UPDATE%20ON%20ANTIPLATELET%20THERAPY%20IN%20THE%20TREATMENT%20AND%20PREVENTION%20OF%20CARDIOVASCULAR%20DISEASE

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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

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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.

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

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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)

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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 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

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Moses Receiving The Tablets From God
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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 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

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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 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

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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 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

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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.
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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, 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
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.
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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
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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
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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
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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.
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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.
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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

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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.
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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
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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
.
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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
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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
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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
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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 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
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Dose-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
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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.
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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
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Dual Antiplatelet Therapy

• Risks versus Monotherapy
• Benefits and risks
• Aspirin Dipyrimadole
• Aspirin Clopidogrel
• Issues with Clopidogrel
• Clopidogrel versus Prasugrel
• Clopidogrel versus Ticagrelor

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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
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Aspirin 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
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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
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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.

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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
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.
44
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.
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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
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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
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.
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.
64
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.
65
Darwinism and Risk of Cardiovascular Disease
66
Walking the Dog
67
A bit of cultural news ..
After a 2 year loan to the United States, David
returns to Italy
68
Proud Sponsors
69
Established 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

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Shifting 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.
73
2005 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
74
1990 2010 Fast Food restaurants in China
75
Selected 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

77
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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