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