced an
acute coronary syndrome.
Faculty
Roger Blumenthal, MD
Professor of Medicine
Johns Hopkins University
School of Medicine
Baltimore, Maryland
Roger S. Blumenthal, MD, is professor of medicine in the division of cardiology at Johns Hopkins University School of Medicine
in Baltimore. Dr Blumenthal graduated with honors from Johns Hopkins and received his medical degree from Cornell
University Medical College. He did his fellowship training at Johns Hopkins Hospital and then joined the medical school
faculty. His principal clinical and research interests involve the optimal management of ischemic heart disease, noninvasive
detection of coronary atherosclerosis, and the development of new strategies to optimize the management of cardiovascular
disease risk factors. Dr Blumenthal was the principal developer of the Johns Hopkins Ciccarone Center for the Prevention of
Heart Disease, and he is the director of preventive cardiology at Johns Hopkins. He has co-written more than 400 original
research articles, state-of-the art reviews, and editorials dealing with many aspects of coronary artery disease and
atherosclerosis management. Dr Blumenthal is on the editorial board of Cardiology Today, the American Heart Journal, and
Clinical Cardiology. He was editor-in-chief of the 2011 textbook Preventive Cardiology – A Companion to Braunwald’s Heart
Disease. For many years he has been the medical editor of the annual Johns Hopkins White Paper on Prevention of Heart Attacks.
Beginning in 1998 he was the official national medical spokesperson for the American Heart Association (AHA)’s Cholesterol
Low Down and was the chairperson of the American College of Cardiology (ACC) prevention of cardiovascular disease
committee. An expert in noninvasive detection of vascular disease, Dr Blumenthal was also on the AHA’s official writing group
about the utility of cardiac CT and CT angiography. He also was a member of the ACC task force dealing with selection of
patients for atherosclerosis imaging techniques such as ultrafast CT scanning and carotid ultrasound. He is currently a director
of the American Society of Preventive Cardiology.
Gregg Stone, MD
Professor of Medicine
Columbia University College
of Physicians & Surgeons
New York, New York
Gregg W. Stone, MD, is professor of medicine at Columbia University College of Physicians and Surgeons, and director of
cardiovascular research and education at the Center for Interventional Vascular Therapies at Columbia University Medical
Center, and the Cardiovascular Research Foundation in New York City. Dr Stone is a director of Transcatheter Cardiovascular
Therapeutics. His medical practice is devoted to interventional cardiology at New York-Presbyterian Hospital/Columbia
University Medical Center. He completed medical school at Johns Hopkins University School of Medicine in Baltimore and his
Session 2
residency at the New York Hospital-Cornell Medical Center in New York City. He completed his general cardiology fellowship
at Cedars-Sinai Medical Center in Los Angeles, California, and subsequently a dedicated fellowship in advanced coronary
angioplasty with Dr Geoffrey Hartzler in Kansas City. Dr Stone has served as the national or international principal investigator
for more than 50 national and international multicenter randomized trials. Dr Stone’s areas of expertise include interventional
therapies of acute coronary syndromes and myocardial infarction; drug-eluting stents; adjunct pharmacology; percutaneous
heart valves, new device angioplasty including distal embolic protection, thrombectomy, vascular brachytherapy and stent
grafts; intravascular ultrasound imaging; saphenous vein graft therapies; chronic total occlusions; vulnerable plaque; contrast
nephropathy; clinical trial design; and regulatory issues. Dr Stone has authored more than 1000 book chapters, manuscripts,
and abstracts published in the peer-reviewed literature.
Faculty Financial Disclosure Statements
The presenting faculty report the following:
Dr Blumenthal has no financial relationships to disclose.
Dr Stone receives fees as a consultant for AstraZeneca, Eli Lilly, and Daiichi-Sankyo.
Education Partner Financial Disclosure Statement
The content collaborator at Voxmedia reports the following:
John F. Kocsis, PhD, has no financial relationships to disclose.
Suggested Reading List
Alexopoulos D, Galati A, Xanthopoulou I, et al. Ticagrelor vs prasugrel in acute coronary syndrome patients with high onclopidogrel platelet reactivity following percutaneous coronary intervention. A pharmacodynamic study. J Am Coll Cardiol.
2012;60:193-199.
American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions, O’Gara PT, Kushner FG,
Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. J Am Coll Cardiol.
2013;61:e78-e140.
Cannon CP, Harrington RA, James S, et al; for the PLATelet inhibition and patient Outcomes Investigators. Comparison of
ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised
double-blind study. Lancet. 2010;375:283-293.
CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, Chrolavicius S, et al. Dose comparisons of clopidogrel and aspirin in
acute coronary syndromes. N Engl J Med. 2010;363:930-942.
Gurbel PA, Tantry US. Clopidogrel response variability and the advent of personalized antiplatelet therapy. A bench to bedside
journey. Thromb Haemost. 2011;106:265-271.
Halim SA, Rao SV. Bleeding and acute coronary syndromes: defining, predicting, and managing risk and outcomes. Curr Drug
Targets. 2011;12:1831-1835.
Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing
coronary artery bypass surgery: results from the PLATO trial. J Am Coll Cardiol. 2011;57:672-684.
Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients with
Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused
Update). J Am Coll Cardiol. 2012;60:645-681.
Session 2
Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of
the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society
for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574-651.
Marchini J, Morrow D, Resnic F, et al. An algorithm for use of prasugrel (effient) in patients undergoing cardiac catheterization
and PCI. Crit Pathw Cardiol. 2010;9:192-198.
Mehta SR, Tanguay JF, Eikelboom JW, et al; for the CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose
clopidogrel and high-dose versus low-dose ASA in individuals undergoing PCI for ACS (CURRENT-OASIS 7): a randomized
factorial trial. Lancet. 2010;376:1233-1243.
Montalescot G, Wiviott SD, Braunwald E, et al; for the TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in
patients undergoing PCI for STEMI (TRITON-TIMI 38): double-blind, randomized controlled trial. Lancet. 2009;373:723-731.
Roe MT, Armstrong PW, Fox KA, et al; for the TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary
syndromes without revascularization. N Engl J Med. 2012;367:1297-1309.
Sabatine MS, Cannon CP, Gibson CM, et al; for the CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and
fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:1179-1189.
Smith SC Jr, Benjamin EJ, Bonow RO, et al; for the World Heart Federation and the Preventive Cardiovascular Nurses
Association. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other
Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of
Cardiology Foundation. Circulation. 2011;124:2458-2473.
Tantry US, Gurbel PA. Current options in oral antiplatelet strategies during percutaneous coronary intervention. Rev Cardiovasc
Med. 2011:12 (suppl 1):S4-S13.
Wallentin L, Becker RC, Budaj A, et al; for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary
syndromes. N Engl J Med. 2009;361:1045-1057.
Wiviott SD, Braunwald E, McCabe CH, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.
Yousuf O, Bhatt DL. The evolution of antiplatelet therapy in cardiovascular disease. Nat Rev Cardiol. 2011;8:547-559.
Yusuf S, Zhao F, Mehta SR, et al; for the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects
of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med.
2001;345:494-502.
Session 2
Presenter Disclosure Information
SESSION 2
The following relationships exist related to this presentation:
9:30–11am
►Dr Blumenthal has no financial relationships to disclose.
Reducing Risk in the Acute Coronary
Syndrome Patient: Insights for Primary
Care Clinicians
►Dr Stone receives fees as a consultant for AstraZeneca, Eli
Lilly, and Daiichi-Sankyo.
Off-Label/Investigational Discussion
SPEAKERS
Roger Blumenthal, MD
Gregg Stone, MD
►In accordance with pmiCME policy, faculty have been asked
to disclose discussion of unlabeled or unapproved use(s) of
drugs or devices during the course of their presentations.
Learning Objectives
Drug List
Generic
Trade
Acetylsalicylic
acid
Aspirin
Clopidogrel
Plavix
Prasugrel
Effient
Ticagrelor
Brilinta
Metformin
Glucophage, Fortamet, Glumetza, Riomet
Glyburide
Diabeta, Glycron, Glynase, Micronase
Lisinopril
Zestril, Prinivil
Nitroglycerin
Nitro-Par, Nitro-Time, NitroMist, Nitrocot, Nitroglyn
E-R, Nitrolingual, Nitroquick, Nitrostat, Nitrotab
Warfarin
Coumadin, Jantoven, Marfarin
Eptifibatide
Integrilin
• Describe fundamental pharmacokinetics, pharmacodynamics,
and pharmacogenetics of oral antiplatelet therapies.
• Discuss efficacy and safety data with oral antiplatelet
therapies from ACS outcome trials.
• Identify therapies to reduce risk and recognize goals to achieve
in the management of patients who have experienced an acute
coronary syndrome (secondary prevention).
CAPRIE Trial: Clopidogrel vs Aspirin
in Secondary Prevention
The Changing Landscape of
Oral Antiplatelet Therapy
in ACS Management
Primary Analysis (MI, Stroke, or Vascular Death)
Placebo1
Aspirin1,2
Cumulative Event Rate - %
16
Gregg W. Stone MD
Columbia University Medical Center
Cardiovascular Research Foundation
Event Rate per Year
Clopidogrel2
12
Relative
Risk
Reduction
7.7%
8
5.83%
4
5.33%
p = 0.045
0
0
3
6
9
12 15
18
21
24
27
30
33
36
Time from Randomization (mo)
*ITT analysis.
1Antiplatelet Trialists’ Collaboration. BMJ. 1994; 308:81–106.
2CAPRIE Steering Committee, Lancet. 1996;348:1329–1339.
1
25%
8.7%*
Dual Antiplatelet Therapy is Effective
in the Setting of ACS: CURE
PCI-CURE: Clopidogrel after NSTE-ACS
Treated with PCI
Composite of MI or cardiovascular death from randomization to end follow-up
0.15
Placebo
+ ASA
Cumulative Hazard Rate
Clopidogrel
+ ASA
P < 0.0001
N = 12,562
12.6%
Placebo
+ ASA*
20%
Relative Risk
Reduction
31%
Overall
Relative Risk
Reduction
8.8%
0.10
Clopidogrel
+ ASA*
0.05
P = 0.002
N = 2658
0.0
0
3
6
9
0
12
100
200
300
* In addition to other standard therapies.
Mehta. et al for the CURE Investigators. Lancet. 2001;358:527-533.
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE Trial
Major Bleeding by ASA Dose
