ΝΕOΤΕΡΟΙ ΘΕΡΑΠΕΥΤΙΚΟI ΠΑΡAΓΟΝΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚH … · new...

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ΝΕOΤΕΡΟΙ ΘΕΡΑΠΕΥΤΙΚΟI ΠΑΡAΓΟΝΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚH ΑΝΕΠAΡΚΕΙΑ. ΠOΤΕ ΚΑΙ ΠΩΣ ΜΠΟΡΕΙ ΝΑ ΧΡΗΣΙΜΟΠΟΙΗΘΟΥΝ ΣΤΗΝ ΚΑΘΗΜΕΡΙΝΗ ΚΛΙΝΙΚΗ ΠΡΑΞΗ

ΣΤΡAΤΟΣ ΘΕΟΦΙΛΟΓΙΑΝΝAΚΟΣ

ΙΑΤΡΕIΟ ΚΑΡΔΙΑΚHΣ ΑΝΕΠAΡΚΕΙΑΣ, Γ’ ΠΑΝΕΠΙΣΤΗΜΙΑΚH ΚΑΡΔΙΟΛΟΓΙΚH ΚΛΙΝΙΚH, Γ.Ν. «ΙΠΠΟΚΡAΤΕΙΟ»

&

ΚΛΙΝΙΚH ΆΓΙΟΣ ΛΟΥΚAΣ

16ο ΒΟΡΕΙΟΕΛΛΑΔΙΚΟ ΚΑΡΔΙΟΛΟΓΙΚΟ ΣΥΝΕΔΡΙΟ ΠΕΜΠΤΗ 25 ΜΑΪΟΥ 2017

NEW DRUGS IN HEART FAILURE

• A. HEART FAILURE WITH REDUCED EJECTION FRACTION

• B. HEART FAILURE WITH PRESERVED EJECTION FRACTION

• C. ACUTE HEART FAILURE

SOLVD-T1 (1991) 2,569 patients Key benefits of enalapril (ACEI) vs placebo: • 16% ! all-cause mortality

1990s 2000s 2010s

ACEIs

ARBs

MRAs

β-blockers

Ivabradine

LCZ696

CIBIS-II2 (1999) 2,647 patients Key benefits of bisoprolol (BB) vs placebo: • 34% ! all-cause mortality

CHARM-Alternative3 (2003) 2,028 patients Key benefits of candesartan (ARB) vs placebo: • 23% ! CV mortality or HF

hospitalization

CHARM-Added4 (2003) 2,548 patients Key benefits of candesartan (ARB) vs placebo: • 15% ! CV mortality or HF hospitalization

SHIFT5 (2010) 6,558 patients Key benefits of ivabradine (If inhibitor) vs placebo: • 18% ! CV mortality or HF

hospitalization

EMPHASIS-HF6 (2014) 2,737 patients Key benefits of eplerenone (MRA) vs placebo: • 37% ! CV mortality or HF hospitalization

PARADIGM-HF7 (2014) 8,442 patients Key benefits of LCZ696 (ARNI) vs enalapril: • 20% ! CV mortality or HF

