Thirteenth International Symposium HEART FAILURE & Co. Il Mio Dolce Cuore My Sweet Heart Napoli 12-13 aprile 2013 E. Gronda, FESC, FANMCO Divisione di

Thirteenth International Symposium

HEART FAILURE & Co.Il Mio Dolce Cuore

My Sweet HeartNapoli

12-13 aprile 2013

E. Gronda, FESC, FANMCOE. Gronda, FESC, FANMCO

Divisione di CardiologiaDivisione di Cardiologia

Dipartimento CardiovascolareDipartimento Cardiovascolare

IRCCS, MultiMedica - S.S. Giovanni IRCCS, MultiMedica - S.S. Giovanni

Ospedale Classificato S. Giuseppe - Milano Ospedale Classificato S. Giuseppe - Milano

Gruppo Gruppo MultiMedicaMultiMedica

Stroke in Diabetics, the Stroke in Diabetics, the Lesson from NOAsLesson from NOAs

Stroke in Diabetics, the Stroke in Diabetics, the Lesson from NOAsLesson from NOAs

• 23% of Ischemic Strokes 23% of Ischemic Strokes are Cardiogenic, the more are Cardiogenic, the more severesevere

• 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]

• 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 – 6383. 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.

Independent risk factors for AFIndependent risk factors for AFin patients with sinus rhythmin patients with sinus rhythm

Benjamin EJ, et al. JAMA. 1994;271:840-844.

0 1 4 6 83 5 7 921 2 3 4 5 6 70

Age (for every 10 years) 2.1 2.2

Diabetes 1.4 1.6

Hypertension 1.5 1.4

4.5 5.9

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

Impact of Glucose Intolerance and Insulin Resistance on Impact of Glucose Intolerance and Insulin Resistance on Atrium SizeAtrium Size

Impact of Glucose Intolerance and Insulin Resistance on Impact of Glucose Intolerance and Insulin Resistance on Atrium SizeAtrium Size

EchoEcho

LA, LA, cmcm

Q1 Q2 Q3 Q4

P - for

Trend

1 3,90 3,94 3,97 4,06 <0,001

2

3

3,98

3,98

3,98

3,97

3,96

3,97

3,95

3,95

0,42

0,56

Echo

LA, cm

Q1 Q2 Q3 Q4

P - for

Trend

1 3,39 3,48 3,48 3,58 <0,001

2

3

3,47

3,47

3,50

3,50

3,48

3,47

3,48

3,48

0,42

0,56

Quartiles of Homa - IRQuartiles of Homa - IR

HOMA-IR

range U0.18–0.940.

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)• Men (n=852) • Women (n=1170)• Women (n=1170)

Rutter MK et al. Circulation. 2003;107:448-454Rutter MK et al. Circulation. 2003;107:448-454

Clinical Correlates in the Community Longitudinal Clinical Correlates in the Community Longitudinal Tracking of Left Atrial Diameter Over the Adult Life CourseTracking of Left Atrial Diameter Over the Adult Life Course

McManus DD et al. McManus DD et al. CirculationCirculation 2010;121;667-674 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 ).

Melenovsky V. et al. JMelenovsky V. et al. J Am Coll Cardiol 2007;49:198–207Am Coll Cardiol 2007;49:198–207

p ValueGender ♀% 84 78 0.28Age yrs 65 ±10 67 ± 10 0.61Creat.(mg/dl) 1,4±0,7 1,0±0,3 <0,01Diabetes M % 61 35 <0,01

(Toh, Hypertension 2010)(Toh, Hypertension 2010)

100

90

80

70

60

100

90

80

70

60

Percentage of Administration of ANTICOAGULATION THERAPY in Percentage of Administration of ANTICOAGULATION THERAPY in Patients with Atrial Fibrillation Patients with Atrial Fibrillation

(the Euro Heart Survey).(the Euro Heart Survey).

Stroke risk: is the Atrial Fibrillation pattern a rationale risk stratification criteria? Stroke risk: is the Atrial Fibrillation pattern a rationale risk stratification criteria?

• 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

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 The anticoagulation strategy mainly should depend of CHA2DS2-VASc score instead of the type of AF (paroxysmal, persistent or permanent). instead of the type of AF (paroxysmal, persistent or permanent).

CHA2DS2VASc better identifies patients at intermediate risk !

CHADS2 Score Stroke Risk Factor 1. Congestive heart failure 12. Hypertension 13. Age ≥75 years 14. Diabetes mellitus 15. Stroke, TIA, or

thromboembolism 2

Maximum score 6

CHA2DS2VASc SCOREStroke Risk Factor

1. Congestive heart failure/ LV dysfunction 1

2. Hypertension 13. Age ≥75 years 24. Diabetes mellitus 15. Stroke, TIA, or

thromboembolism 26. Vascular disease

(previous MI, PAD, or aortic plaque) 1

7. Age 65–74 years 18. Gender category (female) 1

Maximum score 9


1. Congestive heart failure/ LV dysfunction 1





Maximum score 9

LV=left ventricular. MI=myocardial infarction. PAD= peripheral artery disease.LV=left ventricular. MI=myocardial infarction. PAD= peripheral artery disease.

