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1 I BETABLOCCANTI sono utilizzati bene nello scompenso? Verona Slide 1

2 AGENDA Vanno usati perché sono efficaci In quali pazienti sono efficaci? Sono usati bene perché sono usati in tutti i potenziali candidati? Perché sono usati poco? Quando sono presi in considerazione sono utilizzati bene? C'è un motivo fondato per utilizzarne uno invece di un altro? Slide 2

3 US Carvedilol Programme (Packer 1996) 1.0 Survival Carvedilol (n=696) Survival COPERNICUS (Packer 2001) Carvedilol Placebo (n=398) Risk reduction = 65% P < Risk reduction = 35% p = Placebo Survival Days Packer et al (1996) CIBIS-II (1999) 0 Mortality (%) Months Packer et al (2001) MERIT-HF (1999) Bisoprolol 15 Placebo Metoprolol CR/XL 0.6 Risk reduction=34% p< Placebo 5 Risk reduction = 34% P = Time after inclusion (days) Months of follow-up Slide 3

4 Effects of b-blockers on Survival in Patients with CHF Carvedilol (US trials) All cause mortality Sudden death Bisoprolol (CIBIS-II) II) All cause mortality Sudden death Metoprolol (MERIT-HF) All cause mortality Sudden death Risk ratio (95% CI) Slide 4

6 Trattamento con B-BloccantiB Bloccanti INDICAZIONI Potenzialmente tutti i pazienti con SC stabile di grado lieve moderato. I pazienti con SC severo debbono essere valutati dallo specialista Trattamento di prima scelta (assieme agli ACE-I) in pazienti con SC stabile II-III III classe NYHA e nei pazienti con disfunzione VS (classe NYHA I) post-ima CONTROINDICAZIONI Asma bronchiale CAUTELE SC severo (IV classe NYHA) Attuale o recente (< 4 settimane) instabilizzazione FC < 60/min o BAV II grado Segni persistenti di congestione periferica e polmonare INTERAZIONI FARMACOLOGICHE Verapamil, Diltiazem, Amiodarone, Digossina Slide 6

7 TRIAL CRITERI DI INCLUSIONE CRITERI DI ESCLUSIONE COPERNICUS (JAMA 2003) CIBIS II (Lancet 1999) MERIT HF (Lancet 1999) CAPRICORN (Lancet 2001) SENIORS (EHJ 2005) IMPACT HF (JACC 2004) LVEF < 25%, ACE therapy, < 80 yrs,, LVEF < 35%, 6 weeks HF Stability, ACE therapy < 80 yrs, ACE Therapy, Stable clinical conditions, LVEF < 40% Post MI, LVEF < 40%, ACE therapy > 70 yrs,, LVEF < 35% LVEF < 40%, Primary diagnosis of CHF Severe primary pulmonary, renal or hepatic disease, contraindication to BB, Recent PCI or CABG, Ventricular tachyarrhythmias, BP < 85 mmhg,, HR < 68, Creatinine > 2.8. Uncontrolled Hypertension, recent (3m) MI or Unstable AP, recent (6m) PCI or CABG, BP<100, Renal Failure, Reversible Obstructive Lung Disease Recent MI, Amiodarone, Recent (4m) PCI or CABG, AV block, Unstable CHF, BP <100, other serious disease, amiodarone. Uncontrolled HF, Unstable Angina, BP < 90mmHg, HR < 60, Unstable DM, Other indication for BB, B2 agonists therapy, Steroids on therapy.. HR < 60, BP < 90, uncorrected valvular disease, hepatic or renal dysfunction, recent or scheduled PCI or CABG Decompensated CHF, AV Block, SSS, Asthma, Hypotension, hepatic impairment Slide 7

8 Differenze dei pazienti con CHF arruolati nei Trials e osservati in comunità Trial randomizzati controllati Comunità Età media (anni) Sesso (M/F) 4 / 1 1 / 1 EF sin. > 40% Altre Comorbidità Crit.. Esclusione Molto frequente Crit.. Esclusione Molto frequente Creatinina mg/dl Crit.. Esclusione 17 34% F. Atriale 20% 40% CAD instabile, Ipertensione Crit.. Esclusione Frequente Dose Target Compliance Stato psichico-cognitivo cognitivo-sociale Solitamente OK Ottimale conservato Solitamente Scarsa ± compromesso Durata del Trattamento 1 3 anni Tutta la vita Tavazzi Ital. Heart J. Suppl. 2000;1(8) Slide 8

9 Beta-Blocker Blocker treatment of chronic systolic HF improves prognosis even in patients meeting one or more exclusion criteria of the MERIT-HF study Mortality Bblocker No Bblocker 51,2 40 Adj hazard ratio 0.57 ( ) 0.86) 39 Adj hazard ratio 0.72 ( ) 0.97) 36,4 35, ,9 25,4 26,1 25, ,9 17,8 13,9 10 9,8 0 Trial Patients Non Trial Patients 1 year 2 yrs 3 yrs 1 year 2 yrs 3 yrs Ludwigshafen Chronic HF Registry - A. Jost - EHJ 2005;26: Slide 9