hospitalization

ΦΑΡΜΑΚΑ-ΜΕΛΕΤΕΣ ΟΡΟΣΗΜΟ ΚΑΡΔΙΑΚΗΣ ΑΝΕΠΑΡΚΕΙΑΣ

Η ΘΝΗΤΟΤΗΤΑ ΠΑΡΑΜΕΝΕΙ ΥΨΗΛΗ ΠΑΡΑ ΤΙΣ ΝΕΕΣ ΘΕΡΑΠΕΙΕΣ

• HFREF SURVIVAL RATES HAVE IMPROVED OVER TIME WITH THE INTRODUCTION OF NEW THERAPIES

• HOWEVER, SIGNIFICANT MORTALITY REMAINS

16%(4.5% ARR; mean follow

up of 41.4 months) SOLVD1

34% (5.5% ARR; mean follow up

of 1.3 years)CIBIS-II3

Redu

ctio

n in

rel

ativ

e ri

sk o

f m

orta

lity

vs p

lace

bo

ACEI* β-blocker* MRA*

30% (11.0% ARR; mean follow

up of 24 months)RALES4

17% (3.0% ARR; median follow-up

of 33.7 months) CHARM-

Alternative2

ARB*

Roger et al. JAMA 2004;292:344–50

IVABRADINE-SHIFT TRIAL

K Swedberg, et al. Lancet 2010

ΠΑΘΟΦΥΣΙΟΛΟΓΙΑ-ΦΑΡΜΑΚΑ

G Jackson et al BMJ 2000; 320: 167-170

ΑΝΑΣΤΡΟΦΗ ΑΝΑΔΙΑΜΟΡΦΩΣΗ

ΝΕΥΡΟ-ΟΡΜΟΝΙΚA ΣΥΣΤHΜΑΤΑ ΣΤΗΝ Κ/Α

K/A: ΣYΝΔΡΟΜΟ «ΝΕΥΡΟΧΥΜΙΚHΣ ΑΝΙΣΟΡΡΟΠIΑΣ»

ΝΕΟΙ ΘΕΡΑΠΕΥΤΙΚΟΙ ΣΤΟΧΟΙ ΣΤΗΝ Κ/Α

M Volpe et al, Eur Heart J 2013

ΦΑΡΜΑΚΑ ΠΟΥ ΔΡΟΥΝ ΣΤΟ ΣΥΣΤΗΜΑ ΝΑΤΡΙΟΥΡΗΤΙΚΩΝ ΠΕΠΤΙΔΙΩΝ

Vasc Health Risk Manag 2015; 11: 283–295.

▪ Η οµαπατριλάτη αναπτύχθηκε τόσο για την αναστολή της νεπριλυσίνης όσο και την καταστολή του ΣΡΑΑ, µέσω αναστολής του ΜΕΑ4,5

▪ Έδειξε µια τάση για µειωµένη νοσηρότητα και θνησιµότητα στην HFrEF5

▪ Η ανάπτυξη διακόπηκε λόγω της αυξηµένης συχνότητας αγγειοοιδήµατος1,5

ASCEND-HF FDA APPROVAL

(LCZ696) Η ΣΑΚΟΥΜΠΙΤΡΙΛΗ / ΒΑΛΣΑΡΤΑΝΗ (ARNI)

▪ Η σακουµπιτρίλη/ βαλσαρτάνη παρέχει ταυτόχρονα αναστολή της νεπριλυσίνης και αποκλεισµό του υποδοχέα AT1

▪ Η σακουµπιτρίλη/ βαλσαρτάνη είναι ένα σύµπλοκο άλας το οποίο περιλαµβάνει δύο ενεργά συστατικά: – Τη σακουµπιτρίλη (sacubitril) – ένα πρό-φαρµακο, το οποίο µεταβολίζεται περαιτέρω στον αναστολέα της νεπριλυσίνης LBQ657, και

– Τη βαλσαρτάνη – έναν αποκλειστή του υποδοχέα AT1 της Αg II

σε 1:1 µοριακή αναλογία

Η σακουμπιτρίλη/ βαλσαρτάνη είναι διαθέσιμη σε τρεις περιεκτικότητες: 50 mg (24 mg sacubitril / 26 mg valsartan) BID

100 mg (49 mg sacubitril / 51 mg valsartan) BID 200 mg (97 mg sacubitril / 103 mg valsartan BID

