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UPDATE ON ANTIPLATELET THERAPY IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASE

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Title: UPDATE ON ANTIPLATELET THERAPY IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASE


1
UPDATE ON ANTIPLATELET THERAPY IN THE TREATMENT
AND PREVENTION OF CARDIOVASCULAR DISEASE
  • Charles H Hennekens, MD, DrPH
  • Sir Richard Doll Research Professor of Medicine
  • Charles E. Schmidt College of Medicine
  • Florida Atlantic University
  • Clinical Professor of Preventive Medicine
  • Nova Southeastern University
  • Voluntary Professor of Family Medicine and
    Community Health
  • University of Miami Miller School of Medicine

2
Disclosure
  • Dr. Hennekens receives investigator initiated
    research grant support from Bayer to the Charles
    E. Schmidt College of Medicine at Florida
    Atlantic University.
  • He serves as an independent scientist in an
    advisory role to investigators and sponsors,
    including as Chair or member of Data and Safety
    Monitoring Boards to Actelion, Amgen, Anthera,
    Bayer, Bristol-Myers Squibb, Canadian Institutes
    of Health Research, Dainippon-Sumitomo, National
    Association for Continuing Education,, Pozen,
    Pfizer, PriMed, United States (US) Food and Drug
    Administration, U.S.National Institutes of
    Health, and UpToDate.
  • He serves as an independent scientist in an
    advisory role to legal counsel for
    GlaxoSmithKline and Stryker.
  • He serves as speaker for the Association for
    Research in Vision and Ophthalmology,
    AstraZeneca, International Atherosclerosis
    Society, and Pfizer.
  • He receives royalties for authorship or
    editorship of three textbooks and as co-inventor
    on patents held by Brigham and Womens Hospital
    concerning inflammatory markers for
    cardiovascular disease.
  • He has an investment management relationship with
    The West-Bacon Group within SunTrust Investment
    Services who has sole discretionary investment
    authority.
  • He owns no common or preferred stock in any
    pharmaceutical or device industry.

3
  • Death is inevitable but
  • premature death is not.
  • Sir Richard Doll

4
(No Transcript)
5
CONTRIBUTIONS OF DIFFERENT TYPES OF EVIDENCE
  • For hypotheses testing of large effects (i.e.
    smoking and lung cancer where RR20, or even
    smoking and CHD where RR2.0) randomized evidence
    is neither necessary nor desirable.
  • (Hennekens and Buring, Epidemiology in Medicine,
    1987)
  • For small to moderate effects (i.e.10-90) the
    amount of uncontrolled and uncontrollable
    confounding inherent in all case control and
    cohort studies is as big as the effect size so
    large scale randomized evidence from trials
    designed a priori to test the hypothesis is
    crucial.
  • (Hennekens and DeMets, JAMA, 2009).
  • Subgroup analyses are no longer randomized and
    have lower sample sizes and should be viewed, at
    best, as hypothesis formulating and, at worst, as
    rubbish. The biggest danger in interpretation of
    subgroups is acting as if they provide serious
    evidence.
  • ( Peto, personal communication, 2010)

6
OBJECTIVES
  • Aspirin in the treatment of CVD
  • Additive benefits of aspirin and statins
  • Aspirin in the prevention of CVD
  • Dual antiplatelet therapy in CVD
  • Newer antiplatelet agents in CVD

7
Milestones For Aspirin
  • 5th century BC Hippocrates
  • 1897 AD Felix Hoffman/Friedrich Bayer
  • 1900 present Most widely used drug in the
    world
  • 1971 Sir John Vane

8
Moses Receiving The Tablets From God
9
Milestones For Aspirin
  • 5th century BC Hippocrates
  • 1897 AD Felix Hoffman/Friedrich Bayer
  • 1900 present Most widely used drug in the
    world
  • 1971 Sir John Vane

10
(No Transcript)
11
Milestones For Aspirin
  • 5th century BC Hippocrates
  • 1897 AD Felix Hoffman/Friedrich Bayer
  • 1900 present Most widely used drug in the
    world
  • 1971 Sir John Vane

