Università Magna Græcia di Catanzaro Dipartimento di Medicina Sperimentale e Clinica Cattedra di Medicina Interna ed U.O. Malattie Cardiovascolari Scuola di Specializzazione in Geriatria Prof. Francesco Perticone perticone@unicz.it Diabete ed ASA: cosa c è di nuovo?
HR (plus uric acid 1 g/dl increase) Hs-CRP, mg/l Uric acid, mg/dl Ac. Urico e Glicemia 8 * Ac. Urico, Funzione Endoteliale e Diabete 6 2 0.001 4 1,6 0.012 2 1,2 0.340 0.799 0.355 0.192 0.124 0.090 0.071 0 * P<0.0001 0,8 0,4 8 6 * 0 0 100 200 300 400 500 600 700 800 900 4 ACh % of increase 2 Perticone F et al, Int J Cardiol 2012 0 <155 >155 NGT IGT DM Perticone F et al, Int J Cardiol 2011
Reactive Hyperemic Index Endothelial dependent vasodilation after ASA treatment in diabetics * * P=<0.0001 0 1 4 Wash weeks out
Box and whisker plots of urinary excretion of 11-dehydrothromboxane (TX)B 2 n healthy patients and in type 2 diabetic patients. Santilli F. et al. J Am Coll Cardiol 2006;47:391 7.
11-dehydro-TXB 2 n 20 type 2 diabetic patients before and after improved metabolic control. Santilli F. et al. J Am Coll Cardiol 2006;47:391 7.
METAANALYSIS FROM THE ANTITHROMBOTIC TRIALISTS' COLLABORATION (2002) ATC, BMJ 2002; 324: 71-86
Recommendations for primary prevention of CVD in people with diabetes. Antiplatelet agents Aspirin therapy (75 162 mg/day) should be recommended as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are >40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). People with aspirin allergy, bleeding tendency, existing anticoagulant therapy, recent gastrointestinal bleeding, and clinically active hepatic disease are not candidates for aspirin therapy. Other antiplatelet agents may be a reasonable alternative for patients with high risk. Aspirin therapy should not be recommended for patients under the age of 21 years because of the increased risk of Reye s syndrome associated with aspirin use in this population. People under the age of 30 years have not been studied.
Participation in Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Ogawa, H. et al. JAMA 2008;300:2134-2141.
Ogawa, H. et al. JAMA 2008;300:2134-2141. Atherosclerotic Events
Total Percentage of Atherosclerotic Events According to Treatment Group Ogawa, H. et al. JAMA 2008;300:2134-2141.
Subgroup Analysis of Incidence of Atherosclerotic Events Ogawa, H. et al. JAMA 2008;300:2134-2141.
Adverse Effects Ogawa, H. et al. JAMA 2008;300:2134-2141.
Belch, J. et al. BMJ 2008;337:a1840 POPADAD trial: Progress of participants in trial
PRIMARY END POINTS: % 25,0 20,0 15,0 10,0 5,0 0,0 Composite end point* Aspirin No Aspirin % 25,0 20,0 15,0 10,0 5,0 0,0 Death from coronary heart disease or stroke Aspirin No Aspirin Variables Aspirin (n=638) No aspirin (n=638) Effect estimate* (95% CI) Composite end point Death from coronary heart disease or stroke P value 116 (18.2) 117 (18.3) 0.98 (0.76 to 1.26) 0.86 43 (6.7) 35 (5.5) 1.23 (0.79 to 1.93) 0.36 *Death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or above ankle amputation for critical limb ischaemia.