11 Euro HF Survey - HF Medication Use [ pts] Anticoagulant Antithrombotic 78 ARBs IV inotropic agents 5 7 Spironolactone 20 Nitrates Glycosides B Blockers ACE i 62 Diuretic Komajda et Al. Eur Heart J 2003; 24:464 Slide 11

12 Beta-blockers Prescribed in the Euro Heart Survey CHF Patients 115 hospitals 24 European Countries (Years ) 2001) Sotalol 5% Other 8% 37% of pts on BB Carvedilol 12% Metoprolol 38% Bisoprolol 14% Atenolol 23% Komajda et Al. Eur Heart J 2003; 24:464 Slide 12

13 Prescrizione di farmaci raccomandati Target indicatori di qualità di processo Età media della popolazione considerata 75.8 anni ACE-inibitori - ARB 85% Beta-bloccanti 50% ACE Diur Ansa Dig B Blocc Antiald ARB Slide 13

14 IN-CHF betablocker prescriptions by year (%) IN CHF BRING UP BRING UP 1 56,6 51,7 52, , ,9 18,4 24,5 25,7 10 8, Slide 14

15 Betablocker prescriptions by age from 1995 to 2004 IN CHF ,9 53,4 P < , ,9 41, ,1 11,9 25,1 7,4 14,7 1,1 8,8 23,4 14,1 28,6 P < < 65 yrs > 84 yrs Total Slide 15

16 IN CHF Changes over time of the prescription rate of betablockers by NYHA class ,7 P < , , , ,1 13, ,3 22 7,2 15, NYHA 1 (3314) NYHA 2 (12817) NYHA 3 (5251) NYHA 4 (527) Slide 16

17 IMPROVEMENT An international HF Survey Primary care phisicians avareness of drug effectiveness Prescriptions Bblockers Nitrates Symptoms Prognosis 60% % Spironol Dig Diuretics ACE ACEi Bblockers ACE + BB % ESC target dosage Menagement of HF in primary care ( IMPROVEMENT HF PROGRAMME ) - Lancet 2002;360:1631 Slide 17

18 Under-utilization of evidence-based drug treatment in pts with HF : a report from the Euro Heart Survey on HF patients - M.Lenzen Eur Heart J 2005;26: Only Only13% elegible for forat at least leastone trial trial (SOLVD, MERIT-HF, RALES) % of of SOLVD SOLVD eligible eligible patients patients treated treatedwith withace % of of MERIT-HF MERIT-HF eligible eligible patients patients treated treated with with B-Blockers B-Blockers Blockers % of of RALES RALES eligible eligiblepatients patientstreated treatedwith withaldosterone aldosteroneantagonists antagonists % of of pts ptstreated treatedwith withtarget target dose dose recommended in in the the guidelines -- > 50% 50% of of the the SOLVD SOLVD eligible eligiblepatients patientstreated treatedwith withace -- < % of of the the MERIT-HF MERIT-HF eligible eligible patients patients treated treated with withb-blockers Blockers Slide 18

20 BETA-BLOCCANTI BLOCCANTI Molte controindicazioni sono fittizie Il problema è l impegno a trattare e ad impostare un follow-up Sono necessarie strategie organizzative per aumentarne l'uso Slide 20

21 Carvedilol Tolerability According to Traditional Precautions Tolerated Not tolerated Carvedilol in in COPD/asthma 80 % All patients (n = 795) COPD/ asthma (n = 89) Well Well tolerated tolerated in in mild mild to to moderate moderate airways airways disease disease Cardiac Cardiac benefits benefits seen seen in in those those able able to to tolerate tolerate b b Diabetes (n = 127) blockade blockade are are similar similar to to those those without without airways airways disease disease In In those those with with asthma, asthma, half half proved proved intolerant intolerant Potentially Potentially long long latent latent period period with with time time to to withdrawal withdrawal due due to to intolerance intolerance - - up up to to 6 6 months months PVD (n = 58) Amio- darone (n = 230) HR 70 bpm (n = 184) Krum H et al. Heart 2000 Slide 21

22 Survival and Hospitalization in HF Patients With and Without Diabetes Treated With Beta-Blockers Blockers (BRING-UP) DM DM no no / / BB BB yes yes DM DM yes/bb yes yes Carvedilol 79% Metoprolol 15% Bisoprolol 2% Others 4% DM DM no/bb no/bb no no DM DM yes/bb yes/bb no no Bobbio M et al, J Card Fail 2003; 9: Slide 22

