Univ.=Doz.’Dr.’Mar,n’Hülsmann’ ·...

ARNIs: Neuar,ge Therapie für Pa,enten mit chronischer Herzinsuffizienz -‐

Ein Paradigmenwechsel in der Herzinsuffizienz?

Univ.-‐Doz. Dr. Mar,n Hülsmann

Mortality in HFrEF remains high despite the introduc,on of new therapies that improve survival

§  Survival rates in chronic HF have improved with the introduc,on of new therapies1

3%ARR Emphasis

16% (4.5% ARR; mean follow up of 41.4

months)

SOLVD-‐T1,2 34%

(5.5% ARR; mean follow up

of 1.3 years)

CIBIS-‐II3

Red

uct

ion in r

elat

ive

risk

of

m

orta

lity

vs p

lace

bo

30% (11.0% ARR; mean follow up of 24

months) RALES4

17% (3.0% ARR; median follow-‐up of 33.7

months)

CHARM-‐Alterna,ve5

ACEI* β-blocker* MRA* ARB*

*On top of standard therapy at the ,me of study (except in CHARM-‐Alterna,ve where background ACEI therapy was excluded). Pa,ent popula,ons varied between trials and as such rela,ve risk reduc,ons cannot be directly compared. SOLVD (Studies of Le` Ventricular Dysfunc,on), CIBIS-‐II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized Aldactone Evalua,on Study) enrolled chronic HF pa,ents with LVEF≤35%. CHARM-‐Alterna,ve (Candesartan in Heart failure: Assessment of Reduc,on in Mortality and Morbidity) enrolled chronic HF pa,ents with LVEF≤40%

1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Inves,gators. N Engl J Med 1991;325:293–302; 3. CIBIS-‐II Inves,gators. Lancet 1999;353:9–13; 4. Pif et al. N Engl J Med 1999;341:709-‐17;–50;

5. Granger et al. Lancet 2003;362:772–6; 6. Go et al. Circula,on 2014;129:e28-‐e292; 7. Yancy et al. Circula,on 2013;128:e240–327; 8. Levy et al. N Engl J Med 2002;347:1397–402

§  However, significant mortality remains: ~50% of pa,ents die within 5 years of diagnosis6–8

4.5% ARR 5.5%ARR

10%ARR Care-‐HF

ACE-‐I in HF: Mortality reduc,on CONSENSUS severe CHF n=253

RRR=-‐27%

SOLVD mild or moderate CHF

n=2569 RRR=-‐16%

NEJM 1991 NEJM 1987

Placebo

Enalapril

Valiant

Neprilysin

Neprilysin has many substrates that are metabolized with differing levels of affinity

Metabolism of natriure0c and other vasoac0ve pep0des* by NEP1–9

1. Erdos, Skidgel. FASEB J 1989;3:145–51; 2. Levin et al. N Engl J Med 1998;339;321–8; 3. Stephenson et al. Biochem J 1987;243:183–7; 4. Lang et al. Clin Sci 1992;82:619–23; 5. Kenny et al. Biochem J 1993;291:83–8; 6. Skidgel et al. Pep,des 1984;5:769–76; 7. Abassi et al. Metabolism 1992;41:683–5; 8. Murphy et al. Br J Pharmacol 1994;113:137–42; 9. Jiang et al. Hypertens Res 2004;27:109–17;

10. Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9; 11. Richards et al. J Hypertens 1993;11:407–16; 12. Ferro et al. Circula,on 1998;97:2323–30

Rela,ve affinity for NEP

ANP and CNP

Endothelin

Substance P

Bradykinin

Ang II

Adrenomedullin

Ang I

NEP

Inac,ve fragments

or metabolites

Implica4ons for NEP inhibi4on

§ NEP substrates can have opposing biological ac,ons10

§ Overall effect is dependent upon the net effect on NEP metabolism of individual substrates10

