Aspirin

Aspirine et préven,on cardiovasculaire : peut-­‐on encore a5endre des nouveautés ? Patrick HENRY Cardiology – Lariboisiere Hospital – AP-­‐HP Denis Diderot Paris VII University Paris -­‐ France Disclosures •  Research grants and fees for giving lectures and/or consul,ng : Bayer, Astra-­‐Zeneca, BMS, Lilly, Daichi Sankyo, Menarini, Novar,s, Novo, sanofi-­‐aven,s, Servier, Takeda Lancet. 1876;4:342-383
Felix Hoffmann
OH
1897
CH3COO
COOH
Salicylic acid
COOH
Acetylsalicylic acid
(Aspirin)
Alexei, hemophile, Nicolas II et Raspoutine
Aspirin: Mechanism of Action
Platelet Aggrega,on and Ac,va,on Aspirine et préven,on des évènements thrombo,ques Lenfant C. N Engl J Med 2003;349:868-­‐974 Aspirin Efficacy
Aspirin’s Use in Acute Myocardial Infarc,on •  Second Interna,onal Study of Infarct Survival (ISIS-­‐2) –  17,187 pa,ents randomized to aspirin, streptokinase, both, or placebo –  Aspirin showed a 23% RRR (ARR 2.5% NNT 40) in cardiovascular death –  Benefit was addi,ve with streptokinase Lancet 1988; 2: 349-­‐60 Secondary Prevention of
Cardiovascular Events – 400 trials
An,thrombo,c Trialists’ Collabora,on • Meta-­‐analysis of 65 trials using aspirin in over high-­‐risk pa,ent • Over 140,000 pa,ents total • 22% odds reduc,on in all vascular events (2.5% absolute reduc,on) BMJ 2002; 324: 71-­‐86 An,thrombo,c Trialists’ Collabora,on: Results for Secondary Preven,on IDM non fatal
RR
34% + 3%
AVC non fatal
25% + 3%
Décès vasculaires
15% + 2%
Total
22% + 2%
Aspirin in the primary preven,on of vascular disease: collabora,ve meta-­‐analysis of individual par,cipant data from randomised trials Antithrombotic Trialists’ Collaboration. Lancet 2009;373:1849–60.
Aspirin in the primary and secondary preven,on of vascular disease: collabora,ve meta-­‐analysis of individual par,cipant data from randomised trials Antithrombotic Trialists’ Collaboration. Lancet 2009;373:1849–60.
Data for ASA in the primary preven,on of CV events Trial
Patient population
Age range
(years)
ASA
dosage
BDT (1988)1
Apparently healthy male
physicians (n=5,139)
50–78
500mg/day
PHS (1989)2
Apparently healthy male
physicians (n=22,071)
40–84
325mg qod
HOT study
(1998)3
Men and women with DBP
100–115mmHg (n=18,790)
50–80
75mg/day
TPT (1998)4
Men at high risk of heart
disease (n=5,499)
45–69
75mg/day
PPP (2001)5
Men and women with ≥1 major
CV risk factor (n=4,495)
50–80+
100mg/day
WHS (2005)6
Apparently healthy women
(n=39,876)
≥45
100mg qod
BDT, British Doctors’ Trial; HOT, Hypertension Optimal Treatment; PHS, Physicians’ Health Study; PPP, Primary Prevention Project; qod,
every other day; TPT, Thrombosis Prevention Trial; WHS, Women’s Health Study.
1. Peto R, et al. BMJ 1988;296:313–6; 2. Physicians Health Study. N Engl J Med 1989;321:1825–8; 3. Hansson L, et al. Lancet
1998;351:1755–62. 4. The Medical Research Council’s General Practice Research Framework. Lancet 1998;351:233–41;
5. de Gaetano G, et al. Lancet 2001;357:89–95. 6. Ridker PM, et al. N Engl J Med 2005;352:1293–304.
Aspirin meta-­‐analyses in primary preven,on Aspirin vs. placebo for primary prevention
Outcomes
Number of trials (n)
Weighted event rates
At a mean 6 y
Aspirin
Placebo
RRR (95% CI)
NNT (CI)
Total CHD
9 (102 621)
1.9%
2.2%
14% (-1 to 26)
NS
Nonfatal MI
9 (102 621)
1.3%
1.7%
20% (4 to 33)
305 (184 to 1525)
Stroke
9 (102 621)
1.4%
1.5%
6% (-6 to 16)
NS
Total CVD events
9 (102 621)
3.9%
4.3%
10% (4 to 14)
242 (161 to 607)
Cancer mortality
8 (98 126)
1.5%
1.6%
7% (-3 to 16)
NS
All-cause mortality
9 (102 621)
3.6%
3.8%
6% (0 to 12)
NS
RRI (CI)
NNH (CI)
Nontrivial bleeding
9 (100 076)
12%
9.6%
27% (12 to 43)
39 (25 to 84)
Total bleeding
9 (100 076)
50%
37%
35% (10 to 59)
8 (5 to 27)
CVD mortality
9 (102 621)
1.2%
1.2%
1% (-15 to 15)
NS
Fatal MI
9 (102 621)
0.55%
0.52%
6% (-17 to 37)
NS
CHD, coronary heart disease; CI, confidence interval; NNH, numbers needed to harm; NNT, numbers needed to treat;
NS, not significant; RRI, relative risk increase; RRR, relative risk reduction.
