Download I IIa IIb III IIa IIb III - Preventive Cardiovascular Nurses Association

Secondary Prevention and Risk
Reduction for Patients with CHD
Lynne T. Braun, PhD, CNP, FAHA, FPCNA, FAAN
Professor, Rush University College of Nursing
ANP, Rush Heart and Vascular Institute
Chicago, IL
[email protected]
Disclosures
• Salary support, NIH
• Advisory Board, UpToDate
ARS Question #1
Which of the following lifestyle modifications
is associated with the greatest effect on
blood pressure?
1.
2.
3.
4.
Sodium restricted diet
Weight reduction
Regular physical activity
Alcohol restriction
28%
38%
34%
0%
ARS Question #2
Which of the following is true about the
evidence to support referring patients with
ACS, post CABG, and post PCI to cardiac
rehabilitation?
1. Evidence is from a single, randomized trial (I, B)
2. Evidence is from expert opinion (I,C)
3. Some conflicting evidence from multiple
randomized trials or meta-analyses (IIa, A)
4. Sufficient evidence from multiple randomized
trials and meta-analyses (I, A)
1%
2%
14%
84%
Epidemiology:
Coronary Heart Disease
• 15.4 million Americans have
CHD
– Prevalence is estimated to be ≈
18% by 2030
• Estimated direct and indirect
cost of CHD in 2009 $195.2
billion
• CHD is the leading cause of
death in the US
Go AS, et al. Circulation 2013;127:e6-e245.
Smith S et al. Circulation. 2011;124:2458-2473
Secondary Prevention
Areas of Intervention
•
•
•
•
•
•
•
•
•
•
•
•
Smoking
Blood pressure control
Lipid management
Physical activity
Weight management
Type 2 diabetes mellitus management
Antiplatelet agents / anticoagulants
RAAS blockers
β-blockers
Influenza vaccination
Depression
Cardiac rehabilitation
Classification of Recommendations and Levels of Evidence
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Smoking Cessation Algorithm
Ask and document pt’s
tobacco use status
Current User
Recent Quitter
(<6 months)
Advise: Provide a strong, personalized
message to quit using tobacco
Assess readiness to quit in next 30 days
Prevent Relapse
• Congratulate successes
• Encourage to remain tobacco-free
• Discuss benefits experienced by patient
• Address weight gain, negative mood, and lack of support
Not Ready
Ready
Assist
• Negotiate a plan
• STAR**
• Discuss pharmacotherapy
• Social support
• Provide educational materials
Arrange follow-up to check plan or adjust meds
• Call right before and after quit date
• Weekly follow-up x 2 weeks, then monthly x 6 months
• Ask about difficulties (withdrawal, depressed mood)
• Build upon successes
• Seek commitment to stay tobacco-free
Increase Motivation
• Relevance to patients personal situation
• Risks: short and long term, environmental
• Rewards: potential benefits of quitting
• Roadblocks: identify barriers and potential
solutions
• Repetition: repeat motivational intervention
• Reassess readiness to quit
**STAR
Set quit date
Tell family, friends, and coworkers about it
Anticipate challenges: withdrawal, breaks
Remove tobacco from the house, car, and
social life
Treating Tobacco Use and Dependence: 2008
Update, U.S. Department of Health and
Human Services, May 2008
Cigarette Smoking
Recommendations
Goal: Complete Cessation and No
Exposure to Environmental Tobacco
Smoke
•Ask about tobacco use status at every visit.
I IIa IIb III
•Advise every tobacco user to quit.
•Assess the tobacco user’s willingness to quit.
•Assist by counseling and developing a plan for quitting.
I IIa IIb III
•Arrange follow-up, referral to special programs, or
pharmacotherapy (including nicotine replacement and
bupropion.
I IIa IIb III
•Urge avoidance of exposure to environmental tobacco
smoke at work and home.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Blood Pressure Control
Recommendations
Goal: <140/90 mm Hg or <130/80 if diabetes or
chronic kidney disease
Blood pressure 120/80 mm Hg or greater:
I IIa IIb III
· Initiate or maintain lifestyle modification: weight control,
increased physical activity, alcohol moderation, Na + reduction,
and increased consumption of fresh fruits vegetables and low
fat dairy products
I IIa IIb III
Blood pressure 140/90 mm Hg or greater (or 130/80 or
greater for chronic kidney disease or diabetes)
As tolerated, add blood pressure medication, treating initially
with beta blockers and/or ACE inhibitors with addition of other
drugs as needed to achieve goal blood pressure
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
2012 SIHD Guidelines:
Blood Pressure Management
I IIa IIb III
All patients should be counseled about the need for lifestyle
modification: weight control; increased physical activity;
alcohol moderation; sodium reduction; and emphasis on
increased consumption of fresh fruits, vegetables, and low-fat
dairy products.
I IIa IIb III
In patients with SIHD with BP 140/90 mm Hg or higher,
antihypertensive drug therapy should be instituted in addition
to or after a trial of lifestyle modifications.
I IIa IIb III
The specific medications used for treatment of high BP should
be based on specific patient characteristics and may include
ACE inhibitors and/or beta blockers, with addition of other
drugs, such as thiazide diuretics or calcium channel blockers,
if needed to achieve a goal BP of less than 140/90 mm Hg.
