I know the trials in heart failure but how do I manage my patient? Dosing of neurohormones antagonists Alessandro Fucili (Ferrara, IT) Massimo F Piepoli (Piacenza, IT)
Clinical Case: 82 year old woman PH: 1979 Gastrectomy Peptic Ulcer. 1990 COPD 1995 Hypertension and Diabetes 2009 Anterior AMI - Primary PCI on LAD - 2D-Echo: dilated LV with EF=20-30%. Lab Test: - Hb: 10,5 mg/dl - Creatinin 2,8-3 mg/dl - K 5,4 meq/l - GFR 17 ml/min/ mq 2010 Ambulatory visit: - NYHA III -IV - BP 100/70 mmhg
ESC guidelines 2009 for the Diagnosis and Treatment of Acute and Chronic Heart Failure ACE inhibitor All patients Class I Level A ARB ACE intollerant/persisting signs or symptoms on ACEi/B-blokade Class I Level A B-Blocker All patients Class I Level A Aldosterone antagonist Diuretic Severe symptoms on ACEi All patients with signs or symptoms of congestion Class I Level A Class I Level B However application of trial protocols to an individual is immediately limited www.escardio.org
Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure Of the 20,388 patients > 64 years old discharged from acute care hospitals in the US, 18%, 13%, and 25% met the enrollment criteria of the SOLVD, MERIT- HF and RALES trials. Frederick A. Masoudi, et al Am Heart J 2003;146:250 7
Our patients are different from HF Clinical trials ones (RCT) RCT Real World Age 57-64 70-75 Sex M:F 4:1 1:1 EF > 40% Exclusion criteria > 40% of HF patients AF 20% 40% Renale failure Exclusion criteria 20-30% Co-morbildity Exclusion criteria Frequent Disability Exclusion criteria Frequent Drug dose Target dose Low Compliance High Low Follow-up 1-3 years Life-long Even if they are similar, they mirror those patients at the fringes of the trial population in terms of renal function, age, compliance and comorbidities.
Comorbidities in Medicare CHF patients (n=122,630; 65+ years) 60 % 50 40 30 20 10 0 0 to 1 2 to 5 6 to 8 9+ Comorbidities (n) Braunstein JB, JACC 2003; 42: 1226-33 Hypertension 55% Diabetes 31% COPD 26% Ocular disorders 24% Hypercholesterolemia 21% Braunstein JB et al, JACC 2003; 42: 1226-33 Depression 11-56% Turvey CL et al, JAGS 2002; 50: 2003-8 De Geest S et al, Eur J HF 2003; 5: 57-67 Mental impairment Musculoskeletal problems Incontinence Renal failure CVA Anemia Lien CT et al, Eur J HF 2002; 4: 91-8 Krum H & Gilbert RE, Lancet 2003; 362: 147-58
The primary goal of therapy in our patient is different depending on his heart failure stage and expectations Stage A-B: prevent or delay disease progression Stage C-D: relieve symptoms and prolong survival Stage D (end-stage): improve quality over length of life.
Increasing evidence and prescriptions of Neurohormonal Inhibition Activation of the RAAS and the adrenergic system has a pivotal role in the progression of heart failure Christian Funck-Brentano EHJ suppl 2006;8:c19-c27 Gislason GH Circulation 2007;116;737-744 Their importance is shown by the beneficial effects of their long-term pharmacologic inhibition.
