Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.


AIMS:To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). METHODS AND RESULTS:A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS:Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.


Eur J Heart Fail


Senni M,McMurray JJ,Wachter R,McIntyre HF,Reyes A,Majercak I,Andreka P,Shehova-Yankova N,Anand I,Yilmaz MB,Gogia H,Martinez-Selles M,Fischer S,Zilahi Z,Cosmi F,Gelev V,Galve E,Gómez-Doblas JJ,Nociar J,Radomska M,S




Has Abstract


2016-09-01 00:00:00












  • Comparative analysis of the therapeutic effects of long-acting and short-acting loop diuretics in the treatment of chronic heart failure using (123)I-metaiodobenzylguanidine scintigraphy.

    abstract:AIMS:Loop diuretics are essential for the treatment of chronic heart failure (CHF) but short-acting diuretics are reported to induce sympathetic nervous system (SNS) activation. This study was performed to compare therapeutic effects of two loop diuretics, long-acting azosemide and short-acting furosemide, using (123)I...

    journal_title:European journal of heart failure

    pub_type: 杂志文章,随机对照试验


    authors: Hisatake S,Nanjo S,Fujimoto S,Yamashina S,Yuzawa H,Namiki A,Nakano H,Yamazaki J

    更新日期:2011-08-01 00:00:00

  • Nutritional status in tricuspid regurgitation: implications of transcatheter repair.

    abstract:AIMS:To characterize the prevalence and clinical relevance of malnutrition in patients undergoing transcatheter tricuspid valve edge-to-edge repair (TTVR). METHODS AND RESULTS:Overall, 86 consecutive patients (mean age 78 ± 7 years) with moderate-to-severe tricuspid regurgitation (TR) at prohibitive surgical risk were...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Besler C,Unterhuber M,Rommel KP,Unger E,Hartung P,von Roeder M,Noack T,Zachäus M,Halm U,Borger M,Desch S,Thiele H,Lurz P

    更新日期:2020-10-01 00:00:00

  • Serum uric acid, influence of sacubitril-valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF.

    abstract:AIMS:This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies. METHODS AND RESULTS:We analysed 4795 participants from the Prospective Comparison o...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Selvaraj S,Claggett BL,Pfeffer MA,Desai AS,Mc Causland FR,McGrath MM,Anand IS,van Veldhuisen DJ,Kober L,Janssens S,Cleland JGF,Pieske B,Rouleau JL,Zile MR,Shi VC,Lefkowitz MP,McMurray JJV,Solomon SD

    更新日期:2020-11-01 00:00:00

  • Haemodynamic effects of an acute vasodilator challenge in heart failure patients with reduced ejection fraction and different forms of post-capillary pulmonary hypertension.

    abstract:AIMS:The most recent European guidelines have proposed new definitions of pulmonary hypertension (PH) in left heart disease, to better approach the characteristics required to reflect the presence of pulmonary vascular disease. The purpose of this study was to assess whether different haemodynamic definitions of post-c...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Ghio S,Crimi G,Temporelli PL,Traversi E,La Rovere MT,Cannito A,Vizza D,Scelsi L,Raineri C,Guazzi M,Oltrona Visconti L

    更新日期:2018-04-01 00:00:00

  • Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM.

    abstract:BACKGROUND:Limited comparative studies assessing the health-related quality of life (HRQL) in heart failure (HF) patients with preserved vs. low ejection fraction (LVEF) have been disparate. AIMS:The aims of this study were a) to characterize HRQL in a large population of HF patients with preserved and low LVEF and b)...

    journal_title:European journal of heart failure

    pub_type: 杂志文章,多中心研究


    authors: Lewis EF,Lamas GA,O'Meara E,Granger CB,Dunlap ME,McKelvie RS,Probstfield JL,Young JB,Michelson EL,Halling K,Carlsson J,Olofsson B,McMurray JJ,Yusuf S,Swedberg K,Pfeffer MA,CHARM Investigators.

    更新日期:2007-01-01 00:00:00

  • Diabetes mellitus and cardiogenic shock in acute myocardial infarction.

    abstract:AIMS:Cardiogenic shock is the leading cause of in-hospital mortality after acute myocardial infarction (MI). This study investigates the importance of age and preexisting diabetes mellitus on the incidence and prognosis of cardiogenic shock in a large group of consecutive patients with MI. METHODS AND RESULTS:Baseline...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Lindholm MG,Boesgaard S,Torp-Pedersen C,Køber L,TRACE registry study group.

