ASIAM
V Congresso Nazionale
Riccione - 15/17 maggio 2015
Aspirina a basso dosaggio in
prevenzione primaria
Claudio Ferri
Università dell’Aquila
Cattedra e Scuola di Medicina Interna – Dipartimento MeSVA
Divisione di Medicina Interna e Nefrologia – Ospedale San Salvatore
Absolute risk difference in relation to
placebo in primary prevention trials
Absolute number of nontrivial bleedings
caused versus nonfatal MIs averted
Absolute number of nontrivial bleedings caused versus total CV events averted
Seshasai SR et al, Arch Intern Med. 2012;172(3):209-216
Gai
l
/
N
ati
o
nal
Cancer
I
n
sti
t
ute
Approach
of Number
the analysis. needed to treat and number needed to harm
Number needed to treat and number needed to harm
in person-years for primary prevention with lowTable 3B.
Numberaspirin
needed to treat
number needed
harm inage
person-years
for primary
dose
in and
women
for tofour
categories
in eperson-years
for
primary
prevention
with
lowTabl
s
5
and
6
show
t
h
e
absol
u
t
e
numbers
of
expect
e
d
event
s
over
10
years
without or with
Table 3A. Number
needed
to
treat
and
number
needed
to
harm
in
person-years
for
primary
dose aspirin in men for four age categories
prevention
for four
with low-dose aspirin in women for four age categories
low-dose with
aspirlow-dose
in for 1,000aspirin
meninormenwomen,
respectageicategories
vely.65-74Take, for example,75-84men age 55 to 64 prevention
Age category in 45-54
55-64
Age Category in 45-54
55-64
65-74
75-84
years
years. The expected number of MIs per 1,000 untreated men over 10 years was 57. This was a years
Benefit outcomes NNT (95% CI)
Benefit outcomes NNT (95% CI)
MI
1,786 [962 - NA]
1,153 [621 - NA]
769 [414 - NA]
511 [275 - NA]
5,953 [3,206 - NA] 2381 [1,283 - NA]
1,520 [819 - NA]
872 [470 - NA]
lit le less than what would be calculated by simply multiplying the incidence rate of 6.2 MIs per MI
ischemic 8,548 [NNT 4,116 - 3487 [NNT 1852 2,137 [NNT 1,029 - 1,026 [NNT 494 1,000ischemic
person-years
10 years
Table[NNT1) because
consi[NNTdered662 -death as713a[NNTcompet343 -inNNHg risk Major
Major
* 6,411by[NNT
3,087 -(see 3,077
1,482 - we1,374
stroke*
NNH 55,556]
NNH 25,000]
NNH 13,889]
NNH 6,667]
stroke
NNH 41,667]
NNH 20,000]
NNH 8,929]
4,630]
outcomes NNH [ 95% CI]
that prevent
MIs(95%fromCI)occurring in those who die early. As age increased, the impact of death Harm
Harm
outcomessNNH
Major
28,572 [12,346 9,524 [4,116 5,715 [2,470 2,598 [1,123 Major
14,286 [6,173 7,143 [3087 3,572 [1,544 1,786 [772 - 62,501]
hemorrhagic
1,000,001]
333,334]
200,000]
90,910]
became larger. For500,001]
example, the expect250,001]ed number of GI125,001
bleeds in untreated men age 75 to 84 stroke
hemorrhagic
stroke
the number
GI bl- 807]eeds (62 percent
, excess
GI bleedsof maj404or[250
202 [125RR
- 404]increase, e.108g.[67
- 216] of 113 maj
68 [42or- GI
135]bleeds fo
Major
- 404] with deat
101h [63
34 [21 - l68]
yearsGIwasbleeds285 over202 10[125years
as -a202]competing ri54sk.[34Thi- 108]s is considerably
ower than the Major
* The 95% CIs for ischemic stroke (RR 0.87; 95% CI, 073 -1.02) include the possibilities of both benefit and harm and thus we
CI = confidence interval; GI = gastrointestinal; MI = myocardial infarction; NA = not applicable because CIs for RR approximate
men ageNNT65astwello 74as NNHyears)respectively.
over 10Theyears.NNT is lower because it reflects the lower limit of the CI, and the NNH is higher
reported
1;480
NNHthat
= number
needed
toexpect
harm; NNT
=winumber
needed
todtreat;
RR
= relative
risk
woul
d
be
e
d
t
h
out
consi
eri
n
g
deat
h
as
a
compet
i
n
g
ri
s
k
(Tabl
e
1).
events
without
andthewith
aspirin
Expected
*TheExpected
95% CIs for ischemic stroke
(RR 0.87; 95%
CI, 073 -1.02) include
possibilitieslow-dose
of both benefit and harm
and thus we
because
it reflects the upperevents
limit of the CI. without and with low-dose aspirin
report NNT as well as NNH respectively. The NNT is lowerinbecause
it reflects the lower limit of the CI, and the NNH is higher
men
because it reflects the upper limit of the CI.