(ADA 2013 recommendation 140/80 mm Hg--instead of
130 mm Hg--for individuals with diabetes)
Fihn SD et al. J Am Coll Cardiol. 2012;60:e44-e164; 2013 ADA Clinical Practice Recommendations. Diabetes Care 2013;36:S1-110.
JNC 7 Lifestyle Modifications
for BP Control
Modification
Recommendation
Approximate SBP
Reduction Range
Maintain normal body weight
(BMI=18.5-24.9)
5-20 mmHg/10 kg
weight lost
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
2-8 mmHg
Physical activity
Regular aerobic exercise for at least 30
minutes on most days of the week
4-9 mmHg
<2 drinks/day for men and <1
drink/day for women
2-4 mmHg
Weight reduction
Adopt DASH eating
plan
Moderate alcohol
consumption
Chobanian AV, et al. JAMA 2003;289:2560-2572.
Lipid Management
Recommendations
Goal: Treatment with statin therapy
LDL-C < 100 mg/dL
LDL-C < 70 mg/dL for very high risk patients
If TG ≥ 200 mg/dL, non-HDL-C < 130 mg/dL or
< 100 mg/dl for very high risk patients
Very High Risk Patient = Presence of established cardiovascular disease plus:
1. multiple major risk factors (especially diabetes)
2. severe and poorly controlled risk factors (especially continued
smoking)
3. multiple risk factors of the metabolic syndrome (especially high TG ≥ 200 mg/dL
plus non-HDL-C ≥130 mg/dL with low HDL-C < 40 mg/dL), and
4. patients with ACS
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Lipid Management Recommendations
Class I Recommendations
I IIa IIb III
•
Lipid profile established and hospitalized patients should
be started on therapy before discharge.
•
Lifestyle modifications in all patients.
•
Dietary therapy to include intake of < 7% saturated fats, <
1% trans fatty acids, and < 200 mg/day of cholesterol.
•
Treatment with statin therapy
•
Adequate dose of statin to achieve an LDL-C < 100 mg/dL
AND at least a 30% lowering of LDL-C.
•
If TG ≥ 200 mg/dL, treat with statins to achieve a non-HDLC* to < 130 mg/dL.
•
If TG > 500 mg/dL, start fibrate therapy in addition to statin
therapy to prevent acute pancreatitis.
I IIa IIb III
I IIa IIb III
*Non-HDL-C = total cholesterol minus HDL-C
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Lipid Management Recommendations
Class IIa Recommendations
I IIa IIb III
•
If treatment with a statin does not achieve the goal, addition
of a bile acid sequestrant or niacin is reasonable.
•
If patients do not tolerate statins, therapy with a bile acid
sequestrant and/or niacin is reasonable.
•
If TG ≥ 200 mg/dL, lowering the non-HDL-C to < 100 mg/dL
in very high-risk patients is reasonable.
•
Lowering LDL-C to < 70 mg/dL in very high-risk patients is
reasonable.
I IIa IIb III
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Lipid Management Recommendations
Class IIb Recommendations
I IIa IIb III
•
Consider ezetimbe in patients who do not achieve goal or
tolerate statins, bile acid sequestrants, and/or niacin.
•
Consider niacin, fibrate, or fish oil in patients with elevated
non-HDL-C while on statin therapy.
•
Consider omega-3 fatty acids from fish or fish oil capsules
(1 g/d) for CVD risk reduction.
I IIa IIb III
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Relationship between LDL-C Levels and Event Rates in Secondary
Prevention Statin Trials of Patients with Stable CHD
30
Statin
Placebo
Event (%)
25
4S
4S
20
LIPID
CARE
HPS
LIPID
CARE
HPS
TNT (atorvastatin 10 mg/d)
TNT (atorvastatin 80 mg/d)
15
10
5
0
0
70
90
110
130
150
170
190
210
LDL-C (mg/dL)
LaRosa JC, et al. N Engl J Med 2005;352:1425-1435.
Physical Activity
Recommendations
Goal: 30 minutes 7 days/week,
minimum 5 days/week
I IIa IIb III
Assess risk with a physical activity history and/or an
exercise test, to guide prescription
I IIa IIb III
I IIa IIb III
Encourage 30 to 60 minutes of moderate intensity aerobic
activity such as brisk walking, on most, preferably all, days
of the week, supplemented by an increase in daily lifestyle
activities.
Evaluate and counsel patients to report symptoms related
to exercise.
I IIa IIb III
Recommend complementary resistance training at least 2
days per week.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Exercise Evidence: Mortality Risk
Observational study of self-reported physical activity in 772 men with
established coronary heart disease
Light or moderate exercise is associated with lower risk
Wannamethee SG, et al. Circulation 2000;102:1358-1363
Weight Management
Recommendations
Goal: BMI 18.5 to 24.9 kg/m2
Waist Circumference: Men: < 40 inches
Women: < 35 inches
I IIa IIb III
Assess BMI and/or waist circumference on each visit and consistently
encourage weight maintenance/ reduction through an appropriate
balance of physical activity, caloric intake, and formal behavioral
programs when indicated.
I IIa IIb III
If waist circumference (measured at the iliac crest) >35 inches in
women and >40 inches in men, intensify therapeutic lifestyle
interventions and focus 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.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Cardiovascular Risk Increases
with Body Mass Index
Hazard Ratio
Hemorrhagic
Stroke
Ischemic
Stroke
Ischemic Heart
Disease
4.0
4.0
4.0
2.0
2.0
2.0
1.0
1.0
1.0
0.5
0.5
0.5
16 20 24 28 32 36
16 20 24 28 32 36
16 20 24 28 32 36
Body Mass Index (kg/m2)*
Mhurchu N, et al. Int J Epidemiol 2004;33:751-758.
