Come collocare i nuovi trattamenti

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Adamo Marchesi
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1 CONVENTION CENTRI SCOMPENSO SCOMPENSO CARDIACO CRONICO: Come collocare i nuovi trattamenti Andrea Di Lenarda e Università

3 LCZ696 Enalapril RR = 0.84 p < RR = 0.84 p < HR = 0.84 p = RR = 0.70 p = RR = 0.82 p = RR = 0.77 p < Intensification of outpatient HF therapy Total ED visits for HF Total stays in intensive care Total hospitalizations for HF Total hospitalizations for CV reasons Total hospitalizations for any reason Packer et al. Circulation 2015;131:54 61

4 Agenda Ma questi risultati sono generalizzabili alla maggioranza dei pazienti con HFrEF? La tollerabilità al farmaco sarà un limitazione?

PARADIGM-HF: Patient disposition 10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14 21) 10.

4% 8442 underwent randomization 1102 discontinued study: 591 (5.6%) had adverse event 66 (0.6%) had abnormal laboratory or other test result 171 (1.

8%) had other reasons 977 discontinued study: 547 (5.8%) had adverse event 58 (0.6%) had abnormal laboratory or other test result 100 (1.

8%) had other reasons 43 were excluded: 6 did not undergo valid randomization 37 were from four sites prematurely closed because of major Good Clinical

5 PARADIGM-HF: Patient disposition 10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14 21) 10.4% Multivariable Predictors of Noncompletion 9419 entered LCZ696 run-in phase (median duration, 29 days; IQR, 26 35) 10.4% 8442 underwent randomization 1102 discontinued study: 591 (5.6%) had adverse event 66 (0.6%) had abnormal laboratory or other test result 171 (1.6%) withdrew consent 138 (1.3%) had protocol deviation, administrative problem or were lost to follow-up 49 (0.5%) died 87 (0.8%) had other reasons 977 discontinued study: 547 (5.8%) had adverse event 58 (0.6%) had abnormal laboratory or other test result 100 (1.1%) withdrew consent 146 (1.6%) had protocol deviation, had administrative problem, or were lost to follow-up 47 (0.5%) died 79 (0.8%) had other reasons 43 were excluded: 6 did not undergo valid randomization 37 were from four sites prematurely closed because of major Good Clinical Practice violations 4187 were assigned to receive LCZ had known final vital status 11 had unknown final vital status 4212 were assigned to receive enalapril 4203 had known final vital status 9 had unknown final vital status McMurray, et al. N Engl J Med 2014

6 Efficacia nei sottogruppi Il beneficio è stato ottenuto: In tutte le classi di età (ma proporzionalmente meno evidente 75 anni) In tutti gli strati di FEVsin (<35%) In tutte le classi NYHA (ma proporzionalmente meno evidente in NYHA III-IV) In tutti gli strati di NTproBNP (>400/600 pg/ml) Indipendentemente dagli altri trattamenti CV (dose BB, AA, digitale, ICD/CRT)

7 Efficacia nei sottogruppi Il beneficio non è stato testato: Nei pazienti instabili/ricoverati o con evento CV recente (<3 mesi) Nei pazienti naive a ACE/ARB Nei pazienti non tolleranti enalapril 20 mg/die Nei pazienti non trattati con betabloccanti Nei pazienti trattati con ivabradina Nei pazienti con severa IRC/iperK/BPCO Nei pazienti con PA<95/100 mmhg Nei pazienti con storia di angioedema

Il mondo reale (Osservatorio CV TS) Tra i

trattamento con BB e - BNP 150 ng/ml (o 100

8 Il mondo reale (Osservatorio CV TS) Tra i pazienti ambulatoriali con HFrEF (EF 40%) e NYHA II-IV (445 pazienti) 39.6% erano - in trattamento con ACE/ARB e - In trattamento con BB e - BNP 150 ng/ml (o 100 ng/ml se Osp per SCC <12mesi) e - PAS 100 mmhg e - GFR 30 ml/min

9 Agenda Ma questi risultati sono generalizzabili alla maggioranza dei pazienti con HFrEF? La tollerabilità al farmaco sarà un limitazione?

