Rikshospitalet, University of Oslo

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

23.05.2011

DMC for Signify, Improve-it, HPS 2, Schedule, HPS 3

Atherosclerosis (atherothrombosis)

Risk factors in cardiovascular disease

Dyslipidemia Hypertension Diabetes Smoking Inactivity Myocardial infarction Non-fatal MI • Sudden death • Cardiac rupture • Cardiogenic shock

Non-fatal heart failure

Mortal ity (%) 0 5 10 15 20 25 30 35

Effects of

incident heart failure

on Mortality

in patients with CVD

4S

Kjekshus et al., J Cardiac Failure 1997;3:249-54

HF No HF n=288 _{n=1995 n=184} n=2037 Placebo Simvastatin HF No HF

Pathophysiology of heart failure

after non-fatal MI

Inflammation Infarct size Residual ischemia LV dilatation

Heart failure death

Fibrosis LV scar tissue

Re-entry arrhythmias LV dysfunction Sudden arrhythmic death Heterogeneity Sympathetic and RAAS activation Increased cytokine expression Altered fibrinolysis Oxidative stress Endothelial dysfunction Dyslipidemia Hypertension Sleep apnoea Anaemia Iron deficiency Vitamin-D deficiency Mental depression COPD Renal dysfunction

Primary Endpoint by NT-proBNP

Tertile 1 (n= 1221) Tertile 2 (n= 1222) Tertile 3 (n= 1221)

Hazard ratio= 0.651 95% CI 0.47-0.88 Hazard ratio= 1.07 95% CI 0.85-1.35 Hazard ratio= 0.99 95% CI 0.88-1.18 Interaction by treatment p= 0.00642

1_{Adjusted for baseline risk factors} 2_{With NT-proBNP as continous variable}

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

Targets for treatment



Hypertension



Heart rate



Neurohormones

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

Effect of enalapril on mortality

according to SBP

CONSENSUS

10 30 20 40 50 60 <15 10 5 0 5 >10 N=43 N=16 N=17 N=11 N=28 N=25 N=28 N=14 ENALAPRIL PLACEBO

Change in systolic pressure at 6 weeks, mm Hg

Mortal ity at 6 mon ths (%)         ENALAPRIL PLACEBO N=29 N=27 N=19 N=52 N=31 N=24 N=20 N=51         Mortal ity at 6 mon ths (%) Systolic pressure, mm Hg 100 or less 110 120 _{130 >135} 10 30 20 40 50 60 10 20 30 40 50 60



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 30.08.2010

0 10 20 30 40 50 60 70 I II III

IV _{Baseline hormone level (quartile)}

Six

-month

mor

tality (

%)

Baseline Hormone levels (quartiles) and 6

month mortality (Consensus)

Norepinephrine ANP

Angiotensin II Aldosterone

CONSENSUS N Engl J Med 1987; 316:1429-1435

Neurohormonal score: composite of Noradrenaline, Angiotensin and Atrial natriuretic peptide

Mode of death in heart failure



Does the choice of treatment make a

difference for mode of death?

Cause of death

Effect of enalapril on mode of death in patients

with severe heart failure (NYHA class IV)

Effects of metoprolol on mode of

death

MERIT

Total mortality Cardiovascular mortality Sudden death Death from pump failure 0 0.5 _1.0 1.5 Relative risk (95%CI

Risk reduction% 34 38 49 ● ● ● ● 39

The effect of spirolactone on mode of

death in patients with severe heart

failure

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 pro-inflammatory activation and rhythm disturbances

Wang H JACC 2007;49:246-253, Mansfield DR Am J Respir Crit Care Med 2005;169:159-165, Harbison J Chest;2000;118:591-595 Yokoe T Circulation 2003;107:1129-1134

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: 369-376 Sliwa K Circulation 2004;109:750-755, Ross R NEJM 1999;340:115-126, Akar JG Heart Rhythm 2008;5: 1229-1235,

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;305:1863-1872, Anker S Eur Heart J 2009;30: 1331-1339, Silverberg D JACC 2001;37: 1775-1780, Gahli JK Circulation 2008;117:526-535, van Veldhuisen DJ Eur Heart J 2007;28:2208-2216

Young . Am J Cardiol 2008;101:223-30

Anemia is an independent predictor of

in-hospital mortality in AHF

OPIMIZE-HF registry

48.612 pts c. AHF Hgb<12.1: 52% Hgb< 10.7: 25%

Potential targets for treatment:

Vitamin D deficiency and CV disease

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;84:348-350 , Rutledge T JACC 2006;48:1527-1537, Friedmann E Am Heart J 2006;152:1-8, deLeon CF J Cardiopulm Rehabil Prev 2009; 55: 580-592, Jiang W Arch intern med 2001; 161: 1849-1856, Ko DT JAMA 2002;288: 351-357

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;57:2127-2138, Rusinaru D, Am J Cardiol 2008; 101:353–358. Lainscak M, Wien Klin Wochenschr2009;121:309–313. Macchia A, Eur J Heart Fail 2007; 9:942–948.

Risk of all cause mortality among

patients with COPD

Treatments: ICS=inhaled corticosteroid, BB=β blocker, LABA= long-acting β agonist, Tio=tiotropium

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