9. Bénéfice de l’ASA en prévention IR ? De Berardis BMJ 2009 IDM = RRR de 14% p=NS +++ pour les hommes = RRR d’IDM de 43% ** AVC = RRR de 17% p=NS pour les femmes RRR de 25% p=NS Mortalité CV = RRR de 6 % p=NS Mortalité = RRR de 7 % p=NS RRR de 10% *
11. Stable CAD outpatients (n=120) successive doses / randomized / double blinded AS pirin-Induced P latelet E ffe CT (ASPECT) Influence du Diabète sur la réponse à l’Aspirine Gurbel PA. Diabetes. 2007 Dec;56(12):3014-9. + de résistant à l’aspirine Augmenter les doses d’aspirine chez le diabétique
12. Aspirine faible dose et diabète 50 40 30 20 10 0.0 Residual aggregation ≥20% with 0.5mh/mL AA Incidence of HPR (%) H2 P =0.002 H24 100 mg H24 75mg Drouet el al. ESC 2008 Passer à 2 prises par jour chez le diabétique/IMC>30
13. Diabète type 1 ou 2 âge> 40 ans Aspirine 100mg Placebo Omega-3 Placebo Omega-3 Placebo Critères primaires: = événements cardiovasculaires (IDM, AVC) Aspirine (100mg) en prévention IR ASCEND n=10 000 En cours ACCEPT -D n=5 170 ASA + Simvastatine vs. Placebo DT2 asymptomatique Dose suffisante ? 2 prises par jour ?
17. Diabetics in CAPRIE Relative risk reductions for different endpoints – 50% 0% 50% Aspirin better Clopidogrel better Vasc. death, MI, stroke, hosp: ischemia, bleeding Hosp: ischemia, bleeding Stroke MI Vascular death Death D. Bhatt, ACC 2000
18. GP IIb/IIIa – dans le SCAST- Roffi M et al. Circulation. 2001;104:2767-2771 30-Day Mortality In non-diabetics: 3.0 vs 3.0%, p=0.99 In diabetics with PCI: 4.0 vs 1.2%, p=0.002 Metaanalysis 2163 687 362 1677 412 1157 6458 PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON A PARAGON B Pooled 6.1% 4.2% 6.7% 7.8% 6.2% 4.8% 6.2% 5.1% 1.8% 3.6% 5.0% 4.6% 4.9% 4.6% P =.33 P =.07 P =.17 P =.022 P =.51 P =.93 P =.007 Trial N Odds Ratio & 95% Cl Placebo IIb/IIIa Breslow-Day: P =.50 IIb/IIIa Better Placebo Better OR=0.74 0 0.5 1 1.5 2
19. GP IIb/IIIa – dans le SCAST+ Montalescot et al. N Engl J Med 2002 Death, re-MI, revascularization at 30 days ADMIRAL Trial
20. Primary Composite EP @ 12m p=0.91 Presented at AHA Scientific Sessions 2004 Bénéfice des GpIIbIIIa dans l’ATL élective ? % Insulin-dependent Diabetes Subgroup Primary Composite Endpoint at 12 months p=0.66 Benefit of abciximab in elective PCI with 600mg LD clopidogrel ? n=701 ISAR-SWEET Trial
25. Patients diabétiques n=2009 Topol et al . Am J Cardiol 2009;103:1359 –1363) Effet délétère de la bithérapie (ASA+Clopidogrel) chez les diabétiques atteint de néphropathie (Albuminurie )
31. Platelet reactivity after ACS Predicts 5-Year Outcomes Trip MD, et al. N Engl J Med. 1990;322:1549-1554. Avant les stents Platelet Aggregability Status 0 10 20 30 40 50 Death Cardiac Events 10.3 6.4 14.9 24.1 46.2 34.6 Patients (%) Negative (n=94) Intermediate (n=29) Positive (n=26)
32. Platelet response after PCI (DES) Predicts 6-Months Outcomes P < 0.001 P < 0.001 P < 0.001 Antoniucci D et al. JACC 2008. Depuis les stents Double résistance ASA +Plavix ? Thrombose de stent x 3.18 (1.14 to 8.83, p = 0.027) Mortalité CV x 2.94 (1.16 to 7.41, p = 0.022)
38. Withdrawal due to side effects N=4 (migraine, GI symptoms, tachycardia) Withdrawal due to side effects N=1 (GI symptoms) OPTIMUS-2 Cilostazol N=13 Placebo N=12 20 patients Randomized N=25 Crossover Placebo N=9 Cilostazol N=11 Side effects not leading to withdrawal of study medication: cilostazol (N=3) and placebo (N=1) T2DM patients with coronary disease on : aspirin (81 mg) + clopidogrel (75 mg) Angiolillo, et al. Eur Heart J. 2008 Sep;29(18):2202-11. CILOSTAZOL PLACEBO p=0.0002 Primary Endpoint % P2Y12 reactivity Index (VASP) 20 40 60 0 100 80
