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Carlo Patrono
Catholic University School of Medicine,
Rome, Italy
New York Cardiovascular Symposium 2016
New York, 9 December 2016
Aspirin Therapy in Primary
Cardiovascular Prevention
I received consultant and speakers fees from Amgen,
AstraZeneca and Bayer
I received grant support for investigator-initiated
research from:
• European Commission, FP6 and FP7 Programmes
• Bayer AG
Disclosure
Antithrombotic Trialists’ Collaboration
Meta-Analysis of Aspirin Trials in High-Risk Patients
(mg daily) Aspirin Control Reduction (SE)
75-150 10.9% 15.2% 32 (6)
160-325 11.5% 14.8% 26 (3)
500-1500 14.5% 17.2% 19 (3)
Any dose 12.9% 16.0% 23 (2)
(2P<0.00001)
1.00.50.0 1.5 2.0BMJ 2002;324:71-86
Aspirin dose % Vascular Events % Odds
Odds ratio (CI)
Does One Size Fit All?
Probably yes, because:
a) Inactivation of platelet COX-1 and suppression of
thromboxane production are cumulative upon
repeated daily dosing, and saturable at doses as low
as 30-40 mg daily.
b) There is no evidence that higher doses (e.g., 300-
325 mg) are more effective than lower doses (i.e.,
75-100 mg), and the opposite may be true.
Cumulative Inhibition of Platelet COX-1 by Low Doses of
Aspirin Shifts the Dose-Response Curve by a Factor
Equivalent to the Daily Platelet Turnover
100
80
60
40
20
0
1 10 100 mgAspirin
ID50=3.2 mg ID50=26 mg
Daily dose
Single dosePercent
inhibition
of serum
TXB2
Patrono et al., Circulation 1985; 72:1177-84
The ADAPTABLE TrialThe Patient-Centered Outcomes Research Institute(PCORI) has announced a three-year, $14 millionclinical trial comparing the benefits and risk for sideeffects of two commonly used doses of aspirin – low-dose 81 mg (“baby aspirin”) and regular strength 325 mg– in preventing heart attacks and strokes in people withheart disease.
The study, called ADAPTABLE (Aspirin Dosing: APatient-centric Trial Assessing Benefits and Long-TermEffectiveness), aims to enroll and follow as many as20,000 patients with heart disease quickly and efficientlyusing PCORnet’s resources.
Patrignani et al, J Thromb Haemost 2014; 12:1320-30.
Kinetics of Acetylsalicylic Acid in the Systemic Circulation of 24
Healthy Subjects after Dosing with EC-Aspirin 100 mg Daily.
Cmax: 3-4 mM
Does One Dosing Regimen Fit All?
Maybe not, because there is substantial interindividual
variability in the rate of recovery of platelet COX-1
activity during the 24-hour dosing interval, perhaps
requiring more frequent dosing (e.g., bid) in patients with
accelerated renewal of the drug target.
COX-1
COX-1
COX-2
T2DM
Healthy
Aspirin10
8
6
4
2
00 2 4 6 8 10 12 14 16 18 20 22 24
Serum
TXB2
ng/ml
Time (h)
Arachidonic Acid
Prostaglandin H2
Thromboxane A2 Thromboxane B2
Platelet aggregation (inactive metabolite)
Platelet Prostaglandin G/H synthase 1
Aspirin
Altered Pharmacodynamics of Low-Dose Aspirin in Type 2 Diabetes
Patrono, Rocca, De Stefano Blood 2013;121:1701-11.