10 LCZ696 Enalapril

11 PARADIGM-HF: baseline SBP did not influence the treatment effect of LCZ696 compared with enalapril The reduction in the primary outcome (CV death or first hospitalization for HFrEF) for LCZ696 compared with enalapril was consistent across SBP categories (p=0.67 for treatment by SBP category interaction) Hazard ratio (95% CI) p value All patients (n=8,399) 0.80 ( ) SBP category (mmhg) <110 (n=1,747) 0.89 ( ) <120 (n=1,931) 0.84 ( ) <130 (n=2,059) 0.73 ( ) <140 (n=1,477) 0.74 ( ) (n=1,185) 0.81 ( ) Favors LCZ CI=confidence interval; CV=cardiovascular; HFrEF=heart failure with reduced ejection fraction; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; SBP=systolic blood pressure 1.00 Hazard ratio Favors enalapril Bohm et al. Eur J Heart Fail 2015;17(Suppl 1):393 (Abstract P1794 and poster)

12 Dose Reductions (n=3547, 42%): Predictors and Reasons I pazienti più anziani, severi e con IRC hanno dovuto ridurre più frequentemente la dose per ipotensione o peggioramento IRC Vardeny et al. J Cardiac Fail 2015;21(Suppl.) 9 10(Abstract 260).

13 Primary Outcome Events Censored at Dose Reduction and by Mean Dose Vardeny et al. J Cardiac Fail 2015;21(Suppl.) 9 10(Abstract 260).

14 TITRATION STUDY: DESIGN Senni et al EurJHF 2016, in press High RASi stratum: >10 mg total daily dose of enalapril OR >160 mg of valsartan, OR equivalent doses of other ARBs/ACEIs Low RASi stratum: 10 mg total daily dose of enalapril OR 160 mg of valsartan, OR equivalent doses of other ARBs/ACEIs OR ACEI/ARB-naïve patients* Screening Randomisation 1:1 Open-label run-in period LCZ mg BID N=681 N=540 Stratified based on the level of RASi N=498 n=251 LCZ mg BID LCZ mg BID LCZ mg BID Conservative initiation & up-titration: over 6 weeks LCZ mg BID Condensed initiation & up-titration: over 3 weeks n=247 LCZ mg BID 5 days 2 weeks 3 weeks 3 weeks 3 weeks V1 V2 V3 V4 V5 V6 V7/EOS Patients not meeting the tolerability criteria or those who required dose reduction or interruption at any visit after randomisation were considered treatment failures and were switched to open-label LCZ696

15 Proportion of patients, % INCIDENCE OF PRE-SPECIFIED LABORATORY ASSESSMENTS by Up-titration Regimen (Primary Endpoints) 50 Condensed, N= Conservative, N= HR 1.77 (95% CI 0.89, 3.52) p= HR1.93 (95% CI 0.89, 4.17) p= HR 3.14 (95% CI 0.33, 30.18) % p= % 5.2% 4% 1.2% 0.4% 0.4% 0% 0.8% 0.4% 0 n/n events 22/246 13/249 18/245 10/247 3/245 1/247 1/245 0/248 2/245 1/248 SBP <95 mmhg Serum K + >5.5mmol/L Serum K + 6.0mmol/L SCr >3.0mg/dL Doubling of SCr from baseline

Una proposta pratica Modificato da Lillyblad MP, Annals of Pharmacotherapy 2015; 49: 1237 1251 NYHA III/NT pro-bnp ++ ACE/ARB <50% target dose SBP 100-110 mmhg GFR 30-45 (60)

16 Una proposta pratica Modificato da Lillyblad MP, Annals of Pharmacotherapy 2015; 49: NYHA III/NT pro-bnp ++ ACE/ARB <50% target dose SBP mmhg GFR (60) ml/min/1.73m2 Start sacubitril/valsartan 50 mg BID for 3 week 3 Week Follow-up If tolerated increase to 100 mg BID for 3 week 3 Week Follow-up If tolerated increase to 200 mg BID

17 Conclusioni Il sacubitril/valsartan è un farmaco che potrebbe rivoluzionare il trattamento dello scompenso cardiaco (modulazione neuroormonale, terapia ormonale sostitutiva vs ACE/ARB) I benefici del trattamento dovrebbero riguardare la maggioranza dei pazienti con HFrEF anche se quelli più anziani, severi, con PA più bassa e IRC vanno trattati e monitorati con grande attenzione a tollerabilità ed efficacia I pazienti ideali sembrano paradossalmente i numerosi casi con HFrEF stabili, lievemente sintomatici ed in terapia ottimizzata (quelli in cui tendiamo ad accontentarci...)

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