McMurray et al. N Engl J Med 2014; 371

Ηµέρες από την τυχαιοποίηση

Αθροιστική πιθανότητα

1,0

0,6

0,4

0,2

00 180 360 540 720 900 1.080 1.260

Λόγος κινδύνου = 0,80 (95% CI: 0,73-0,87) p<0,001

Εναλαπρίλη Σακουµπιτρίλη / Βαλσαρτάνη

ΘΑΝΑΤΟΣ ΑΠΟ ΚΑΡΔΙΑΓΓΕΙΑΚΗ ΑΙΤΙΟΛΟΓΙΑ Ή ΠΡΩΤΗ ΝΟΣΗΛΕΙΑ ΛΟΓΩ ΚΑ

Reducing the risk of primary endpoint by incremental 20%

ΘΑΝΑΤΟΣ ΑΠΟ ΚΑΡΔΙΑΓΓΕΙΑΚΗ ΑΙΤΙΟΛΟΓΙΑ




1,0

0,6

0,4

0,2

00 180 360 540 720 900 1.080 1.260



Reducing the risk of CV death by incremental 20%

Desai et al. Eur Heart J; 2015

Επίδραση της σακουμπιτρίλης /βαλσαρτάνης στον αιφνίδιο καρδιακό θάνατο

Λόγος κινδύνου = 0.80(95% CI: 0.68–0.94) p=0.008

Εναλαπρίλη

Σακουμπιτρίλη / Βαλσαρτάνη

0 180 360 540 720 900 1,080 1,2600

0.02

0.04

0.06

0.08

0.10

Ημέρες από την τυχαιοποίηση

Αθροιστική

πιθανότητα

συμβάντων

Desai et al. Eur Heart J; 2015

Επίδραση της σακουμπιτρίλης /βαλσαρτάνης στο θάνατο από επιδείνωση Κ/Α

Ημέρες από την τυχαιοποίηση

Εναλαπρίλη

Σακουμπιτρίλη / Βαλσαρτάνη

0 180 360 540 720 900 1,080 1,260

0.02

0.04

0.06

0.08

0.10

Αθροιστική

πιθανότητα

συμβάντων Λόγος κινδύνου = 0.79 (95% CI: 0.64–0.98),

p=0.034

Πρώτη νοσηλεία λόγω ΚΑ




1,0

0,6

0,4

0,2

00 180 360 540 720 900 1.080 1.260



Reducing the risk of HF hospitalization by incremental 21%


Μείωση νοσηλείας λόγω KA εντός 30 πρώτων ημερών

HR 0,60 (95% CI: 0,38-0,94), p=0,027


Εκτίµηση αθροιστικού

ποσοστού

κατά

Kap

lan-

Mei

er

1,5

1,0

0,5

00 10 20 30

Εναλαπρίλη (Ν=4.212) Σακουµπιτρίλη / Βαλσαρτάνη (Ν=4.187)


Θάνατος από οποιαδήποτε αιτιολογία



1,0

0,6

0,4

0,2

00 180 360 540 720 900 1.080 1.260



Reducing all-cause mortality by incremental 16%

Pharmacological treatments indicated in patients with symptomatic (NYHA Class II-IV) HFrEF

Recommendations Class Level

An ACEi is recommended, in addition to a beta blocker, for symptomatic patients with HFrEF to reduce the risk of HF hospitalization and death I A

A beta blocker is recommended, in addition an ACEi, for patients with stable, symptomatic HFrEF to reduce the risk of HF hospitalization and death I A

An MRA is recommended for patients with HFrEF, who remain symptomatic despite treatment with an ACEi and a beta-blocker, to reduce the risk of HF hospitalization and death I A

Sacubitril/valsartan is recommended as a replacement for an ACEi to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACEi, a beta-blocker and an MRA* I B

Heart Failure ESC Guidelines 2016

Patient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma NT-proBNP ≥600 pg/mL, or if HF hospitalization within the last 12 months, plasma BNP ≥100 pg/mL or plasma NT-proBNP ≥400 pg/mL) and able to tolerate enalapril 10 mg b.i.d.

Ponikowski et al. Eur Heart J. 21 May 2016.

Recommendations for the management of ventricular tachyarrhythmias in heart failure


Treatment with beta-blocker, MRA and sacubitril/valsartan reduces the risk of sudden death

and is recommended for patients with HFrEF and ventricular arrhythmias (as for other

patients) (Section 10.2). I A

Sacubitril/valsartan in management of ventricular arrhythmias

Ponikowski et al. Eur Heart J. 21 May 2016.


The clinical strategy of inhibition of the renin-angiotensin system with ACEi (Level of Evidence: A), OR ARBs (Level of Evidence: A), OR ARNI (Level of Evidence: B-R) in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality.

I

ACEi: A

ARB: A

ARNI: B-R

The use of ACEi is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality I A

The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACEi because of cough or angioedema I A

In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality

I B-R

.Yancy et al. JACC. Published 21 May 2016.

ACC/AHA/HFSA Focused Update treatment for Stage C* HFrEF

.ESC Guidelines 2016.