12
(No Transcript)
13
Milestones For Aspirin
  • 5th century BC Hippocrates
  • 1897 AD Felix Hoffman/Friedrich Bayer
  • 1900 present Most widely used drug in the
    world
  • 1971 Sir John Vane

14
The Most Plausible Mechanism Of Aspirin In
Reducing Risks Of Cardiovascular Disease
  • Aspirin irreversibly acetylates the active
  • site of cyclooxygenase, which is required
  • for the production of thromboxane A2, a
  • powerful promoter of platelet aggregation

Vane JR. Inhibition of prostaglandin synthesis as
a mechanism of action of aspirin like drugs.
Nat New Biol. 1971231232-5.
15
Totality Of Evidence
  • Basic research (why)
  • Epidemiology (whether)
  • descriptive studies
  • case reports
  • case series
  • ecological studies
  • analytic studies
  • observational
  • case-control
  • cohort
  • randomized trials

Hennekens. Epidemiology in Medicine. 1987.
16
Observational Epidemiologic Studies
  • Some but not all case-control cohort studies
    indicate that individuals and/or their health
    care providers who self-select for aspirin have
    lower risks of CVD.
  • For most epidemiologic hypotheses, randomized
    trials are neither necessary nor desirable
  • For small to moderate effects, however, the only
    reliable design strategy is the large
    randomized trial because the amount of
    uncontrolled uncontrollable confounding factors
    inherent in observational studies can be as large
    as the effect sizes

Hennekens CH, DeMets D The need for large scale
randomized evidence without undue emphasis on
small trials, their meta-analyses or subgroup
analyses JAMA 2009
17
Evolution of Antiplatelet (AP) Therapy Trials
Year No Of Trials No Of Patients 1988 25
25,000 1997 194 212,000 AP vs control
(135,000) Different AP (77,000)
Antithrombotic Trialists Collaboration. BMJ.
200232471.
18
Aspirin in the Treatment of CVD
  • In a wide range of patients who have survived a
    prior occlusive event (including MI, occlusive
    stroke or transient ischemic attack, or other
    high risk categories including unstable and
    stable angina, angioplasty, or coronary artery
    bypass graft), antiplatelet therapy, principally
    with aspirin, prevents 25 of serious vascular
    events, including significant reductions on MI,
    stroke, and CVD death.
  • All these patients have 10-year risks of CHD of
    20 or more based on the Framingham risk score
    recommended by the US NHLBI.

AntiThrombotic Trialists Collaboration. Lancet,
2002
19
Benefits of Aspirin on Risk of Stroke
  • In 158 trials, there were 3,522 nonfatal and
    1,424 fatal strokes after randomization.
  • Antiplatelet therapy, principally with aspirin,
    reduced stroke by about 25, regardless of
    whether the patient entered the trial with prior
    MI, stroke, TIA, or other high-risk conditions.
  • Antiplatelet therapy, principally with aspirin,
    increases the absolute risk of hemorrhagic stroke
    by 3 per 10,000 treated patients. The upper bound
    of the 95 confidence interval is less than 1 per
    1000 treated patients.

AntiThrombotic Trialists Collaboration. Lancet,
2002
20
Second International Study of Infarct Survival
ISIS-2 Collaborative Croup Lancet. 1988 Aug
13332 349-60.
21
Hypothesis Additive Benefits of Statins and
Aspirin to Decrease Risks of CVD
  • ATHEROSCLEROSIS
  • The principal underlying cause of occlusive
    CVD events
  • which is inhibited by statins
  • THROMBOSIS
  • The principal proximate cause of occlusive CVD
    events
  • which is inhibited by aspirin

Hebert P, Pfeffer MA, Hennekens CH Use of
Statins and Aspirin to Decrease Risks of CVD J
CV Pharm Ther. 2002777-80
22
Summary Additive Benefits of Aspirin and Statins
in Secondary Prevention of CVD
  • A meta-analysis of 5 trials in secondary
    prevention of CVD of over 15,000 patients with
    over 73,000 patient-years of observation
    demonstrated that the combination of aspirin and
    statins provided statistically significant and
    clinically important additive benefits for the
    prespecified individual endpoints of fatal or
    non-fatal MI as well as ischemic stroke and a
    combined endpoint of CHD death, non-fatal MI,
    CABG, PTCA or ischemic stroke
  • The probability of synergy (i.e. greater than
    additive benefits) was 0.92.
  • These statistically significant and clinically
    important benefits were also present in
    individual analyses of data from the LIPID and
    CARE trials

