Rikshospitalet, University of Oslo

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1 Rikshospitalet, University of Oslo Controversies in the optimal management of ischemic heart failure From myocardial infarction to heart failure How do we prevent this? European Society of Cardiology DMC for Signify, Improve-it, HPS 2, Schedule, HPS 3

2 Risk factors in cardiovascular disease Dyslipidemia Hypertension Diabetes Smoking Inactivity Atherosclerosis (atherothrombosis) Sudden death Cardiac rupture Cardiogenic shock Myocardial infarction Non-fatal MI? Non-fatal heart failure

3 Mortality (%) Effects of incident heart failure on Mortality in patients with CVD 4S HF HF No HF n=288 n=1995 n=184 n=2037 Placebo No HF Simvastatin Kjekshus et al., J Cardiac Failure 1997;3:249-54

4 Pathophysiology of heart failure after non-fatal MI Infarct size Residual ischemia Inflammation Sympathetic and RAAS activation Increased cytokine Dyslipidemia expression Hypertension LV dilatation Fibrosis LV Sleep scar apnoea tissue Altered fibrinolysis Anaemia LV dysfunction Heterogeneity Re-entry Iron deficiency arrhythmias Oxidative stress Vitamin-D deficiency Endothelial dysfunction Mental depression Heart failure death Sudden arrhythmic COPD Renal death dysfunction

5 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

6 Targeting treatment with biomarkers and devices Pharmacophenomics NT probnp correlates with functional class and heamodynamic status Galectin-3 correlates with cardiac fibrosis and adverse remodeling Hs TroponinT correlates with myocyte necrosis Implantable hemodynamic monitoring

7 Targets for treatment Hypertension Heart rate Neurohormones

8 Hypertension and risk for heart failure HF is preceded by hypertension in >90% Treatment of hypertension effectively prevents AMI, stroke and HF Lower limit for blood pressure not defined HF reverse the relationship between blood pressure and mortality

9 Mortality at 6 months (%) Mortality at 6 months (%) Effect of enalapril on mortality according to SBP CONSENSUS 60 N= N=51 N=24 N=20 PLACEBO N=52 N=31 N=19 N=29 N=27 ENALAPRIL N=43 N=17 N=11 PLACEBO N=25 N=28 ENALAPRIL N=28 N= or less >135 Systolic pressure, mm Hg < >10 Change in systolic pressure at 6 weeks, mm Hg Kjekshus J, Cardiac and Renal Failure, Hanley & Belfus Inc., 1989:

10 Heart rate in heart failure Heart rate > 70 beats per min is a risk marker for CV death and HF hospitalizations a treatment target, reduction by beta blockade effectively reduces risk for CV mortality ivabradine which inhibits the sinus node can be given safely on top of a β-blocker if heart rate remains >70 beats per min Ivabradine is better tolerated than a β-blocker, but does not reduce sudden death Kjekshus J, ESC

11 Six-month mortality (%) Baseline Hormone levels (quartiles) and 6 month mortality (Consensus) Norepinephrine ANP Angiotensin II Aldosterone I II III IV Baseline hormone level (quartile) Consensus 1990

12 Neurohormonal score: composite of Noradrenaline, Angiotensin and Atrial natriuretic peptide CONSENSUS N Engl J Med 1987; 316:

13 Mode of death in heart failure Does the choice of treatment make a difference for mode of death?

14 Effect of enalapril on mode of death in patients with severe heart failure (NYHA class IV) CONSENSUS Cause of death

15 Effects of metoprolol on mode of death MERIT Total mortality Cardiovascular mortality Sudden death Death from pump failure Risk reduction% Relative risk (95%CI

16 The effect of spirolactone on mode of death in patients with severe heart failure RALES

17 Potential targets for treatment: Sleep disordered sleeping Obstructive and central sleep apnea are more common(35-40%) in heart failure than in the general population (2-4%) Closely associated with obesity, inflammatory and neurohormonal activation Increase CV death rate in HF populations by 3-fold Weight loss and CPAP decreases sympathetic activation, improves systolic function, reverse proinflammatory activation and rhythm disturbances Wang H JACC 2007;49: , Mansfield DR Am J Respir Crit Care Med 2005;169: , Harbison J Chest;2000;118: Yokoe T Circulation 2003;107:

