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The bitter fate of acute coronary syndrome in diabetics: diabetics have more adverse outcomes after PCI Sergio Berti Fondazione CNR-Reg. Toscana G. Monasterio.

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Presentation on theme: "The bitter fate of acute coronary syndrome in diabetics: diabetics have more adverse outcomes after PCI Sergio Berti Fondazione CNR-Reg. Toscana G. Monasterio."— Presentation transcript:

1 The bitter fate of acute coronary syndrome in diabetics: diabetics have more adverse outcomes after PCI Sergio Berti Fondazione CNR-Reg. Toscana G. Monasterio Ospedale del Cuore, Massa

2 Diabetes in 2000 and forecast for 2030
500 400 Prevalenza mondiale (%) 300 forecast 200 100 Wild S et al. Diabetes Care 2004; 27:

3 Diabetes in 2000 and forecast for 2030
Hossain P et al. N Engl J Med 2007; 356:

4 Early mortality of diabetic and non-diabetic patients with acute myocardial infarction: Historical perspective

5 UA/NSTEMI Diabetes CVD(+) Diabetes CVD(-) No Diabetes CVD(+)
69 Hosp Pts Il registro OASIS (Organization to Assess Strategies for Ischemic Syndromes)7 ha raccolto in maniera prospettica i dati relativi ai pazienti con angina instabile e IMA non Q, seguiti per 2 anni in 6 differenti paesi occidentali e in 69 centri ospedalieri. Degli 8013 pazienti oggetto dell’osservazione, il 21% (n = 1718) aveva una storia clinica di diabete mellito in trattamento dietetico o farmacologico (ipoglicemizzanti orali o insulina). I soggetti diabetici sono stati più spesso sottoposti a interventi di rivascolarizzazione chirurgica (23 vs 20%, p < 0.001), mentre le angiografie coronariche e l’angioplastica sono risultate ovrapponibili nei due gruppi. Il diabete si è confermato associato a un incremento significativo di mortalità globale e mortalità per cause cardiovascolari, ictus e scompenso cardiaco, sia nella fase intraospedaliera che durante l’intero follow- up. I pazienti diabetici hanno inoltre richiesto una permanenza media in ospedale superiore a quella dei soggetti non diabetici (11.4 ± 8 vs 10.3 ± 8 giorni, p < ) OASIS Registry Malmberg K et al, Circulation 2000;102:1014

6 Diabetes and Mortality Following Acute Coronary Syndromes Sean M
Diabetes and Mortality Following Acute Coronary Syndromes Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

7 Pooled TIMI Trials 11 study del TIMI group 62036 pts
Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

8 Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS
Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

9 Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS
30 days 8.5% 5.4% 2.1% 1.1% Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

10 Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS
13.2% 8.1% 7.2% 3.1% Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

11 STEMI network Massa-Carrara / Versilia
Spoke E 55 km STEMI network Massa-Carrara / Versilia 11

12 Zona Lunigiana 55 Km 58 Km 74 Km 12

13 Matrix Network STEMI 1496 pts

14 Heart Hospital: STEMI network: Door to balloon
Andamento del tempo tra insorgenza del dolore e angioplstica DtB sta per door to balloon (angioplastica)

15 Heart Hospital: STEMI network: 1 year follow-up mortality
È l’andamento della mortalità ad un anno, circa il 7%, è un effetto della DIA precedente, riducendo i tempi di intervento migliora la mortalità

16 Patients presenting with STEMI our experience (1496 pts)
* Mettere il numero di pazienti totali inseriti nel DB 1518 totale 293 diabetici 1214 non diabetici (54 diabetici +74 prediabed= 128) Definizione di Prediabete LG esc Hb glicata tra 6-6,49 per gli americani tra 5,7 e 6,49 *= HbA1c 6>x<6.49

17 Overall Mortality Patients presenting with STEMI our center experience
DM- DM+ Survival, % Se si riesce modificare il le curve di sopravvivenza con inviato nella precedente mail (perché i pazienti nel DB sono circa 1500 e ne compaiono meno di 1000? Log rank, p<0.001 Follow-up, days

18 Overall Mortality Patients presenting with STEMI our center experience
DM- * Pre-diabetes DM+ Survival, % Se si riesce modificare il le curve di sopravvivenza con inviato nella precedente mail Log rank, p<0.001 for both comparisons Follow-up, days *= HbA1c 6>x<6.49