Diabetes Mellitus
Recommendations
Class I Recommendations
I IIa IIb III
I IIa IIb III
Coordinate care for diabetes with patient’s
primary care provider or endocrinologist.
Lifestyle modification including daily physical
activity, weight management, blood pressure
control, and lipid management are
recommended for all patients with diabetes.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Diabetes Mellitus
Recommendations
Class IIa Recommendations
I IIa IIb III
Metformin is an effective first-line
pharmacotherapy and can be useful if not
contraindicated.
I IIa IIb III
It is reasonable to individualize the intensity of
blood sugar-lowering interventions based on the
individual patient’s risk of hypoglycemia during
treatment.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
2012 SIHD Guidelines:
Diabetes Management
I IIa IIb III
For selected individual patients, such as those
with a short duration of diabetes mellitus and a
long life expectancy, a goal HbA1c of 7% or less
is reasonable.
I IIa IIb III
A goal HbA1c between 7% and 9% is reasonable
for certain patients according to age, history of
hypoglycemia, presence of microvascular or
macrovascular complications, or presence of
coexisting medical conditions.
Fihn SD et al. J Am Coll Cardiol. 2012;60:e44-e164.
2012 SIHD Guidelines:
Diabetes Management
I IIa IIb III
I IIa IIb III
Initiation of pharmacotherapy interventions to
achieve target HbA1c might be reasonable.
Therapy with rosiglitazone should not be initiated
in patients with SIHD.
Harm
Fihn SD et al. J Am Coll Cardiol. 2012;60:e44-e164.
Aspirin Recommendations
I IIa IIb III
I IIa IIb III
I IIa IIb III
Start and continue indefinitely aspirin 75 to 162
mg/d in all patients unless contraindicated
For patients undergoing CABG, aspirin (100 to
325 mg/d) should be started within 6 hours after
surgery to reduce saphenous vein graft closure
In post-PCI-stented patients, it is reasonable to
use 81 mg of aspirin per day in preference to
higher maintenance doses.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Antiplatelet Trialists’
Collaboration: Meta-analysis
Aspirin Dose
# Trials
OR* (%)
500-1500 mg
34
19
160-325 mg
19
26
75-150 mg
12
32
<75 mg
3
13
Any aspirin
65
23
0
Odds Ratio
0.5
Antiplatelet Better
1.0
1.5
2.0
Antiplatelet Worse
*Odds reduction.
Treatment effect p<0.0001.
Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71-86.
P2Y12 Receptor Inhibitor
Recommendations
I IIa IIb III
Clopidogrel 75 mg/d for patients allergic or
intolerant to aspirin.
I IIa IIb III
A P2Y12 inhibitor (plus aspirin) for patients post
ACS or post PCI with stent placement.
I IIa IIb III
For patients receiving a stent during PCI for ACS,
a P2Y12 inhibitor should be given for at least 12
months:
Clopidogrel 75 mg daily or
Prasugrel 10 mg daily or
Ticagrelor 90 mg twice daily
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
RAAS Inhibitor
Recommendations
I IIa IIb III
ACE inhibitors should be used in all patients with LVEF < 40%,
and in those with hypertension, diabetes, or chronic kidney
disease indefinitely, unless contraindicated
I IIa IIb III
Consider ACE inhibitors for all other patients
It is reasonable to use an ARB in patients intolerant to ACE
inhibitors
I IIa IIb III
Use of aldosterone blockage in post-MI patients without renal
dysfunction or hyperkalemia is recommended in patients who
are already receiving therapeutic doses of an ACE inhibitor
and β-blocker, who have a LVEF < 40%, and who have either
diabetes or heart failure.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
ACE Inhibitor Evidence
Secondary Prevention
Meta-Analysis of the HOPE, EUROPA, and PEACE Trials*
Clinical Trial
N
HOPE
9,297
1051
HR=0.84 p=0.005
EUROPA
12,218
795
HR=0.89 p=0.10
PEACE
8,290
633
HR=0.89 p=0.13
33,960
>3000
All Trials*
Deaths
0.4
0.6
RR of Mortality
HR=0.86 p<0.001
0.8
ACE-I Better
1.0
1.2
1.4
1.6
Placebo Better
*7 RCTs, 33,960 randomized patients, and 4.4 years of mean follow-up.
Other findings include a CVD HR=0.81, MI HR=0.82, and stroke HR=0.77
Danchin N, et al. Arch Intern Med 2006;166:787-796.
EMPHASIS-HF Study:
Aldosterone Receptor Antagonism for Secondary Prevention
in Patients with Mild (Class II) HF Symptoms
Death or HF
Hospitalization
Zannad F, et al. N Engl J Med 2011;364:11-21.
β-blocker Recommendations
I IIa IIb III
Should be used in all patients with LV dysfunction with
heart failure or prior MI, unless contraindicated.
I IIa IIb III
Started and continued for 3 years in all patients with
normal LV function who have had MI or ACS
I IIa IIb III
Reasonable to continue beyond 3 years as chronic
therapy in all patients with normal LV function who have
had MI or ACS.