CLARITY: Is Clopidogrel Useful as Adjunct to
Fibrinolysis in STEMI?
(1° Endpt: TIMI 0/1, D/MI)
25
21.7
36%
Odds Ratio 0.64
Odds Reduction
ASA Dose
Placebo
+ ASA
<100 mg
100 – 200 mg
>200 mg
2.0%
2.3%
4.0%
20
Clopidogrel
+ ASA
10
5
n=1752
n=1739
Clopidogrel
Placebo
NEJM 2005; 352:1179. Age <76 with STEMI <12 h. Clopidogrel 300/75mg.
COMMIT: CLOPIDOGREL in 46,000 AMI Pts
0.4
0.6
0.8
1.0 1.2
Clopidogrel
better
Limitations of Clopidogrel
Placebo + ASA:
2311 events (10.1%)
• Heterogenous antiplatelet response
• Genetic polymorphisms associated with
poor response
• Drug-drug interaction
• Smoking interaction
Placebo + ASA:
1846 deaths (8.1%)
Clopidogrel +ASA:
1728 deaths (7.5%)
Dead (%)
Clopidogrel + ASA:
2125 events (9.3%)
7% RRR
(P=0.03)
Bonello L, JACC 2010;56:919-33
Ho PM, JAMA 2009;301:937-44
Berger JS, Circulation 2009;120:2337-44
Days since randomisation
Chen et al. Lancet. 2005;366:1607-1621.
2
1.6
Placebo
better
D, Death; MI, myocardial infarction
Mortality
Death, Re-MI or Stroke
Death, MI Stroke (%)
P=0.00000036
15
Yusuf S, et al. N Engl J Med. 2001;345:494-502.
Days since randomisation
(95% CI 0.53-0.76)
15.0
%
2.6%
3.5%
4.9%
0
9% RRR
(P=0.002)
400
Days of follow-up
Months of Follow-Up
COGENT Trial Design
Risk of All-Cause Mortality and Recurrent ACS in
Patients Taking Clopidogrel and PPI
0.70
0.60
Proportion of
Deaths or Recurrent ACS
Non-STEMI, STEMI, or
Elective Stent
n=3627
Neither clopidogrel nor PPI
PPI without clopidogrel
Clopidogrel + PPI
Clopidogrel without PPI
0.50
Aspirin
0.40
0.30
Clopidogrel 75 mg
and
Omeprazole
(Prilosec) 20 mg
Clopidogrel 75 mg
and
Placebo
0.20
0.10
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Planned enrollment: 5000; stopped due to bankruptcy
Days Since Discharge
Mean follow-up 133 days (maximum, 362 days)
Ho PM et al. JAMA. 2009;301(9):937-944.
Bhatt D, et al. NEJM 2010;363:1909-17
COGENT Trial – Effect of PPI on
Composite GI Events
Composite Cardiovascular Events
COGENT Trial
Omeprazole
1.00
N=3627
Placebo: 67 events; 1821 at risk
Treated: 69 events; 1806 at risk
Probability of Freedom from
Primary GI Endpoint
Survival Probability
1.00
0.98
HR=1.02
95% CI=0.70;1.51
0.96
0.94
Placebo
0.92
Placebo
0.90
HR = 0.34, 95% CI = 0.18-0.63
P < 0.001 by the log-rank test
0.00
0
Omeprazole
0.90
0
30
60
90
50
100
150
Time (Days)
Adjusted with Cox Proportional Hazards Model for
NSAID use and positive H. pylori status.
Carriers vs Noncarriers
1.61 (1.28-2.02)
<0.001
Heterozygotes vs Wildtype
1.50 (1.08-2.08)
0.016
Homozygotes vs Wildtype
1.81 (1.21-2.71)
0.004
Carriers vs Noncarriers
2.76 (1.77-4.30)
<0.001
Heterozygotes vs Wildtype
2.51 (1.59-3.98)
<0.001
Homozygotes vs Wildtype
4.78 (2.01-11.39)
<0.001
Relative Risk
951
523
260
231
Omeprazole
1876
1500
987
553
250
215
See full prescribing information for complete boxed warning.
•
Effectiveness of clopidogrel depends on activation to an active metabolite by the
cytochrome P450 (CYP) system, principally CYP2C19. (5.1)
•
Poor metabolizers treated with clopidogrel at recommended doses exhibit higher
cardiovascular event rates following acute coronary syndrome (ACS) or
percutaneous coronary intervention (PCI) than patients with normal CYP2C19
function. (12.5)
•
Tests are available to identify a patient’s CYP2C19 genotype and can be used as
an aid in determining therapeutic strategy. (12.5)
•
Consider alternative treatment or treatment strategies in patients identified as
CYP2C19 poor metabolizers. (2.3, 5.1)
Stent Thrombosis (N=5772)
1.0
1455
WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
P Value
0.5
1885
Clopidogrel Label Changes
Risk Ratio
(95% CI)
Risk Lower With
CYP2C19 Variant
Placebo
Bhatt DL, et al. N Engl J Med. 2010;363(20):1909-1917.
CYP2C19 Genetic Polymorphisms
and Outcomes With Clopidogrel
Major Adverse CV Events (N=9684)
200
No. at Risk
120 150 180 210 240 270 300 330 360 390
Bhatt D, et al. NEJM 2010;363:1909-17
180
Time (Days)
15.0
Risk Higher With
CYP2C19 Variant
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s055lbl.pdf
Mega JL, et al. JAMA 2010; 304:1821-1830.
Courtesy of JL Mega and MS Sabatine.
3
The therapeutic target for thienopyridines
and CPTPs is the platelet P2Y12 receptor
P2Y12 Receptor Antagonists
Agent
Prasugrel
Esterification and
2-step oxidation to
active metabolite
Active metabolite
IPA
Time to
(20 uM ADP) peak
mean
onset
Reversibility
(d/c before CABG)
Ticlopidine 250 mg bid
thienopyridine
(pro-drug)
25%
48 hrs
non reversible
5 days
Clopidogrel
Clopidogrel
Clopidogrel
Clopidogrel
Thienopyridine
(pro-drug)
30% - 40%
35% - 50%
30% - 35%
45% - 50%
12 hrs
6 hrs
-
non reversible
5 days
Thienopyridine
(pro-drug)
80%
60%
40%
1-2 hrs
-
non reversible
7 days
cyclo-pentyltriazolopyrimidine*
80%
70%
1-2 hrs
-
reversible
2-5 days
300 mg LD
600 mg LD
75 mg qd
150 mg qd
Prasugrel 60 mg LD*
Prasugrel 10 mg qd*
Prasugrel 5 mg qd*
Ticagrelor
1-step oxidation to
active metabolite
Class
Ticagrelor 180 mg LD*
Ticagrelor 90 mg bid*
Ticagrelor is a CPTP*, cyclo-pentyl-triazolo-pyrimidine
*Less affected by genetic polymorphisms and drug interactions (e.g. PPIs)
**ticagrelor not a pro-drug
PRINCIPLE TIMI 44: Comparison with Higher Dose
Clopidogrel
IPA (%; 20 M ADP)
N=201
TRITON TIMI-38: Study Design
ACS (UA/NSTEMI or STEMI) & Planned PCI*
ASA
N= 13,600
*Except STEMI
IPA (%; 20 M ADP)
P<0.0001
P<0.0001 for each
Double-blind
Prasugrel 60 mg
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy – 12 months
Clopidogrel 600 mg
endpoint:
2o endpoints:
1o
Clopidogrel Prasugrel
150 mg
10 mg
Hours
Safety endpoints:
Key Substudies:
14 Days
Wiviott SD et al. Circulation. 2007;116:2923-32.
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
TIMI major bleeds, Life-threatening bleeds
Pharmacokinetic, Genomic
Wiviott SD et al. Am Heart J. 2006;152:627-35.
40
TRITON TIMI-38
TRITON TIMI-38: Efficacy endpoints
13,608 pts with ACS (unstable angina, NSTEMI, acute STEMI, or recent STEMI)
undergoing PCI with known coronary anatomy (except for primary PCI pts) were treated
with aspirin and randomized to clopidogrel 300 mg load + 75 mg qd vs. prasugrel 60 mg
load + 10 mg qd and followed for 6-15 mos (median 12 mos)
Prasugrel Clopidogrel
(n=6813)
(n=6795)
HR [95%CI]
P
Primary Endpoint
CV death, MI, or stroke (%)
15
HR 0.80
P=0.0003
12.1%
Clopidogrel
HR 0.77
P=0.0001
10
9.9%
Prasugrel
7.4%
HR 0.81
(0.73-0.90)
P=0.0004
5.7%
5
0
0
30 60 90
180
Days
270
360
CV death, MI, stroke
9.9%
12.1%
0.81 [0.73, 0.90]
<0.001
- CV death
2.1%
2.4%
0.89 [0.70, 1.12]
0.31
- Nonfatal MI
7.3%
9.5%
0.76 [0.67, 0.85]
<0.001
- Non fatal stroke
1.0%
1.0%
1.02 [0.71, 1.45]
0.93
Urgent TVR
2.5%
3.7%
0.66 [0.54, 0.81]
<0.001
Death, all-cause
3.0%
3.2%
0.95 [0.78, 1.16]
0.64
450
Wiviott SD, et al. NEJM. 2007;357:2001-15.
Wiviott SD, et al. NEJM. 2007;357:2001-15.
4
TRITON TIMI-38
TRITON TIMI-38: Bleeding endpoints
Definite or probable stent thrombosis
in 12,844 pts receiving any stent
Stent thrombosis (%)
2.5
CLOPIDOGREL
Prasugrel Clopidogrel
(n=6813)
(n=6795)
PRASUGREL
2.4%
2.0
HR [95%CI]
0.48 [0.36-0.64]
P<0.0001
1.5
Definite ST: 0.9% vs. 2.0%
HR 0.42 [0.31, 0.59]
P<0.0001
0.5
0
P
0.002
TIMI bleed, major or minor
5.0%
3.8%
1.31 [1.11, 1.56]
- Major, CABG related
13.4%
3.2%
4.73 [1.90, 11.82] <0.001
- Major, non CABG related
2.4%
1.8%
1.32 [1.03, 1.68]
0.03
- Life-threatening
1.4%
0.9%
1.52 [1.08, 2.13]
0.01
- Fatal
0.4%
0.1%
4.19 [1.58, 11.11]
0.002
4.0%
3.0%
1.34 [1.11, 1.63]
<0.001
1.1%
1.0
DAYS
HR [95%CI]
0
50
100
150
200
250
300
350
400
- Requiring transfusion
450
Wiviott SD, et al. NEJM. 2007;357:2001-15.
Wiviott SD, et al. Lancet. 2008;371:1353-63.
TRITON TIMI-38: Net Clinical Benefit
CV Death / MI / CVA / TIMI Major Bleeding
Post-hoc analysis
Prior
Stroke / TIA
Age (years)
“Boxed Warning”
WARNING: BLEEDING RISK
Risk (%)
See full prescribing information for complete boxed warning
+37
Yes
Pint = 0.006
No
Prasugrel can cause significant, sometimes fatal, bleeding (5.1, 5.2, and 6.1).
Do not use prasugrel in patients with active pathological bleeding or a history of
transient ischemic attack or stroke (4.1 and 4.2).
-16
In patients > 75 years of age, prasugrel is generally not recommended because
of the increased risk of fatal and intracranial bleeding and uncertain benefit, except
in high-risk patients (diabetes or prior MI), where its effect appears to be greater and
its use may be considered (8.5).
-1
≥75
Pint = 0.18
<75
Weight
Prasugrel – FDA Label
<60 kg
Pint = 0.36
≥60 kg
OVERALL
-16
Do not start prasugrel in patients likely to undergo urgent coronary artery bypass
graft surgery (CABG). When possible, discontinue prasugrel at least 7 days prior to
surgery.
+3
Additional risk factors for bleeding include:
• body weight < 60 kg
• propensity to bleed
• concomitant use of medications that increase the risk of bleeding
-14
Suspect bleeding in any patient who is hypotensive and has recently undergone
coronary angiography, percutaneous coronary angiography, percutaneous coronary
intervention (PCI), CABG, or other surgical procedures in the setting of prasugrel.
-13
0.5
Prasugrel Better
1
HR
Clopidogrel Better
If possible, manage bleeding without discontinuing prasugrel. Stopping prasugrel,
particularly in the first few weeks after acute coronary syndrome, increases the risk
of subsequent cardiovascular events (5.3).
2
Wiviott SD, et al. NEJM. 2007;357:2001-15.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022307s003lbl.pdf
Primary Efficacy: CV death,
MI, or stroke (Age < 75 years)
TRILOGY ACS: Study Design
Medically managed UA/ or NSTEMI (68%)
(n=9,326)
With (42%) or w/o
prior angiography;
If with, required CAD
with DS ≥30%
Randomization stratified by:
age, country, prior clopidogrel treatment
(Primary analysis cohort — Age <75 years; n=7,243)
Median time to
enrollment = 4.5 days
Medical Management Decision ≤72 hrs
(No prior clopidogrel given) — 4% of total
Clopidogrel*
300 mg LD
+
75 mg MD
Prasugrel*
30 mg LD
+
5 or 10 mg MD
Median FU 17 months
Medical Management Decision ≤ 10 days
(Clopidogrel started ≤ 72 hrs in-hospital OR
on chronic clopidogrel) — 96% of total
Clopidogrel*
Prasugrel*
75 mg MD
5 or 10 mg MD
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, Stroke
*All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given.
Among pts <75 years, 7.9% underwent revascularization (median 113 [40-334] days)
Adapted from Chin CT, et al. Am Heart J. 2010;160:16-22.
Roe MT, et al. NEJM. 2012;367:1297-1309.
5
Primary Efficacy: CV death,
MI, or stroke (Age < 75 years)
Ticagrelor:
an Oral Reversible P2Y12 Antagonist
HO
HR (95% CI) ≤1 Year:
0.99 (0.84, 1.16)
HR (95% CI) >1 Year:
0.72 (0.54, 0.97)
Median FU 17 months
N
N
N
H
N
HO
O
N
F
N
Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP)
F
S
OH
• Direct acting
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21