Background: previous data suggest that biological platelet resistance to low dose aspirin occurs frequently in diabetic patients in secondary prevention. The higher platelet turn over described in this population could contribute to shorten the duration of aspirin effect. We therefore aimed to assess the rate of biological aspirin resistance in diabetic patients soon after aspirin intake (peak effect) as compared to 24 hours after the last aspirin intake. Methods: 52 type-2 diabetic patients with stable coronary artery disease and treated with 75 mg (n=21) or 100 mg (n=31) aspirin daily for at least 10 days were studied. Platelet aggregation to arachidonic acid and closure time on the platelet function analyzer-100 (PFA-100) were performed 2 hours and 24 hours after the last aspirin intake. Aspirin resistance was defined as a residual aggregation ≥20% with 0.5mg/ml arachidonic acid. Results: all the patients were sensitive to aspirin at 2h after ingestion but 16 patients (31%) were aspirin resistant 24 h after the last aspirin intake: 48% in the 75 mg group and 23% in the 100 mg group. Concordant results were found concerning PFA-100 especially with the collagen-epinephrine cartridge. Moreover, in the resistant group, PFA 100 was increased (mean >300sec) as compared to sensitive patiens (mean 152 sec). In patients with aspirin resistance, a trend towards a higher platelet volume (10.8± 0.9 in aspirin resistant vs. 10.2±0.7)) and a higher plasma factor VIII level were found (163±54 IU/dl in aspirin resistant vs 132± 61 IU/dl). Aspirin resistance was not related to the presence or absence of metabolic syndrome (IDF) nor other clinical or to biological parameters. Conclusion: low dose aspirin does not offer a 24-hour biological protection in a high proportion of diabetic patients in secondary prevention. Further studies are needed to define the optimal aspirin dose and regimen in this population.
DC ou DC+MI
Among diabetic patients undergoing elective PCI and pretreated with high-dose clopidogrel, treatment with abciximab was not associated with a difference in the primary endpoint of death or MI at 12 months compared with placebo, but was associated with a lower rate of binary restenosis and target lesion revascularization. These data are similar to the ISAR REACT trial, which showed no difference in 30 day major cardiac events with abciximab compared with placebo in low-risk patients undergoing PCI who were pretreated with 600 mg clopidogrel. While there was no difference in the primary endpoint of death or MI in the present trial, it should be noted that the trial was powered to detect a 50% reduction with abciximab, a relatively large improvement in clinical events that may have been over-estimated
In the CAPRIE study, 3866 patients had co-existing diabetes 1 Patients without diabetes treated with clopidogrel were at lower risk of MI, ischemic stroke, vascular death or rehospitalization for ischemic events/bleeding than those treated with ASA (11.8 vs 12.7%; p=0.096; 9 events prevented per 1000 patients per year with clopidogrel versus ASA) 1 Similarly, patients with diabetes treated with clopidogrel were at lower risk of MI, ischemic stroke, vascular death or rehospitalization for ischemic events/bleeding than those treated with ASA (15.6 vs 17.7%; p=0.042) 1 The benefits of clopidogrel over ASA were even further amplified in the higher risk, insulin-dependent patients (17.7 vs 21.5%; p=0.106; 38 events prevented per 1000 patients per year with clopidogrel versus ASA) 1 Reference 1. Bhatt DL et al. Am Heart J 2002; 148: 67–73.
