1. Thirteenth International Symposium HEART FAILURE & Co. Il Mio Dolce Cuore My Sweet Heart Napoli 12-13 aprile 2013 E. Gronda, FESC, FANMCO Divisione di Cardiologia Dipartimento Cardiovascolare IRCCS, MultiMedica - S.S. Giovanni Ospedale Classificato S. Giuseppe - Milano Gruppo MultiMedica Stroke in Diabetics, the Lesson from NOAs

2. 23% of Ischemic Strokes 23% of Ischemic Strokes are Cardiogenic, the more severe

3. A clustering of risk factors: insulin resistance, lipid abnormalities and hypertension (the metabolic syndrome), links diabetes to other risk-factors, endothelial dysfunction bears: proinflammatory states, haemostasis/fibrinolysis abnormalities, angiogenesis, extracellular matrix turnover [2,3] abnormal sympathetic tone links to left ventricular hypertrophy, cardiac dysfunction, and autonomic neuropathy [4] abnormalities in inflammatory and thrombotic states impair the ability of myocardial and vascular tissue to remodel, to recover and to sustain functionality [5]. 1.Kannel WB et al. N Engl J Med 1982;306(17):1018– 2. 2.Grundy SM et al. Circulation 2004 (Jan 27); 109(3):433–8. 3.Tayebjee MH et al. Diabetes Care 2004 (Aug);27(8):2049– 51. 4.Lim HS Arch Intern Med 2004 (Sep 13);164(16):1737– 48. 5.Lip GY et al. Eur Heart J 2000 (Oct);21(20):1653– 65. DM commonly associated with AF on an epidemiological basis [1]

4. VHAH study [1]: AF occurrence in 14.9% of DM pts vs 10.3% in control group (p<0.0001) On multi-variate analysis : DM independently associated with AF (OR of 2.13, 95% CI: 2.10–2.16; p <0.0001) and Flutter (OR 2.20, CI: 2.15 – 2.26; p <0.0001). Independently associated with DM:. HF (OR 3.1), LVH (OR 1.85), CAD (OR 2.39. 1.Movahed MR, et al. Int J Cardiol 2005;105:315– 8. 2.Aksnes TA et al,.Am J Cardiol 2008;101:634 – 638 3.Nichols CA et al. Diabetes care,vol.32,no.10,pp.1851-1856,2009. 4.Johansen OE et al. Cardiovascular diabetology,vol 7, no.28, 2008. VALUE trial [2]: DM linked to significant increase of new-onset of AF (RR 1.49, P=0.0031) higher chance of developing persistent AF (RR 1.87, P=0.0014). diabetics presenting AF new-onset have much higher occurrence of HF (RR 3.56, P<0.0001) Large Nichols’ follow up study (7.2±2.8-year) [3], Risk of AF occurrence increased by 26% in diabetic women Prevalence of abnormal glucose metabolism in AF (75 y.o. patients) [4]: AF occurrence could be associated with long-term hyperglycemia AF history >5 years, proactive DM pre-diabetes screening to be performed.

5. Independent risk factors for AF in patients with sinus rhythm Benjamin EJ, et al. JAMA. 1994;271:840-844. 014683579212345670 Age (for every 10 years) 2.12.2 Diabetes 1.41.6 Hypertension 1.5 1.4 4.55.9 Valvular heart disease 1.8 3.4 Men (n = 2090) Myocardial infarction 1.4 NS Women (n = 2641) Odds ratio* Framingham Heart failure *2-year pooled logistic regression

6. Impact of Glucose Intolerance and Insulin Resistance on Atrium Size Echo LA, cm Q1Q2Q3Q4 P - for Trend 13,903,943,974,06 <0,001 2323 3,98 3,97 3,96 3,97 3,95 0,42 0,56 Echo LA, cm Q1Q2Q3Q4 P - for Trend 13,393,48 3,58 <0,001 2323 3,47 3,50 3,48 3,47 3,48 0,42 0,56 Quartiles of Homa - IR HOMA-IR range U 0.18– 0.940. 0.95– 1.57 1.58– 2.60 2.61– 12.09 HOMA-IR range U 0.16– 0.700. 0,71– 1.231. 1,24– 1.971. 1,98– 14.38 Men (n=852) Women (n=1170) Rutter MK et al. Circulation. 2003;107:448-454

7. Clinical Correlates in the Community Longitudinal Tracking of Left Atrial Diameter Over the Adult Life Course McManus DD et al. Circulation 2010;121;667-674 1.Low risk group : BMI of 25 kg/m2 with normal BP (defined as having a median BP of 113/73) 2.Intermediate risk group: BMI of 27.5 kg/m2 and pre-hypertension (defined as having a median BP of 133/86) not receiving anti-hypertensive medications 3.High risk group : BMI of 30 kg/m2 and hypertension (defined as having a median BP of 146/91 ).