Aspirin
T2DM
Aspirin
Determinants of the Rate of Recovery of Platelet
COX-1 in Patients Treated with Low-Dose Aspirin
1Pascale et al, Blood 2012; 2Rocca et al, JTH 2012; 3Rocca et al, AHA 2016
Clinical Setting
Essential Thrombocythemia1
Type 2 Diabetes Mellitus2
CHD or CVD without Diabetes2
CABG ± AVR with CPB 3
Pharmacokinetic Determinant
Body Weight
Body Weight
Pharmacodynamic Determinant
Abnormal Megakaryopoiesis
Platelet Turnover
Platelet Turnover
Annual risk of a vascular event on placebo
Subjects
in whom a
vascular event
is prevented by
aspirin per 1,000
treated for 1 year
0
10
20
30
40
50
60
0 5 10 15 20%
Healthy Subjects
Stable Angina
Survivors of MI
Unstable
Angina
The Risk of Vascular Complications is the Major
Determinant of the Absolute Benefit of Antiplatelet Therapy
Patrono et al, Chest
2008;133:199S-233S
NNT
20
55
100
1000
Gastrointestinal Lesions Induced by NSAIDs
1. Acute Mucosal Lesions:
70-90% of patients
2. Chronic/Deep GD Ulcers
Endoscopic ulcers: 30-50% of patients
Symptomatic ulcers: <10% of patients
3. Complications:
1-2% of patients
Estimates of UGIC Rates in Male Subjects, as a Function of Age, Prior History and Low-Dose Aspirin
Rate of
UGIC per
1,000
person-yrs
0
15
30
45
60
75
90
105
120
Age
Patrono, García Rodríguez, Landolfi & Baigent, NEJM 2005; 353:2373-83
<50 50-59 60-69 70-79 80
NNH=17
NNH=1667
None
UGI pain
Uncomplicated Ulcer
Complicated Ulcer
Control Aspirin History
0
Vascular Events ( ) Avoided vs Major Bleeds ( )
Caused per 1,000 Treated with Aspirin per Year
Annual risk of a serious vascular event on placebo
0
2
4
6
8
10
12
1.0 2.0 3.0 4.0 %
( )
0
2
4
6
8
10
12
( )
UK Doc
US PhysPPP
HOT
SAPAT
TPT
WHS
Patrono, García Rodríguez,
Landolfi & Baigent, NEJM
2005;353:2373-83
Non-fatal MI 596 (0.18%/y) 756 (0.23%/y) 0.77 (0.67-0.89)
CHD death 372 (0.11%/y) 393 (0.12%/y) 0.95 (0.78-1.15)
(a) Any major
coronary event934 (0.28%/y) 1115 (0.34%/y) 0.82 (0.75-0.90)
P=0.00002
Non-fatal stroke 553 (0.17%/y) 597 (0.18%/y) 0.92 (0.79-1.07)
Stroke death 119 (0.04%/y) 98 (0.03%/y) 1.21 (0.84-1.74)
(b) Any Stroke 655 (0.20%/y) 682 (0.21%/y) 0.95 (0.85-1.06) P=0.4
(c) Vascular death 619 (0.19%/y) 637 (0.19%/y) 0.97 (0.87-1.09) P=0.7
0.5 0.75 1.0 1.25 1.5
End-point Allocated
aspirinAdjusted control
Ratio of annual event rates (& CI)
Aspirin : Control
Events (% per annum)
(a/b/c) any serious
vascular event1671 (0.51%/y) 1883 (0.57%/y) 0.88 (0.82-0.94)
P=0.0001
99% or 95% confidence intervals
Aspirin better Aspirin worse
Serious Vascular Events in Primary Prevention Trials
ATT Collaboration, Lancet 2009;373:1849-60
American College of Chest Physicians
2012 Guidelines
For persons aged 50 years or older without
symptomatic cardiovascular disease, we
suggest low-dose aspirin 75 to 100 mg
daily over no aspirin therapy (Grade 2B).
Vandvik et al, CHEST 2012; 141(Suppl):e637S–e668S
2016 European Guidelines on
Cardiovascular Disease Prevention in
Clinical Practice
Aspirin is not recommended in individuals
without CVD due to the increased risk of
major bleeding (Grade IIIB).
Piepoli et al, Atherosclerosis 2016;252:207-274
Release of pro-thrombotic
prostanoids
Release of pro-inflammatory, mitogenic
and pro-angiogenic autacoids
Release of microparticles
Platelet surface for
clotting factors
assembly
AA
PGH2
TXA2, PGE2
aspirin
Patrono, JACC 2015;66:74-85
- Evidence from >50 RCTs
and meta-analyses
- Evidence from several
RCTs and meta-analyses
- Evidence from observational studies and meta-analyses
- Evidence from post-hoc long-term follow-up of RCTs and
meta-analyses
- Currently being tested prospectively in primary
prevention and adjuvant RCTs
- Limited evidence from
observational studies
- Currently being tested in
the ASPREE primary
preventional trial
Coronary
Atherothrombosis
Venous
ThromboembolismColorectal Cancer Cognitive Impairment
Sources of Evidence Supporting a Chemopreventive
Effect of Aspirin Against Gastrointestinal Cancers
1. Over 40 observational case-control studies and their meta-
analysis (Algra & Rothwell, Lancet Oncol 2012).
2. Four randomized, placebo-controlled clinical trials in subjects
with sporadic colorectal adenomas (Cole, JNCI 2009).
3. A placebo-controlled RCT in the Lynch syndrome with post-
trial follow-up (CAPP2, NEJM 2008; Lancet 2011).
