PMID- 22932717 OWN - NLM STAT- MEDLINE DCOM- 20121031 LR - 20220318 IS - 1474-547X (Electronic) IS - 0140-6736 (Linking) VI - 380 IP - 9851 DP - 2012 Oct 20 TI - The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. PG - 1387-95 LID - S0140-6736(12)61227-6 [pii] LID - 10.1016/S0140-6736(12)61227-6 [doi] AB - BACKGROUND: Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder. METHODS: PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II-III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588. FINDINGS: 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512-714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 835 [710-981]; ratio LCZ696/valsartan, 0.77, 95% CI 0.64-0.92, p=0.005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event. INTERPRETATION: In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively. FUNDING: Novartis. CI - Copyright (c) 2012 Elsevier Ltd. All rights reserved. FAU - Solomon, Scott D AU - Solomon SD AD - Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. ssolomon@rics.bwh.harvard.edu FAU - Zile, Michael AU - Zile M FAU - Pieske, Burkert AU - Pieske B FAU - Voors, Adriaan AU - Voors A FAU - Shah, Amil AU - Shah A FAU - Kraigher-Krainer, Elisabeth AU - Kraigher-Krainer E FAU - Shi, Victor AU - Shi V FAU - Bransford, Toni AU - Bransford T FAU - Takeuchi, Madoka AU - Takeuchi M FAU - Gong, Jianjian AU - Gong J FAU - Lefkowitz, Martin AU - Lefkowitz M FAU - Packer, Milton AU - Packer M FAU - McMurray, John J V AU - McMurray JJ CN - Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators LA - eng SI - ClinicalTrials.gov/NCT00887588 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20120826 PL - England TA - Lancet JT - Lancet (London, England) JID - 2985213R RN - 0 (Aminobutyrates) RN - 0 (Angiotensin Receptor Antagonists) RN - 0 (Biphenyl Compounds) RN - 0 (Drug Combinations) RN - 0 (Peptide Fragments) RN - 0 (Tetrazoles) RN - 0 (pro-brain natriuretic peptide (1-76)) RN - 114471-18-0 (Natriuretic Peptide, Brain) RN - 80M03YXJ7I (Valsartan) RN - EC 3.4.24.11 (Neprilysin) RN - HG18B9YRS7 (Valine) RN - WB8FT61183 (sacubitril and valsartan sodium hydrate drug combination) SB - IM CIN - Lancet. 2012 Oct 20;380(9851):1363-5. PMID: 22932711 CIN - Nat Rev Cardiol. 2012 Nov;9(11):612. PMID: 22965107 MH - Aged MH - Aminobutyrates/*therapeutic use MH - Angiotensin Receptor Antagonists/*therapeutic use MH - Biphenyl Compounds MH - Double-Blind Method MH - Drug Combinations MH - Female MH - Heart Failure/blood/*drug therapy/physiopathology MH - Humans MH - Male MH - Middle Aged MH - Natriuretic Peptide, Brain/blood MH - Neprilysin/*antagonists & inhibitors MH - Peptide Fragments/blood MH - Stroke Volume MH - Tetrazoles/*therapeutic use MH - Valine/analogs & derivatives/therapeutic use MH - Valsartan FIR - Zucchiatti, Noemi IR - Zucchiatti N FIR - Jure, Horacio IR - Jure H FIR - Milesi, Rodolfo IR - Milesi R FIR - Kuschnir, Emilio IR - Kuschnir E FIR - Perna, Eduardo IR - Perna E FIR - Majul, Claudio IR - Majul C FIR - Llanos, Javier IR - Llanos J FIR - Grosse, Alejo IR - Grosse A FIR - Hominal, Miguel IR - Hominal M FIR - Oliveira, Mucio Jr IR - Oliveira M Jr FIR - Bodanese, Luiz IR - Bodanese L FIR - Greco, Oswaldo IR - Greco O FIR - Rassi, Salvador IR - Rassi S FIR - Gianetti, Nadia IR - Gianetti N FIR - Gupta, Milan IR - Gupta M FIR - Huynh, Thao IR - Huynh T FIR - Edelmann, Frank IR - Edelmann F FIR - Reddy, P Naveen IR - Reddy P FIR - Gupta, J B IR - Gupta JB FIR - Sarna, Mukesh Kumar IR - Sarna MK FIR - Kumar, Padma IR - Kumar P FIR - Jagtap, Prashant IR - Jagtap P FIR - Khan, Aziz IR - Khan A FIR - Rao, Srinivasa IR - Rao S FIR - Rao, Maddury IR - Rao M FIR - Kumbla, Mukund IR - Kumbla M FIR - Ronchi, Esio IR - Ronchi E FIR - Primo, Casorate IR - Primo C FIR - Bertoli, Daniele IR - Bertoli D FIR - Mos, Lucio IR - Mos L FIR - Sprovieri, Mario IR - Sprovieri M FIR - Senni, Michele IR - Senni M FIR - Schizzarotto, Alberto IR - Schizzarotto A FIR - Voors, A A IR - Voors AA FIR - Lenderink, Timo IR - Lenderink T FIR - Den Hartog, F IR - Den Hartog F FIR - Liem, Anho H IR - Liem AH FIR - Tjeerdsma, G IR - Tjeerdsma G FIR - Pinto, Y IR - Pinto Y FIR - Derks, A IR - Derks A FIR - Ponikowski, Piotr IR - Ponikowski P FIR - Makowiecka-Ciesla, Magdalena IR - Makowiecka-Ciesla M FIR - Pop, Calin Florin IR - Pop CF FIR - Militaru, Constantin IR - Militaru C FIR - Opris, Constantin IR - Opris C FIR - Militaru, Constantin IR - Militaru C FIR - Stanciulescu, Gabriela IR - Stanciulescu G FIR - Konrady, Alexandra IR - Konrady A FIR - Shoustov, Sergey IR - Shoustov S FIR - Simanenkov, Vladimir IR - Simanenkov V FIR - Kobalava, Zhanna IR - Kobalava Z FIR - Boitsov, Sergey IR - Boitsov S FIR - Lam, Carolyn IR - Lam C FIR - Ding, Zee Pin IR - Ding ZP FIR - Gonzalez Juanatey, Jose Ramon IR - Gonzalez Juanatey JR FIR - Parreno, Luis de Teresa IR - Parreno Lde T FIR - Puig, Juan Garcia IR - Puig JG FIR - Chivite, David IR - Chivite D FIR - Calvo, Carlos IR - Calvo C FIR - Manzano, Luis IR - Manzano L FIR - Pena, Gonzalo IR - Pena G FIR - Coruna, A IR - Coruna A FIR - Modi, Mayank IR - Modi M FIR - Leimbach, Wayne IR - Leimbach W FIR - Adamson, Philip IR - Adamson P FIR - Promisloff, Steven IR - Promisloff S FIR - Krueger, Steven IR - Krueger S FIR - Montgomery, Baxter IR - Montgomery B FIR - Colan, David IR - Colan D EDAT- 2012/08/31 06:00 MHDA- 2012/11/01 06:00 CRDT- 2012/08/31 06:00 PHST- 2012/08/31 06:00 [entrez] PHST- 2012/08/31 06:00 [pubmed] PHST- 2012/11/01 06:00 [medline] AID - S0140-6736(12)61227-6 [pii] AID - 10.1016/S0140-6736(12)61227-6 [doi] PST - ppublish SO - Lancet. 2012 Oct 20;380(9851):1387-95. doi: 10.1016/S0140-6736(12)61227-6. Epub 2012 Aug 26.