I IIa IIb III
Consider chronic therapy for all other patients with
coronary or other vascular disease.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
β-blocker Evidence
Summary of Secondary Prevention Trials of
β-blocker Therapy
Phase of
Treatment
Total #
Patients
Acute
treatment
28,970
0.87 (0.77-0.98)
Secondary
prevention
24,298
0.77 (0.70-0.84)
Overall
53,268
0.81 (0.75-0.87)
0.5
RR (95% CI)
2.0
1.0
RR of death
b-blocker
Placebo
better
better
Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of
Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.
Influenza Vaccination
I IIa IIb III
Patients with cardiovascular disease
should have an annual influenza
vaccination.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Influenza Vaccination Evidence
Effectiveness of Influenza Vaccination during the Influenza Seasons Community cohort
of 140,055 subjects in the 1998–1999 season of which 55.5 % were immunized.
Vaccinated
Subjects
(N=77,738)
Unvaccinated
Subjects
(N=62,317)
Adjusted Odds
Ratio
P value
Pneumonia or influenza
495 (0.6)
581 (0.9)
0.68
(0.60–0.78)
<0.001
Cardiac disease
888 (1.1)
1026 (1.6)
0.81
(0.73–0.89)
<0.001
Ischemic heart disease
457 (0.6)
535 (0.9)
0.80
(0.70–0.91)
0.001
Heart failure
466 (0.6)
538 (0.9)
0.81
(0.70–0.92)
0.002
Cerebrovascular disease
398 (0.5)
427 (0.7)
0.84
(0.72–0.97)
0.018
Death
943 (1.2)
1361 (2.2)
0.52
(0.47–0.57)
<0.001
Hospitalization or death
2387 (3.1)
2910 (4.7)
0.65
(0.62–0.70)
<0.001
Hospitalization
Nichol KL, et al. N Engl J Med 2003;348:1322-1332.
Depression
Recommendations
I IIa IIb III
I IIa IIb III
For patients with CABG or MI, it is
reasonable to screen for depression if
patients have access to case
management, in collaboration with
PCP and mental health specialist.
Treatment of depression has not been
shown to improve CVD outcomes, but
may be reasonable for its other clinical
benefits.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Cardiac Rehabilitation
Recommendations
I IIa IIb III
• Patients with ACS, post CABG, or post PCI
should be referred to a comprehensive
outpatient CR program either prior to hospital
discharge or during the first follow-up
outpatient visit.
• Outpatients with diagnosis of ACS, CABG,
PCI, or PAD within the past year should be
referred to a comprehensive outpatient CR
program.
• A home-based CR program can be
substituted for a supervised, center-based
program for low-risk patients.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Cardiac Rehabilitation
Recommendations
I IIa IIb III
Outpatients with a diagnosis of chronic
angina within the past year should be referred
to a comprehensive outpatient CR program.
I IIa IIb III
A comprehensive outpatient CR program can
be safe and beneficial for clinically stable
outpatients with heart failure.
Smith SC Jr., et al. Circulation 2011;124:2458-2473.
Evidence for
Cardiac Rehabilitation
• Meta-analysis of 63 randomized trials
(21,295 patients) randomly assigned to
exercise-based rehab or usual care
• Cardiac rehab reduced total mortality by
15% (95% CI, 0.77 to 0.94) and recurrent
MI by 17% (95% CI, .74 to .94)
Clark et al., Ann Intern Med 2005;143:659-672.
Medication Adherence and
CAD Costs and Outcomes
• Systematic review shows that medication
adherence is associated with:
– Reduced CVD events, mortality, readmissions, and
costs across a variety of adherence measures and
medication classes.
• However, few studies considered the “healthy
adherer effect”
– Patients who adhere to medications are also more
likely to adhere to a healthy diet, exercise regularly,
and generally lead a healthy lifestyle
Bitton A et al, Am J Med 2013;126:357.e7-357.e27.
“The nurse is a key link in the successful implementation of
medical and life-saving therapies in different patient
care settings.”
Journal of Cardiovascular Nursing 2011;26:145-167.
Nurse Case Management
Nurse case management involves:
• Overseeing discharge planning and follow-up
• Acting as the key point of contact for patients and
families
• Responding to questions
• Assessing the patient’s ability to understand and
adhere to complex medical therapies
• Oversee the integration of care by multiple providers
• Evaluating a patient’s response to therapy and
managing untoward effects
Berra K, Journal of Cardiovascular Nursing 2011;26:145-167.
Trials and Outcomes
SCRIP
MULTIFIT
CHAMP
EUROACTION
GWTG
•Improved adherence to guidelines
•Improved CVD risk factors
•Improved diet and exercise
•Fewer clinical events, less CAD progression
•Decreased mortality
Fletcher GF, Berra K, Fletcher BJ, Gilstrap L, Wood MJ. Current Problems in Cardiology
2012;37:363-398.
Oral Antiplatelet Therapy in
ACS Management
Robert A. Kloner, MD, PhD
Director of Research
Heart Institute, Good Samaritan Hospital
Professor of Medicine
Keck School of Medicine
University of Southern California
Los Angeles, California
Disclosure Statement
• Honorarium: AstraZeneca, Gilead Sciences
• Grants/Research Support: Gilead Sciences
In the TRITON-TIMI 38 trial, when
comparing prasugrel with clopidogrel, in
terms of efficacy, prasugrel was shown
to ______
1) Decrease the incidence of the
composite of CV death, MI, or
stroke
2) Decrease the incidence of CV
death
3) Both
4) Neither
25%
15%
51%
9%
A 73 year old female s/p NSTEMI was
treated with aspirin plus ticagrelor and
a drug-eluting stent. What discharge
aspirin dose should be prescribed with
ticagrelor?