Table 5. Expected number of events without and with low-dose aspirin in men *
Outcomes
Number of Expected Events Over 10 Years Per 1,000 Men
Without aspirin
With aspirin
Table 6. Expected events without and with low-dose aspirin in women *
CI = confidence interval; GI = gastrointestinal; MI =in
myocardial
infarction; NA = not applicable because CIs for RR approximate
women
1; NNH = number needed to harm; NNT = number needed to treat; RR = relative risk
Outcomes
Number of expected events over 10 years per 1,000 women
Sensitivity AnalysisWifor
Needed WitothTreat
thoutthe
aspirNumber
in
aspirin and Number
Needed to Harm Approach Using Baseline Incidence Rates from the
Age categories in years 45-54 55-64 65-74 75-84 45-54 55-64 65-74 75-84 Age categories in years 45-54 55-64 65-74 75-84 45-54 55-64 65-74 75-84
Trials
MI
MI
12 29 42 63 10 25 37 54
38 57 79 96 33 49 68 83
Major ischemic stroke 12 24 48 74 11 21 42 64
MajoBelow
r ischemiwecpresent
stroke the results
9 of the20 sensitivity
33 analysis
58 for the7 NNT 17and NNH29approach51
using baseline incident rates from the trials. Since the baseline incidence rates in the trials were
Major hemorrhagic stroke 2 4 7 9 11 2 5 10 15
Major hemorrhagi
strokeobservational
1 3studies (Appendix
5 9Table A-4),
2 the respective
4 7NNTs and12
lower
than that ofc the
Major GI bleeds
75 141 231 285 119 218 344 411
Major GIinblthiseedssensitivity analysis
NNHs
and women
39 were74 higher129for all four171outcomes
62 for both
117 men 200
260
Puhan
No.:4A
12(14)-EHC149-EF.
and 4B).
GI = gastrMA
ointestetinalal.; MIAgency
= myocardiaforl infarctHealthcare
ion; RR = relatiResearch
ve risk and Quality (US); 2013 Nov. Report(Tables
Association of NSAID Use With Risk of Bleeding during Antithrombotic Therapy
Schjerning Olsen AM et al JAMA. 2015;313(8):805-814.
ESC – CV prevention Guidelines 2012
Aspirin is not recommended in primary
prevention
Aspirin is recommended only in patients
with established vascular disease or
previous cardiovascular events
Aspirina e Prevenzione cardiovascolare primaria
Summary of Recommendations
2.1.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).
Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular
risk profile if taken over 10 years. In people at moderate to high risk of
cardiovascular events, the reduction in myocardial infarction (MI) is closely
balanced with an increase in major bleeds. Whatever their risk status, people who
are averse to taking medication over a prolonged time period for very small
benefits will be disinclined to use aspirin for primary prophylaxis. Individuals
who value preventing an MI substantially higher than avoiding a GI bleed will
be, if they are in the moderate or high cardiovascular risk group, more likely to
choose aspirin.
Copyright: American College of Chest Physicians 2012© - Chest. 2012; 141(2 Suppl): e637S–e668S.
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
ESC-EASD Diabetes and Prediabes Guidelines 2013
Low-dose aspirin for primary
prevention may be considered
in high risk patients with
diabetes mellitus on an
individual basis.
High risk = all patients with diabetes mellitus
Very high risk = patients with diabetes
mellitus and >1 cardiovascular risk factor
ESH-ESC Hypertension Guidelines 2013
Low-dose aspirin should be prescribed
to controlled hypertensive patients with
previous CV events and considered in
hypertensive patients with reduced
renal function or a high CV risk.
Aspirin is not recommended in low-tomoderate risk hypertensive patients in
whom absolute benefit and harm are
equivalent.
Lower incidences of cancer and mortality
has been suggested in aspirin treated
patients (primary prevention trials). If
confirmed, this additional action of aspirin
may lead to a more liberal
reconsideration of its use.
Low-dose aspirin may be considered in
pre-eclampsia
Effectiveness of quality improvement strategies on the management of diabetes:
a systematic review and meta-analysis – 48 cluster trials 84.865 patients
Variables
HbA1c
Changes vs usual care
LDL cholesterol
Statin use
0·10 mmol/L (0·05—0.14; 47 trials)
(RR 1·12, 0·99—1·28, 10 trials)
SBP
3·13 mm Hg (2·19—4·06, 65 trials)
•DBP
•Hypertension control
1·55 mm Hg (0·95—2·15, 61 trials)
(RR 1·01, 0·96—1·07, 18 trials)
Smoking cessation
Likelihood to receive:
Aspirin
0·37% (95% CI 0·28—0·45; 120 trials)
(RR 1·13, 0·99—1·29, 13 trials)
(RR 1·33, 1·21—1·45,11 trials)
Antihypertensive drugs
(RR 1·17, 1·01—1·37, 10 trials)
Screening for: Retinopathy
(RR 1·22, 1·13—1·32, 23 trials)
Renal function
(RR 1.28, 1·13—1·44, 14 trials)
Foot abnormalities (RR 1·27, 1·16—1·39, 22 trials)
Tricco AC et al Lancet. 2012;379(9833):2252-61.