Hennekens CH, et al. Arch Int Med, 2001.
23
Greater Relative Risk Reductions (RRR) for
Pravastatin (Prava) Aspirin (ASA) versus
Prava or ASA alone
Relative Risk (95 CI)
RRR
Fatal or Non-Fatal MI
PravaASA vs ASA Alone
PravaASA vs Prava Alone
Hennekens CH et al. Arch Int Med 2004
164945-948.
24
(No Transcript)
25
Potential Public Health Impact of Prevention of
Myocardial Infarction in Secondary and Primary
Prevention
  • In the US each year a reduction in risk of MI by
    about 1/3 would avoid about
  • 25,000 events in secondary prevention
  • 250,000 events in primary prevention

26
Summary Aspirin in Primary Prevention of CVD
  • In a comprehensive worldwide meta analysis of the
    6 randomized trials of primary prevention aspirin
    produces a statistically significant and
    clinically important reduction in risk of a first
    myocardial infarction by about 1/3 but the
    available data on stroke and cardiovascular death
    remain inconclusive
  • In these apparently healthy men and women at low
    risk aspirin is of uncertain net value as the
    reduction in occlusive events needs to be weighed
    against any increase in major bleeds.
  • The average 10 year risk of a first CHD event
    among the apparently healthy men and women in the
    6 randomized trials is less than 5.
  • The chief need is for randomized evidence in
    apparently healthy individuals whose 10 year risk
    of a first CHD event is 10-19.
  • Until then any decision to use aspirin in primary
    prevention should be an individual clinical
    judgement by the healthcare provider.

Writing Group (Baigent C, Blackwell L, Buring J,
Collins R, Emberson J, Godwin J, Hennekens C,
Kearney P, Meade T, Patrono C, Peto R,
Roncaglioni R, Zanchetti A). Aspirin in the
primary and secondary prevention of vascular
disease collaborative meta-analysis of
individual participant data. Lancet.
20093731849-60.
27
10-Year Risk of a First CHD Event in the Six
Major Trials of Aspirin in Primary Prevention of
CVD
28
Dose Of Aspirin Indirect Comparisons
Reduction Regimen No Trials (SE) 3P
value Aspirin Alone (mg) 500-1500 34 19
(3) lt0.00001 160-325 19 26 (3) lt0.00001 75-150 1
2 32 (6) lt0.0001 lt75 3 13 (8) NS Total 68 23
(2) lt0.0001
X32 het 8.2, P.04.
AntiThrombotic Trialists Collaboration. Lancet,
2002
.
29
Time To Achieve Maximal Inhibition Of Serum
Thromboxane B2 With 75 mg ASA
Hennekens CH and Schneider W. Expert Rev
Cardiovasc Ther. 2008 6 95-107
30
Indirect and Direct Comparisons Between Daily
Aspirin Doses of 325mg or less and Major
Extracranial Bleeding in the Secondary Prevention
Trials
  • Indirect comparisons In meta-analyses of trials
    of daily aspirin doses of 325mg or less
    (160-325, 75-160, or lt75), risks of major
    extracranial bleeds were similar.
  • Direct comparisons In the two trials that
    directly compared daily aspirin doses of
    75-325mg with lt75mg, risks of major extracranial
    bleeds were similar.