1) < 100 mg
2) > 100 but < 300 mg
3) > 300 mg
66%
19%
15%
Commonly Used Antiplatelet Agents
1) Thromboxane A2 Inhibitor (Cyclo oxygenase
inhibitor) - Acetylsalicylic acid (Aspirin, ASA)
2) Adenosine diphosphate (ADP) receptor antagonists
- Clopidogrel (Plavix)
- Prasugrel (Effient)
- Ticagrelor (Brilinta)
- Ticlopidine (Ticlid)
3) Parenteral Glycoprotein (GP) Ilb/IIIa blockers
- Abciximab (ReoPro)
- Eptifibatide (Integrilin)
- Tirofiban (Aggrastat)
CURE: Clopidogel in UA/NSTEMI
0.14
All Patients
Placebo
(n=6303)
0.12
0.10
20% RRR
0.08
Clopidogrel
(n=6259)
0.06
0.04
P <.001
N=12,562
0.02
0.00
0
3
6
9
12
Cumulative Hazard Rates
Cumulative Hazard Rates
1o Outcome (CV death/MI/stroke) by Management Strategy
0.20
Medical Rx Group
0.15
Placebo
0.10
Clopidogrel
0.05
RR:0.80 (0.69-0.92)
0.00
0
0.20
PCI Group
0.15
Placebo
0.10
Clopidogrel
0.05
RR:0.72 (0.57-0.90)
0.00
0
100
200
200
300
Days of Follow-up
300
Cumulative Hazard Rates
Cumulative Hazard Rates
Months of Follow-up
100
0.20
CABG Group
Placebo
0.15
0.10
Clopidogrel
0.05
RR:0.89 (0.71-1.11)
0.00
0
Days of Follow-up
100
200
300
Days of Follow-up
CURE: Clopidogrel vs Placebo (all pts aspirin)
Yusuf S, et al. N Engl J Med. 2001;345:494-502.
Fox KAA, et al. Circulation. 2004;110:1202-1208.
CLARITY-TIMI 28: Clopidogrel with Thrombolysis for STEMI
1O Endpoint: Occluded Artery (or D/MI)
20%
Odds
Reduction
25
36%
Odds Reduction
21.7
15
20
End Point (%)
Occluded Artery or Death/MI (%)
P<.0001
15.0
10
15
10
Placebo
5
Clopidogrel
5
n=1752
P=.03
n=1739
0
0
Clopidogrel
Placebo
0
All patients received aspirin.
Sabatine et al. N Engl J Med. 2005;352:1179-1189.
5
10
15
Days
20
25
30
COMMIT: CLOPIDOGREL in 46,000 AMI Pts
Mortality
Death, Re-MI or Stroke
Placebo + ASA:
1846 deaths (8.1%)
Clopidogrel +ASA:
1728 deaths (7.5%)
Clopidogrel + ASA:
2125 events (9.3%)
Dead (%)
Death, MI Stroke (%)
Placebo + ASA:
2311 events (10.1%)
9% RRR
(P=0.002)
Days since randomization
7% RRR
(P=0.03)
Days since randomization
Chen et al. Lancet. 2005;366:1607-1621.
CURE: Major Bleeding by Aspirin
Dose Through Follow-up
Aspirin
Dose
Placebo
+ Aspirin#
Clopidogrel +
Aspirin#
1.9%*
2.8%*
3.7%*
3.0%**
3.4%**
4.9%**
75–100 mg
101–199 mg
200–325 mg
#, Other standard therapies were
used as appropriate.
Peters RJ et al. Circulation. 2003;108:1682-87.
* P = 0.0001 for comparison of increasing
ASA doses in Placebo Group;
** P = 0.0009 for comparison of increasing
ASA doses in Clopidogrel group
CURRENT-OASIS 7: Clopidogrel Results
Patients with UA/NSTEMI or STEMI planned for early invasive strategy
(ie, intended for PCI as early as possible within 72 hours)
Randomize
Clopidogrel Standard-dose Group
Clopidogrel 300 mg (+ placebo) day 1 followed
by 75 mg (+ placebo) from days 2 to 7;
75 mg from days 8 to 30
Clopidogrel High-dose Group
Clopidogrel 600 mg LD day 1
followed by 150 mg from days 2 to 7;
75 mg from days 8 to 30
Standard Double
CV death/MI/Stroke
Overall (N=25,086)
PCI (n=17,263)
No PCI (n=7823)
4.4
4.5
4.3
4.2
3.9
4.9
HR (95% CI)
P-value
0.94 (0.83-1.06)
0.86 (0.74-0.99)
1.14 (0.92-1.40)
0.30
0.039
0.23
LD = loading dose.
CURRENT-OASIS 7 Investigators, et al. N Engl J Med. 2010;363:930-942.
Mehta SR, et al. Lancet. 2010;376:1233-1243.