Ace-inhibitor - modest benefit of high vs low doses -Neurohormonal effect- 75 pz Enalapril 40mg/die vs 5 mg/die Follow-up: 6 month The study could not demonstrate a difference between high- and low-dose enalapril in terms of serum aldosterone and plasma AT-II suppression, despite a dose-dependent reduction in serum ACE activity. WH Wilson Tang et al. JACC 2002 39 (1) 70-78
Ace-inhibitor -modest benefit of high vs. low doses- Several outcome studies did not find overwhelming clinical benefit with a high-dose versus low-dose ACE-I in systolic CHF. Suggesting that maximising the dose of a single RAAS blocker might be of little therapeutic benefit. Atlas study 100 *Combined all-cause mortality plus all-cause hospitalisations 75 Event-free* survival % 50 25 Risk reduction 12% p=0.002 High-dose Low-dose 0 0 6 12 18 24 30 36 42 48 Follow-up (months) Packer M et all Circulation 1999;100:2312-8
Effects of Adding -Blockers vs Increasing ACE-I Dose in HF Symptoms Morbidity Mortality Increase dose No 10-15% NS of ACE inhibitor 1 effect Add -blockade 2 20-35% 35% No evidence for the need to maximize ACE-I doses before starting b-blocker therapy (BB + ACE-I better than high dose ACE alone) 1 Packer M et al. Circulation. 1999;100:2312 2318. 2 Lechat P et al. Circulation. 1998;98:1184 1191.
Beta-blocker drugs Dose of Metoprolol CR/XL and Clinical Outcomes in Patients With Heart Failure in Metoprolol CR/XL Randomized Intervention Trial in CHF (MERIT-HF) Risk reduction was similar in the high- and low-dose subgroups, which, at least partly, may be the result of similar beta-blockade as judged from the HR response. Wikstrand J, J Am Coll Cardiol 2002;40:491 498.
Beta-blocker drugs Bisoprolol dose response relationship in patients with CHF: a subgroup analysis in the Cardiac Insufficiency Bisoprolol Study (CIBIS II) CIBIS II Investigators and Committees. Lancet 1999; 353: 9 13
Bristow et al (1996). Beta-blocker drugs MOCHA - Effect of Carvedilol on LVEF Placebo (n=84); Carvedilol (n=261) Treatment: diuretic, ACE-i ±digoxin; Follow-up 6 Month; 16 Mortality 0.4 Cardiovascular hospitalizations * p=0.07 vs Placebo 12 0.3 ** p<0.05 vs Placebo 8 4 * 0.2 0.1 * * * 0 Placebo 6.25 mg bid 12.5 mg bid 25 mg bid * 0 Placebo 6.25 mg bid 12.5 mg bid 25 mg bid Carvedilol Carvedilol
Change in Heart Rate and CHF Mortality Change in mortality (%) 60 40 20 0-20 -40-60 -80 CIBIS NOR TIMOLOL MOCHA BHAT *ANZ XAMOTEROL VHeFT (Prazosin) SOLVD US CARVEDILOL CONSENSUS PROFILE PROMISE VHeFT (HDZ/ISDN) * GESICA -100-20 -16-12 -8-4 0 4 8 12 Change in heart rate (bpm) Kjekshus & Gullestad (1999)
Mortality Reduction with Beta-blockers is Directly Related to HR Reduction For every 5 beats/minute reduction in HR there is an 18% decrease in mortality McAlister FA et al. Ann Int Med 2009;150:784-92
N Engl J Med 2004; 351:543-551 Aldosterone antagonist - The importance to use evidence based dose in selected patient - Population-based analysis in Ontario Canada Probability of survival 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 Risk reduction 30% p<0.001 Randomized Aldactone Evaluation Study (RALES) Spironolactone Placebo 0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Pitt B et al. N Engl J Med 1999;10:709 717 Background therapy: - Ace-i 94% - Beta-Blockers 10% Rate of Renal AE: ns
Hidden below the management of a study there is an organization which is not common in the real world 150 mg qd 150 mg group Losartan 12.5 mg- 25 mg qd 50 mg qd 100 mg qd 50 mg qd +P 50 mg qd + P 50 mg group 2 weeks 1 week 1 week (1 week) Screen Open Titration Randomization Follow-up - Dedicated physician and/or heart failure nurse during the follow-up, - Frequent blood samples and visit, -Selected inclusion and exclusion criteria Disease management program