Not a prodrug; does not require metabolic activation

Rapid onset of inhibitory effect on the P2Y12 receptor

Greater inhibition of platelet aggregation than clopidogrel
• Reversibly bound
Interaction P = 0.07
Clopidogrel vs. Ticagrelor
Ticagrelor 180mg
*
80
60
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
*
40
Clopidogrel 600 mg
20
0
0 .5
4
8
12
16
20
24
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure (median 9 mos)
Hours
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
Note: ASA 325 mg load, then 75-100 mg QD (325 mg x6 mo permitted if stented
*P<0.0001; †P<0.005; ‡, P<0.05, ticagrelor vs clopidogrel.
Gurbel PA et al. Circulation. 2009;120:2577-85.
Wallentin L, et al. NEJM. 2009;361:1045-57.
PLATO: Primary Efficacy Endpoint
PLATO
Composite of CV Death, MI or Stroke
Stent Thrombosis
13
12
11
10
9
8
7
6
5
4
3
2
1
0
11.7%
Clopidogrel
9.8%
12 Month Event Rate %
CV death, MI or stroke
(%)
IPA (%; 20 mM ADP, Final)
Functional recovery of all circulating platelets
NSTE-ACS (moderate-to-high risk) or STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
Maintenance and Offset
Loading
*
Faster offset of effect than clopidogrel