AntiThrombotic Trialists Collaboration. Lancet,
2002
31
Optimal Dosing For Aspirin In CHD
Secondary Prevention 75 mg 325 mg Primary
Prevention Acute CVD Syndrome 162.5 mg 325 mg
Hennekens CH, Dyken M, Fuster VCirc. 1997
32
Effects On Platelets
Hennekens CH, Borzak S JCPT, 2008
33
Dose-Dependent Side Effects of Aspirin The 5 Year
UK-TIA Trial of about 2400
Side Effects Placebo 300 mg 1200 mg GI
Symptoms 25 29 39 GI bleeding
requiring transfusion 1.6 2.6
4.9
Warlow C. et al. BMJ, 1988
34
Possible Additional Beneficial Mechanisms of
Action of Higher Doses of Aspirin on CVD
  • Enhance nitric oxide formation
  • Decrease inflammation
  • Stabilize endothelial function

Hennekens CH, Sechenova, O, Hollar D, Serebruany
VL. Dose of Aspirin in the Treatment and
Prevention of Cardiovascular Disease Current and
Future Directions. JCPT 2006. Hennekens CH, et
al. A randomized trial of aspirin at usual
clinical doses and increased nitric oxide
formation in humans. JCPT 2010.
35
Lack of Sex Differences in Response to Aspirin
ATT Patients with Prior MI or Stroke
Percent Reductions
Endpoint Men Women Major coronary
events 19 25 Stroke 17 22
Hennekens CH, Hollar D, Baigent C. Sex
differences in response to aspirin in CVD an
hypothesis formulated but not tested. Nature
Cardiovascular Medicine 2006,34-5
36
Dual Antiplatelet Therapy
  • Risks versus Monotherapy
  • Benefits and risks
  • Aspirin Dipyrimadole
  • Aspirin Clopidogrel
  • Issues with Clopidogrel
  • Clopidogrel versus Prasugrel
  • Clopidogrel versus Ticagrelor

37
DUAL ANTIPLATELET THERAPY AND INCREASED RISKS OF
BLEEDING
  • In a meta-analysis of 18 randomized trials which
    included 129,314 patients
  • Those assigned to dual antiplatelet therapy have
    about a 50 increase in risks of major bleeding
    compared with those given single agent therapy
  • The magnitude of these excess risks are about as
    high as the approximately 60 increase observed
    in the trials comparing single antiplatelet
    agents to placebo
  • These excess risks of major bleeding should be
    considered in relation to the benefits on
    occlusive CVD events in choosing the optimal
    antiplatelet strategy, especially for long-term
    treatment of patients with prior events or those
    at high risk of developing CVD.

Fund Clin Pharm 2008 22315-321
38
Aspirin Dipyrimadole Second European Stroke
Study (ESPS-2)
  • Randomized, double-blind placebo controlled 2x2
    factorial trial
  • 6602 patients with prior ischemic stroke or TIA
  • ASA (25mg bid) and/or dipyrimadole (200mig bid
    sustained release)
  • Deaths from stroke were reduced
  • 13 by ASA (p0.016)
  • 15 by dipyrimadole (p0.039)
  • 24 by the combination of ASA and dipyrimadole
  • (plt0.001)

Diener, HC et al J Neurol Sci .1996 Nov 143
(1-2)1-13
39
Aspirin Dipyridamole PROFESS
  • 20,332 post-ischemic stroke patients within 120
    days
  • Randomized to aspirin 25mg extended release
    dipyrimadole 200mg bid vs clopidogrel 75mg qd
  • After 2.5 years there were similar rates of the
    primary prespecified composite endpoint of
    stroke, MI or vascular death.

NEJM, 20083591238-1251
40
Clopidogrel Aspirin
  • Clopidogrel adds to the benefit of aspirin in
    some circumstances.
  • CURE, a randomized trial of acute MI, showed that
    clopidogrel adds to the benefit of aspirin on
    CVD events but increased major bleeding.
  • COMMIT/CCS-2, a randomized trial of acute
    coronary syndromes in China, showed that
    clopidogrel adds to the benefit of aspirin on CVD
    and total mortality but did not increase major
    bleeding.