The First Clopidogrel Resistance Study (300 mg):
A Fingerprint of Clopidogrel Response Variability
2 Hours
Resistance = 63%
Resistance
Patients (%)
Patients (%)
24
24 Hours
12
Resistance = 31%
20
Resistance
10
≤ -30
(-20,-10]
(0,10]
(20,30]
(40,50]
>60
(-30,-20]
(-10,0]
(10,20]
(30,40]
(50,60]
≤ -30
(-20,-10]
(0,10]
(20,30]
(40,50]
>60
(-30,-20]
(-10,0]
(10,20]
(30,40]
(50,60]
 Aggregation (%)
 Aggregation (%)
5 Days
Resistance = 31%
Resistance = 15%
28
Patients (%)
22
Patients (%)
30 Days
Resistance
11
14
≤ -10
(0,10]
(-10,0]
(20,30]
(10,20]
(40,50]
(30,40]
>60
(50,60]
 Aggregation (%)
Gurbel PA, et al. Circulation. 2003;107:2908-2913.
Resistance
≤ -30
(-20,-10]
(0,10]
(20,30]
(40,50]
>60
(-30,-20]
(-10,0]
(10,20]
(30,40]
(50,60]
 Aggregation (%)
66
Clopidogrel Metabolism
P-Glycoprotein
Intestinal
Absorption
15%
2C19
1A2
2B6
Inactive
metabolite
2 Step
Hepatic CYP
Conversion
2C19
2C9
3A4
2B6
Variable and inefficient
active metabolite generation
Note: clopidogrel
irreversible binding
To P2Y12 receptor
Slow,
Variable IPA
Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-9.
IPA, inhibition of platelet aggregation
Factors Influencing On-treatment Platelet Reactivity
SNP’s
CYP2C19, ABCB1?
CYP
Metabolizer
Status
Ultra
Fast
Intermediate
Poor
DDI
PPI, CCB, Warfarin
SJW, Smoking
Renal Function
Age
BMI
Clinical
Outcomes
CAD state
Variable Response
ADP, adenosine diphosphate; CAD, coronary artery disease;
to
CCB, calcium channel blocker; CYP,cytochrome;BMI, body mass index;
DDI, drug-drug interaction; PPI, proton pump inhibitor; SJW, St. John’s Wort;
SNP, single nucleotide polymorphism
Gurbel PA et al. Eur Heart J. 2012;33:1187-89.
Diabetes
ADP
Unknown
Factors
TRITON TIMI-38: Cardiovascular risk with
CYP2C19 reduced function allele
Patients Receiving Clopidogrel
Incidence of CV death, MI and stroke (%)
12.1
Carriers
12
10
8.0
Noncarriers
8
6
4
Hazard ratio: 3.09
95% CI: 1.19 – 8.00
P=0.01
2
0
0 30
90
180
270
360
Days since Randomization
Mega J et al. N Engl J Med. 2009;360:354-62
450
FDA Boxed Warning on Clopidogrel
3/12/2010 - The Boxed Warning in the drug label
includes information to:
• Warn about reduced effectiveness in patients who are poor
metabolizers of clopidogrel. Poor metabolizers do not
effectively convert clopidogrel to its active form in the body.
• Inform healthcare professionals that tests are available to
identify genetic differences in CYP2C19 function.
• Advise healthcare professionals to consider use of other
anti-platelet medications or alternative dosing strategies for
clopidogrel in patients identified as poor metabolizers.
Accessed March 29, 2011 at:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm
Clopidogrel: in ACS
Who:
UA/NSTEMI (Invasive and Conservative)
STEMI (PCI, Fibrinolysis, Med Rx)
Who not: Planned CABG,
?2C19 known homozygous
Active / very high risk for bleeding
Where:
Emergency Department
When:
Early and late – 1 year ?longer
How:
300 mg load (or 600 mg load pre-PCI).
Platelet and genetic testing unproven.
Use with PPI if GI bleed risk factors.
Prasugrel
Ticagrelor
- More rapid onset and greater antiplatelet effect
- Lesser/no resistance
- No influence of gene polymorphism and major drugdrug interactions
Irreversible
Reversible binding
Prasugrel Is Effective for Clopidogrel Nonresponders
100
Interaction
Variability
60
40
20
Interaction
Variability
IPA at 24 hours (%)
80
Clopidogrel Responder
0
-20
Clopidogrel Non-responder
Response to
Clopidogrel 300 mg
Response to
Prasugrel 60 mg
* Responder 25% IPA at 4 and 24 hours
Brandt JT. Am Heart J. 2007;153:66e9.
IPA, inhibition of platelet aggregation
PRINCIPLE TIMI 44:
Comparison with Higher Dose Clopidogrel
IPA (%; 20 mM ADP)
N=201
P<0.0001 for each
IPA (%; 20 mM ADP)
P<0.0001
Prasugrel 60 mg
Clopidogrel 600 mg
Hours
Wiviott SD et al. Circulation. 2007;116:2923-32.
Clopidogrel Prasugrel
150 mg
10 mg
14 Days
IPA, inhibition of platelet aggregation
74
Prasugrel Labeling
Prasugrel was approved for reducing thrombotic
cardiovascular events, including stent thrombosis, in
the following patients with acute coronary syndrome
who will be managed with percutaneous coronary
intervention (PCI): those with unstable angina or nonST elevation myocardial infarction (NSTEMI) and those
with ST-elevation MI (STEMI), when managed with
either primary or delayed PCI.