PLATO: Study Design
ONSET/OFFSET Study
* *
Degree of inhibition reflects plasma concentration

Wallentin L, et al. NEJM. 2009;361:1045-57.
Roe MT, et al. NEJM. 2012;367:1297-1309.
100

Ticagrelor
HR[95%CI] =
0.84 [0.77–0.92]
P=0.0003
0
60
120
180
240
300
360
6,743
5,161
4,147
6,743
5,096
4,047
HR(95%CI) =
0.67 (0.50–0.91)
P=0.009
HR(95%CI) =
0.75 (0.59–0.95)
P=0.02
Days after randomization
No. at risk
Ticagrelor
9,333
8,628
8,460
8,219
Clopidogrel
9,291
8,521
8,362
8,124
Definite or Probable
Wallentin L, et al. NEJM. 2009;361:1045-57.
Wallentin L, et al. NEJM. 2009;361:1045-57.
6
HR(95%CI) =
0.77 (0.62–0.95)
P=0.01
PLATO: Total Major Bleeding
PLATO
Primary and Secondary Endpoint Events
13
12
P=0.43
11.2
Clopidogrel (n=9,291)
11.6
Ticagrelor (n=9,333)
HR(95%CI) =
0.84 (0.77–0.92)
P<0.001
Adverse event rate (%)
11
HR(95%CI) =
0.78 (0.69–0.89))
P<0.001
HR(95%CI) =
0.84 (0.75–0.95)
P=0.005
HR(95%CI) =
1.17 (0.91–1.52)
P=0.22
HR(95%CI) =
0.79 (0.69–0.91)
P=0.001
P=0.96
10
P=0.57
9
7.7
8
8.9
8.9
7.9
P=0.70
7
5.8
6
5.8
5
4
3
2
P=0.66
1
0.3
0.3
0
PLATO
major
bleeding
PLATO: Non-CABG and CABG-related
Major Bleeding
Adverse event rate (%)
8
Clopidogrel (n=9,291)
Ticagrelor (n=9,333)
PLATO: Substudy in pts intended for medical Rx
P=0.32
Efficacy endpoints
7.4
P=0.32
5.8
P=0.026
5
4
Fatal
bleeding
PLATO lifethreatening/
fatal
bleeding
5216 (28%) of 18,624 ACS pts were specified for non-invasive management
before randomization. UA in 35.4%, NSTEMI in 55.9%; STEMI in 8.7%.
7.9
7
6
Red cell
transfusion
Wallentin L et al. New Engl J Med 2009;361:1045-57.
Wallentin L, et al. NEJM. 2009;361:1045-57.
9
TIMI major
bleeding
5.3
4.5
3.8
P=0.025
2.8
3
2.2
2
1
0
Non-CABG
PLATO major
bleeding
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
James SK, et al. BMJ. 2011;342:d3527 doi: 10.1136/bmj.d3527
Wallentin L et al. New Engl J Med 2009;361:1045-57.
PLATO: Substudy in pts intended for medical Rx
PLATO: Regional Outcomes According
to ASA Maintenance Dose
5216 (28%) of 18,624 ACS pts were specified for non-invasive management
before randomization. UA in 35.4%, NSTEMI in 55.9%; STEMI in 8.7%.
Safety endpoints
ASA Dose
(mg)
Clopidogrel
N
E
Ticagrelor
E
N
HR (95% CI)
Overall
≥300
464
68
492
50
1.45 (1.01, 2.09)
>100-<300
525
64
527
65
0.99 (0.70, 1.40)
≤100
7733
565
7706
723
0.77 (0.69, 0.86)
0.125
X2=16.1
P=0.00006
0.5
Ticagrelor
Better
1.0
2
4
8
Clopidogrel
Better
N, number of patients; E, number of events
James SK, et al. BMJ. 2011;342:d3527 doi: 10.1136/bmj.d3527
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm221382.htm
7
Ticagrelor – FDA Label
PLATO: Dyspnea
“Boxed Warning”
Ticagrelor blocks rbc re-uptake of adenosine, and thus causes
the sensation of dyspnea in some pts
WARNING: BLEEDING RISK
HR(95%CI) =
12 Month Event Rate %
• Ticagrelor, like other antiplatelet agents, can cause significant, sometimes
fatal, bleeding (5.1, 6.1).
• Do not use ticagrelor in patients with active pathological bleeding or a
history of intracranial hemorrhage (4.1, 4.2).
• Do not start ticagrelor in patients planned to undergo urgent coronary
artery bypass graft surgery (CABG). When possible, discontinue ticagrelor
at least 5 days prior to any surgery (5.1).
• Suspect bleeding in any patient who is hypotensive and has recently
undergone coronary angiography, percutaneous coronary intervention (PCI),
CABG, or other surgical procedures in the setting of ticagrelor (5.1).
• If possible, manage bleeding without discontinuing ticagrelor. Stopping
ticagrelor increases the risk of subsequent cardiovascular events. (5.5)
1.84 (1.68–2.02)
P<0.001
HR(95%CI) =
6.12 (3.41–11.01)
P<0.001
WARNING: ASPIRIN DOSE AND TICAGRELOR EFFECTIVENESS
Maintenance doses of aspirin above 100 mg reduce the effectiveness
of ticagrelor and should be avoided. After any initial dose, use with aspirin
75-100 mg per day (5.2, 14).
Wallentin L, et al. NEJM. 2009;361:1045-57.
http://www.pdr.net/drugpages/productlabeling.aspx?mpcode=04020155
Why did ticagrelor reduce mortality in
pts with ACS whereas prasugrel did not?
UA/NSTEMI Guidelines: Key Points on
Antiplatelets (Class I and III)
1. Increased fatal bleeding with prasugrel (but not
ticagrelor), negating its beneficial effects in
preventing MI and stent thrombosis
• ASA to all (clopidogrel if allergic)
• Medium - high risk and an invasive strategy get dual Rx
2. Off-target effects of ticagrelor (blocks rbc
adenosine re-uptake) not present with prasugrel
•
•
•
•
3. Different study designs and other factors,
including higher risk pts in PLATO than TRITON

Before PCI: clopidogrel, ticagrelor, GP IIb/IIIa

At PCI: clopidogrel, ticagrelor, prasugrel, GP IIb/IIIa
Conservative strategy: dual Rx w/ ASA + clopidogrel or ticagrelor
Use loading doses of ADP blockers
Duration for at least 12 months
Class III (harm or no benefit)

low risk and on ASA/ADP blocker no benefit to GP IIb/IIIa

history stroke/TIA, prasugrel potentially harmful
4. Play of chance
Jneid H et al. J Am Coll Cardiol. 2012;60:645-81.
STEMI Guidelines: Key Points on Antiplatelets
(Class I and III)
•
ASA for all and indefinitely
•
Primary PCI
•
•

Loading dose as early as possible or at PCI: clopidogrel, ticagrelor, prasugrel

ADP blockers for 1 year

Class III (harm or no benefit): prasugrel potentially harmful (if h/o stroke/TIA)
Optimizing Secondary
Prevention in the ACS Patient
Roger S. Blumenthal, MD
Kenneth Jay Pollin Professor of Cardiology
Director, The Johns Hopkins Ciccarone Center
For the Prevention of Heart Disease
Fibrinolysis