41
CURE Trial Investigators NEJM. 2001345 494-502
42
Second Chinese Cardiac Study COMMIT
  • Randomized, double-blind, 2x2 factorial trial of
    clopidogrel and metoprolol
  • 45,852 patients within 24 hours of onset of
    symptoms of suspected acute myocardial infarction
  • Randomization in clopidogrel arm to daily 75mg
    clopidogrel162mg aspirin(22,960) or placebo
    160mg aspirin(22,891)

COMMIT Collaborative Group. Lancet 2005 366
1607-1621.
43
COMMIT Clopidogrel Arm Primary Outcomes
COMMIT Collaborative Group. Lancet 2005 366
1607-1621.
44
COMMIT Major Bleeding
COMMIT Collaborative Group. Lancet 2005 366
1607-1621.
45
CHARISMA
  • A randomized, double-blind placebo controlled
    trial of 15,603 patients (79 ) with established
    CVD and 21 with multiple risk factors designed
    to test whether clopidogrel should be continued
    beyond 1 year in addition to aspirin.
  • All patients received daily aspirin(75-162mg) and
    were randomized to daily clopidogrel(75mg) or
    placebo
  • Clopidogrel patients had an event rate of 6.8
    and placebo patients had an event rate of 7.3.
  • CHARISMA demonstrated no significant benefit long
    term when clopidogrel is added to aspirin.
  • Rates of severe bleeding were similar but
    clopidogrel patients experienced significantly
    higher rates of moderate bleeding.
  • There was possible effect modification by
    presence or absence of prior events, a post hoc
    formulated hypothesis not directly tested in this
    trial.

Bhatt DL, et al N Engl J Med. 2006. 54
1706-1717
46
ISIS-2 Investigators, Lancet, 1988
47
Issues with Clopidogrel
  • Onset 4-6 hours (after loading dose with 8 x
    maintenance dose)
  • Offset 5-7 days
  • Variable response 25-30 of patients achieve
    less than 25 inhibition of platelet activity
  • Must undergo 2 step metabolism (CYP3A4 mediated)
    to active agent
  • Binds irreversibly to P2Y12 receptor
  • Postulated but unproven interaction with PPIs.

Gurbel, PA, et al, Circulation 2003
1072908-2913 Laine L, Hennekens CH Am J
Gastro. Published online 11/13/09
48
Dose of Clopidogrel CURRENT- Oasis7
  • Randomized, double-blind, 2x2 factorial trial
  • 25,087 ACS patients (70.8 UA/non-STEMI)
  • Clopidogrel arm double dose (600mg then 150mg
    dailyx7days then 75mg dailyx22 days) vs standard
    dose (300mg then 75mg daily x29 days)
  • Aspirin arm 300-325mg daily vs 75-100mg daily x
    30 days.

Mehta, S et al. Am Heart J. Nov 6 2008 156
1080-1088
49
Clopidogrel Dose Comparison
  • Overall, for efficacy, double-dose clopidogrel
    (600 loading dose 150 for 7 days then 75 mg for
    22 days) versus standard dose ( 300 75 for 29
    days) produced no significant reduction in the
    primary composite of major CV events (CV death,
    MI or stroke)
  • The hazard ratio of 0.95 was a weighted average
    of 0.85 (p.03) among the subgroup undergoing PCI
    and 1.17 (p0.14) among the subgroup not
    undergoing PCI
  • Overall, for safety, using the CURRENT
    definitions, double dose clopidogrel produced
    significant increases in severe and major
    bleeds.

Presented at ESC Congress 2009, Barcelona Spain
50
ASA Dose Comparison
  • ASA 300-325 mg versus
  • ASA 75-100 mg showed
  • no significant differences in
  • efficacy or bleeding.

Presented at ESC Congress 2009, Barcelona Spain
51
Proton Pump Inhibitor and Clopidogrel Interaction
  • Hennekens CH and DeMetsD The need for large
    scale randomized evidence without undue emphasis
    on small trials, their meta-analyses or subgroup
    analyses. JAMA, December 2, 2009.
  • When effect sizes are small to moderate (relative
    risks lt 1.5 2.0), it is only possible to
    conclude whether statistical associations are
    valid in randomized trials with sufficient
    numbers of clinical endpoints and designed a
    priori to test the hypothesis
  • Bhatt D, et al The COGENT trial. Presented at TCT
    September 24, 2009.
  • COGENT is the only large scale randomized trial
    tested omeprazole versus placebo on CV events in
    clopidogrel users . This trial showed no
    significant difference in CV events (hazard ratio
    1.02, 95 confidence limits from 0.70 1.51)
    as well as a significant reduction in GI events
    (hazard ratio 0.55, 95 confidence limits from
    0.36-0.85).
  • Laine L and Hennekens CH. PPI and Clopidogrel
    Interaction Fact or Fiction. AJG, Published
    online November 13, 2009.
  • The current totality of evidence does not justify
    a conclusion that PPIs are associated with
    clinical cardiovascular disease (CV) events among
    clopidogrel users, let alone support a judgment
    of causality.