EMPAGLIFLOZIN- DIABETES TYPE 2❖ Inhibitors of sodium–glucose cotransporter 2 decreases renal glucose reabsorption,

thereby increasing urinary glucose excretion

❖Empagliflozin reduced hospitalization for HF and mortality, but not myocardial infarction or stroke, in patients with diabetes at high cardiovascular risk.

EMPA-REG Trial NEJM 373;22: 2015

❖EMPEROR HF (HFRF + HFPF) clinical trial programme will evaluate the efficacy and safety of empagliflozin in patients with chronic heart failure, including those with and without type 2 diabetes. Estimated completion: 2020

CLINICAL TRIALS PERFORMED IN HEART FAILURE WITH HEART FAILURE WITH PRESERVED EF

HEART FAILURE WITH REDUCED EF HEART FAILURE WITH PRESERVED EF

HFPF ONGONING TRIALS

ESC RECOMMENDATIONS FOR HEART FAILURE WITH PRESERVED EF

INOTROPES IN ACUTE HEART FAILURE

Use the smallest dose of the most appropriate medication for the shortest length of time

Francis GS et al. J Am Coll Cardiol 2014;63:2069–2078.

LEVOSIMEDAN IN ACUTE HEART FAILURE

REVIVE II TRIAL

M Packer, JACC: Heart Failure 2013

In ADHF, levosimendan provided rapid and durable symptomatic relief, but it was associated with an increased risk of adverse cardiovascular events.

SURVIVE TRIAL

Levosimendan may be better than dobutamine in patients with a history of CHF or those on b-blocker when they are hospitalized with acute decompensations.

A Mebazaa, European Journal of Heart Failure 2009

ΝΕΣΙΤΙΡΙΔΗ: ΑΝΑΣΥΝΔΥΑΣΜΕΝΟ BNP (FDA APPROVAL)

N Engl J Med 2011; 365:32-43

ASCEND-HF

❖ Not associated with an increase or a decrease in the rate of death and rehospitalization

❖ A small effect on dyspnea ❖ Associated with an increase in rates

of hypotension.

RELAX-AHF-2

TRUE AHF TRIAL- ULARITIDE

• ULARITIDE IS A NOVEL NATRIURETIC PEPTIDE THAT RESULTS IN SYSTEMIC AND RENAL VASODILATION, DIURESIS AND NATRIURESIS, AND INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM.

• There was no difference in the risk of cardiovascular death up to 34 months between the two groups despite the drug exerting the expected physiological effects.

M Packer et al, N Engl J Med 2016; 365:32-43

Serelaxin- RELAX AHF-2 Trial

❖ Serelaxin, a relaxin receptor agonist, is a recombinant form of the naturally-occurring human relaxin-2 hormone.

❖ Serelaxin is recombinant human relaxin-2, with vasodilatory and end-organ protective effects. It is naturally present in all humans, with higher concentrations in pregnant women to prepare for the extra cardiovascular and renal stresses of pregnancy.

❖ Serelaxin has failed to meet the primary endpoints of the phase 3 RELAX-AHF-2 trial.

❖ RELAX-AHF-2 was a multicentre trial enrolling approximately 6 600 patients hospitalised for AHF. Patients were randomised within 16 hours from presentation to 48-hour intravenous infusions of serelaxin (30 µg/kg/day) or placebo.

❖ RELAX-AHF-2 did not meet either of its primary endpoints. There was no difference in cardiovascular mortality at 180 days and the trend for a reduction of worsening heart failure through day five with serelaxin was not statistically significant.

ΤΑΚΕ ΗΟΜE MESSAGES

❖ Sacubitril/valsartan is recommended as a replacement for an ACE-I in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA.

❖ Metformin should be considered as a first line treatment of glycaemic control in patients with diabetes and HF, but empagliflozin is the only anti-diabetic that reduces hospitalization for HF and mortality in patients with diabetes at high cardiovascular risk.

❖ No treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF or HFmrEF.

❖ Serelaxin, Nesitiride failed to meet the primary endpoints of their phase 3 acute heart failure trials.

ΝΕOΤΕΡΟΙ ΘΕΡΑΠΕΥΤΙΚΟI ΠΑΡAΓΟΝΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚH … · new...

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