Myocardial injury
Cardiac function
Acute (adaptive)
1950s-1980s
1980s-2000s
Hemodynamic model
Reduced contractility Pump dysfunction
Neurohormonal model
Progressive remodeling & impaired myocard function Treatment: Neurohormone blockers: ACE inhibitors, ARBs -blockers Conventional drugs Diuretics Digitalis
Stroke Atherosclerosis Vasoconstriction Vascular hypertrophy Endothelial dysfunction LV hypertrophy Fibrosis Remodeling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis Hypertension
AT1 receptors
Heart failure MI
DEATH
Renal failure
Angiotensinogen
Nitric oxide Renin
Angiotensin I
Bradykinin
ACE inhibitor
Inactive peptides
ACE
Non-ACE pathways
Angiotensin II
AT1R
Vasoconstriction Proatherosclerosis Proinflammation Prothrombosis
AT2R
CV protection Vasodilatation Anti fibrosis Anti growth
Vasodilatory effects
ACE inhibitors
Plaque stabilization
Regression of LV hypertrophy
CONSENSUS
Risk Continuum
SOLVD Rx V-HeFT II
HOPE
CV Risk Factors
50 40 Placebo
Mortality (%) 30
20 10 0 0
Randomized large (>1000 patients), long term (1 year) trials ACE inhibitors vs placebo 12,763 patients in 4 trials
Yancy CW, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure : A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:000-000.
McMurray JJV, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. European heart Journal 2012; 33:1787-1847
ACE inhibitors Captopril Ramipril Trandolapril Enalapril Fosinopril Lisinopril Quinapril Perindopril
Initial doses 6,25 mg t.i.d 2,5 mg o.d. 1 mg o.d. 2,5 mg b.i.d. 10 mg o.d. 2,5-5 mg o.d. 5 mg b.i.d. 2 mg o.d.
Target doses 50 mg t.i.d. 10 mg o.d. 4 mg o.d. 10-20 mg b.i.d. 40 mg o.d. 20-40 mg o.d. 20 mg b.i.d. 8-16 mg o.d.
Alternative agents
ELITE II
OPTIMAAL
RESOLVD VALHEFT
VALIANT
CHARM
Captopril
Losartan
Captopril/Losartan Hazard Ratio (95% C.I.): 0.88 (0.75, 1.05) P=0.16 100 200 300 400 500 600 700
Days of Follow-up
35 30 25 20 15 10 5 0 -5
* *
**
0 Weeks
17 Weeks
43 Weeks
* P <0.01 compared with 0 weeks. **P <0.05 compared with enalapril. McKelvie RS et al. Circulation. 1999;100:1056-1064.
Mortality by treatment
0.1
0.05
0
Months
12
18
24
30
36
3 component trials comparing candesartan to placebo in patients with symptomatic heart failure
CHARM Alternative
n=2028
LVEF 40% ACE inhibitor intolerant
CHARM Added
n=2548
LVEF 40% ACE inhibitor treated
CHARM Preserved
n=3025
LVEF >40% ACE inhibitor treated/not treated
Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death
50
40 30 20
Placebo
Candesartan
10
0 0
3.5 years
% 50 40
Placebo
30
20 10 0
0 1 2
Candesartan
CV mortality : HR 0.84 (95% CI 0.72-0.98) p=0.02 Covariate Adjusted HR p=0.021 MI : Not reported
% 30
25
20 15 10 5 0 0
Candesartan Placebo
Placebo
Candesartan
3.5 years
833 182 824 195
Yancy CW, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure : A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:000-000.
McMurray JJV, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. European heart Journal 2012; 33:1787-1847
Yancy CW, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure : A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:000-000.
McMurray JJV, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. European heart Journal 2012; 33:1787-1847
Initial doses 4 mg o.d. 75-150 mg o.d. 12,5-50 mg o.d. 20-40 mg b.i.d. 40 mg o.d.
Target doses 32 mg o.d. 300 mg o.d. 150 mg o.d. 160 mg b.i.d. 80 mg o.d.
Adverse effects: Hypotension Hyperkalemia Renal dysfunction More AE when combined to ACEIs
One strategy to manage heart failure is RAS blockade with ACE inhibitors or ARBS.
ACE inhibitors are beneficial in all stages of heart failure and remain to be the first-line therapy ARBs are alternative agents for heart failure in patients who are ACE inhibitors intolerant.
Combination therapy of ACE inhibitors and ARBs reduce morbidity in heart failure patients, with more adverse effects.
3 component trials comparing candesartan to placebo in patients with symptomatic heart failure
CHARM Alternative
n=2028
LVEF 40% ACE inhibitor intolerant
CHARM Added
n=2548
LVEF 40% ACE inhibitor treated
CHARM Preserved
n=3025
LVEF >40% ACE inhibitor treated/not treated
Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death
Agent
Target Doses
Findings 40% RRR of all-cause mortality at 6 months 50% RRR of deaths from progressive heart failure
16% decrease in 3.5-year mortality 26% decrease in death or hospitalization for CHF
NYHA class I, 20% decrease in death or EF 35% hospitalization for CHF Non significant mortality trend favoring enalapril NYHA III-IV or class II with exacerbation in prior 6 months 8% mortality reduction in high-dose group 24% RRR of hospitalization for HF
Lisinopril
ACEIs
RESOLVD
ELITE II
ARBs
CHARM-Programme
VALHEFT
OPTIMAAL
Composite CV risk = cardiovascular mortality + non-fatal myocardial infarction + hospitalisation for congestive heart failure + non-fatal stroke The ONTARGET Investigators. N Engl J Med 2008;358:15471559
ACE Inhibitors
-blockers
ARBs
RESOLVD : Neurohormones
10
Candesartan Candesartan + enalapril Enalapril
5
BNP 0 (pmol/mL) -5 -10
0 Weeks
*P <0.01 compared with 0 weeks. P <0.01 compared with enalapril. McKelvie RS et al. Circulation. 1999;100:1056-1064.
*
17 Weeks
*
43 Weeks
* *
**
0 Weeks
17 Weeks
43 Weeks
* P <0.01 compared with 0 weeks. **P <0.05 compared with enalapril. McKelvie RS et al. Circulation. 1999;100:1056-1064.