The INTERHEART study
1000
2.9
2.4
1.9 3.3 13.0 42.3 68.5 182.9 333.7
334 (90.4 PAR)
1000
68.5
Odds ratio (99% CI)
Odds ratio (99% CI)
100
2 (circa)
10
1
100
12.9
10
1
All
RF
s
l
l
cia
1
oA
cia
oso
ity
ych
be s
4
+Ps
+O
All
/Ap
s
+3
oB
N
1+ 2
Ap
HT
RF
oso
1
oA
DM
ng
ok i
Sm
All
ity
ych
be s
+Ps
+O
All4
/Ap
+3
oB
N
1+ 2
Ap
HT
DM
ng
ok i
Sm
Modificato da: Yusuf S et al Lancet 2004;364:937-52
Low dose Aspirin in Primary prevention – Position
paper – ESC working Group on Thrombosis
Magnitude of Antithrombotic Benefit and of Bleeding Risk
Connected With the Use of Aspirin, and Absolute CV Risk, in Various
A Proposed Practical Stepwise Approach to
Subsets of Subjects in Primary Prevention
the Use of Aspirin in Primary CV Prevention
While awaiting the results of several ongoing studies, this document argues for a pragmatic approach to the
use of low-dose aspirin in primary cardiovascular prevention, and suggests its use in patients at high
cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke)
projected per 100 person-years, who are not at increased risk of bleeding. G Ital Cardiol 2014;15(7-8):442-451
Halvorsen S et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology Working Group on Thrombosis. J Am Coll Cardiol 2014;64:319-27
Low dose Aspirin in Primary prevention
CV Cancer Bleeding
Risk Risk
Risk
YES ASA
Battistoni A et al Clin Cardiol. 2015 Apr 14.
CV Cancer Bleeding
Risk
Risk
Risk
Clinical Judgement
CV Cancer Bleeding
Risk
Risk
Risk
NO ASA
Aspirin use and risk of cancer
Algra AM and Rothwell PM Lancet Oncol. 2012;13(5):518-27.
Ongoing trials in intermediate CV risk conditions
Aspirin to Reduce Risk of Initial VascularEvents
(ARRIVE)
Aspirin in Reducing Events in the Elderly (ASPREE)
Cardiovascular Events in Diabetes (ASCEND)
Aspirin and Simvastatin Combination for
Cardiovascular Events Prevention Trials in Diabetes
(ACCEPT-D)
Japanese Primary Prevention trial (JPPP)
ENVIS-ion Elderly neurovascular imaging study
(ASPREE substudy)
ESH-ESC Hypertension Guidelines 2013
Low-dose aspirin should be prescribed
to controlled hypertensive patients with
previous CV events and considered in
hypertensive patients with reduced
renal function or a high CV risk.
Aspirin is not recommended in low-tomoderate risk hypertensive patients in
whom absolute benefit and harm are
equivalent.
Lower incidences of cancer and mortality
has been suggested in aspirin treated
patients (primary prevention trials). If
confirmed, this additional action of aspirin
may lead to a more liberal
reconsideration of its use.
Low-dose aspirin may be considered in
pre-eclampsia
Global Health Benefits from ASA: Number of Events Averted or Incurred
Should 10,000 Persons Be Treated With Aspirin in Primary CVD Prevention
and Followed-Up for 10 Years
Events averted
Deaths (any cause)
MCE (CV death, MI, or stroke)
Total CHD events
CRC deaths
Cancer deaths
Events incurred
Major bleeds
GI bleeds
Hemorrhagic strokes
Sutcliffe P et al Health Technol Assess 2013;17:1–253.
Range
Mean
33–46
60–84
47–64
34–36
17–85
39.5
72.0
55.5
35.0
51.0
46–48
117–182
8–10
47.0
149.5
9.0
The role of aspirin in cancer prevention
Females, age 50–59 years
Females, age 65–74 years
Males, age 50–59 years
Males, age 65–74 years
Michael J. Thun, Eric J. Jacobs and Carlo Patrono Nat. Rev. Clin. Oncol. 2012, 9, 259–267
Evidence That Acetylsalicylic Acid Attenuates Inflammation in
the Walls of Human Cerebral Aneurysms
Hasan DM et al J. Am. Heart Assoc. 2013, 2
RR of colorectal cancer for highest vs lowest categories of ASA use
Dose of ASA use and risk of colorectal cancer
Years of ASA use and risk of colorectal cancer
Frequency of ASA use and risk of colorectal cancer
18% decreased risk for 10
years aspirin increment
Ye X et al Plos One 2013; 8(2): e57578.