Clopidogrel 300 mg loading dose, < 75 years; 75 mg, > 75 years

Clopidogrel at least 14 days and up to 1 year
PCI after fibrinolytic therapy

Clopidogrel 300 mg if no prior loading dose + PCI within 24 hours of
fibrinolytic therapy; 600 mg if PCI > 24 hours afterwards

Duration of clopidogrel: BMS, 30 days to 1 year; DES, at least 1 year

Class III (harm or no benefit): prasugrel potentially harmful (if h/o stroke/TIA)
Disclosures: None
O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-140.
8
Definitions of Different Types of Prevention
Case Study
Primordial Prevention: Prevention of CHD risk
factors
• H.S is a 55 y/o Male with a PMH sig
for HTN, HL, DM and an elevated
BMI who presents to an ED with
chest pain.
Primary Prevention: Modification of risk factors in
order to prevent or delay the onset of ASCVD
Secondary Prevention: Initiation of Rx to reduce
recurrent CHD events & decrease cardiac mortality
in patients with established ASCVD
CHD=Coronary heart disease
Case Study
• Cath lab is activated
• Angiography: 90% proximal LAD stenosis
with 30-50% diameter stenoses in Cx and
RCA
• PCI is performed with 1 DES
• Started on Aspirin, a P2Y12 inhibitor, a
beta blocker, and an ACE inhibitor
Case Study
Case Study
Antiplatelet Rx
• H.S is discharged on Asprin 325 mg
• Following day: ECHO - EF of 40% with
anterior HK.
• Observed in the hospital for 2 days and
discharged
• Presents to your office for follow up
with many questions and concerns
• Is there a role for life-long Aspirin in a post
ACS patient?
• He is concerned that his dose is too “high” is he correct?
9
Dual Antiplatelet Rx
Aspirin Recommendations (Continued)
Secondary Prevention
I IIa IIb III
Aspirin (75-162 mg daily) if known CAD† or NSTEACS‡
• Also concerned that he is now on a
P2Y12 inhibitor.
• Is there a role in a post ACS patient?
• For how long?
I IIa IIb III
Aspirin (81-325 mg daily) following PCI or
fibrinolytic therapy for a STEMI*
I IIa IIb III
Aspirin (preferentially at 81 mg daily) following PCI
for NSTE-ACS# or STEMI* or lytic therapy for a
ASVD=Atherosclerotic vascular disease, CAD=Coronary artery disease, NSTEACS=Non-ST segment elevation acute coronary syndrome, PCI=Percutaneous
STEMI*
coronary intervention, STEMI=ST-segment elevation myocardial infarction
†\Smith
Sources:
SC Jr. et al. JACC 2011;58:2432-2446
RS et al. JACC 2011;57:e215-367
PT et al. JACC 2013;61:e78-e140
#Jneid H et al. JACC 2012;60:645-681
‡Wright
*O’Gara
P2Y12 Receptor Antagonist
Recommendations
JNC VII Guidelines:
Measurement of Blood Pressure
Secondary Prevention
I IIa IIb III
Method
Clopidogrel (75 mg daily), prasugrel (10 mg daily), or
ticagrelor (90 mg twice daily) in addition to aspirin for 1
year following PCI for a NSTE-ACS† or a STEMI‡
In-office
Brief Description
Two readings, 5 minutes apart, sitting in chair
Confirm elevated reading in contralateral arm
I IIa IIb III
Clopidogrel (75 mg daily) in addition to aspirin for a
minimum of 14 days (Class I, Level A) and up to 1 year
(Class I, Level C) following fibrinolytic therapy for a
STEMI‡
I IIa IIb III
Ambulatory BP monitoring
Indicated for evaluation of “white-coat” HTN.
Absence of 10–20% BP decrease during sleep
indicates increased CVD risk
Self-measurement
Provides information on response to Rx. May
help improve adherence to Rx and evaluate
“white-coat” HTN
NSTE-ACS=Non ST-segment elevation acute coronary
syndrome; PCI=Percutaneous coronary intervention,
STEMI=ST-segment elevation myocardial infarction
BP=Blood pressure, CVD=Cardiovascular disease, HTN=Hypertension, Rx=Treatment
Sources:
H et al. JACC 2012;60:645-681
PT et al. JACC 2013;61:e78-e140
†Jneid
Chobanian AV et al. JAMA 2003;289:2560-2572
Blood Pressure Lowering Therapy Evidence:
Effect of Intensive Blood Pressure Control
Blood Pressure Lowering Therapy Evidence:
Effect of Intensive Blood Pressure Control
Cardio-SIS Trial
Action to Control Cardiovascular Risk in Diabetes (ACCORD)
Blood Pressure Trial
1,111 patients >55 years with SBP >150 mm Hg randomized to
treatment to achieve usual BP control (SBP <140 mm Hg) or intensive
BP control (SBP <130 mm Hg)
4,733 diabetic patients randomized to intensive BP control (target SBP <120
mm Hg) or standard BP control (target SBP <140 mm Hg) for 4.7 years
P=0.013
11.4
7
0
Usual Control
Tight Control
10
9.4
4.8
5
0
Nonfatal MI, nonfatal
stroke, or CV death
14
P=0.003
15
17.0
Composite of CV
events* (%)
Incidence of LVH
(%)
21
Usual Control
HR=0.88
95% CI (0.73-1.06)
HR=0.59
95% CI (0.39-0.89)
Total stroke
‡O’Gara
Tight Control
More intensive blood pressure control provides greater benefit
Intensive BP control in DM does not reduce a composite of adverse CV
events, but does reduce the rate of stroke
*Composite of death, MI, CVA, TIA, CHF, angina, new AF,
revascularization, aortic dissection, PAD, and ESRD
AF=Atrial fibrillation, ESRD=End stage renal disease, CHF=Congestive heart failure,
CVA=Cerebrovascular accident, LVH=Left ventricular hypertrophy, MI=Myocardial infarction,
PAD=Peripheral artery disease, SBP=Systolic blood pressure, TIA=Transient ischemic attack
BP=Blood pressure, DM=Diabetes mellitus,
HR=Hazard ratio, SBP=Systolic blood pressure
Source: Verdecchia P et al. Lancet 2009;374:525-533
ACCORD study group. NEJM 2010;362:1575-1585
10
ACE Inhibitor Evidence:
Secondary Prevention
Modification
Recommendation
Approximate SBP
Reduction Range
Weight reduction
Maintain normal body weight (BMI=18.525)
5-20 mmHg/10 kg weight
lost
DASH eating plan
Diet rich in fruits, vegetables, low fat dairy
and reduced in fat
8-14 mmHg
Restrict sodium
intake
<2.4 grams of sodium per day
Physical activity
Regular aerobic exercise for at least 30
minutes most days of the week
Moderate alcohol
Probability of Event
JNC VII Guidelines:
Lifestyle Modifications for BP Control
2-8 mmHg
4-10 mmHg
AIRE
Clinical and/or
radiographic
signs of HF
TRACE
Echocardiogram
EF <35%
0.4
0.35
Placebo
0.3
ACE-I
0.25
0.2
0.15
0.1
OR 0.74 (0.66–0.83)
0.05
0
<2 drinks/day for men and <1 drink/day
for women
SAVE
Radionuclide
EF <40%
0
1
2
2-4 mmHg
4
3
Years
An ACE-I provides substantial benefit in post-MI LVSD
BMI=Body mass index, BP=Blood pressure, SBP=Systolic blood pressure
ACE-I=Angiotensin converting enzyme inhibitor, EF=Ejection fraction, LVSD=Left
ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
Source: Flather MD et al. Lancet 2000;355:1575–1581
Beta-blocker Evidence:
Benefit in HF and/or LVSD
ACE Inhibitor Recommendations
Secondary Prevention
I IIa IIb III
An ACE inhibitor should be started and continued
indefinitely in all patients with left ventricular ejection
fraction <40% and in those with hypertension, DM, or CKD,
unless contraindicated
I IIa IIb III
An ACE inhibitor in all other patients
Study
Drug
HF
Severity
Patients
(n)
Follow-up
Mean Dosage
Effects on
Outcomes
CIBIS
Bisoprolol*
ModerateSevere
641
1.9 Years
3.8
mg/day
All cause mortality
(p=NS)
CIBIS-II
Bisoprolol*
ModerateSevere
2,647
1.3 Years
7.5
mg/day
All cause mortality
34% (P<0.0001)
BEST
Bucindolol*
ModerateSevere
2,708
2.0 Years
152
mg/day
All cause mortality
(p=NS)
MERIT-HF
Metoprolol
succinate#
MildModerate
3,991
1.0 Years
159
mg/day
All cause mortality
34% (P=0.0062)
MDC
Metoprolol
tartrate*
MildModerate
383
1.0 Years
108
mg/day
Death or Need for TX
(P=NS)
CAPRICORN
Carvedilol
Mild
1,989
1.3 Years
40
mg/day
All cause mortality
23% (P =0.03)
US Carvedilol
Carvedilol
MildModerate
1,094
0.5 Years
45
mg/day
All-cause mortality†
65% (P=.0001)
COPERNICUS
Carvedilol
Severe
