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Transcript
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
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 Women’s 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.
Death is inevitable but
premature death is not.
Sir Richard Doll
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
Milestones 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
Physician’s 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
Moses Receiving The Tablets
From God
Milestones 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
Physician’s 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
Milestones 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
Physician’s 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
Milestones 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
Physician’s 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
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. 1971;231:232-5.
Totality Of Evidence


Basic research (why)
Epidemiology (whether)

descriptive studies
 case reports
 case series
 ecological studies
Hennekens. Epidemiology in Medicine. 1987.

analytic studies
 observational
case-control
 cohort
 randomized trials

Observational Epidemiologic Studies



Some but not all case-control & cohort studies indicate that
individuals and/or their health care providers who selfselect 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
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. 2002;324:71.
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
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
Second International Study of Infarct Survival
ISIS-2 Collaborative Croup Lancet. 1988 Aug 13;332: 349-60.
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. 2002;7:77-80
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, nonfatal 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.
Greater Relative Risk Reductions (RRR) for
Pravastatin (Prava) + Aspirin (ASA)
versus Prava or ASA alone
RRR
Relative Risk (95% CI)
Fatal or Non-Fatal MI
0.69
Prava+ASA vs ASA Alone
31%
0.74
26%
Prava+ASA vs Prava Alone
0.400
0.600
0.800
1.000
Ischemic Stroke
0.71
Prava+ASA vs ASA Alone
0.69
Prava+ASA vs Prava Alone
0.400
29%
0.600
31%
0.800
1.000
CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke
0.76
Prava+ASA vs ASA Alone
0.87
Prava+ASA vs Prava Alone
0.400
24%
0.600
Hennekens CH et al. Arch Int Med 2004; 164:945-948.
0.800
13%
1.000
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. 2009;373:1849-60.
10-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%
Dose Of Aspirin:
Indirect Comparisons
No Trials
% Reduction
(SE)
3P value
500-1500
34
19 (3)
<0.00001
160-325
19
26 (3)
<0.00001
75-150
12
32 (6)
<0.0001
<75
3
13 (8)
NS
68
23 (2)
<0.0001
Regimen
Aspirin Alone (mg)
Total
X32 het = 8.2, P=.04.
.
AntiThrombotic
Trialists Collaboration. Lancet, 2002
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
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 (160325, 75-160, or <75), risks of major extracranial
bleeds were similar.
Direct comparisons: In the two trials that directly
compared daily aspirin doses of 75-325mg with
<75mg, risks of major extracranial bleeds were
similar.
AntiThrombotic Trialists Collaboration. Lancet, 2002
Optimal Dosing For Aspirin In CHD
Secondary Prevention
&
Primary Prevention
75 mg – 325 mg
Acute CVD Syndrome
162.5 mg – 325 mg
Hennekens CH, Dyken M, Fuster V:Circ. 1997
Effects 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
Acetaminophen
Hennekens CH, Borzak S: JCPT, 2008
Prothrombotic effects and
risks of similar magnitude
to NSAIDS on CVD
No effects on platelets
but risks on liver and
kidneys
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
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.
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 2006,3:4-5
Dual Antiplatelet Therapy


Risks versus Monotherapy
Benefits and risks:
Aspirin + Dipyrimadole
Aspirin + Clopidogrel
Issues with Clopidogrel
Clopidogrel versus Prasugrel
Clopidogrel versus Ticagrelor
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; 22:315-321
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 (p=0.016)
15% by dipyrimadole (p=0.039)
24% by the combination of ASA and dipyrimadole
(p<0.001)
Diener, HC et al J Neurol Sci .1996 Nov; 143: (1-2)1-13
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, 2008;359:1238-1251
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.
CURE Trial Investigators NEJM. 2001;345: 494-502
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 clopidogrel+162mg aspirin(22,960) or
placebo +160mg aspirin(22,891)
COMMIT Collaborative Group. Lancet 2005; 366: 1607-1621.
COMMIT Clopidogrel Arm:
Primary Outcomes
End point
Clopidogrel,
n=22 961 (%)
Placebo,
n=22 891 (%)
Odds ratio (95% P value
CI)
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.
COMMIT: 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.
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
ISIS-2 Investigators, Lancet, 1988
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; 107:2908-2913;
Laine L, Hennekens CH: Am J Gastro. Published online 11/13/09
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
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 (p=0.14) 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
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
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.