Black Box Warning with Prasugrel

Prasugrel can cause significant, sometimes fatal, bleeding

Do not use prasugrel in patients with active pathological bleeding
or a history of transient ischemic attack or stroke

In patients age 75 and older, prasugrel is generally not
recommended because of the increased risk of intracranial and
fatal bleeding and uncertain benefit, except in high-risk situations
(patients with diabetes or a history of prior MI). In these situations,
the drug's effect appears to be greater, and its use may be
considered.

Additional risk factors for bleeding include:
 body weight < 60 kg
 propensity to bleed
 concomitant use of medications that increase the risk of
bleeding
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022307s003lbl.pdf
TRITON-TIMI 38 Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
n=13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint: CV death, MI, stroke
2o endpoints: CV death, MI, stroke, rehosp-rec isch
CV death, MI, UTVR
UTVR = urgent target vessel revascularization; NSTEMI = non-ST segment elevation MI
Wiviott SD et al. Am Heart J. 2006;152:627-635.
TRITON TIMI-38: Efficacy and Safety
15
End Point (%)
CV Death/MI/Stroke
Clopidogrel
12.1
9.9
10
Prasugrel
5
TIMI Major
Non-CABG Bleeds
0
30 60
90
180
270
Days
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
HR 0.81
(0.73-0.90)
P=0.0004
NNT=46
35
events
Prasugrel
Clopidogrel
0
138
events
360
2.4
1.8
HR 1.32
(1.03-1.68)
P=0.03
NNH=167
450
HR = hazard ratio;
NNT = number needed to treat; NNH = number needed to harm
Triton TIMI-38: Major efficacy end points in overall cohort at
15 mo.
Pras
Clop
(N=6813)
(N=6795)
no. of patients (%)
643 (9.9)
781 (12.1)
HR for
Prasugrel
(95% CI)
0.81 (0.73–0.90)
133 (2.1)
475 (7.3)
150 (2.4)
620 (9.5)
0.89 (0.70-1.12)
0.76 (0.67-0.85)
0.31
<0.001
Nonfatal stroke
61 (1.0)
60 (1.0)
1.02 (0.71-1.45)
0.93
Death from any cause
188 (3.0)
197 (3.2)
0.95 (0.78-1.16)
0.64
CV Death, nonfatal MI, or
urgent TVR
652 (10.0)
798 (12.3)
0.81 (0.73-0.89)
<0.001
Death from any cause,
692 (10.7)
822 (12.7)
0.83 (0.75-0.92)
<0.001
156 (2.5)
233 (3.7)
0.66 (0.54-0.81)
<0.001
938 (14.6)
0.84 (0.76-0.92)
<0.001
142 (2.4)
0.48 (0.36-0.64)
<0.001
End Point
CV Death, non-fatal MI or
non-fatal stroke (1o end pt)
CV Death
Nonfatal MI
p value
<0.001
nonfatal MI, or nonfatal stroke
Urgent TVR
CV Death, nonfatal MI, nonfatal 797 (12.3)
stroke or rehosp for ischemia
Stent thrombosis ‡
68 (1.1)
‡ Definite or Probable
Wiviott et al. New Engl J Med 2007
TRITON TIMI-38: Bleeding Events
ICH in patients w/
prior stroke/TIA
(N = 518)
Events (%)
Clopidogrel
Prasugrel
Clop 0 (0%)
Pras 6 (2.3%)
(P = 0.02)
ARD 0.6%
HR = 1.32
P = 0.03
NNT =167
ARD 0.5%
HR = 1.52
P = 0.01
ARD 0.2%
P = 0.23
ARD 0.3%
P = 0.002
ARD 0%
P = 0.74
ICH = intracranial hemorrhage; ARD = absolute risk difference; TIA = transient ischemic attack.
Wiviott SD et al. N Engl J Med. 2007:357:2001-2015.
TRILOGY ACS Study Design
Medically Managed UA/NSTEMI Patients
Randomization Stratified by:
Age, Country, Prior Clopidogrel Treatment
(Primary analysis cohort — Age < 75 years)
Medical Management Decision ≤ 10 days
(Clopidogrel started ≤ 72 hrs in-hospital OR
on chronic clopidogrel) — 96% of total
Medical Management Decision ≤72 hrs
(No prior clopidogrel given) — 4% of total
Clopidogrel1
300 mg LD
+
75 mg MD
Median Time to
Enrollment = 4.5 Days
Prasugrel1
30 mg LD
+
5 or 10 mg MD
Clopidogrel1
Prasugrel1
75 mg MD
5 or 10 mg MD
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, Stroke
1. 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. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.
LD, loading dose; MD, maintenance dose
TRILOGY ACS: Primary Efficacy Endpoint to 30 Months
(Age < 75 years)
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
Roe MT et al. N Engl J Med. 2012;367:1297-1309.
Summary: Prasugrel
• Prasugrel superior to clopidogrel in ACS undergoing
PCI
• Prasugrel not superior to clopidogrel in medical
management of ACS
• Prasugrel is administered initially with a single 60
mg oral loading dose (at time of ACS). Thereafter,
treatment is continued with 10 mg orally once daily.
– Consider lowering maintenance dose to 5 mg in
patients < 60 kg.