2,289
0.9 Years
37
mg/day
All-cause mortality
35% (P =0.0014)
SENIORS
Nebivolol
Moderate
2,128
3.0 Years
7.7
mg/day
All-cause mortality or
CV hospitalization
14% (P =0.039)
ACE=Angiotensin converting enzyme, CKD=Chronic kidney disease,
DM=Diabetes mellitus, LVSD=Left ventricular systolic dysfunction
#Not
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Beta-Blocker Recommendations
Beta-Blocker Recommendations (Continued)
Secondary Prevention
I IIa IIb III
I IIa IIb III
I IIa IIb III
*Not an approved indication,
†Not a planned end point
approved for severe HF/mortality reduction alone
HF=Heart failure, LVSD=Left ventricular systolic dysfunction, NS=Not significant, TX=Transplant
I IIa IIb III
Beta-blocker should be used in all patients with LVSD
(ejection fraction <40%) with HF or prior MI, unless
contraindicated*. (Use carvedilol, metoprolol succinate, or
bisoprolol, which have been shown to reduce mortality.)
Secondary Prevention
Beta-blocker in patients with LVSD (ejection fraction <40%)
without HF or prior MI
I IIa IIb III
Beta-blocker as chronic therapy for all other patients with
coronary or other vascular disease
Beta-blocker for 3 yrs in all patients with normal left
ventricular function who have had a MI or ACS
Beta-blocker beyond 3 yrs as chronic therapy in all patients
with normal left ventricular function who have had a MI or
ACS
*Relative contraindications include asthma, chronic obstructive
pulmonary disease, insulin dependent diabetes mellitus, severe
peripheral arterial disease, and a PR interval >0.24 seconds
ACS=Acute coronary syndrome, HF=Heart failure, LVSD=Left
ventricular systolic dysfunction, MI=Myocardial infarction
HF=Heart failure, LVSD=Left ventricular systolic
dysfunction, MI=Myocardial infarction
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
11
Therapies to Lower Levels of LDL-C
Statin Rx
• H.S. has a fasting lipid panel with a
total cholesterol of 240, HDL: 40,
TG:150, LDL: 170. He was
discharged on Atorvastatin 80 mg.
• Should this be continued?
Class
Drug(s)
3-Hydroxy-3-Methylglutaryl Coenzyme A
(HMG-CoA) reductase inhibitors [Statins]
Atorvastatin (Lipitor)
Fluvastatin (Lescol XL)
Lovastatin (generic and Mevacor)
Pitavastatin (Livalo)
Pravastatin (Pravachol)
Rosuvastatin (Crestor)
Simvastatin (Zocor)
Bile acid sequestrants
Cholestyramine (generic and Questran)
Colesevelam (Welchol)
Colestipol (Colestid)
Cholesterol absorption inhibitor
Ezetimibe (Zetia)
Nicotinic acid
Niacin
Dietary Adjuncts
HMG-CoA Reductase Inhibitor:
Chronological Order of Event Driven Trials
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Study populations:
Pravastatin or Atorvastatin Evaluation and Infection Therapy
(PROVE-IT)—TIMI 22 Study
Primary prevention
4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin
(40 mg) for 24 months
Acute coronary syndromes (Secondary prevention)
1994
4S
2002
PROSPER
1995
WOSCOPS
2002
ALLHAT -LLA
1996
CARE
2002
ASCOT-LLA
1998
AFCAPS/TEXCAPS
2004
PROVE- IT
1998
LIPID
2004
A to Z
2001
MIRACL
2005
TNT
HPS
2005
IDEAL
2008
JUPITER
2010
SEARCH
Recurrent MI, cardiac death,
UA, revascularization, or stroke
Chronic coronary heart disease (Secondary prevention)
2002
Soluble fiber
Soy protein
Stanol esters
30
16% RRR
Pravastatin
25
Atorvastatin
20
15
10
5
0
P=0.005
3
6
9
12
15
18
21
24
27
30
Follow-up (months)
Acute intensive statin therapy provides significant CV benefit
ACS=Acute coronary syndrome, CV=Cardiovascular,
MI=Myocardial infarction, RRR=Relative risk reduction, UA=Unstable angina
Source: Cannon CP et al. NEJM 2004;350:1495-1504
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Scandinavian Simvastatin Survival Study (4S)
Long-term Intervention with Pravastatin in Ischemic Disease
(LIPID) Study
4,444 patients with angina pectoris or previous MI randomized to
simvastatin (20-40 mg) or placebo for 5.4 yrs
9,014 patients with a history of MI or hospitalization for unstable angina
randomized to pravastatin (40 mg) or placebo for 6 yrs
30% RRR
24% RRR
11.5
8.2
9
8
CHD Death (%)
Mortality (%)
12
4
0
P<0.001
Placebo
Simvastatin
6.4
3
0
A statin provides significant benefit in those with average LDL-C levels
8.3
6
P<0.001
Placebo
Pravastatin
A statin provides significant benefit across a broad range of cholesterol levels
LDL-C=Low density lipoprotein cholesterol,
MI=Myocardial infarction, RRR=Relative risk reduction
CHD=Coronary heart disease, MI=Myocardial
infarction, RRR=Relative risk reduction
Source: 4S Group. Lancet 1994;344:1383–1389
Source: LIPID Study Group. NEJM 1998;339:1349–1357
12
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Heart Protection Study (HPS)
Treating to New Targets (TNT) Trial
10,001 patients with stable CHD randomized to atorvastatin (80 mg) or
atorvastatin (10 mg) for 5 yrs
Event Rate Ratio (95% CI)
Statin
(n = 10,269)
Placebo
(n = 10,267)
<100
282 (16.4%)
358 (21.0%)
100–129
668 (18.9%)
871 (24.7%)
130
1083 (21.6%)
1356 (26.9%)
All patients
2033 (19.8%)
2585 (25.2%)
Statin Better
Statin Worse
0.15
Major CV Event* (%)
Baseline
LDL-C (mg/dL)
0.76 (0.72–0.81)
P<0.0001
0.4
0.6
0.8
1.0
1.2
22% RRR
Atorvastatin (10 mg)
0.10
Atorvastatin (80 mg)
0.05
P<0.001
0.00
1.4
0
A statin provides significant CV benefit regardless of baseline LDL-C level
1
2
3
Years
4
5
6
High-dose statin therapy provides benefit in chronic CHD
*Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke
CAD=Coronary artery disease, CI=Confidence interval,
CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol
CHD=Coronary heart disease, CV=Cardiovascular,
MI=Myocardial infarction, RRR=Relative risk reduction
Source: HPS Collaborative Group. Lancet 2002;360:7-22
Source: LaRosa JC et al. NEJM 2005;352:1425-35
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
HMG-CoA Reductase Inhibitor Evidence:
Effect of Intensive Therapy
Relationship between LDL-C levels and event rates in secondary prevention
statin trials of patients with stable CHD
30
Event (%)
Duration
(years)
LDL-C Reduction
(mg/dL)
RR in Primary
End Point (%)
RR in MI or
CHD Death (%)
PROVE ITTIMI 22
ACS
(N = 4162)
2
33
16
16
A to Z
ACS
(N = 4497)
2
14
11
15
TNT
Stable CAD
(N =10,001)
5
24
22
21
IDEAL
Stable CAD
(N = 8888)
5
23
11
11
4S
20
LIPID
CARE
HPS
HPS
TNT (atorvastatin 10 mg/d)
TNT (atorvastatin 80 mg/d)
LIPID
15
CARE
10
5
0
Population
4S
Statin
Placebo
25
Magnitude of event reduction among trials of intensive statin therapy
Trial
0
70
90
110
130
150
LDL-C (mg/dL)
170
190
210
Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259
CARE=Cholesterol and Recurrent Events Trial, CHD=Coronary heart
disease, HPS=Heart Protection Study, LDL-C=Low density lipoprotein
cholesterol, LIPID=Long-term Intervention with Pravastatin in Ischaemic
Disease, 4S=Simvastatin Survival Study, TNT=Treating to New Targets
ACS=Acute coronary syndrome, CAD=Coronary artery disease,
CHD=Coronary heart disease, LDL-C=Low density lipoprotein
cholesterol, MI=Myocardial infarction, RR=Relative reduction
Source: LaRosa JC et al. NEJM 2005;352:1425-1435
Source: Cannon CP et al. JAMA 2005;294:2492-2494
Nicotinic Acid Evidence:
Secondary Prevention
Cholesterol Management
Recommendations (Continued)
Atherothrombosis Intervention in Metabolic Syndrome with
Low HDL/High Triglycerides: Impact of Global Health
Outcomes (AIM-HIGH) Trial
Secondary Prevention
I IIa IIb III
Primary outcome (%)**
3414 patients with established CV disease randomized to niacin (up to 2000
mg/day) or placebo on a background of statin therapy for a mean of 3 years*