8. Melenovsky V. et al. JAm Coll Cardiol 2007;49:198–207 Melenovsky V. et al. J Am Coll Cardiol 2007;49:198–207 p Value Gender ♀% 84 78 0.28 Age yrs 65 ±10 67 ± 10 0.61 Creat.(mg/dl) 1,4±0,7 1,0±0,3 <0,01 Diabetes M % 61 35<0,01

9. (Toh, Hypertension 2010) 100 90 80 70 60 100 90 80 70 60

10. Percentage of Administration of ANTICOAGULATION THERAPY in Patients with Atrial Fibrillation (the Euro Heart Survey). Stroke risk: is the Atrial Fibrillation pattern a rationale risk stratification criteria?

11. Similar risk for thromboembolic events in paroxysmal versus sustained AF in patients under treatment This risk can be significantly lowered with OAC Only intermittent monitoring used in this study S. Hohnloser. J Am Coll Cardiol 2007; 50: 2156–61

12. Copyright © 2012 American Medical Association. All rights reserved. From: Validation of Clinical Classification Schemes for Predicting Stroke: Results From the National Registry of Atrial Fibrillation JAMA. 2001;285(22):2864-2870. doi:10.1001/jama.285.22.2864 Figure Legend : - + - + The anticoagulation strategy mainly should depend of CHA2DS2-VASc score instead of the type of AF (paroxysmal, persistent or permanent).

13. CHA 2 DS 2 VASc better identifies patients at intermediate risk ! CHADS 2 Score Stroke Risk Factor 1.Congestive heart failure 1 2.Hypertension 1 3.Age ≥75 years 1 4.Diabetes mellitus 1 5.Stroke, TIA, or thromboembolism 2 Maximum score 6 CHA 2 DS 2 VASc SCORE Stroke Risk Factor 1.Congestive heart failure/ LV dysfunction 1 2.Hypertension 1 3.Age ≥75 years 2 4.Diabetes mellitus1 5.Stroke, TIA, or thromboembolism 2 6.Vascular disease (previous MI, PAD, or aortic plaque) 1 7.Age 65–74 years 1 8.Gender category (female)1 Maximum score9 LV=left ventricular. MI=myocardial infarction. PAD= peripheral artery disease.

14. CHADS2CHA2DS2VASc Proportion of patients with score Stroke rate at 1 year (95% CI) Proportion of patients with score Stroke rate at 1 year (95% CI) 022% 1·7% (1·5–1·9) 8% 0·8% (0·6–1·0) 131% 4·7% (4·4–5·1) 12% 2·0% (1·7–2·4) 223% 7·3% (6·9–7·8) 18% 3 ·7% (3·3–4·1) 315% 15·5% (14·6–16·3) 23%5·9% (5·5–6·3) 4 7%21·5% (20·0–23·2)19% 9·3% (8·7–9·9) 5 2%19·7% (16·9–22·9)12%15·3% (14·3–16·2) 6 0·2%22·4% (14·6–34·3)6%19·7% (18·2–21·4 ) 72%21·5% (18·7–24·6) 80·4% 22·4% (16·3–30·8) 9 0·1%23·6% (10·6–52·6) Mark J A, Lancet Neurol 2012; 11: 1066–81 Score at baseline and stroke rate at 1 year according to CHADS 2 and CHA 2 DS 2 VASc scores (after AMI #73 538)

15. Dabigatran treatment effects consistent in patients at higher and lower risk of myocardial ischemic events. Hohnloser SH et al. Circulation. 2012;125:669-676

16. Diabetes, a Stroke specific risk factor? CHADS 2 VASC Risk factors Diabetes links Diabetes (if present) 1 Hypertension 1 40% in NIDDM >80% in IDDM with macroalbuniria [1] Age >75 2 ♂ 17,9% - ♀ 20,6% diabetes [2] Age 65-74 1 ♂ 15,3% - ♀ 12,4% diabetes Stroke 2 incidence per year in diabetics ♂ 13,7/1000 ♀ 10,8/1000 when one or more CVD present [3] Vascular disease 1 In a cohort (aged > 65 years) with hypertension, roughly half had PAD (ABI <1.0) [4] Tarnw L et al. Diabetes Care 1994 Nov;17(11):1247-51Tarnw L et al. Diabetes Care 1994 Nov;17(11):1247-51 Giorda CB et al Stroke. 2007;38:1154-1160Giorda CB et al Stroke. 2007;38:1154-1160 http://www3.istat.it/dati/catalogo/20111216_00/http://www3.istat.it/dati/catalogo/20111216_00/http://www3.istat.it/dati/catalogo/20111216_00/ 1Newman AB et al. Circulation. 1993;88:837-845.1Newman AB et al. Circulation. 1993;88:837-845.