SECONDARY END POINTS: 2,0 % % 6,0 4,0 2,0 0,0 Coronary Heart Disease Death Aspirin No Aspirin % 1,5 1,0 0,5 0,0 Stroke Death Aspirin No Aspirin % 10,0 8,0 6,0 4,0 2,0 0,0 Non-fatal myocardial infarction Aspirin No Aspirin % 6,0 4,0 2,0 0,0 Non-fatal stroke Aspirin No Aspirin Variables Aspirin (n=638) No aspirin (n=638) Effect estimate* (95% CI) P value Death (any cause) 94 (14.7) 101 (15.8) 0.93 (0.71 to 1.24) 0.63 Coronary heart disease death 35 (5.5) 26 (4.1) 1.35 (0.81 to 2.25) 0.24 Stroke death 8 (1.3) 9 (1.4) 0.89 (0.34 to 2.30) 0.80 Non-fatal myocardial infarction 55 (8.6) 56 (8.8) 0.98 (0.68 to 1.43) 0.93 Non-fatal stroke 29 (4.6) 41 (6.4) 0.71 (0.44 to 1.14) 0.15
Cause of death in patients with diabetes according to treatment group. Causes of death Myocardial infarction Other coronary heart disease Stroke: Aspirin plus antioxidant (n=56) Aspirin plus placebo (n=38) Placebo plus antioxidant (n=59) Placebo plus placebo (n=42) 11 10 8 5 4 10 7 6 Ischaemic 3 0 3 2 Haemorrhagic 2 0 1 2 Unknown cause 3 0 0 1 Other cardiac 5 0 4 1 Other vascular 3 1 2 2 Cancer 16 9 18 13 Trauma 0 0 2 0 Other 9 8 14 10 Belch, J. et al. BMJ 2008;337:a1840
Kaplan-Meier estimates in aspirin and no aspirin groups of proportion of patients who experienced the composite end point of death from coronary heart disease or stroke, nonfatal myocardial infarction or stroke, or above ankle amputation for critical limb ischaemia; and death from coronary heart disease or stroke. Belch, J. et al. BMJ 2008;337:a1840
Kaplan-Meier estimates for aspirin and no aspirin groups of proportion of patients who died from any cause, compared with proportion expected based on age and sex specific population rates for Scotland, 2002 Belch, J. et al. BMJ 2008;337:a1840
Picotamide, a combined inhibitor of thromboxane A 2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study Randomised n=1209 Study profile Assigned picotamide n=603 (49.9%) Assigned aspirin n=606 (50.1%) Lost to follow-up n=32 (5.3%) Completed trial n=571 (94.7%) Completed trial n=580 (95.7%) Lost to follow-up n=26 (4.3%) Neri Serneri et al. EHJ 2004; 25:1845 1852
Kaplan-Meier analysis of the time-to-death according to treatment assignment DAVID trial: 2-year mortality benefit of picotamide vs ASA Neri Serneri et al. EHJ 2004; 25:1845 1852
Mortality and morbidity events by treatment groups: the DAVID Study Type of event Myocardial infarction (fatal and non-fatal) Picotamide (n = 603) n Cumulative incidence (%) n Aspirin (n = 606) Cumulative incidence (%) 15 2.9 19 3.6 Stroke (fatal and non-fatal) 14 2.7 12 2.2 Amputation 4 0.8 4 0.8 Other deaths 12 2.2 19 3.8 At least one event 43 53 Neri Serneri et al. EHJ 2004; 25:1845 1852
O 2 - O 2 - PLA 2 AA F 2 -Isoprostanes Gp IIb/IIIa COX1 TxA2
O 2 - O 2 - PLA 2 AA F 2 -Isoprostanes Gp IIb/IIIa COX1 TxA2 ASA
Oxidative stress and platelet activation in diabetic patients ASA - + - + ASA - + - + ASA - + - + ASA - + - + Diabetes 2012 C T2DM
O 2 - O 2 - PLA 2 AA F 2 -Isoprostanes Gp IIb/IIIa COX1 TxA2 ASA
Diabetes 2012 Oxidative stress and platelet activation in diabetic patients
Diabetes 2012 Platelet recruitment in diabetic patients
Conclusion Aspirin treatment alone is not sufficient to reduce cardiovascular events in diabetes mellitus This lack of efficacy may be dependent upon NOX2-dependent platelet isoprostane overproduction Down-regulation of isoprostanes may represent a new avenue to optimize antithrombotic treatment