23 IMPACT HF TRIAL Predischarge Initiation of Carvedilol in Pts Hospitalized for Decompensated HF Primary EP : % of pts treated with BB at 60 days after randomization Carvedilol pre-discharge ,2 73,4 100 Physician discretion post-discharge 79, ,5 BB at 60 days Any BB initiated 100% BB target dosage 3,2 Gattis WA J Am Coll Cardiol 2004;43: Slide 23

24 Improving Guideline Adherence A Randomized Trial Evaluating Strategies to Increase Beta-blocker Use in HF Control Nurse facilitator p< p< On BB at EOS At target BB doses Ansari M et al, Circulation 2003; 107: Slide 24

25 Significato degli studi BRING-UP L.Tavazzi - Italian Heart Journal 2000;1: BRING-UP, as already known, is an observational study of outcome of the e use of beta-blocker blocker therapy for heart failure. This has been an extraordinary event in clinical medicine: a class of drugs, the beta-blockers, blockers, which clinical evidence transformed from being considered as contraindicated into being recommended. This exceptional situation, together with the growing awareness of the limited spread and applicability of evidence produced by trials into clinical practice led to undertaking observational studies to evaluate the feasibility, safety and practical results of the implementation of new therapies recommended for widespread use on the basis of results of controlled, randomized clinical trials. BRING-UP has started a new line of research which does not substitute randomized trials, but t complements and completes them. For this type of study to become common practice in clinical research, there must be greater interaction and acceptance by pharmaceutical companies and a national and international regulatory bodies and a widespread conviction among g doctors that this research has a paramount scientific, clinical and social value. Slide 25

26 AGENDA 1. Vanno usati perché sono efficaci 2. In quali pazienti sono efficaci? 3. Sono usati bene perché sono usati in tutti i potenziali candidati? 4. Perché sono usati poco? 5. Quando sono presi in considerazione sono utilizzati bene? 6. C'è un motivo fondato per utilizzarne uno invece di un altro? Slide 26

27 Trattamento con b bloccanti b bloccanti DOVE Nella comunità in pazienti stabili Non in pazienti instabili ospedalizzati con peggioramento dello SC QUALE β BLOCCANTE E A QUALE DOSAGGIO? Dose iniziale (mg) Dose target (mg) Bisoprololo 1,25 10 Carvedilolo 3,25 x x 2 Metoprololo CR 12, Nevibololo 1,25 10 Slide 27

28 IMPROVEMENT An international HF Survey Prescriptions ACEi Bblockers ACE + BB % ESC target dosage Menagement of HF in primary care ( IMPROVEMENT HF PROGRAMME ) - Lancet 2002;360:1631 Slide 28

29 Adherence to (ESC) guidelines is a predictor of outcome in Chronic Heart Failure : the MAHLER survey GAI3 = Global Adherence Indicator for first 3 classes of Evidence Based Therapy ACE, BB, Spironolactone CHF hospitalization rate Cardiovascular hospitalization rate GAI3 GAI GAI3 GAI ,6 GAI3 GAI ,9 14, ,2 10 9, ,7 Perfect Adherence Moderate Adherence Low Adherence Komajda EHJ 2005;26: Slide 29

30 Ragioni dell inadeguata prescrizione dei betabloccanti nel paziente reale con SCC Pregiudizio storico ancora irrisolto Inerzia clinica Inquadramento eziopatogenetico spesso insufficiente Pazienti anziani con frequenti comorbidità Intolleranza alla terapia beta-bloccante bloccante Carenze strutturali che impediscono l inizio l e l adeguato l monitoraggio clinico nella fase di titolazione Slide 30

32 In Heart Failure all beta-blockers blockers are not necessarly equal W.H. Wilson - Cleveland Clinic Journal 2003;70:1081 B-blockers in HF: are pharmacological differences clinically important? M. Metra - Heart Failure Reviews 2004;9: Is selectivity important in beta-blockers blockers? No one knows Xamoterol (Lancet 1990) was associated with significant increase in mortality Bucindolol (Best), Nebivolol (Seniors) did not show a significant survival benefit Carvedilol (Copernicus), Bisoprolol (CIBIS II) and Metoprolol succinate s (Merit( Merit-HF) all reduce mortality by about 35% Patients doing well on metoprolol or bisoprolol probably need not switch to carvedilol. Slide 32

33 Primary endpoint Mortality (%) 40 Metoprolol hazard ratio 0.83, 95% CI , 0.93, p= Carvedilol years Number at risk Carvedilol Metoprolol Slide 33

34 Carvedilol Improves Renal Blood Flow in CHF Patients Change in RBF from baseline (%) * P = 0.02 vs placebo and metoprolol (6 months) P = 0.03 vs baseline METOPROLOL % PLACEBO % CARVEDILOL 41.2 %* Abraham WT et al Slide 34

35 GFR Mean Profile by Study Medication RR 95% CI P Value 75 Carvedilol vs Metoprolol tartrate Inc Δ GFR at 12 months * P < 0.05 GFR * * Carvedilol 65 Metoprolol Error bars represent 1 standard error Time (years) Slide 35

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