I know the trials in heart failure but how do I manage my patient? Dosing of neurohormones antagonists

Transcription

1 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)

2 Clinical Case: 82 year old woman PH: 1979 Gastrectomy Peptic Ulcer 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

3 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

4 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

5 Our patients are different from HF Clinical trials ones (RCT) RCT Real World Age 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.

6 Comorbidities in Medicare CHF patients (n=122,630; 65+ years) 60 % to 1 2 to 5 6 to 8 9+ Comorbidities (n) Braunstein JB, JACC 2003; 42: Hypertension 55% Diabetes 31% COPD 26% Ocular disorders 24% Hypercholesterolemia 21% Braunstein JB et al, JACC 2003; 42: Depression 11-56% Turvey CL et al, JAGS 2002; 50: De Geest S et al, Eur J HF 2003; 5: 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:

7 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.

8 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; Their importance is shown by the beneficial effects of their long-term pharmacologic inhibition.

9 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 (1) 70-78

10 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 % Risk reduction 12% p=0.002 High-dose Low-dose Follow-up (months) Packer M et all Circulation 1999;100:2312-8

11 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 % 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: Lechat P et al. Circulation. 1998;98:

12 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:

13 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

14 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 ** p<0.05 vs Placebo 8 4 * * * * 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

15 Change in Heart Rate and CHF Mortality Change in mortality (%) CIBIS NOR TIMOLOL MOCHA BHAT *ANZ XAMOTEROL VHeFT (Prazosin) SOLVD US CARVEDILOL CONSENSUS PROFILE PROMISE VHeFT (HDZ/ISDN) * GESICA Change in heart rate (bpm) Kjekshus & Gullestad (1999)

16 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

17 N Engl J Med 2004; 351: Aldosterone antagonist - The importance to use evidence based dose in selected patient - Population-based analysis in Ontario Canada Probability of survival Risk reduction 30% p<0.001 Randomized Aldactone Evaluation Study (RALES) Spironolactone Placebo Months Pitt B et al. N Engl J Med 1999;10: Background therapy: - Ace-i 94% - Beta-Blockers 10% Rate of Renal AE: ns

18 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

19 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 (%) ELITE-II (Chronic HF) Hazard Ratio = 0.88 ( ) 0.2 P = 0.16 Captopril (N=1574) 250 Events Losartan (N=1578) 280 Events Days of follow-up Probability of Survival (%) OPTIMAAL (Post-MI) Relative risk = 1.13 ( ) 0.2 P = Captopril (N=2744) 447 Events Losartan (N=2733) 499 Events Months of follow-up

20 Konstam MA et al, Lancet 2009; 374: Percentage of patients with first event ARBs - Higher doses are better than lower one - 50 HEAAL Losartan 50 mg Losartan 150 mg Hazard ratio: 0.90, p=0.027 Primary Endpoint Death or Hospitalization for HF HEAAL demonstrates improved efficacy with losartan at 150 mg compared to 50 mg daily 0 Years Number of patients at risk Losartan 50 mg Losartan 150 mg

21 HEAAL Selected Adverse Events All AEs * p <.001 ** p = Resulting in Discontinuation of Study Drug Hyperkalemia * Hypotension ** Losartan 150 mg (n=1912) Losartan 50 mg (n=1905) Renal Impairment * Hyperkalemia Hypotension Renal Impairment Konstam MA et al, Lancet 2009; 374:

22 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 Valsartan Placebo P= Time since randomization (months) Event-free probability Valsartan Placebo 13.3% Risk Reduction P= Time since randomization (months) Val-Heft (Valsartan 320) demonstrated a significant reduction in adverse clinical outcomes versus placebo

23 Pfeffer Lancet 2003;362: ARBs - Higher doses are effective in add-on strategy - CHARM-Added CV death or CHF hospitalisation % RRR=15% Placebo 538 (42.3%) 483 (37.9%) 30 Candesartan HR 0.85 (95% CI ), p=0.011 Adjusted HR 0.85, p= years

24 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

25 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, ,6.55) RAP Weir Eur J of Heart Failure 10 (2008)

26 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.