Title: UPDATE%20ON%20ANTIPLATELET%20THERAPY%20IN%20THE%20TREATMENT%20AND%20PREVENTION%20OF%20CARDIOVASCULAR%20DISEASE
1UPDATE 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
2Disclosure
- 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)
5CONTRIBUTIONS 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)
6OBJECTIVES
- 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
7Milestones For Aspirin
- 5th century BC Hippocrates
- 1897 AD Felix Hoffman/Friedrich Bayer synthesize
aspirin - 20th Century Aspirin becomes
the most widely used drug in the world for pain
relief - 1971 John Vane
discovers CVD mechanism - 1988 Physicians Health Study shows aspirin
prevents first MI - 1988 APT shows
aspirin decreases MI, stroke, and CVD death for
survivors of MI and stroke - 1988 ISIS-2 shows
aspirin decreases mortality during acute MI
8Moses Receiving The Tablets From God
9Milestones For Aspirin
- 5th century BC Hippocrates
- 1897 AD Felix Hoffman/Friedrich Bayer synthesize
aspirin - 20th Century Aspirin becomes
the most widely used drug in the world for pain
relief - 1971 John Vane
discovers CVD mechanism - 1988 Physicians Health Study shows aspirin
prevents first MI - 1988 APT shows
aspirin decreases MI, stroke, and CVD death for
survivors of MI and stroke - 1988 ISIS-2 shows
aspirin decreases mortality during acute MI
10(No Transcript)
11Milestones For Aspirin
- 5th century BC Hippocrates
- 1897 AD Felix Hoffman/Friedrich Bayer synthesize
aspirin - 20th Century Aspirin becomes
the most widely used drug in the world for pain
relief - 1971 John Vane
discovers CVD mechanism - 1988 Physicians Health Study shows aspirin
prevents first MI - 1988 APT shows
aspirin decreases MI, stroke, and CVD death for
survivors of MI and stroke - 1988 ISIS-2 shows
aspirin decreases mortality during acute MI
12(No Transcript)
13Milestones For Aspirin
- 5th century BC Hippocrates
- 1897 AD Felix Hoffman/Friedrich Bayer synthesize
aspirin - 20th Century Aspirin becomes
the most widely used drug in the world for pain
relief - 1971 John Vane
discovers CVD mechanism - 1988 Physicians Health Study shows aspirin
prevents first MI - 1988 APT shows
aspirin decreases MI, stroke, and CVD death for
survivors of MI and stroke - 1988 ISIS-2 shows
aspirin decreases mortality during acute MI
14The 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.
15Totality 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.
16Observational 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, theonly
reliable design strategy is the large
randomizedtrial 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
17Evolution 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.
18Aspirin 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
19Benefits 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
20Second International Study of Infarct Survival
ISIS-2 Collaborative Croup Lancet. 1988 Aug
13332 349-60.
21Hypothesis 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
22Summary 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.
23Greater 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)
25Potential 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
26Summary 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.
2710-Year Risk of a First CHD Event in the Six
Major Trials of Aspirin in Primary Prevention of
CVD
WHS 2.5
HOT 3.6
PPP 4.3
PHS 4.8
BMD 8.9
TPT 12.4
28Dose 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
.
29Time 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
31Optimal 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
32Effects On Platelets
ASA Irreversible inhibition
NSAIDS Reversible inhibition Possible but unproven small clinical CVD benefits of naproxen Possible but unproven inhibition of clinical CVD benefits of aspirin by ibuprofen
COXIBS Prothrombotic effects and risks of similar magnitude to NSAIDS on CVD
Acetaminophen No effects on platelets but risks on liver and kidneys
Hennekens CH, Borzak S JCPT, 2008
33Dose-Dependent Side Effects of AspirinThe 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
34Possible 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.
35Lack 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
36Dual Antiplatelet Therapy
- Risks versus Monotherapy
- Benefits and risks
- Aspirin Dipyrimadole
- Aspirin Clopidogrel
- Issues with Clopidogrel
- Clopidogrel versus Prasugrel
- Clopidogrel versus Ticagrelor
37DUAL 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
38Aspirin DipyrimadoleSecond 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
39Aspirin 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
40Clopidogrel 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.
41CURE Trial Investigators NEJM. 2001345 494-502
42Second 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.
43COMMIT Clopidogrel Arm Primary Outcomes
End point Clopidogrel, n22 961 () Placebo, n22 891 () Odds ratio (95 CI) P value
Death/MI/stroke 9.2 10.1 0.91 (0.86-0.97) 0.002
Death from any cause 7.5 8.1 0.93 (0.87-0.99) 0.03
COMMIT Collaborative Group. Lancet 2005 366
1607-1621.
44COMMIT Major Bleeding
Bleeding Clopidogrel () Placebo () Excess per 1000 p
Any major bleed 0.58 0.55 0.4 0.59
COMMIT Collaborative Group. Lancet 2005 366
1607-1621.
45CHARISMA
- 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
46ISIS-2 Investigators, Lancet, 1988
47Issues 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
48Dose 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
49Clopidogrel 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
50ASA 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
51Proton 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.
52Proton 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
53Proton Pump Inhibitor and Clopidogrel
InteractionAccording 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.
54Clopidogrel 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
55New 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
56Triton-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
57TRITON-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
58PLATO 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
59PLATO 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
60PLATO 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
61Risks Associated with ADP receptor Antagonists in
Patients with ACS by Trial
Sch?mig, A NEJM 2009 361 1108-1111
62Issues in Clinical Practice
- Unfortunately, for healthcare providers and
- their patients, most patients prefer the
- prescription of pills to the proscription of
- harmful lifestyles.
63Double 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.
64French 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.
65Darwinism and Risk of Cardiovascular Disease
66Walking the Dog
67A bit of cultural news ..
After a 2 year loan to the United States, David
returns to Italy
68Proud Sponsors
69Established Risk Factors for CHD
- Blood cholesterol10 ? 20-30 ? in CHD
- High blood pressure5-6 mm Hg ? 42 ? in
Stroke - 16 ? in CHD
- Cigarette smokingCessation 50-70 ? in CHD
- Body weight BMIlt25 vs BMIgt27 35-55 ? in CHD
- Physical activity20-minute brisk walk daily
35-55 ? in CHD
70(No Transcript)
71(No Transcript)
72Shifting Worldwide Burden of Disease
1990
2020
Cancer 11.9
Cancer 18.0
All Other 25.5
All Other 33.2
CVD 28.4
CVD 33.7
Communicable,Perinatal, Nutritional 15.1
Communicable,Perinatal, Nutritional 34.2
Murray CJL, Lopez AD, eds. The Global Burden of
Disease. Cambridge, Mass Harvard University
Press 1996.
732005 Beijing, China vs US
Beijing
US
58
Same as 1950
Cigarette smokingin men
24.8
Same as 1990
Body Mass IndexWeight in Kg/Height in m2
741990 2010 Fast Food restaurants in China
75Selected Worldwide Death Rates From CHD in Adults
Aged 34 to 74 Years
Death Rate (per 100,000) Death Rate (per 100,000) Death Rate (per 100,000)
Country Men Women Total
Russian Federation 638 231 869
Bulgaria 353 133 486
United Kingdom 265 97 362
United States 214 87 301
Austria 223 74 297
Germany 206 72 278
France 87 20 107
Japan 57 20 77
All values are for 1997.British Heart
Foundation. Coronary Heart Disease Statistics
British Heart Foundation Statistics Database.
London, England British Heart Foundation 2002.
76- We must all hang together, or assuredly we shall
all hang separately. - Benjamin FranklinJuly 4, 1776
77GOALS 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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