Rembold CM. Ann Intern Med 2012;156:JC6-3.
Diabetes -­‐ Aspirin in primary preven,on De Berardis et al. BMJ 2009; 339: e4531
Low-­‐dose aspirin is beneficial in hypertensive CKD pa,ents (HOT study) CKD, chronic kidney disease; GFR, glomerular filtration rate;
JPAD primary endpoint: time to atherosclerotic events.
Jardine MJ, et al. J Am Coll Cardiol 2010;56:956-65.
Low-dose aspirin is contraindicated in patients with renal failure/insufficiency.
.
Summary of Guidelines • AHA: CHD risk above 10%; stroke prevention in
older women
• US Preventive Task Force (2009): Men 45-79 and
women 55-79 at higher risk.
• ESC: Higher risk
•  UK: JBS and SIGN (50y: CVD>20%); NICE
• ACCP: estimate risk, then consider benefit vs. risk
for those over 50 years.
Can we minimise the GI risks in
primary prevention ?
Propor,onal effects of aspirin on vascular events in high-­‐risk pa,ents Aspirin dose
% odds reduction*
500–1500 mg daily
160–325 mg daily
75–150 mg daily
<75 mg daily
Any aspirin dose
23%±2
(p<0.0001)
0.0
0.5
1.0
Aspirin better
*Vascular events: MI, stroke or vascular death
Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71
1.5
Control better
Reasons for discon,nua,on of low-­‐dose aspirin in primary preven,on1 •  Risk factors for GI damage2 –  High aspirin dose –  History of pep,c or ulcer complica,ons –  History of GI bleeding –  Use of a non-­‐selec,ve or COX-­‐2 selec,ve NSAID –  Advanced age (especially >70 years) –  H pylori infec,on COX, cyclooxygenase; NSAID, non-steroidal anti-inflammatory drugs.
Figure based on a questionnaire sent to US adults.
1. Moberg C, et al. Patient 2011;4:103-113;
2. Casado-Arroyo R et al. Best Pract Res Clin Gastroenterol 2012;26:173-84.
Minimising GI bleeding in low-­‐dose aspirin users Addition of PPI to aspirin (80 mg)
users with peptic ulcers/erosions
more effective than H2RA1
•  Recommenda,ons2,3 –  Use the lowest effec,ve ≤100 mg/
day –  Co-­‐therapy with gastroprotec,ve drug (misoprostol but preferably PPI) at standard doses is recommended in at-­‐risk* pa,ents –  Eradicate H Pylori, especially in at-­‐
risk pa,ents with ulcer history –  Add a PPI in pa,ents receiving concomitant non-­‐selec,ve or COX-­‐2 selec,ve NSAIDs *Presence of one or more risk factors: age > 70 years, history of GI events, presence of comorbidities, concomitant therapy with
nonsteroidal anti-inflammatory drugs, coxibs, anticoagulants, or high-dose corticosteroids; PPI, proton pump inhibitor.