§ Benefits in enhancing NP system may be offset by increased Ang II11

§ Needs to be complemented by simultaneous RAAS suppression2,11,12

*Not an exhaus0ve list of all neprilysin substrates; the most relevant substrates for cardiovascular physiology are listed

BNP

Ang=angiotensin; ANP=atrial natriure,c pep,de; BNP=B-‐type natriure,c pep,de; CNP=C-‐type natriure,c pep,de; NEP=neprilysin; NP=natriure,c pep,de; RAAS=renin angiotensin aldosterone system

Braunwald Textbook, 2006; M. Hülsmann, R. Pacher

Effects of human brain natriuretic peptide (hBNP) and placebo infusion on (A) mean pulmonary artery pressure (PAP), (B) mean pulmonary capillary wedge pressure (PCWP), (C) mean right atrial pressure, (D) mean arterial pressure, (E) cardiac index, and (F) heart rate in

19 patients with severe congestive heart failure.

Marcus L S et al. Circulation. 1996;94:3184-3189

Copyright © American Heart Association, Inc. All rights reserved.

Changes in Base-Line Hemodynamic Values at Six Hours in the Efficacy Trial.

Colucci WS et al. N Engl J Med 2000;343:246-‐253.

Changes in Dyspnea at 6 and 24 Hours and the Primary Clinical End Points at 30 Days.

O'Connor C et al. N Engl J Med 2011;365:32-‐43.

Omapatrilat ACE-‐Hemmer und Neprilysininhibitor

Figure 4 Change in NYHA functional class Change in NYHA functional class in patients with NYHA class III or IV heart failure from baseline to final visit.

Jean L Rouleau , Marc A Pfeffer , Duncan J Stewart , Debra Isaac , Francois Sestier , Edmund K Kerut , Charles B ...

Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial

The Lancet, Volume 356, Issue 9230, 2000, 615 - 620

http://dx.doi.org/10.1016/S0140-6736(00)02602-7

Figure 3 Death and congestive heart failure comorbidity Top: Kaplan-Meier estimates of the combined endpoints of death or admission for heart failure. Bottom: death or admission for heart failure or discontinuation of treatment for worsening heart failure...

Jean L Rouleau , Marc A Pfeffer , Duncan J Stewart , Debra Isaac , Francois Sestier , Edmund K Kerut , Charles B ...

Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial


http://dx.doi.org/10.1016/S0140-6736(00)02602-7

OVERTURE

Packer M et al. Circulation. 2002;106:920-926


In addi,on, there were 1275 pa,ents who died or were hospitalized for a cardiovascular reason in the enalapril group and 1178 such pa,ents in the omapatrilat group (hazard ra,o 0.91 [95% CI, 0.84 to 0.99]), P=0.024

OVERTURE



Omapatrilat vs Enalapril und Hypertonie

•  OCTAVE (25.267 Pa,enten) – Mortalität 0.15% vs 0.18% – Angioödeme 2.17% vs 0.68 % Subgruppen von Afroamerikanern und Rauchern besonders ausgeprägt)

LCZ696 angiotensin receptor neprilysin inhibitor (ARNI)

§  LCZ696 is a novel drug which delivers simultaneous neprilysin inhibi,on and AT1 receptor blockade1–3

§  LCZ696 is a salt complex that comprises the two ac,ve moie,es:2,3

–  sacubitril (AHU377) – a pro-‐drug; further metabolized to the neprilysin inhibitor LBQ657, and

–  valsartan – an AT1 receptor blocker in a 1:1 molar ra,o

1. Bloch, Basile. J Clin Hypertens 2010;12:809–12; 2. Gu et al. J Clin Pharmacol 2010;50:401–14; 3. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9

ARNI=angiotensin receptor neprilysin inhibitor; AT1=angiotensin II type 1

3D LCZ696 structure2

28

•  Omapatrilat inhibits three enzymes (ACE, APP, NEP) involved in the breakdown of bradykinin, which is likely to be responsible for the development of angioedema2