In CHARISMA, major atherothrombotic risk factors were as follows: 1 Type 1 or 2 diabetes currently under drug therapy Diabetic nephropathy ABI 0.9 Asymptomatic carotid stenosis 70% Presence of at least one carotid plaque evidenced by intima–media thickness In CHARISMA, minor atherothrombotic risk factors were as follows: 1 SBP 150 mmHg, despite therapy for at least 3 months Primary hypercholesterolemia Currently smoking 15 cigarettes per day Male aged 65 years or female aged 70 years Reference 1. Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause), or cardiovascular death (including haemorrhagic death). There was no statistical difference in the primary endpoint between the two treatment arms. An analysis of the population with documented atherothrombotic disease (symptomatic) and that with multiple atherothrombotic risk factors (asymptomatic) was pre-specified in the CHARISMA statistical analysis plan. In the 12,153 patients with documented atherothrombosis, there was a significant 12.5% RRR in the primary endpoint (CV death/MI/stroke) from 7.9% in the placebo + ASA group to 6.9% clopidogrel+ ASA group (p=0.046, 95% CI: 0.2%, 23.2%). At the end of follow-up, the event rate in the multiple risk factor population (N=3284) for the primary outcome in the clopidogrel plus ASA arm was 6.57% as compared to 5.48% in the placebo plus ASA arm (RRR -20.0% [-58.8%, 9.3%])
Figure 1. Roles in Clopidogrel Activity of Proteins with Known Genetic Polymorphisms. Intestinal absorption of the prodrug clopidogrel is limited by an intestinal efflux pump P-glycoprotein coded by the ABCB1 gene. The majority of the prodrug is metabolized into inactive metabolites by ubiquitous esterases. The minority is bioactivated by various cytochrome P450 (CYP) isoforms into active metabolites. These metabolites irreversibly antagonize the adenosine diphosphate (ADP) receptor (coded by the P2RY12 gene), which in turn inactivates the fibrinogen receptor (the glycoprotein [GP] IIb/IIIa receptor coded by the ITGB3 gene) involved in platelet aggregation.
Platelet aggregation offers useful prognostic information after myocardial infarction (MI). Investigators assessed platelet aggregation in 149 patients post-MI within 3 months of the index event. Spontaneous platelet aggregation (SPA) was graded as negative when there was no aggregation within 20 minutes of the addition of a platelet intermediate when aggregation occurred between 10 and 20 minutes and positive when aggregation occurred within 10 minutes. Clinical outcomes, including cardiac events—nonfatal recurrent MI or cardiac death (defined as death occurring in hospital post-MI or death occurring suddenly without previous symptoms or within 24 hours of the onset of new symptoms of heart disease)—were recorded over 5 years. A total of 14.9% SPA-negative patients experienced at least 1 cardiac event over 5 years vs 24.1% of SPA-intermediate patients and 46.2% of SPA-positive patients. The relative risk (RR) for a cardiac event was 1.6 (95% CI range: 0.7-3.5) in patients in the SPA-intermediate group and 3.1 (95% CI range: 1.6-5.8) in those in the SPA-positive group. Mortality was also highest in the SPA-positive group (34.6%) compared with the SPA-intermediate and SPA-negative groups (10.3% and 6.4%, respectively). Compared with patients in the SPA-negative group, the RR for death was 1.6 (95% CI range: 0.5-5.5) in patients in the SPA-intermediate group and 5.4 (95% CI range: 2.2-13.4) in those in the SPA-positive group. Overall, a positive association between platelet hyperreactivity and both cardiac events and mortality was demonstrated in post-MI patients over 5 years. References Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med . 1990;322:1549-1554.
OBJECTIVES: This study sought to determine the incidence of aspirin nonresponsiveness in addition to clopidogrel nonresponsiveness and whether this association identifies patients at an increased risk of drug-eluting stent (DES) thrombosis. BACKGROUND: Nonresponsiveness to clopidogrel is a predictor of DES thrombosis. No prospective data exist about the possible association of dual nonresponsiveness to clopidogrel and aspirin with DES thrombosis. METHODS: Platelet function was assessed after a loading dose of 600 mg clopidogrel in 746 patients who had successful DES implantation followed by 6-month dual-antiplatelet therapy. Platelet reactivity was assessed by light transmittance aggregometry using adenosine 5'-diphosphate, arachidonic acid, and collagen. The primary end point was definite/probable DES thrombosis at 6 months. The secondary end point was the composite of cardiac mortality and DES thrombosis. RESULTS: The incidence of dual nonresponsiveness to aspirin and clopidogrel was 6%. Definite/probable DES thrombosis was significantly higher in dual aspirin and clopidogrel nonresponders (11.1%) than in clopidogrel and aspirin responders (2.1%, p < 0.001), isolated clopidogrel nonresponders (2.2%, p < 0.05), or aspirin nonresponders (2.3%, p < 0.05). The incidence of the secondary end point was 4.4% in isolated clopidogrel nonresponders, 2.3% in isolated aspirin nonresponders, and 13.3% in dual aspirin and clopidogrel nonresponders. Dual clopidogrel and aspirin nonresponsiveness was an independent predictor of. CONCLUSIONS: Dual nonresponsiveness to aspirin and clopidogrel is a relatively infrequent condition that identifies patients at a very high risk of DES thrombosis or death.
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