16.4%
20
Combination Therapy
Monotherapy
I IIa IIb III
16.2%
10
HR 1.02, p=0.79
0
0
1
2
3
4
I IIa IIb III
Time (years)
Niacin provides no benefit to those with CV disease and low HDL-C levels
*The study was stopped prematurely
**Composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for
ACS, or symptom-driven coronary/cerebral revascularization
Patients who have triglycerides >500 mg/dL should be
started on fibrate therapy in addition to statin therapy to
prevent acute pancreatitis
If treatment with a statin (including trials of higher-dose
statins and higher-potency statins) does not achieve the
goal selected for a patient, intensification of LDL-C–
lowering drug therapy with a bile acid sequestrant or
niacin is reasonable
For patients who do not tolerate statins, LDL-C–lowering
therapy with bile acid sequestrants and/or niacin is
reasonable
CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Source: AIM-HIGH Investigators. NEJM 2011;365:2255-2267
13
Cholesterol Management
Recommendations (Continued)
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III
Secondary Prevention
It is reasonable to treat very high-risk* patients with statin
therapy to lower LDL-C to <70 mg/dL
I IIa IIb III
I IIa IIb III
I IIa IIb III
In patients who are at very high risk* and who have
triglycerides >200 mg/dL, a non–HDL-C goal of <100
mg/dL is reasonable
For patients who continue to have an elevated non-HDL-C
while on adequate statin therapy, consider niacin or fibrate
therapy
For all patients, it may be reasonable to recommend
omega-3 fatty acids from fish or fish oil capsules
(1 gram/day) for CV disease risk reduction
The use of ezetimibe may be considered for patients who
do not tolerate or achieve target LDL-C with statins, bile
acid sequestrants, and/or niacin
*Presence of established CVD plus 1) multiple major risk
factors (especially diabetes), 2) severe and poorly controlled
risk factors (especially continued cigarette smoking), 3)
multiple risk factors of the metabolic syndrome (especially
high triglycerides >200 mg/dL plus non-HDL-C >130 mg/dL
with low HDL-C <40 mg/dL, and 4) patients with an ACS
ACS=Acute coronary syndrome, CVD=Cardiovascular
disease, HDL-C=High density lipoprotein cholesterol,
LDL-C=Low density lipoprotein cholesterol
CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Cigarette Smoking Cessation:
Pharmacotherapy*
Tobacco Cessation Recommendations
Agent
Caution
Side Effects
Dosage
Duration
Instructions
Bupropion SR
(Zyban®)**
Seizure disorder
Eating disorder
Taking MAO
inhibitor
Pregnancy
Insomnia
Dry mouth
150 mg QAM
then
150 mg BID
3 days
Start 1-2 weeks
before quit date.
Take 2nd dose in
early afternoon or
decrease to 150 mg
QAM for insomnia.
Transdermal
Nicotine
Patch***
Varenicline
(Chantix®)**
Depression/
Suicide
Within 2 weeks
of a MI
Unstable angina
Arrhythmias
Heart failure
Skin reaction
Insomnia
Pregnancy
Nausea
Sleep
disorder
Depression/
Suicide
CV risk
8 weeks, but up
to 6 months
21 mg QAM
14 mg QAM
7 mg QAM
or
15 mg QAM
4 weeks
2 weeks
2 weeks
0.5 mg QD
then
0.5 mg BID
then
1 mg BID
3 days
8 weeks
Secondary Prevention
Goals:
Complete tobacco cessation and no environmental tobacco
smoke exposure
I IIa IIb III
Patients should be asked about tobacco use status at every
office visit
Apply to different
hairless site daily.
Remove before bed
for insomnia.
Start at <15 mg for
<10 cigs/day
I IIa IIb III
Every tobacco user should be advised at every visit to quit
Start 1 week before
the quit date
I IIa IIb III
4 days
The tobacco user’s willingness to quit should be assessed at
every visit.
12 weeks
*Pharmacotherapy combined with behavioral support provides the best success rate
**The FDA has placed a black box warning on varenicline and buproprion SR
due to the risk of depression and/or suicidal thoughts
***Other nicotine replacement therapy options include: nicotine gum,
lozenge, inhaler, nasal spray
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Weight Management
Recommendations
Tobacco Cessation Recommendations (Continued)
Secondary Prevention
I IIa IIb III
Secondary Prevention
Patients should be assisted by counseling and by
development of a plan for quitting that may include
pharmacotherapy and/or referral to a smoking cessation
program
Goals:
I IIa IIb III
I IIa IIb III
Arrangement for follow up is recommended.
I IIa IIb III
All patients should be advised at every office visit to avoid
exposure to environmental tobacco smoke at
work, home, and public places
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
BMI 18.5-24.9 kg/m2, Waist circumference for women: <35
inches, men: <40 inches*
BMI and/or waist circumference should be assessed at
every visit, and the clinician should consistently encourage
weight maintenance/reduction through an appropriate
balance of lifestyle physical activity, structured exercise,
caloric intake, and formal behavioral programs when
indicated to maintain/achieve a body mass index between
18.5 and 24.9 kg/m2
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
14
American Heart Association Nutrition
Committee Dietary Recommendations
Weight Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III
If waist circumference (measured horizontally at the iliac
crest) is >35 inches (>89 cm) in women and >40 inches
(>102 cm) in men, therapeutic lifestyle interventions should
be intensified and focused on weight management
I IIa IIb III
The initial goal of weight loss therapy should be to reduce
body weight by approximately 5% to 10% from baseline.
With success, further weight loss can be attempted if
indicated.
Recommendations for CVD Risk Reduction
• Balance calorie intake & physical activity to achieve healthy weight
• Diet rich in fruits and vegetables, whole-grain, high-fiber foods
• Consume fish > 2 x/ week
• Limit intake of saturated fat to <7% of energy, and cholesterol <300
mg/day by:
– Choosing lean mean & vegetable alternatives
– Fat free (skim) or low-fat dairy products,
– Minimizing partially hydrogenated fats
• Minimize beverages and foods with added sugar
• Choose and prepare foods with little or no salt
• If alcohol is consumed, do so in moderation
AHA=American Heart Association
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Source: AHA Nutrition Committee. Circulation 2006;114:82-96
Physical Activity
Recommendations
Physical Activity
Recommendations (Continued)
Secondary Prevention
Goal:
I IIa IIb III
Secondary Prevention
I IIa IIb III
> 30 minutes, 7 days per week) of physical activity
For all patients, the clinician should encourage 30 to 60
minutes of moderate-intensity aerobic activity, such as brisk
walking, > 5 days per week, supplemented by an increase in
daily lifestyle activities (e.g., walking breaks at work,
gardening, household work) to improve cardiorespiratory
fitness and move patients out of the least fit, least active
high-risk cohort
Risk assessment with a physical activity history and/or an
exercise test is recommended to guide prognosis and
prescription
I IIa IIb III
Clinician should counsel patients to report and be evaluated
for symptoms related to exercise.
I IIa IIb III
Reasonable to recommend complementary resistance
training > 2 days per week
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Cardiac Rehabilitation
Recommendations
Physical Activity
Recommendations
Secondary Prevention
I IIa IIb III
Secondary Prevention
All eligible patients with ACS or whose status is