•  In contrast, LCZ696 selec,vely inhibits only NEP and is thus not expected to be associated with an increased risk of angioedema1,3,4

Angiotensin receptor neprilysin inhibitors (ARNIs), such as LCZ696, are not expected to excessively increase bradykinin1

The informa0on presented in this slide is from publically available data and not head-‐to–head clinical trials 1. McMurray et al. Eur J Heart Fail. 2014;16:817–25; 2. Fryer et al. Br J Pharmacol 2008;153:947–55; 3. Gu et al. J Clin Pharmacol 2010;50:401–14; 4. McMurray et al. Eur J Heart Fail. 2013;15:1062–73

Ac4ve bradykinin

Inac4ve bradykinin

ACE APP NEP DPP-4

Bradykinin breakdown

Omapatrilat inhibits ACE, APP and NEP

LCZ696 inhibits only NEP

Ac4ve bradykinin

Inac4ve bradykinin

ACE=angiotensin-‐conver,ng enzyme; APP=aminopep,dase P; AT1=angiotensin II type 1; DPP-‐4=dipep,dyl pep,dase-‐4; NEP=neprilysin

Figure 2 Change in placebo-subtracted mean sitting systolic blood pressure (A) and mean sitting diastolic blood pressure (B) during the 8-week treatment period Patients who discontinued the study drug without a blood pressure measurement after randomisati...

Luis Miguel Ruilope , Andrej Dukat , Michael Böhm , Yves Lacourcière , Jianjian Gong , Martin P Lefkowitz

Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study


http://dx.doi.org/10.1016/S0140-6736(09)61966-8

Figure 4 Change in 24-h (A), daytime (B), and night-time (C) ambulatory blood pressure during the 8-week treatment period NA=not applicable.




http://dx.doi.org/10.1016/S0140-6736(09)61966-8

Figure 3 Mean sitting systolic blood pressure (A) and mean sitting diastolic blood pressure (B) at study visits *Includes only patients who were assigned to placebo at second randomisation.




http://dx.doi.org/10.1016/S0140-6736(09)61966-8

Original Article Angiotensin–Neprilysin Inhibition versus Enalapril

in Heart Failure

John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., Michael R. Zile, M.D., for the PARADIGM-HF Investigators and Committees

N Engl J Med Volume 371(11):993-1004

September 11, 2014

Screening Criteria, Run-in Periods, and Randomization.

McMurray JJV et al. N Engl J Med 2014;371:993-1004

Characteristics of the Patients at Baseline.


Kaplan–Meier Curves for Key Study Outcomes, According to Study Group.


Prespecified Subgroup Analyses.


Primary and Secondary Outcomes.


Adverse Events during Randomized Treatment.


39

Conclusions

•  LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure.

Kaplan–Meier curve for the time to first hospitalization for heart failure during first 30 days after randomization, according to study group.



Cumulative number of hospitalizations for heart failure in the enalapril and LCZ696 groups per 100 patients.



A, Median values for N-terminal pro-BNP and troponin T at entry and during single-blind run-in and double-blind periods.



Amyloid-ß und Neprilysin Alzheimer Erkrankung

Verhältnis von Auftreten von Alzheimer Erkrankungen zur genetisch bedingten

ACE- Aktivität

Lehmann D J et al. Am. J. Epidemiol. 2005;162:305-317 American Journal of Epidemiology Copyright © 2005 by the Johns Hopkins Bloomberg School of

Public Health All rights reserved

Zusammenfassung

Wie wirken ARNI? „There is room for religion also in

medicine“ Mitlton Packer 2014

Zusammenfassung

•  ARNI reduzieren die Sterblichkeit •  ARNI reduzieren die Hospitalisa,onsrate •  ARNI haben ein ausgezeichentes Sicherheitsprofil

Wann wird LCZ696 getau`?

Univ.=Doz.’Dr.’Mar,n’Hülsmann’ ·...

Documents

Transcript of Univ.=Doz.’Dr.’Mar,n’Hülsmann’ ·...