• Duration of dual oral antiplatelet therapy (DAPT)
1 year or more
Ticagrelor:
an oral reversible P2Y12 antagonist
HO
N
N
N
H
N
HO
O
F
N
N
S
F
Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP);
not a thienopyridine
OH
• Direct acting
– 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
– Degree of inhibition reflects plasma concentration
– Faster offset of effect than clopidogrel
– Functional recovery of all circulating platelets
Clopidogrel vs. Ticagrelor
ONSET/OFFSET Study
Maintenance and Offset
Loading
IPA (%; 20 mM ADP, Final)
100
* *
*
Ticagrelor 180mg
*
80
60
*
40
Clopidogrel 600 mg
20
0
0 .5
4
8
12
16
20
24
Hours
*P<0.0001; †P<0.005; ‡, P<0.05, ticagrelor vs clopidogrel.
Gurbel PA et al. Circulation. 2009;120:2577-85.
IPA, inhibition of platelet aggregation
PLATO study design
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
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)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular
Wallentin L et al. NEJM . 2009;361:1045-57.
PLATO Primary efficacy endpoint: CV death, MI or stroke
Cumulative incidence (%)
18,624 Patients w/in 24 hrs of onset of ACS
13
12
11
10
9
8
7
6
5
4
3
2
1
0
HR 0.84
(95% CI 0.77–0.92)
P=0.0003
11.7
Clopidogrel
9.8
Ticagrelor
Cardiovascular Death: 4.0% vs. 5.1%, HR 0.79 (0.69-0.91), P=0.001
All-cause Mortality: 4.5% vs. 5.9%, HR 0.78 (0.69-0.89), P<0.001
0
No. at risk
Ticagrelor 9,333
Clopidogrel 9,291
60
120
180
240
300
360
5,161
5,096
4,147
4,047
Days after randomisation
8,628
8,521
HR = hazard ratio; CI = confidence interval
Wallentin L, et al. NEJM 2009;361:1045-57;
Wallentin 2009 ESC Presentation
8,460
8,362
8,219
8,124
6,743
6,743
Treating 54 pts with ticagrelor instead of with clopidogrel for
1 year will prevent one event of CV death, MI or stroke.
PLATO: major efficacy endpoints
All patients*
Primary objective, n (%)
CV death + MI + stroke
Secondary objectives, n (%)
Total death + MI + stroke
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Ticagrelor Clopidogrel
(n=9,333) (n=9,291)
864 (9.8)
HR for
(95% CI)
p value†
1,014 (11.7) 0.84 (0.77–0.92)
<0.001
901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92)
<0.001
1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95)
<0.001
Myocardial infarction
504 (5.8)
593 (6.9)
0.84 (0.75–0.95)
0.005
CV death
353 (4.0)
442 (5.1)
0.79 (0.69–0.91)
0.001
Stroke
125 (1.5)
106 (1.3)
1.17 (0.91–1.52)
0.22
Stent thrombosis (Definite or probable)
118 (2.2)
158 (2.9)
0.75 (0.59 – 0.95)
0.02
Total death
399 (4.5)
506 (5.9)
0.78 (0.69–0.89)
<0.001
The percentages are K-M estimates of the rate of the endpoint at 12 months.
Wallentin L et al. NEJM .2009;361:1045-57
PLATO: Primary Efficacy Outcome
US and Non-US and by ASA Dose
Mahaffey K et al. Circulation. 2011;124:544-54
PLATO: Major Bleeding, Holter Monitoring
and Other Related Events
Bleeding
Ticagrelor (n=9235)
Clopidogrel (n=9186)
Total Major — PLATO criteria, %
Total Major — TIMI criteria , %
11.6
7.9
11.2
7.7
0.43
0.57
Non-CABG Major — PLATO criteria, %
Non-CABG Major — TIMI criteria , %
4.5
2.8
3.8
2.2
0.026
0.025
Ticagrelor (n=1451)
Clopidogrel (n=1415)
P-value
5.8
2.0
3.6
1.2
0.01
0.10
Ticagrelor (n=9235)
Clopidogrel (n=9186)
P-value*
13.8
0.9
7.8
0.1
<0.001
<0.001
Holter Monitoring at First Week
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
All Patients
Dyspnea, %
Any
With discontinuation of study treatment
Bradycardia-related Event, %
Syncope
Bradycardia
P-value
P-value
1.1
4.4
*P-values were calculated using Fischer’s exact test.
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
0.8
4.0
0.08
0.21
Ticagrelor – FDA Label
“Boxed Warning”
WARNING: BLEEDING RISK
• 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
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).
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).
http://www.pdr.net/drugpages/productlabeling.aspx?mpcode=04020155
Summary: Ticagrelor
• Reduces major cardiovascular events (including
cardiovascular mortality and all-cause mortality) in
ACS patients managed invasively or medically.
• Ticagrelor is administered initially with 180 mg (2 90 mg
tablets) as an oral loading dose (at time of ACS).
Thereafter, treatment is continued with 90 mg TWICE
DAILY
• Should be used with low dose aspirin (75-100 mg/day)
• Duration of dual oral antiplatelet therapy (DAPT)
1 year or more
UA/NSTEMI Guidelines: Key Points
on Antiplatelets (Class I and III)
• ASA to all (clopidogrel if allergic)
• Medium - high risk and an invasive strategy get dual Rx
– 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 (clopidogrel, prasugrel and
ticagrelor)
• Duration of ADP blockers 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
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
– Clopidogrel, prasugrel, or ticagrelor for 1 year
– Class III (harm or no benefit): prasugrel potentially harmful (if h/o
stroke/TIA)
•
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)
O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-140.