convention centri scompenso scompenso cardiaco …€¦ · il mondo reale… (osservatorio cv ts)...

CONVENTION CENTRI SCOMPENSO SCOMPENSO CARDIACO CRONICO:

Come collocare i nuovi trattamenti

Andrea Di Lenarda

Centro Cardiovascolare e Università Trieste

Centro Cardiovascolare Trieste

Packer et al. Circulation 2015;131:54–61

0

500

1000

1500

2000

2500

3000

3500

4000

4500

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

LCZ696

Enalapril

RR = 0.70

p = 0.017

HR = 0.84

p = 0.003

RR = 0.82

p = 0.005

RR = 0.77

p < 0.001

RR = 0.84

p < 0.001

RR = 0.84

p < 0.001


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)

9419 entered LCZ696 run-in phase (median duration, 29 days; IQR, 26–35)

8442 underwent randomization

4187 were assigned to receive LCZ696

4176 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

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

McMurray, et al. N Engl J Med 2014

10.4%

10.4% Multivariable Predictors of Noncompletion


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)


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

Centro Cardiovascolare

Trieste

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

Agenda

• Ma questi risultati sono generalizzabili alla maggioranza dei pazienti con HFrEF?

• La tollerabilità al farmaco sarà un limitazione?


LCZ696 Enalapril

PARADIGM-HF: baseline SBP did not influence the treatment effect of LCZ696 compared with enalapril

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

Bohm et al. Eur J Heart Fail 2015;17(Suppl 1):393 (Abstract P1794 and poster)

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 (0.73–0.87) 0.0000004

SBP category (mmHg)

<110 (n=1,747) 0.89 (0.74–1.06) 0.195

110–<120 (n=1,931) 0.84 (0.70–1.01) 0.058

120–<130 (n=2,059) 0.73 (0.60–0.87) 0.001

130–<140 (n=1,477) 0.74 (0.59–0.92) 0.006

≥140 (n=1,185) 0.81 (0.64–1.01) 0.061

1.00 0.80

Favors LCZ696 Favors enalapril Hazard ratio

Dose Reductions (n=3547, 42%):

Predictors and Reasons

Vardeny et al. J Cardiac Fail 2015;21(Suppl.) 9–10(Abstract 260).

I pazienti più anziani, severi e con IRC hanno dovuto ridurre più

frequentemente la dose per ipotensione o peggioramento IRC


Primary Outcome Events Censored at Dose Reduction and by Mean Dose

Vardeny et al. J Cardiac Fail 2015;21(Suppl.) 9–10(Abstract 260).


Open-label

run-in period

LCZ696

50 mg BID Screening

LCZ696

50 mg BID

LCZ696

100 mg BID

LCZ696

200 mg BID

Condensed initiation & up-titration: over 3 weeks

LCZ696

100 mg BID

Conservative initiation & up-titration: over 6 weeks

Randomisation 1:1 LCZ696

200 mg BID

TITRATION STUDY: DESIGN

3 weeks 5 days 2 weeks 3 weeks 3 weeks

V1 V2 V3 V4 V5 V6 V7/EOS

N=681 N=540

N=498

n=247

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

n=251

Stratified based on the

level of RASi

• 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*


Senni et al EurJHF 2016, in press

INCIDENCE OF PRE-SPECIFIED LABORATORY ASSESSMENTS by Up-titration Regimen (Primary Endpoints)

8.9% 7.3%

1.2% 0.4% 0.8%

5.2% 4%

0.4% 0% 0.4% 0

10

20

30

40

50

SBP

<95 mmHg

Serum

K+ >5.5mmol/L Serum

K+ ≥6.0mmol/L SCr

>3.0mg/dL

Doubling of SCr

from baseline

HR 1.77

(95% CI 0.89, 3.52)

p=0.1020

HR1.93

(95% CI 0.89, 4.17)

p=0.0966

HR 3.14

(95% CI 0.33, 30.18)

p=0.3222

Condensed, N=247

Conservative, N=251

Pro

po

rtio

n o

f p

ati

en

ts, %

n/N events 22/246 13/249 18/245 10/247 3/245 1/247 1/245 0/248 2/245 1/248


Una proposta pratica…

• NYHA III/NT pro-BNP ++ • ACE/ARB <50% target dose • SBP 100-110 mmHg • GFR 30-45 (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


Modificato da Lillyblad MP, Annals of Pharmacotherapy 2015; 49: 1237–1251

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”...)

Conclusioni


convention centri scompenso scompenso cardiaco …€¦ · il mondo reale… (osservatorio cv ts)...

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