ARBs - Low-dose are not as efficacious as Ace-i - In ELITE II and OPTIMAAL, ARBs failed to demonstrate superiority and even non-inferiority versus ACE-inhibitor. Probability of Survival (%) 1.0 0.8 0.6 0.4 ELITE-II (Chronic HF) Hazard Ratio = 0.88 (0.75-1.05) 0.2 P = 0.16 Captopril (N=1574) 250 Events Losartan (N=1578) 280 Events 0.0 0 100 200 300 400 500 600 700 Days of follow-up Probability of Survival (%) 1.0 0.8 0.6 0.4 OPTIMAAL (Post-MI) Relative risk = 1.13 (0.99-1.28) 0.2 P = 0.069 Captopril (N=2744) 447 Events Losartan (N=2733) 499 Events 0.0 0 6 12 18 24 30 36 42 Months of follow-up
Konstam MA et al, Lancet 2009; 374: 1840 48 Percentage of patients with first event ARBs - Higher doses are better than lower one - 50 HEAAL Losartan 50 mg Losartan 150 mg 40 30 Hazard ratio: 0.90, p=0.027 Primary Endpoint Death or Hospitalization for HF 20 10 HEAAL demonstrates improved efficacy with losartan at 150 mg compared to 50 mg daily 0 Years 0 1 2 3 4 5 Number of patients at risk Losartan 50 mg 1646 1421 1275 1126 644 Losartan 150 mg 1683 1492 1343 1205 711
HEAAL Selected Adverse Events 8 7 6 5 All AEs * p <.001 ** p =.002 7.12 4.73 8 7 6 5 Resulting in Discontinuation of Study Drug 4 3 2 1 0 2.79 2.92 1.87 2.07 Hyperkalemia * Hypotension ** Losartan 150 mg (n=1912) Losartan 50 mg (n=1905) Renal Impairment * 4 3 2 1 0 0.12 0.05 0.26 0.22 0.65 0.49 Hyperkalemia Hypotension Renal Impairment Konstam MA et al, Lancet 2009; 374: 1840 48
Cohn JN et al. Circulation. 2000;102:2672b ARBs - Higher doses are effective in add-on strategy - Val-Heft trial All cause mortality Mortality and morbidity Survival probability 1.000 0.957 0.9 0.914 0.871 0.829 0.8 0.786 0.743 0.7 0.700 Valsartan Placebo P=0.8 0 3 6 9 12 15 18 21 24 27 Time since randomization (months) Event-free probability 1.000 0.939 0.9 0.877 0.816 0.8 0.754 0.693 0.7 Valsartan 0.631 0.6 0.570 Placebo 13.3% Risk Reduction P=0.009 0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 18 21 24 27 Time since randomization (months) Val-Heft (Valsartan 320) demonstrated a significant reduction in adverse clinical outcomes versus placebo
Pfeffer Lancet 2003;362:759-66 ARBs - Higher doses are effective in add-on strategy - CHARM-Added CV death or CHF hospitalisation % 50 40 RRR=15% Placebo 538 (42.3%) 483 (37.9%) 30 Candesartan 20 10 0 HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010 0 1 2 3 3.5 years
Relationship of dose of background ACE inhibitor to the benefits of candesartan in CHARM study Baseline treatment with a combination of both a maximum dose of ACE inhibitor and b-blocker did not modify the effect of candesartan John J.V. McMurray et all Am Heart J 2006;151:985291
Efficacy and tolerability of adding an ARB in patient already treated with ACE-I plus Aldosterone Antagonist and Beta-blokers in CHARM study Adverse Event (Candesartan vs Placebo- HR) Hypotension 15,3 vs 13,9 1,11 (0.32,3.38) Increase K + 35,1 vs 16,6 2,11 (0.78,5.69) Hyperkalemia 12,1 vs 8,2 1.47 0.33,6.55) RAP Weir Eur J of Heart Failure 10 (2008) 157-163
Conclusion Activation of the RAAS and the adrenergic system has a pivotal role in the progression of heart failure. A dose response relationship is present for ACE-I, Betablockers and especially for ARBs. Neuro-hormonal antagonist doses should be titrated to higher level when tolerated. Higher neuro-hormonal antagonization increases the risk of adverse event: hypotension, renal dysfunction and hyperkalaemia. A closer patient monitoring is necessary during follow-up in high degree of neuro-hormonal antagonization.