Bhatt D, et al The COGENT trial. Presented at TCT September 24, 2009.


When effect sizes are small to moderate (relative risks < 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
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.
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/PostmarketDrugSafetyInformationforPati
entsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm19078
7.htm
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 lowdose 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.
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
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-triazopyrimidine (CPTP)
More rapid onset of action
than clopidogrel
Reversible inhibitor of the
P2Y12 receptor
* Not approved by FDA
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
TRITON-TIMI 38: EFFICACY and SAFETY
15
138
events
Clopidogrel
12.1
Endpoint (%)
CV
CVDeath/MI/Stroke
Death / MI / Stroke
9.9
10
Prasugrel
5
TIMI Major Non-CABG Bleeds
35
events
Prasugrel
Clopidogrel
2.4 HR 1.32
1.8 (1.03-1.68)
p=0.03
0
0 30 60 90
180
270
Days
360
HR 0.81
(0.73-0.90)
p=0.0004
NNT = 46
450
NNT = 167
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
Cumulative incidence (%)
PLATO: Time to first primary efficacy event
(CV death, MI or stroke)
13
12
11
10
9
Completeness of follow-up 99.97% = 5 pts lost to follow-up
9.8
Ticagrelor
8
7
6
5
4
3
2
1
0
HR 0.84 (95% CI 0.77–0.92), p=0.0003
0
No. at risk
Ticagrelor
11.7
Clopidogrel
60
120
180
240
300
360
Days after randomisation
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel 9,291
8,521
8,362
8,124
6,743
5,096
4,047
Wallentin, L Presented at ESC Congress 2009 Barcelona Spain
PLATO Time to Major Bleeding - Primary Safety
Event
K-M estimated rate (% per year)
Completeness of follow-up 99.97% = 5 pts lost to follow-up
15
Ticagrelor
10
Clopidogrel
11.58
11.20
5
HR 1.04 (95% CI 0.95–1.13), p=0.434
0
0
60
120
180
240
300
360
Days from first IP dose
No. at risk
Ticagrelor
9,235
7,246
6,826
6,545
5,129
3,783
3,433
Clopidogrel
9,186
7,305
6,930
6,670
5,209
3,841
3,479
Wallentin, L Presented at ESC 2009 Barcelona Spain
Risks Associated with ADP receptor
Antagonists in Patients with ACS by Trial
Schӧmig, A NEJM 2009; 361: 1108-1111
Issues in Clinical Practice
Unfortunately, for healthcare providers and
their patients, most patients prefer the
prescription of pills to the proscription of
harmful lifestyles.
Double Cheeseburger,
Large Fries, Jumbo
Coffee.. Oh And An
Aspirin -Gotta Take
Care Of The Ticker
Y’Know.
Aspirin May
Reduce Risk Of
Heart Attack
New Yorker Magazine. 1988.
French Fries
20 years ago
210 calories
2.4 ounces
Today
610 calories
How many
calories are
ounces
in6.9
these
fries?
Calorie difference: 400 Calories
How to burn* 400 calories:
Walk 2 hour 20 minutes
*Based on 130-pound person.
Darwinism and Risk
of Cardiovascular Disease
Walking the Dog
A bit of cultural news …..
After a 2 year loan
to the United States,
David returns to
Italy…
…Proud Sponsors
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
BMI<25 vs BMI>27 = 35%-55%  in CHD
Physical activity
20-minute brisk walk daily = 35%-55%  in CHD
Shifting Worldwide Burden of Disease
1990
All Other
25.5%
2020
Cancer
11.9%
All Other
33.2%
Cancer
18.0%
CVD
28.4%
Communicable,
Perinatal, Nutritional
34.2%
Communicable,
Perinatal, Nutritional
15.1%
CVD
33.7%
Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996.
2005: Beijing, China vs US
Beijing
US
Cigarette smoking
in men
58%
Same as 1950
Body Mass Index
Weight in Kg/
Height in m2
24.8
Same as 1990
1990 – 2010: Fast Food restaurants
in China
1990
2010
McDonalds
1
800 mainland
200 Hong Kong
KFC
–
1,900
Selected Worldwide Death Rates
From CHD in Adults Aged 34 to 74
Years*
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.
“We must all hang together, or
assuredly we shall all hang separately.”
– Benjamin Franklin
July 4, 1776
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)