CHADS2 CHA2DS2VASc

Proportion of patients with score

Stroke rate at 1 year (95% CI)

Proportion of patients with score

Stroke rate at 1 year (95% CI)

0022%22% 1·7% (1·5–1·9)1·7% (1·5–1·9) 8% 8% 0·8% (0·6–1·0)0·8% (0·6–1·0)

11

31%31% 4·7% (4·4–5·1)4·7% (4·4–5·1) 12%12% 2·0% (1·7–2·4)2·0% (1·7–2·4)

22

23%23% 7·3% (6·9–7·8)7·3% (6·9–7·8) 18%18% 3 ·7% (3·3–4·1)3 ·7% (3·3–4·1)

33

15%15% 15·5% (14·6–16·3)15·5% (14·6–16·3) 23% 5·9% (5·5–6·3)

4

7% 21·5% (20·0–23·2) 19%19% 9·3% (8·7–9·9)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 )

7

2%2% 21·5% (18·7–24·6)

8

0·4%0·4% 22·4% (16·3–30·8)22·4% (16·3–30·8)

90·1% 23·6% (10·6–52·6)

Mark J A, Lancet Neurol 2012; 11: 1066–81Mark J A, Lancet Neurol 2012; 11: 1066–81 Mark J A, Lancet Neurol 2012; 11: 1066–81Mark J A, Lancet Neurol 2012; 11: 1066–81

Score at baseline and stroke rate at 1 year according to CHADS2 and CHA2 DS2VASc scores

(after AMI #73 538) Score at baseline and stroke rate at 1 year according to CHADS2 and CHA2 DS2VASc scores

(after AMI #73 538)

Dabigatran treatment effects consistent in patients at higher and lower risk of myocardial ischemic events.

Hohnloser SH et al. Circulation. 2012;125:669-676

Diabetes, a Stroke specific risk factor?

CHADS2VASC 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):1247-51 Tarnw 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/• 1Newman AB et al. Circulation. 1993;88:837-845.1Newman AB et al. Circulation. 1993;88:837-845.

• Tarnw L et al. Diabetes Care 1994 Nov;17(11):1247-51 Tarnw 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/• 1Newman AB et al. Circulation. 1993;88:837-845.1Newman AB et al. Circulation. 1993;88:837-845.

http://www3.istat.it/dati/catalogo/20111216_00/

http://www3.istat.it/dati/catalogo/20111216_00/

Outcome DiabetesAnnual rate dabigatran150 mg bid

Annual rate dabigatran110 mg bid

Annual ratewarfarin

DE 150 mg vswarfarin HR (95% CI)

DE 110 mg vswarfarin HR (95% CI)

Stroke +systemic embolism

No 1.01 1.47 1.52 0.66 (0.51, 0.86) 0.97 (0.76, 1.23)

Yes 1.46 1.76 2.35 0.62 (0.42, 0.91) 0.74 (0.51, 1.08) p-inter = 0.7555 p-inter = 0.2349

Ischemic stroke(incl. Uncertain)

No 0.82 1.25 1.08 0.76 (0.56, 1.02) 1.16 (0.89, 1.52)


Major bleedingNo 2.92 2.59 3.38 0.86 (0.73, 1.02) 0.76 (0.64, 0.90)


Intracranial bleedingNo 0.27 0.23 0.75 0.36 (0.23, 0.57) 0.31 (0.19, 0.50)


Vascular deathNo 1.93 2.17 2.29 0.84 (0.69, 1.02) 0.95 (0.78, 1.15)


DeathNo 3.20 3.45 3.71 0.86 (0.74, 1.00) 0.93 (0.79, 1.08)

Yes 5.15 4.74 5.51 0.93 (0.74, 1.17) 0.85 (0.68, 1.08)

p-inter = 0.5912 p-inter = 0.568517

Comparison of Dabigatran versus Warfarin in Diabetic Patients with Atrial Fibrillation: Results from the RE-LY Trial Darius AHA 2012, Abstract No. 15937

CHA2DS2VASc Score vs HAS-BLED Score a fair balance?

LV=left ventricular. MI=myocardial infarction. PAD=peripheral artery disease.LV=left ventricular. MI=myocardial infarction. PAD=peripheral artery disease.

HAS-BLED ScoreBleeding Risk Factor

1. Hypertension 12. Abnormal renal /liver function

(1 pt. each) 1 or 2

3. Stroke 14. Bleeding 15. Labile INRs 16. Elderly (age > 65 years) 17. Drugs or alcohol (1pt. each) 1

or 2

Max Score 9

HAS-BLED ScoreBleeding Risk Factor

1. Hypertension 12. Abnormal renal /liver function

(1 pt. each) 1 or 2

3. Stroke 14. Bleeding 15. Labile INRs 16. Elderly (age > 65 years) 17. Drugs or alcohol (1pt. each) 1

or 2

Max Score 9


1. Congestive heart failure/LV dysfunction 1





Maximum score 9


1. Congestive heart failure/LV dysfunction 1





Maximum score 9

Net clinical benefit for warfarin, dabigatran, rivaroxaban and apixabanby CHA2DS2-VASc

Banerjee A et al. Thromb Haemost 2012; 107: 584–589

Net clinical benefit for warfarin, dabigatran, rivaroxaban and apixabanby CHA2DS2-VASc and HAS-BLED ≤2.

Banerjee A et al. Thromb Haemost 2012; 107: 584–589

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 CHA2DS2-VASc score=0, reflecting the ‘truly low risk’ status of these patients

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.

What does Banerjee’s paper add?

● In patients with CHA2DS2-VASC =0 but at high bleeding risk, apixaban and dabigatran 110 mg bid have a positive net clinical benefit.

● At CHA2DS2-VASc=1, apixaban and both doses of dabigatran (110 mg and 150 mg bid) have a positive net clinical benefit.

● In patients with CHA2DS2-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

Documents

Thirteenth International Symposium HEART FAILURE & Co. Il Mio Dolce Cuore My Sweet Heart Napoli 12-13 aprile 2013 E. Gronda, FESC, FANMCO Divisione di