Aspirin in the primary and secondary prevention of vascular diseases

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. ROUND TABLE DISCUSSION ON
ANTI-PLATELETS THERAPY
• Speaker : Dr. Thin Thin
M.B.,B.S, M.Med,Sc(Int.Med)
Senior Consultant (Physician)
Medical Unit, Monywar General Hospital
• Date : 27.5.2017 (Saturday)
• Time : 7:00 pm onward
• Venue : Sizzle-7, Monywar

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

5. 0
100
200
300
400
500
600
Total
admission
Stroke Refer S/L
Jan 486 60 0 18
Feb 403 34 0 6
Mar 500 66 0 17
Apr 538 42 0 21
Axis
Title
Cerebrovascular accident cases admitted
to Monywa General Hospital in the year of
2017

6. 0
100
200
300
400
500
600
Total
admission
ACS Refer S/L
Jan 486 11 0 3
Feb 403 12 1 2
Mar 500 17 3 3
Apr 538 10 1 6
Axis
Title
Acute coronary syndrome cases admitted
to Monywa General Hospital in the year of
2017

7. 0
100
200
300
400
500
600
700
800
Jan Feb Mar Apr May June July Aug Sep Oct Nov Dec
Total admission 709 567 432 579 793 628 660 495 588 690 584 464
Stroke 46 38 29 31 34 44 37 52 51 45 37 36
Refer 0 0 0 0 0 0 0 1 0 0 2 0
S/L 9 9 8 15 11 12 15 14 12 11 11 10
Cerebrovascular accident cases admitted
to Monywa General Hospital in the year of
2016

8. 0
100
200
300
400
500
600
700
800
Jan Feb Mar Apr Ma
y
Jun
e
July Aug Sep Oct Nov Dec
Total admission 709 567 432 579 793 628 660 495 588 690 584 464
ACS 12 13 12 19 13 8 9 20 14 16 8 11
Refer 0 0 0 0 0 0 0 0 0 0 0 0
S/L 3 3 2 2 1 0 3 5 4 1 1 2
Acute coronary syndrome cases
admitted to Monywa General
Hospital in the year of 2016

14. 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

15. Aspirin
◦Chemical Name
◦Acetylsalicylic acid (ASA)

16. Aspirin Timeline / History

18. 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

20. 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

22. 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.

23. Hennekens. Epidemiology in Medicine. 1987.
Totality Of Evidence
Basic research (why)
Epidemiology (whether)
◦ descriptive studies
case reports
case series
ecological studies
 analytic studies
 observational
 case-control
 cohort
 randomized trials

24. 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

25. 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.

26. 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

27. 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

28. ISIS-2 Collaborative Croup Lancet. 1988 Aug 13;332: 349-60.
Second International Study of Infarct Survival

29. 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

30. 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
Summary: Additive Benefits of Aspirin and Statins in
Secondary Prevention of CVD
Hennekens CH, et al. Arch Int Med, 2001.

31. Hennekens CH et al. Arch Int Med 2004; 164:945-948.
Relative Risk (95% CI) RRR
Prava+ASA vs ASA Alone
Prava+ASA vs Prava Alone
Fatal or Non-Fatal MI
0.400 0.800 1.000
0.600
0.400 0.800 1.000
0.600
CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke
Prava+ASA vs ASA Alone
Prava+ASA vs Prava Alone
24%
0.76
13%
0.87
31%
0.69
26%
0.74
Prava+ASA vs ASA Alone
Prava+ASA vs Prava Alone
29%
0.71
31%
0.69
Ischemic Stroke
0.400 0.800 1.000
0.600
Greater Relative Risk Reductions (RRR) for
Pravastatin (Prava) + Aspirin (ASA)
versus Prava or ASA alone

32. 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.

33. 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%

34. Dose Of Aspirin:
Indirect Comparisons
% Reduction
Regimen No Trials (SE) 3P value
Aspirin Alone (mg)
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
Total 68 23 (2) <0.0001
X3
2 het = 8.2, P=.04.
.
AntiThrombotic Trialists Collaboration. Lancet, 2002

35. 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

36. 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
<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

37. 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 V:Circ. 1997

38. 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

39. 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

40. 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.

41. Lack of Sex Differences in Response to
Aspirin: ATT Patients with Prior MI or Stroke
Endpoint Men Women
Major coronary events 19% 25%
Stroke 17% 22%
Percent Reductions
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

42. Dual Antiplatelet Therapy
Risks versus Monotherapy
Benefits and risks:
Aspirin + Dipyrimadole
Aspirin + Clopidogrel
Issues with Clopidogrel
Clopidogrel versus Prasugrel
Clopidogrel versus Ticagrelor

43. 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

44. 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

45. 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

46. 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.

47. CURE Trial Investigators NEJM. 2001;345: 494-502

48. 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.

49. 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%
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

50. COMMIT: Major Bleeding
COMMIT Collaborative Group. Lancet 2005; 366: 1607-1621.
Bleeding Clopidogrel (%) Placebo
(%)
Excess per
1000
p
Any major
bleed
0.58 0.55 0.4 0.59

51. 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

52. ISIS-2 Investigators, Lancet, 1988

53. 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

54. 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

55. 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

56. 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

57. 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 < 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.

58. 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

59. 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.

60. 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

61. New Oral Antiplatelet Drugs
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
Adenosine Diphosphate-Receptor Antagonists
* Not approved by FDA

62. 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

63. 0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81
(0.73-0.90)
p=0.0004
Prasugrel
Clopidogrel
Days
Endpoint
(%)
12.1
9.9
HR 1.32
(1.03-1.68)
p=0.03
Prasugrel
Clopidogrel
1.8
2.4
138
events
35
events
TRITON-TIMI 38: EFFICACY and SAFETY
CV Death / MI / Stroke
NNT = 46
NNT = 167
CV Death/MI/Stroke
TIMI Major Non-CABG Bleeds

64. 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

65. PLATO: Time to first primary efficacy event
(CV death, MI or stroke)
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
12
11
10
9
8
7
6
5
4
3
2
1
0
13
Cumulative
incidence
(%)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
Completeness of follow-up 99.97% = 5 pts lost to follow-up
Wallentin, L Presented at ESC Congress 2009 Barcelona Spain

66. PLATO Time to Major Bleeding - Primary Safety Event
No. at risk
Clopidogrel
Ticagrelor
9,186
9,235
7,305
7,246
6,930
6,826
6,670
Days from first IP dose
5,209
5,129
3,841
3,783
3,479
3,433
0 60 120 180 240 300 360
10
5
0
15
Clopidogrel
Ticagrelor
11.20
11.58
6,545
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-M
estimated
rate
(%
per
year)
Completeness of follow-up 99.97% = 5 pts lost to follow-up
Wallentin, L Presented at ESC 2009 Barcelona Spain

67. Schӧmig, A NEJM 2009; 361: 1108-1111
Risks Associated with ADP receptor
Antagonists in Patients with ACS by Trial

68. Issues in Clinical Practice
Unfortunately, for healthcare providers and
their patients, most patients prefer the
prescription of pills to the proscription of
harmful lifestyles.

69. 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.

70. French Fries
How to burn* 400 calories:
Walk 2 hour 20 minutes
20 years ago Today
210 calories
2.4 ounces How many calories are
in these fries?
610 calories
6.9 ounces
Calorie difference: 400 Calories
*Based on 130-pound person.

71. Darwinism and Risk
of Cardiovascular Disease

72. Walking the Dog

73. 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

76. “We must all hang together, or assuredly
we shall all hang separately.”
– Benjamin Franklin
July 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)