4. A post-hoc individual patient data (IPD) meta-analysis of 51
randomized controlled trials in prevention of vascular events
(Rothwell et al, Lancet 2012).
Females, age 50-59 years Females, age 65-74 years
Bleeding CVD Cancer Bleeding CVD Cancer
A
Non-fatal bleeding events
Vascular death
Non-fatal MI/stroke
All cancers
Five-Year Risk of Vascular Events and Major Bleeding
Based on Primary Prevention Trials of Aspirin vs Placebo,
and Hypothetical 10% Reduction in Cancer Incidence by
Age and Sex
Thun, Jacobs, Patrono Nature Rev Clin Oncol 2012;9:259-67
5-year
risk
(%)
A
2.8%
C
3.1%
A
0.9%
C
1.1%
A C
0.3% 0.2%
0
5
10
15
A
5.8%
C
6.5%
A C
0.9%0.5%
3.9%
C
4.5%
0
5
10
15
+0.1% -0.2%
-0.3%
+0.4%
-0.6%
-0.7%
Five-Year Risk of Vascular Events and Major Bleeding
Based on Primary Prevention Trials of Aspirin vs Placebo,
and Hypothetical 10% Reduction in Cancer Incidence by
Age and SexMales, age 50-59 years Males, age 65-74 years
Bleeding CVD Cancer Bleeding CVD Cancer
Non-fatal bleeding events
Vascular death
Non-fatal MI/stroke
All cancers
Thun, Jacobs, Patrono Nature Rev Clin Oncol 2012;9:259-67
5-year
risk
(%)
A
3.1%
C
3.5%
A
3.4%
C
3.9%
0.3%
A C
0.5%
0
5
10
15
A
9.9%
C
11.0%
A
8.0%
9.2%
CA C
1.2%0.7%
0
5
10
15
+0.2%
-0.5%-0.4%
+0.5%
-1.2%
-1.1%
Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force
Recommendation StatementPopulation Recommendation Grade
Adults aged 50
to 59 years
The USPSTF recommends initiating low-dose aspirin use
for the primary prevention of cardiovascular disease (CVD)
and colorectal cancer (CRC) in adults aged 50 to 59 years
who have a 10% or greater 10-year CVD risk, are not at
increased risk for bleeding, have a life expectancy of at
least 10 years, and are willing to take low-dose aspirin daily
for at least 10 years.
B
Adults aged 60
to 69 years
The decision to initiate low-dose aspirin use for the primary
prevention of CVD and CRC in adults aged 60 to 69 years
who have a 10% or greater 10-year CVD risk should be an
individual one. Persons who are not at increased risk for
bleeding, have a life expectancy of at least 10 years, and
are willing to take low-dose aspirin daily for at least 10
years are more likely to benefit. Persons who place a higher
value on the potential benefits than the potential harms may
choose to initiate low-dose aspirin.
C
Bibbins-Domingo et al. Ann Intern Med 2016;164:836-45
Ongoing Randomised Trials of Aspirin vs Placebo:
High-Risk IndividualsStudy Regimen(s) Treatment
duration
N Eligibility Primary
endpoint
Estimated total of
all cancers
End
date
≤5
years
>5
years
ACCEPT-D A100 vs open
control;
simvastatin
for all
5 y 5170 Diabetes, no
CVD
CV death, non-
fatal stroke,
nonfatal MI,
other CV
hospitalisation
~300 - 2015
ARRIVE A100 enteric
coated vs P
5y 12,000 10-20%
estimated 10y
risk of CHD
MI, stroke, CV
death, unstable
angina, TIA
~800 - 2016
ASPREE A100 vs P 5 y 19,000 Elderly, no
diabetes or
CVD
Death,
dementia or
significant
disability
~1000 - 2017
ASCEND A100 vs P
(ω3FA vs P)
7.5 y 15,000 Diabetes, no
CVD
MI, stroke or
TIA, or CV
death
~900 ~500 in
trial,
then
registry)
2018
Patrono, JACC 2015;66:74-85
Vascular Events ( ) Avoided vs Major Bleeds ( )
Caused by Aspirin per 1,000 Treated per Year
0
2
4
6
8
10
12
0 1 2 3 % per annumRisk of Occlusive Vascular Events
( )
( )
NNT=500-1,000
NNH=500-1,000
Consider aspirin on
an individual basis,
after evaluating
potential benefits
and risks
NNT=?
NNH=?
Need for new trials:
ASCEND
ACCEPT-D
ASPREE
ARRIVE
NNT=≤100
NNH=500-1,000
Use aspirin routinely unless contraindicated
BENEFIT
HARM
Patrono, JACC 2015;66:74-85