17. OutcomeDiabetes Annual rate dabigatran 150 mg bid Annual rate dabigatran 110 mg bid Annual rate warfarin DE 150 mg vs warfarin HR (95% CI) DE 110 mg vs warfarin HR (95% CI) Stroke + systemic embolism No1.011.471.520.66 (0.51, 0.86)0.97 (0.76, 1.23) Yes1.461.762.350.62 (0.42, 0.91)0.74 (0.51, 1.08) p-inter = 0.7555p-inter = 0.2349 Ischemic stroke (incl. Uncertain) No0.821.251.080.76 (0.56, 1.02)1.16 (0.89, 1.52) Yes1.281.621.650.77 (0.49, 1.20)0.98 (0.65, 1.47) p-inter = 0.9553p-inter = 0.4839 Major bleeding No2.922.593.380.86 (0.73, 1.02)0.76 (0.64, 0.90) Yes4.663.814.191.12 (0.87, 1.44)0.91 (0.70, 1.19) p-inter = 0.0917p-inter = 0.2656 Intracranial bleeding No0.270.230.750.36 (0.23, 0.57)0.31 (0.19, 0.50) Yes0.470.220.810.58 (0.29, 1.16)0.26 (0.11, 0.65) p-inter = 0.2446p-inter = 0.2656 Vascular death No1.932.172.290.84 (0.69, 1.02)0.95 (0.78, 1.15) Yes3.463.274.010.86 (0.65, 1.13)0.81 (0.62, 1.07) p-inter = 0.8788p-inter = 0.3794 Death No3.203.453.710.86 (0.74, 1.00)0.93 (0.79, 1.08) Yes5.154.745.510.93 (0.74, 1.17)0.85 (0.68, 1.08) p-inter = 0.5912p-inter = 0.5685 17 Comparison of Dabigatran versus Warfarin in Diabetic Patients with Atrial Fibrillation: Results from the RE-LY Trial Darius AHA 2012, Abstract No. 15937

18. CHA 2 DS 2 VASc Score vs HAS-BLED Score a fair balance? LV=left ventricular. MI=myocardial infarction. PAD=peripheral artery disease. HAS-BLED Score Bleeding Risk Factor 1.Hypertension1 2.Abnormal renal /liver function (1 pt. each)1 or 2 3.Stroke1 4.Bleeding1 5.Labile INRs1 6.Elderly (age > 65 years)1 7.Drugs or alcohol (1pt. each)1 or 2 Max Score9 CHA2DS 2 VASc SCORE Stroke Risk Factor 1.Congestive heart failure/ LV dysfunction 1 2.Hypertension 1 3.Age ≥75 years 2 4.Diabetes mellitus1 5.Stroke, TIA, or thromboembolism 2 6.Vascular disease (previous MI, PAD, or aortic plaque) 1 7.Age 65–74 years 1 8.Gender category (female)1 Maximum score9

19. Net clinical benefit for warfarin, dabigatran, rivaroxaban and apixaban by CHA2DS2-VASc Banerjee A et al. Thromb Haemost 2012; 107: 584–589

20. Net clinical benefit for warfarin, dabigatran, rivaroxaban and apixaban by CHA2DS2-VASc and HAS-BLED ≤2. Banerjee A et al. Thromb Haemost 2012; 107: 584–589

21. Key Messages NOAs (dabigatran, rivaroxaban and apixaban) tested in large randomized controlled multicenter international trials, although with different study design, show favourable effects on both ischaemic stroke/thromboembolism and bleeding risk. Regardless of associated medical conditions, including diabetes. The net clinical benefit balancing ischaemic stroke against intracranial haemorrhage is only negative with warfarin at a CHA 2 DS 2 -VASc score=0, reflecting the ‘truly low risk’ status of these patients

22. Key Messages Diabetes per se, runs increasing risk of atrial fibrillation & stroke by clustering a number of cardiovascular risk factors in the same patient. Multiple noxae hit cardiovascular apparatus and haemo- coagulative system exposing diabetic patient to the opposite risk of thrombus and of bleeding. The preventive NOAs administration in this high risk subpopulation have shown, in the balance, a prominent net clinical benefit over bleeding risk, as well as in the overall treated population.

23. What does Banerjee’s paper add? ● In patients with CHA 2 DS 2- VASC =0 but at high bleeding risk, apixaban and dabigatran 110 mg bid have a positive net clinical benefit. ● At CHA 2 DS 2 -VASc=1, apixaban and both doses of dabigatran (110 mg and 150 mg bid) have a positive net clinical benefit. ● In patients with CHA 2 DS 2 - VASC score ≥1 or ≥2, the three new NOAs (dabigatran, rivaroxaban and apixaban) appear superior to warfarin for net clinical benefit, regardless of risk of bleeding. ● When risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit than warfarin. Key Messages