Mortality among Patients with known
Colorectal Cancer, According to Regular
Use or Nonuse of Aspirin after Diagnosis
and PIK3CA Mutation Status.
HR = 0.18
Liao X et al. N Engl J Med 2012;367:1596-1606.
Regular Use of Aspirin and Incident
Colorectal Cancer by PTGS2 Status and
Combination of BRAF-PTGS2 Mutation
Status
HR = 0.93
Nishihara R et al JAMA. 2013;309(24):2563-2571.
Aspirin Is Associated With Lower Melanoma Risk Among
Postmenopausal Caucasian Women
ASA users: p linear trend = 0.01
NSAID users: p linear trend = 0.8
1.2
1
1.0
Hazard Ratio
0.8
ASA users
NSAID users
(NON-ASA)
0.6
0.4
0.2
0
A
S
A
A
S
A
u
s
e
r
s
u
s
e
r
s
<1 year
1-4 years
A
S
A
NONE (ref)
u
s
e
r
s
≥5
Incidence per 100.000 person per year HR (fully adjusted, vs NSAID nonusers)
ASA users
69.8
0.79 (0.63-0.98)
NSAID users (NON-ASA)
87.9
1.05 (0.83-1.34)
Gamba CA et al Cancer 2013
Aspirin use and risk of cancer metastasis
Algra AM and Rothwell PM Lancet Oncol. 2012;13(5):518-27.
Platelet contribution to cancer progression
PG-mediated lymphatic
vessel dilation
N. M. Bambace, Journal of Thrombosis and Haemostasis, 2011 9: 237–249
Conclusioni
ASA a basso dosaggio sembra essere indicato anche
in prevenzione cardiovascolare primaria
La prescrizione consegue alla valutazione individuale
ed al bilancio rischio emorragico / rischio
cardiovascolare
ASA a basso dosaggio sembra proteggere dal rischio
oncologico (per diversi tipi di neoplasia ed anche nei
confronti delle metastasi a distanza), paradossalmente
in modo COX-2 mediato
La rivalutazione delle evidenze in merito ad ASA e
rischio oncologico porterà necessariamente ad una
rivisitazione dei due punti precedenti
Conclusioni
ASA a basso dosaggio sembra essere indicato anche
in prevenzione cardiovascolare primaria
La prescrizione consegue alla valutazione individuale
ed al bilancio rischio emorragico / rischio
cardiovascolare
ASA a basso dosaggio sembra proteggere dal rischio
oncologico (per diversi tipi di neoplasia ed anche nei
confronti delle metastasi a distanza), paradossalmente
in modo COX-2 mediato
La rivalutazione delle evidenze in merito ad ASA e
rischio oncologico porterà necessariamente ad una
rivisitazione dei due punti iniziali
Conclusioni
ASA a basso dosaggio sembra essere indicato anche
in prevenzione cardiovascolare primaria
La prescrizione consegue alla valutazione individuale
ed al bilancio rischio emorragico / rischio
cardiovascolare
ASA a basso dosaggio sembra proteggere dal rischio
oncologico (per diversi tipi di neoplasia ed anche nei
confronti delle metastasi a distanza), paradossalmente
in modo COX-2 mediato
La rivalutazione delle evidenze in merito ad ASA e
rischio oncologico porterà necessariamente ad una
rivisitazione dei due punti iniziali
Conclusioni
ASA a basso dosaggio sembra essere indicato anche
in prevenzione cardiovascolare primaria
La prescrizione consegue alla valutazione individuale
ed al bilancio rischio emorragico / rischio
cardiovascolare
ASA a basso dosaggio sembra proteggere dal rischio
oncologico (per diversi tipi di neoplasia ed anche nei
confronti delle metastasi a distanza), paradossalmente
in modo COX-2 mediato
La rivalutazione delle evidenze in merito ad ASA e
rischio oncologico porterà necessariamente ad una
rivisitazione dei due punti iniziali
Conclusioni
ASA a basso dosaggio sembra essere indicato anche
in prevenzione cardiovascolare primaria
La prescrizione consegue alla valutazione individuale
ed al bilancio rischio emorragico / rischio
cardiovascolare
ASA a basso dosaggio sembra proteggere dal rischio
oncologico (per diversi tipi di neoplasia ed anche nei
confronti delle metastasi a distanza), paradossalmente
in modo COX-2 mediato
La rivalutazione delle evidenze in merito ad ASA e
rischio oncologico porterà necessariamente ad una
rivisitazione dei due punti iniziali