Post on 25-Apr-2018
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
The Lancet, Volume 356, Issue 9230, 2000, 615 - 620
http://dx.doi.org/10.1016/S0140-6736(00)02602-7
OVERTURE
Packer M et al. Circulation. 2002;106:920-926
Copyright © American Heart Association, Inc. All rights reserved.
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
Packer M et al. Circulation. 2002;106:920-926
Copyright © American Heart Association, Inc. All rights reserved.
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
The Lancet, Volume 375, Issue 9722, 2010, 1255 - 1266
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.
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
The Lancet, Volume 375, Issue 9722, 2010, 1255 - 1266
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.
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
The Lancet, Volume 375, Issue 9722, 2010, 1255 - 1266
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.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
Kaplan–Meier Curves for Key Study Outcomes, According to Study Group.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
Prespecified Subgroup Analyses.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
Primary and Secondary Outcomes.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
Adverse Events during Randomized Treatment.
McMurray JJV et al. N Engl J Med 2014;371:993-1004
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.
Packer M et al. Circulation. 2015;131:54-61
Copyright © American Heart Association, Inc. All rights reserved.
Cumulative number of hospitalizations for heart failure in the enalapril and LCZ696 groups per 100 patients.
Packer M et al. Circulation. 2015;131:54-61
Copyright © American Heart Association, Inc. All rights reserved.
A, Median values for N-terminal pro-BNP and troponin T at entry and during single-blind run-in and double-blind periods.
Packer M et al. Circulation. 2015;131:54-61
Copyright © American Heart Association, Inc. All rights reserved.
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`?