19 …Worst outcome… WHY ? Widespread and more aggressive atherosclerotic disease in patients with Diabetes Lower response to the antiaggreganting agents Greater incidence of the “No reflow” phenomenon Comorbidities Less aggressive treatment strategies in diabetic patients

20 Angiographic data in patients with and without Diabetes presenting with ACS
All ACS P value < 0.001 Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

21 Angiographic data in patients with and without Diabetes presenting with ACS
UA/NSTEMI P value < 0.001 Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

22 Angiographic data in patients with and without Diabetes presenting with ACS
STEMI * * P value < 0.001 *P value 0.02 Sean M. Donahoe, MD at al. JAMA. 2007;298(7):

23 Mechanisms contributing to platelet dysfunction In patients with diabetes mellitus
HYPERGLYCAEMIA Increased P-selectin expression Osmotic effect Activation of PKC Decreased membrane fluidity by glycation of surface proteins DEFICIENT INSULIN ACTION Impaired response to NO and PGI2 IRS-dependent factors: Increased intracellular Ca++ degranulation ASSOCIATED METABOLIC CONDITIONS Obesity Dyslipidemia Inflammation OTHER CELLULAR ABNORMALITIES PLATELET ENDOTHELIAL DYSFUNCTION Increased platelet turnover Upregulation of P2Y12 signalling Increased intracellular Ca++ Oxydative stress Increased P-selectin and GP expression Increased production of TF Decreased NO and PGI2 production PKC IRS-1 Ca++ P2Y12 H2O ADP ROS/NOS Figure 1. Mechanisms involved in platelet dysfunction in patients with DM. Several mechanisms contribute to platelet dysfunction in diabetes mellitus (DM) patients, including hyperglycemia, insulin deficiency, associated metabolic conditions, and other cellular abnor- malities. Hyperglycemia may increase platelet reactivity by inducing P-selectin (a surface adhesion protein) expression, glycating plate- let surface proteins (decreasing membrane fluidity and, thus, increasing platelet adhesion), and activating protein kinase C (PKC; a mediator of platelet activation) and as a result of the osmotic effect of glucose. Insulin deficiency also contributes to platelet dysfunc- tion by different mechanisms. Some have been suggested to be IRS dependent such as the increase in intracellular calcium concentra- tion, which leads to enhanced platelet degranulation and aggregation. Other factors associated with insulin resistance are not depen- dent on IRS, eg, the impaired response to NO and PGI2, which enhances platelet reactivity. Some metabolic conditions frequently associated with DM may play a role in platelet hyperreactivity, including obesity, dyslipidemia, and enhanced systemic inflammation. In addition to being associated with insulin resistance, obesity contributes to platelet dysfunction, mainly in terms of adhesion and activa- tion, with factors like augmented cytosolic calcium concentration and increased oxidative stress. Abnormalities of the lipid profile, especially hypertriglyceridemia, also affect platelet reactivity by different mechanisms, which include inducing endothelial dysfunction. The presence of endothelial dysfunction is another characteristic feature associated with DM, which enhances platelet reactivity by decreasing the production of NO and PGI2 and contributes to a prothrombotic state through increased production of tissue factor (TF). Other platelet abnormalities present in DM patients can enhance platelet adhesion and activation, including increased expression of surface proteins (P-selectin and GP IIb/IIIa), augmented cytosolic calcium concentration, upregulation of certain pathways like P2Y12 signaling, increased platelet turnover, and oxidative stress, which causes an impairment in platelet function as a result of overproduc- tion of reactive oxygen (ROS) and nitrogen species (NOS). TF NO PGI2 Endothelial cells Ferreiro JL, Angiolllo DJ. Circulation 2011; 123: 23

24 Diabetes and Clopidogrel
Angiolillo DJ et al Diabetes 2005; 54:2430-5 Angiolillo DJ J Am Coll Cardiol 2006; 48:

25 Diabetes and Prasugrel TRITON TIMI 38
Tale problematica (resistenza a antiaggreganti) vede una, per lo meno parziale, soluzione nei nuovi antiaggreganti PRASUGREL (Triton timi 38) e.. Wiviott SD Circulation 2008;118;

26 PLATO diabetes: All-cause mortality
10 8 6 4 2 [James 2010:H,I] Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.82(0.66–1.01) 8.7% 7.0% p for interaction = 0.66 All-cause mortality (%) 5.0% 3.7% No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.77(0.65–0.91) Days after randomisation All-cause mortality benefit with ticagrelor was consistent with the overall PLATO trial results[Wallentin 2009:J] No interaction between diabetes status and treatment was observed (p=0.66)[James 2010:G,H] CI, confidence interval; HR, hazard ratio. James S, et al. Eur Heart J 2010;31:3006–3016.