1. Ng FH. Gastroenterology 2010;138:82-88;
2. Casado-Arroyo R et al. Best Pract Res Clin Gastroenterol 2012;26:173-84;
3. Lanas A. Expert Opin Drug Saf 2011;10:45-54.
Interac,on with PPI ? Retrospective
registry
Denmark
1997 - 2006
Charlot et al BMJ 2011
Other impacts Effect of daily aspirin on long-­‐term risk of death due to cancer Rothwell et al, Lancet 2011; 377: 31–41
Effect of daily aspirin on long-­‐term risk of death due to cancer Rothwell et al, Lancet 2011; 377: 31–41
Effect of daily aspirin on long-­‐term risk of death due to cancer Unrelated
to dose
Rothwell et al, Lancet 2011; 377: 31–41
ASPIRE Background •  Even aser completed a tradi,onal course of oral an,coagula,on (3-­‐6 months), pa,ents with a history of unprovoked DVT have a rela,vely high long-­‐term risk of recurrent VTE (around 25% at 5 years) Ques,on •  Would aspirin be effec,ve in preven,ng a recurrence of VTE in pa,ents with first episode of unprovoked VTE who have completed a tradi,onal course of an,coagula,on? ASPIRE DVT Methods •  822 pa,ents who completed ini,al an,coagula,on therapy aser a first episode of unprovoked VTE (DVT or PE) •  Randomized to aspirin 100 mg daily or placebo •  Primary Endpoint: Recurrent symptoma,c VTE •  Mean Follow-­‐Up = 37.2 months •  Results pooled with another similar previously reported studied (WARFASA) ASPIRE DVT -­‐ Results Improving our knowledge of aspirin Diabetes Cardiovascular outcome in diabe,c pa,ents Plato diabetes
Diabetes in secondary preven,on Antiplatelet Trialists’ Collaboration BMJ 2002;324:71-86
Aspirin in primary preven,on De Berardis et al. BMJ 2009; 339: e4531
Altered pharmacodynamics of low-­‐dose aspirin in diabe,cs Faster renewal of mature platelets Recovery of prostaglandin
G/H synthase 1 activity
leads to TxA2 production
and platelet aggregation
TxB2, thromboxane B2.
Patrono C. Nat Rev Cardio 2012 (online).
Time dependance of aspirin Henry et al, Thrombosis hemostasis, 2011
Rela,ve risk of aspirin resistance Odds ratio
Fibrinogen > 4 g/L
3.7*
hsCRP > 8.5 mg/L
3.3*
Platelets count > 270.109/L
2.8*
Current smoking
2.4*
Platelets size > 10.4 fL
2.2*
Diabetes
2.0*
Aspirin ≤ 100 mg/day
1.8
Insulin treatment
1.7
hypertension
1.6
Proton-pump inhibitor treatment
1.5
Henry et al, Thrombosis hemostasis, 2011
Sideris et al. Eur Heart J 2007;28:267 and presentation at ESC 2007
12-15%
Normal turn over
0
ASA
24 h
ASA
No aggregation
Aggregation
>20%
Accelerated turn over
0
ASA
Plaque5es inhibées Plaque5es ac,ves 24 h
ASA
Could increased dosing frequency in diabetes overcome these issues? HS, healthy subjects.
Rocca B et al. J Thromb Haem 2012;10:1220-30.
Aspirin resistance and Platelet turnover Patients with essential thrombocytemia
Dillinger JG & Henry P. Thromb Research 2011
Pa,ents with DM and CAD with one of the following criteria (current smoking, hsCRP >4 mg/L, fibrinogen >4g/L, platelets >270 103 cells/mm3 Randomisation
Aggregation
test *
Day 1
*
OPD
150mg morning
BID
75mg morning
75 mg evenning
BID
75mg morning
75 mg evenning
OPD
150mg morning
Day 8
Aggregation
test *
Day 16
Blood sample with LTA-AA 0.5mg/ml, PFA-100, hsCRP, fg, platelet, Hb, VPM, HbA1c, Glycemia
Dillinger JG and Henry P. Am Heart journal 2012;164:600-6.
Primary endpoint
Op,cal platelet aggrega,on -­‐ LTA-­‐AA 0.5mg/ml 70
P<0,0001
50
LTA-AA 0.5mgml
Maximum Agregation intensity (%)
60
43%
16%
40
30
20
10
0
OPD
BID
Dillinger JG and Henry P. Am Heart journal 2012;164:600-6.
Dillinger JG and al. Am Heart journal 2012;164:600-6.
Op,cal platelet aggrega,on -­‐ LTA-­‐AA 0.5mg/ml Pa,ents resistant who became sensi,ve with change of treatment 70
P=0,002
50
LTA-AA 0.5mgml
Maximum Agregation intensity (%)
60
40
30
20
10
0
OPD
BID
Dillinger JG and Henry P. Am Heart journal 2012;164:600-6.
Dillinger JG and al. Am Heart journal 2012;164:600-6.
Dillinger JG and Henry P. Eurointervention 2013. Submitted
Dillinger JG and Henry P. Eurointervention 2013. Submitted
Dillinger JG and Henry P. Eurointervention 2013. Submitted
Conclusion •  L’aspirine est très efficace pour en préven,on secondaire •  L’u,lisa,on en préven,on primaire peut être discutée chez des pa,ents à haut risque •  Préven,on de certains cancer et des récidives de thrombose veineuse •  L’u,lisa,on dans certain cas de 2 prises par jour pourrait vaincre les résistances observées chez certains pa,ents (diabé,ques, syndrome inflammatoire)