immediately post coronary artery bypass surgery or postPCI should be referred to a comprehensive outpatient
cardiovascular rehabilitation program either prior to hospital
discharge or during the first follow-up office visit
Goal:
I IIa IIb III
I IIa IIb III
I IIa IIb III
All eligible outpatients with the diagnosis of ACS, coronary
artery bypass surgery or PCI (Level of Evidence: A),
chronic angina (Level of Evidence: B), and/or peripheral
artery disease (Level of Evidence: A) within past year
should be referred to a comprehensive outpatient
cardiovascular rehabilitation program.
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
At least 30 minutes, 7 days per week (minimum 5 days per
week) of physical activity
For all patients, the clinician should encourage 30 to 60
minutes of moderate-intensity aerobic activity, such as brisk
walking, at least 5 days and preferably 7 days per week,
supplemented by an increase in daily lifestyle activities (e.g.,
walking breaks at work, gardening, household work) to
improve cardiorespiratory fitness and move patients out of
the least fit, least active high-risk cohort
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
15
Physical Activity
Recommendations (Continued)
Cardiac Rehabilitation
Recommendations (Continued)
Secondary Prevention
I IIa IIb III
Secondary Prevention
I IIa IIb III
For all patients, risk assessment with a physical activity
history and/or an exercise test is recommended to guide
prognosis and prescription
I IIa IIb III
I IIa IIb III
The clinician should counsel patients to report and be
evaluated for symptoms related to exercise.
Home-based cardiac rehabilitation program can be
substituted for a supervised, center-based program for lowrisk patients
Comprehensive exercise-based outpatient cardiac
rehabilitation program can be safe and beneficial for
clinically stable outpatients with a history of Heart Failure
I IIa IIb III
It is reasonable for the clinician to recommend
complementary resistance training at least 2 days per week
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Mr. Smith is a 62-year-old man that presents to a local
emergency department with 3 hours of intermittent chest pain
PMH: hypertension and diabetes
Case Study
Home Meds: Aspirin 81mg daily, HCTZ 25mg daily, lisinopril
20mg daily, and Metformin 1000mg bid
ECG: Sinus tachycardia at 86 bpm; ST segment depression
Percutaneous Revascularization in UA/NSTEMI
• He is taken urgently to the cardiac catheterization
lab where he is found to have a 90% stenosis of
the left anterior descending coronary artery and
is treated with a drug-eluting stent
PCI-CURE Study
2,658 patients with a NSTE-ACS undergoing PCI treated with aspirin and
clopidogrel (300 mg load, 75 mg thereafter) for 4 weeks and then randomized
to continued use of clopidogrel vs. placebo for 8 months
• He is treated with aspirin, P2Y12 inhibitor,
bivalirudin, lisinopril, and metoprolol.
12.6%
• The following day he is feeling well and has an
ejection fraction of 55% on an echocardiogram
Placebo + ASA
0.10
Death or MI
8.8%
• He is discharged home 5 days later
• You see Mr. Smith 1 week after discharge for
follow-up.
Clopidogrel + ASA
0.05
0.00
31% RRR, p=0.002
0
100
200
Days of follow-up
Mehta SR, et al. Lancet. 2001;358:527-533.
16
300
400
Antiplatelet Therapy to Support PCI
for UA/NSTEMI
I IIa IIb III
Medical Management in UA/NSTEMI
CURE Trial
12,562 patients with a NSTE-ACS randomized to daily
aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg
thereafter) plus aspirin (75-325 mg) for 9 months
In UA/NSTEMI patients undergoing PCI, P2Y12
inhibitor therapy should be given for at least 12
months in patients receiving DES and up to 12
months for patients receiving BMS
I IIa IIb III
If the risk of morbidity because of bleeding outweighs
the anticipated benefits afforded by P2Y12 receptor
inhibitor therapy, earlier discontinuation should be
considered
P < 0.0001
N = 12,562
0
The CURE Investigators. New Engl J Med.
2001;345:494-502.
CV death, MI or stroke (%)
3
6
9
12
Months of Follow-Up
Antiplatelet Therapy to Support
Medical Therapy for UA/NSTEMI
PLATO non invasive: primary outcome
Number at risk
Invasive
Ticagrelor
Clopidogrel
Non-invasive
Ticagrelor
Clopidogrel
Relative
Risk
Reduction
Clopidogrel + ASA
Jneid H, et al. Circulation. 2012;126:875-910.
Non-invasive
HR, 0.85, 95% CI: (0.73–1.0)
20%
Placebo + ASA
14.3%
I IIa IIb III
12.0%
10.7%
9.0%
For UA/NSTEMI treated medically without
stenting, clopidogrel or ticagrelor should be
prescribed for up to 12 months
Invasive
HR, 0.84, 95% CI: (0.75–0.94)
Days after randomization
6732
6676
6236
6129
6134
6034
5972
5881
4889
4815
3735
3680
3048
2965
2601
2615
2392
2392
2326
2328
2247
2243
1854
1835
1426
1416
1099
1109
Jneid H, et al. Circulation. 2012;126:875-910.
James S, et al. BMJ. 2011;342:d3527.
What is the optimal aspirin dose
following ACS? OASIS-7
You are familiar with data supporting the use
of aspirin following an acute MI
Category
Acute MI
Acute CVA
Prior MI
Prior CVA/TIA
Other high risk
CVD
(e.g. unstable angina, heart failure)
PAD
(e.g. intermittent claudication)
High risk of embolism (e.g. Afib)
Other (e.g. DM)
All trials
0.0
% Odds Reduction
N=25,086; 30 day follow-up; Aspirin 325mg vs 81mg (day 2-30)
325mg
0.5
1.0
Antiplatelet better
1.5
81mg
MACE
4.2
4.4
0.61
CV death
2.1
2.3
0.22
Major Bleeding
2.3
2.3
0.9
Minor Bleeding
5.0
4.4
0.04
2.0
Control better
The CURRENT-OASIS 7 Investigators. New Engl J Med. 2010;363:930-42.
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-96.
17
P value
Antiplatelet Therapy to Support
Primary PCI for STEMI
Indirect comparisons of aspirin doses on
vascular events in high-risk patients
Aspirin Dose
No. of Trials
(%)
500-1500 mg
34
19
160-325 mg
19
26
75-150 mg
12
32
<75 mg
3
13
Any aspirin
65
23
0
I IIa IIb III
Odds Ratio for
Vascular Events
It is reasonable to use 81 mg of aspirin per day in
preference to higher maintenance doses after PCI
P<.0001
0.5
Antiplatelet Better
1.0
1.5
2.0
Antiplatelet Worse
Antithrombotic Trialist Collaboration. BMJ. 2002;324:71-86.
Jneid H, et al. Circulation. 2012;126:875-910.
Heart Protection Study (HPS)
Lipid Lowering Intensity: PROVE IT-TIMI 22
• 20,536 patients with CHD
• Simvastatin (40 mg qd) vs placebo
• ↓ Total mortality by simvastatin
4,162 patients with ACS; Atorvastatin 80 mg qd vs Pravastatin 40mg
The median LDL cholesterol level achieved during treatment was 95 mg/dl in the pravastatin group and 62 mg/dl in the atorvastatin group (P<0.001)
― ↓ Total CHD, total stroke, revascularization
― ↑ Benefit over time, irrespective of initial cholesterol level
and
in broad spectrum of patients (e.g., women, elderly
& patients
with diabetes)
• Recommend: Statin in all patients at discharge regardless of
baseline LDL-C (Class I, LOE: A)
Heart Protection Collaborative Group. Lancet. 2002;360:7–22.
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157.
Cannon CP, et al. New Engl J Med. 2004;350:1495-1504.
Lipid Management
I IIa IIb III
Influenza
I IIa IIb III
Hydroxymethyl glutaryl-coenzyme A reductase
inhibitors (statins), in the absence of
contraindications, regardless of baseline LDL-C
and diet modification, should be given to postUA/
NSTEMI patients, including postrevascularization patients.
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157.
An annual influenza vaccination is
recommended for patients with cardiovascular
disease.
Smith SC Jr., et al. Circulation. 2011;124:2458-73.
18
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