    更新日期:2005-08-01 00:00:00

  • High prevalence of myocarditis in patients with hypertensive heart disease and cardiac deterioration.

    abstract:AIMS:Structural abnormalities causing cardiac deterioration in hypertensive heart disease (HHD) are poorly understood. The aim of the study was to evaluate left ventricular (LV) myocardial changes in patients with HHD and cardiac failure. METHODS AND RESULTS:Among 1229 patients undergoing an LV or biventricular endomy...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Frustaci A,Francone M,Petrosillo N,Chimenti C

    更新日期:2013-03-01 00:00:00

  • Usefulness of anti-oxidized LDL antibody determination for assessment of clinical control in patients with heart failure.

    abstract:BACKGROUND:It has been suggested that oxidative stress may play a role in the pathogenesis of heart failure, this may have potential implications for therapeutic strategies. However, measures of oxidative stress are subject to confounding inaccuracies. IgG antibodies to oxidized LDL reflect exposure to the lipoprotein ...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: George J,Wexler D,Roth A,Barak T,Sheps D,Keren G

    更新日期:2006-01-01 00:00:00

  • Ambulatory blood pressure monitoring in heart failure: a systematic review.

    abstract::Ambulatory blood pressure monitoring has established its use in the definition of white coat hypertension and monitoring of treatment of essential hypertension. Any role for ambulatory blood pressure monitoring in heart failure is not well defined. However, from the limited studies available, ambulatory blood pressure...

    journal_title:European journal of heart failure

    pub_type: 杂志文章,评审


    authors: Goyal D,Macfadyen RJ,Watson RD,Lip GY

    更新日期:2005-03-02 00:00:00

  • Prognostic importance of cognitive impairment in chronic heart failure patients: does specialist management make a difference?

    abstract:BACKGROUND:Cognitive impairment is common among chronic heart failure (CHF) patients. AIMS:To determine the prognostic significance of cognitive impairment in patients participating in a randomized study of a CHF management program (CHF-MP). METHODS:CHF patients were randomized to a CHF-MP (n=100) or usual care (n=10...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: McLennan SN,Pearson SA,Cameron J,Stewart S

    更新日期:2006-08-01 00:00:00

  • Long-term outcome in patients with Takotsubo syndrome presenting with severely reduced left ventricular ejection fraction.

    abstract:AIM:To evaluate the long-term outcome of patients with Takotsubo syndrome (TTS) and severely reduced left ventricular ejection fraction (LVEF ≤ 35%) at presentation. METHODS AND RESULTS:The study population included 326 patients (mean age 69.5 ± 10.7 years, 28 male) with TTS enrolled in the Takotsubo Italian Network, ...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Citro R,Radano I,Parodi G,Di Vece D,Zito C,Novo G,Provenza G,Bellino M,Prota C,Silverio A,Antonini-Canterin F,Rigo F,Vriz O,Galasso G,Bossone E,Salerno-Uriarte J,Piscione F

    更新日期:2019-06-01 00:00:00

  • Mega-trials in heart failure: effects of dilution in examination of new therapies.

    abstract:AIMS:Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or t...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Davison BA,Takagi K,Senger S,Koch G,Metra M,Kimmoun A,Mebazaa A,Voors AA,Nielsen OW,Chioncel O,Pang PS,Greenberg BH,Maggioni AP,Cohen-Solal A,Ertl G,Sato N,Teerlink JR,Filippatos G,Ponikowski P,Gayat E,Edwards C,

    更新日期:2020-09-01 00:00:00

  • New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

    abstract::Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk ...

    journal_title:European journal of heart failure

    pub_type: 杂志文章,评审


    authors: Cowie MR,Filippatos GS,Alonso Garcia MLA,Anker SD,Baczynska A,Bloomfield DM,Borentain M,Bruins Slot K,Cronin M,Doevendans PA,El-Gazayerly A,Gimpelewicz C,Honarpour N,Janmohamed S,Janssen H,Kim AM,Lautsch D,Laws I,Lefk

    更新日期:2017-06-01 00:00:00

  • The increase in serum uric acid concentration caused by diuretics might be beneficial in heart failure.

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    journal_title:European journal of heart failure

    pub_type: 杂志文章,评审


    authors: Reyes AJ

    更新日期:2005-06-01 00:00:00

  • Tobacco smoke-induced left ventricular remodelling is not associated with metalloproteinase-2 or -9 activation.