52
Proton Pump Inhibitor and Clopidogrel Interaction
According to US FDA November 17, 2009
  • New data show that when clopidogrel and
    omeprazole are taken together, the effectiveness
    of clopidogrel is reduced. Patients at risk for
    heart attacks or strokes who use clopidogrel to
    prevent blood clots will not get the full effect
    of this medicine if they are also taking
    omeprazole.

http//www.fda.gov/Drugs/DrugSafety/PostmarketDrug
SafetyInformationforPatientsandProviders/DrugSafet
yInformationforHeathcareProfessionals/ucm190787.ht
m
53
Proton Pump Inhibitor and Clopidogrel
Interaction According to Laine and Hennekens
November 13, 2009
  • In randomized trials, PPIs seem to decrease
    recurrent ulcer bleeding in patients who bled on
    low-dose aspirin and continue aspirin.
  • In addition, randomized, placebo-controlled
    trials show that both PPIs and histamine-2
    receptor antagonists decrease the development of
    endoscopic ulcers in low-dose aspirin users.
  • Current consensus recommendations do not
    specifically address clopidogrel monotherapy, but
    do state that patients taking dual antiplatelet
    therapy should receive a PPI.

Laine L and Hennekens CH. PPI and Clopidogrel
Interaction Fact or Fiction. AJG, Published
online November 13, 2009.
54
Clopidogrel and PPI Summary
  • In several studies, omeprazole decreases
    pharmacodynamic effect of clopidogrel on
    surrogate markers such as platelet aggregation.
    Studies of the other individual PPIs have not
    shown such effects.
  • Some, but not all, observational studies show
    that patients prescribed clopidogrel have small
    but significant effects of all 5 PPIs on
    increased rates of CV events in clopidogrel
    users.
  • In one randomized trial designed to test the
    hypothesis, clopidogrel users randomized to
    omeprazole have no increased risk of CV events.
  • Despite an insufficient totality of evidence,
    the FDA suggests that health care providers avoid
    prescribing omeprazole, esomeprazole, or
    cimetidine to patients receiving clopidogrel.
  • When the totality of evidence is incomplete it is
    appropriate to remain uncertain.
  • If a healthcare provider chooses to heed the FDA
    then use one of the other PPIs (e.g.,
    pantoprazole, rabeprazole) and separate the PPI
    and clopidogrel by around 14-18 hrs by
    prescribing the PPI before breakfast and
    clopidogrel at bedtime or PPI at dinner and
    clopidogrel at lunchtime

55
New Oral Antiplatelet Drugs
Adenosine Diphosphate-Receptor Antagonists
  • Prasugrel
  • Thienopyridine
  • More rapid onset of action than clopidogrel
  • Irreversible inhibitor of the P2Y12 receptor
  • Ticagrelor
  • Cyclo-pentyl-triazo-pyrimidine (CPTP)
  • More rapid onset of action than clopidogrel
  • Reversible inhibitor of the P2Y12 receptor

Not approved by FDA
56
Triton-TIMI 38
  • 13,608 patients with moderate to high-risk acute
    coronary syndromes with scheduled PCI
  • Randomized to prasugrel (60 mg loading dose and a
    10 mg daily maintenance dose) or clopidogrel (300
    mg loading dose and a 75 mg daily maintenance
    dose) for 6-15 months.