18 Potential targets for treatment: Pro-inflammatory activation and endothelial dysfunction Heart failure development and worsening of symptoms are closely related to enhanced inflammatory activation and endothelial dysfunction Pro-inflammatory activation and endothelial dysfunction are associated with neurohormonal activation, obesity, hypoxia, diabetes and hypertension Treatment with statins reduce inflammatory markers and improves endothelial function, but has no effect on survival Specific treatment with TNFα antagonist (enbrel) has no effect on survival Inhibition of proinflammatory cytokines with pentoxifylline improves clinical status, LV EF, reduce markers of inflammation and NTpro-BNP Wang LM Cardiovasc Drug Ther 2009; 23: Sliwa K Circulation 2004;109: , Ross R NEJM 1999;340: , Akar JG Heart Rhythm 2008;5: ,

19 Potential targets for treatment: Anaemia in heart failure Anaemia is frequent in HF (6-43%) and relates to HF severity Anaemia is associated with increased morbidity and mortality Anaemia is associated with renal dysfunction inadequat production of erythropoietin Renal dysfunction and anaemia aggravates HF prognosis Erythropoietin in small HF studies improve cardiac function and renal impairment. Larger clinical studies could not demonstrate improvement in exercise capacity, mortality or non-fatal cardiac events Intravenous ferric carboxymaltose in chronic heart failure improves symptom, functional capacity and QoL (FAIR HF) Najjar SS JAMA 2011;305: , Anker S Eur Heart J 2009;30: , Silverberg D JACC 2001;37: ,

20 Anemia is an independent predictor of in-hospital mortality in AHF OPIMIZE- HF registry pts c. AHF Hgb<12.1: 52% Hgb< 10.7: 25% Young. Am J Cardiol 2008;101:223-30

21 Potential targets for treatment: Vitamin D deficiency and CV disease Lee JH. Am. Coll. Cardiol. 2008;52;

22 Potential targets for treatment: Depression in heart failure Mental depression is observed in one-third of patients with heart failure Depression is associated with CV risk factors: high sympathoadrenergic activity, elevated heart rate and reduced heart rate variability, prothrombotic and pro-inflammatory state Depression leads to worse outcomes and higher cost in heart failure Beta-blockers do not raise the risk of depression Inconclusive effects of treatment Silver MA Cleveland Clin J Med 2010;77:7-11, Koenig HG Gen Hosp Psyciatry 1998; 20:29-43, Havranek EP Am J Cardiol 1999;84: , Rutledge T JACC 2006;48: , Friedmann E Am Heart J 2006;152:1-8, deleon CF J Cardiopulm Rehabil Prev 2009; 55: , Jiang W Arch intern med 2001; 161: , Ko DT JAMA 2002;288:

23 Potential targets for treatment: COPD Chronic obstructive pulmonary disease (COPD) and heart failure are prevalent comorbidities COPD adversely impact on prognosis of heart failure patients, being an independent predictor of mortality and hospitalization Beta-blockers and beta-receptor agonists respectively are the optimal treatment choices Beta receptor agonist has been associated with incident decompensation in patients with existing heart failure Reluctance in prescribing beta-blockers to COPD patients Hawkins NM JACC 2011;57: , Rusinaru D, Am J Cardiol 2008; 101: Lainscak M, Wien Klin Wochenschr2009;121: Macchia A, Eur J Heart Fail 2007; 9:

24 Risk of all cause mortality among patients with COPD Treatments: ICS=inhaled corticosteroid, BB=β blocker, LABA= long-acting β agonist, Tio=tiotropium Short P BMJ 2011;342:d2549

25 Conclusion Atherothrombosis is the primary preventive target in non-heart failure After a non fatal infarct evolving myocardial dysfunction is a complex process involving local and systemic maladaptive mechanisms. Secondary prevention of fatal heart failure and sudden death calls for better defined targets or markers and more specified pharmacological treatment regimens (pharmacophenomics) Co-morbidities that aggravate heart failure should be considered for treatment

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