Rikshospitalet, University of Oslo

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1 Rikshospitalet, University of Oslo Preventing heart failure by preventing coronary artery disease progression European Society of Cardiology Dyslipidemia

2 Objectives The trends in cardiovascular diseases Effect of statins in preventing heart failure Dose dependency Effect of statins in established chronic heart failure Risk factors and cause of end points in chronic heart failure

3 Temporal trends in mortality rate and the development of heart failure after a first MI J.A. Ezekowitz et al. J Am Coll Cardiol 2009;53:13-20

4 Effect of statin therapy on coronary artery stenoses (quantitative coronary angiography) C.M.Ballantyne et al. Circulation 2008;117:00-00

5 Risk factors in cardiovascular disease Dyslipidemia Hypertension Diabetes Smoking Inactivity STATINS Atherosclerosis Sudden death Cardiac rupture Cardiogenic shock Myocardial infarction Non-fatal MI Non-fatal heart failure

6 ApoB/apoA-1 and glucose are associated with late development of heart failure in healthy individuals Follow up 11.8 years Holme I, Eur J Heart Fail 2009;11:1036

7 Objectives The trends in cardiovascular diseases Effect of statins in preventing heart failure Dose dependency Effect of statins in established heart failure Risk factors and cause of end points in chronic heart failure

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9 Proportion without Heart Failure Prevention of Heart Failure by Simvastatin 4S 1.00 post hoc analysis Mo significant: -21%, p< Mo diverge Simvastatin 0.92 Placebo Months Since Randomization Kjekshus et al., J Cardiac Failure 1997;3:249-54

10 Effect of statin treatment on new onset heart failure in patients with CHD RCT post hoc Hazard ratio and 95% CI 4S PROSPER CARE MIRACLE LIPID ALLHAT ASCOT S40: 184/2221(8.3%) 288/2223(10.3%) P:112/2891(3.9%) 122/2913 (4.2%) P:146/2081(7.0%) 160/2078 (7.7%) A:40/1538 (2.6%) 43/1548 (2.8%) P:36/4512 (0.8%) 46/4502 (1.02%) P:243/5170 (4.7%) 248/5185(4.8%) A: 41/5168 (0.8%) 36/5137(0.7%) ALL 508/14975 (3.4%) 371/15015 (2.5%) p< Favours statin Favours placebo

11 Objectives Trend changes in targets for cardiovascular treatment Effect of statins in preventing heart failure Dose dependency Effect of statins in established heart failure Risk factors and cause of end points in chronic heart failure

12 Benefit of agressive and moderate statin doses on HF hospitalisation Acute coronary syndrome PROVE-IT Atorvastatin 80mg vs pravastatin 40 mg Stable coronary disease TNT Atorvastatin 80 mg vs atorvastatin 10 mg Scirica BM J Am Coll Cardiol 2006;47: Kush KK Circulation 2007;115:

13 Benefit of intensive vs moderate statin therapy on HF hospitalisation in patients with CHD RCT Hazard ratio and 95% CI IDEAL TNT PROVE-IT A-Z ALLIANCE A80: 99/24439 (2.2%) S40: 123/4449 (2.8%) A 80: 122/4995(2.4%) A10 :164/5006(3.3%) A 80: 36 /2099(1.6%) P40: 67/2063 (3.1%) S80: 72/2265 (3.7%) S20: 98/2232 (5.0%) A80: 42/1217 (3.5%) MOD: 56/1225 (4.5%) ALL 943/23586 (4.0%) 802/23581 (3.5%) p< Favours intensive statin Favours moderate statin

14 Benefit of atorvastatin 80 vs 10 mg on hospitalization for heart failure - with and without prior heart failure (classii-iiia) Kush KK Circulation 2007;115:

15 Objectives Trend changes in targets for cardiovascular treatment Effect of statins in preventing heart failure Dose dependency Effect of statins in chronic heart failure Risk factors and cause of end points in chronic heart failure

16 Effect of Rosuvastatin on left ventricular ejection fraction in patients with heart failure of ischemic and non-ischemic etiology Change in Left Ventricular EF (%) Ischemic and nonischemic CM LVEF <40% Randomised to rosuvastatin 20-40mg or placebo Follow up 6 months H.Krum et al. J Card Fail 2007;13:1-7

17 GISSI-HF investigators. Lancet, 2008 Kjekshus J, N Engl J Med 2007;357 Effects of rosuvastatin in patients with chronic heart All cause death failure GISSI-HF CORONA All cause death Primary outcome Cardiovascular events Death from any cause

18 Statins and mortality among patients with heart failure A meta analysis of observational and RCT studies GISSI Observational RCT K.Ramasubbu et al. JACC 2008;51:415-26

19 Total Number of Hospitalizations Placebo Rosuvastatin All cause p=0.007 CV cause p<0.001 Heart failure p=0.01 Unstable angina p=0.30 Non-CV cause Kjekshus J et al, N Engl J Med 2007;357

20 Risk factors in cardiovascular disease Non-fatal heart failure Dyslipidemia Hypertension LV dilatation Diabetes Asynchrony Smoking Hypertrophy Inactivity Inflammation Endothelial dysfunction Iron deficiency Ischemia Renal dysfunction Atherosclerosis Myocardial Progressive infarction heart failure Sudden death Cardiac rupture Non-fatal MI Cardiogenic shock Non-fatal heart Fatal heart failure failure Sudden arrhythmic death Stroke

21 Effects of Simvastatin on vascular events in participants subdivided by baseline N-BNP level Heart Protection Study Collaborative Group. JACC 2007;49:311-19

22 Primary Endpoint by NT-proBNP Tertile 1 (n= 1221) Tertile 2 (n= 1222) Tertile 3 (n= 1221) Hazard ratio= % CI Hazard ratio= % CI Interaction by treatment p= Hazard ratio= % CI Adjusted for baseline risk factors 2 With NT-proBNP as continous variable Cleland J et al. on behalf of CORONA Study Group

23 Primary Endpoint hs-crp <2.0 mg/l hs-crp 2.0 mg/l Per cent Placebo Rosuvastatin Per cent Placebo Rosuvastatin Hazard ratio % CI Hazard ratio % CI Months of follow-up No. at risk Placebo Rosu Interaction by treatment p= Months of follow-up

24 Coenzyme Q 10 and outcome in heart failure Effect of rosuvastatin A prespecified substudy of CORONA Coenzyme Q 10 μg/ml Tertile1 Tertile 2 Tertile 3 Placebo Rosuvastatin Placebo Rosuvastatin Placebo Rosuvastatin Baseline 6months Median change (%) P< P< P< probnppmol/l All cause mortality + hosp. for worsening HF HR(CI) 1.16( ) 0.82 ( ) Interaction by treatment p= ( ) McMurray JJV JACC 2010, in press

25 Conclusion Onset of heart failure increase mortality fourfold Statins preven de novo heart failure in a dose dependent manner The effect of statin declines with onset of heart failure with a cut point at NT-proBNP 100pmol/L (845pg/ml) Moderate and severe HF are determined by arrhythmic sudden death and progressive myocardial dysfunction, probably not driven by coronary atherosclerosis We need more accurate understanding of the causal pathway of cardiovascular death in mild, moderate and severe heart failure The importance of modulation of inflammatory actvity, coenzyme Q 10, irondeficiency, endothelial dysfunction and renal impairment need to be defined

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