27 The “no reflow” phenomenon
Multivariable Predictors of the No-Reflow Phenomenon Iwakura et al. JACC Vol. 41, No. 1, 2003 January 1, 2003:1–7

28 The “no reflow” phenomenon
Myocardial Blush Grade Incidence % Abhiram Prasad, MD at al. ACC Vol. 45, No. 4, 2005 February 15, 2005:508–14

29 Co-morbidities impact
PVD, peripheral vessel disease; CHF congestive heart failure Solomon et al. Eur J Heart Fail 2010;12:

30 Under utilization of an early invasive treatment strategy in diabetic patients with ACS
A nationwide study N= pts. The present study was performed to evaluate if diabetic patients with ACS are offered coronary angiography (CAG) and revascularisation to the same extent as patients without diabetes. The study is a prospective observational nationwide cohort study linking Danish national registers containing information on hospitalisation, revascularisation procedures, claiming of drug prescriptions, and coronary pathology revealed by CAG. The cohort comprises all patients hospitalized with ACS (both STEMI, non-STEMI and UAP) for the first time in Patients discharged or not surviving the day of admission were excluded. Patients were followed for 60 days. Diabetes was defined as claiming of a prescription of insulin and/or oral hypoglycaemic agents within 6 months prior to the ACS event. Information on comorbidity, medicine use, socioeconomic status and vital status was available for each patient. From the Danish Heart Registry invasive procedures (CAG) were identified. Cox proportional-hazard models were used to estimate the difference in the rate of CAG and subsequent revascularization (PCI or CABG) within 60 days of the admission adjusting for explanatory variables.

31 What kind of stent? DES vs BMS

32 DES vs BMS in diabetic patients
Restenosis TLR Patti G Am J Cardiol 2008;102:1328 –1334

33 DES vs BMS in diabetic patients
Death Stent Thrombosis MI Patti G Am J Cardiol 2008;102:1328 –1334

34 DES vs. BMS in Diabetic patients
William B. Hillegass, MD, at al. Journal of the American College of Cardiology Vol. 60, No. 22, 2012

35 How to prevent cardiovascular events
in diabetic patients? Better glycemic control?

36 Sospeso per mortalità elevata
VADT ACCORD Sospeso per mortalità elevata ADVANCE Tre studi molto recenti hanno dimostrato che l’ottimizzazione del controllo glicemico (HbA1C < 6,5%o < 7,0%) non ha portato a una riduzione significativa degli eventi cardiovascolari, anzi: in uno di essi e stato riportato un aumento della mortalita totale e cardiovascolare nel gruppo a controllo glicemico ottimizzato (3‑5). Tali risultati, tuttavia, sono almeno in parte riconducibili ai limiti intrinseci negli studi disponibili (inclusione di diabetici con lunga durata di malattia, alta percentuale di pazienti con neuropatia e altre complicanze croniche, eccessiva e rapida riduzione dell’HbA1c, aumento di frequenza dell’ipoglicemia, insufficiente durata del follow‑up).

37 UKPDS Trial N Engl J Med 2008;359:

38 Diabetes and ACS: “dangerous liasons”
65% of Diabetic Patients dies following cardiovascular events 37% of ACS Patients is diabetic Diabetics with NSTEMI/UA, outcome is similar to non-diabetic patients with STEMI Future risk cardiovascular events: Diabetic Patients = non-diabetic patients with previous MI

39 Conclusions Improve antithrombotic strategy
3939 Conclusions Improve antithrombotic strategy Acute and chronic tight glycemic control Optimal revascularization strategy Optimal management of LV dysfunction 39

40 The bitter fate of acute coronary syndrome in diabetics: diabetics have more adverse outcomes after PCI Sergio Berti Fondazione CNR-Reg. Toscana G. Monasterio Ospedale del Cuore, Massa


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