Triton TIMI Investigators. NEJM 357 2001 2015
57
TRITON-TIMI 38 EFFICACY and SAFETY

138 events
15
Clopidogrel
HR 0.81 (0.73-0.90) p0.0004
12.1
CV Death / MI / Stroke
CV Death/MI/Stroke
9.9
10
NNT 46
Prasugrel
Endpoint ()
5
35 events
TIMI Major Non-CABG Bleeds
Prasugrel
2.4
HR 1.32 (1.03-1.68) p0.03
1.8
Clopidogrel
0
NNT 167
0
180
270
360
30
60
90
450
Days
58
PLATO Ticagrelor vs Clopidogrel in Patients with
Acute Coronary Syndromes
  • 18,624 patients with acute coronary syndromes
  • Randomization
  • Ticagrelor 180 mg loading dose, 90mg BID
  • Clopidogrel 300-600 mg loading dose, 75 mg QD
  • All patients received ASA 75-325 mg

Wallentin, L et al NEJM 2009 361 1045-1057
59
PLATO Time to first primary efficacy event
(CV death, MI or stroke)
Completeness of follow-up 99.97 5 pts lost to
follow-up
13
12
11.7
Clopidogrel
11
10
9.8
9
Ticagrelor
8
7
Cumulative incidence ()
6
5
4
3
2
HR 0.84 (95 CI 0.770.92), p0.0003
1
0
0
60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,628
8,460
6,743
5,161
4,147
8,219
Clopidogrel
9,291
8,521
8,362
8,124
6,743
5,096
4,047
Wallentin, L Presented at ESC Congress 2009
Barcelona Spain
60
PLATO Time to Major Bleeding - Primary Safety
Event
Completeness of follow-up 99.97 5 pts lost to
follow-up
15
Ticagrelor
11.58
11.20
10
Clopidogrel
K-M estimated rate ( per year)
5
HR 1.04 (95 CI 0.951.13), p0.434
0
0
60
120
180
240
300
360
Days from first IP dose
No. at risk
6,826
9,235
7,246
5,129
3,783
3,433
6,545
Ticagrelor
Clopidogrel
9,186
7,305
6,930
6,670
5,209
3,841
3,479
Wallentin, L Presented at ESC 2009 Barcelona
Spain
61
Risks Associated with ADP receptor Antagonists in
Patients with ACS by Trial
Sch?mig, A NEJM 2009 361 1108-1111
62
Issues in Clinical Practice
  • Unfortunately, for healthcare providers and
  • their patients, most patients prefer the
  • prescription of pills to the proscription of
  • harmful lifestyles.

63
Double Cheeseburger, Large Fries, Jumbo Coffee..
Oh And An Aspirin -Gotta Take Care Of The Ticker
YKnow.
Aspirin May Reduce Risk Of Heart Attack
New Yorker Magazine. 1988.
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French Fries
20 years ago
Today
210 calories 2.4 ounces
610 calories 6.9 ounces
How many calories are in these fries?
Calorie difference 400 Calories
How to burn 400 calories  Walk 2 hour 20 minutes
Based on 130-pound person.
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Darwinism and Risk of Cardiovascular Disease
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Walking the Dog
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Established Risk Factors for CHD
  • Blood cholesterol 10 ? 20-30 ? in CHD
  • High blood pressure 5-6 mm Hg ? 42 ? in
    Stroke
  • 16 ? in CHD
  • Cigarette smoking Cessation 50-70 ? in CHD
  • Body weight BMIlt25 vs BMIgt27 35-55 ? in CHD
  • Physical activity 20-minute brisk walk daily
    35-55 ? in CHD

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  • We must all hang together, or assuredly we shall
    all hang separately.
  • Benjamin Franklin July 4, 1776

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GOALS OF HEALTH CARE PROVIDERS AND ACADEMIC
RESEARCHERS
  • Maximize benefit and minimize risk which is not
    to be confused with avoidance of risk.
  • Make clinical decisions based on the totality of
    evidence not dependence on particular subgroups
    of particular studies.
  • Avoid misstatements of benefit to risk ratios
    which may increase publicity, academic promotions
    and grant support in the short run but confuse
    colleagues and frighten patients and make it
    more difficult to conduct high quality research
  • ( COX-2 inhibitors and glitazones)

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