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    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Castardeli E,Duarte DR,Minicucci MF,Azevedo PS,Matsubara BB,Matsubara LS,Campana AO,Paiva SA,Zornoff LA

    更新日期:2007-11-01 00:00:00

  • Effects of applying a standardised management algorithm for moderate to severe renal dysfunction in patients with chronic stable heart failure.

    abstract:BACKGROUND:No specific guidelines exist on how to manage renal dysfunction (RD) in patients with chronic heart failure (CHF). AIMS:To identify the proportion of patients with moderate to severe RD and CHF who showed an improvement in their renal function in response to a systematic management algorithm. METHODS:Stabl...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: de Silva R,Nikitin NP,Witte KK,Rigby AS,Loh H,Nicholson A,Bhandari S,Clark AL,Cleland JG

    更新日期:2007-04-01 00:00:00

  • Annual rates of admission and seasonal variations in hospitalizations for heart failure.

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    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Martínez-Sellés M,García Robles JA,Prieto L,Serrano JA,Muñoz R,Frades E,Almendral J

    更新日期:2002-12-01 00:00:00

  • Clinical trials update from the European Society of Cardiology: CHARM, BASEL, EUROPA and ESTEEM.

    abstract::This article contains a series of reports on recent research developments in the field of heart failure. Reports of key presentations made at the European Society of Cardiology meeting, held in Vienna, Austria, between 30 August and 3 September 2003 are reported. In the CHARM study, candesartan reduced cardiovascular ...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Coletta AP,Cleland JG,Freemantle N,Loh H,Memon A,Clark AL

    更新日期:2003-10-01 00:00:00

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    journal_title:European journal of heart failure

    pub_type: 杂志文章,多中心研究


    authors: Rudolph V,Huntgeburth M,von Bardeleben RS,Boekstegers P,Lubos E,Schillinger W,Ouarrak T,Eggebrecht H,Butter C,Plicht B,May A,Franzen O,Schofer J,Senges J,Baldus S

    更新日期:2014-11-01 00:00:00

  • Oral sucrosomial iron improves exercise capacity and quality of life in heart failure with reduced ejection fraction and iron deficiency: a non-randomized, open-label, proof-of-concept study.

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    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Karavidas A,Troganis E,Lazaros G,Balta D,Karavidas IN,Polyzogopoulou E,Parissis J,Farmakis D

    更新日期:2021-01-09 00:00:00

  • Bi treatment with hydralazine/nitrates vs. placebo in Africans admitted with acute HEart Failure (BA-HEF).

    abstract:AIMS:Patients with acute heart failure (HF) in Africa are rarely being treated with a hydralazine/nitrates combination. Therefore the effect of this treatment was studied here. METHODS AND RESULTS:The study was planned to enrol 500 patients during an acute HF admission, from nine sub-Saharan African countries. Patient...

    journal_title:European journal of heart failure

    pub_type: 杂志文章,多中心研究,随机对照试验


    authors: Sliwa K,Damasceno A,Davison BA,Mayosi BM,Sani MU,Ogah O,Mondo C,Ojji D,Dzudie A,Kouam CK,Yonga G,Ba SA,Ogola E,Edwards C,Milo O,Cotter G

    更新日期:2016-10-01 00:00:00

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    pub_type: 杂志文章


    authors: Khan MS,Samman Tahhan A,Vaduganathan M,Greene SJ,Alrohaibani A,Anker SD,Vardeny O,Fonarow GC,Butler J

    更新日期:2020-06-01 00:00:00

  • Lung function with carvedilol and bisoprolol in chronic heart failure: is beta selectivity relevant?

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    journal_title:European journal of heart failure

    pub_type: 杂志文章,随机对照试验


    authors: Agostoni P,Contini M,Cattadori G,Apostolo A,Sciomer S,Bussotti M,Palermo P,Fiorentini C

    更新日期:2007-08-01 00:00:00

  • Family caregiving and congestive heart failure. Review and analysis.

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    journal_title:European journal of heart failure

    pub_type: 杂志文章,评审


    authors: Molloy GJ,Johnston DW,Witham MD

    更新日期:2005-06-01 00:00:00

  • Phosphodiesterase 5 inhibition with sildenafil reverses exercise oscillatory breathing in chronic heart failure: a long-term cardiopulmonary exercise testing placebo-controlled study.

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    journal_title:European journal of heart failure

    pub_type: 杂志文章,随机对照试验


    authors: Guazzi M,Vicenzi M,Arena R

    更新日期:2012-01-01 00:00:00

  • Residual stress ischaemia is associated with blood markers of myocardial structural remodelling.

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    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Radauceanu A,Moulin F,Djaballah W,Marie PY,Alla F,Dousset B,Virion JM,Capiaumont J,Karcher G,Aliot E,Zannad F

    更新日期:2007-04-01 00:00:00

  • Fluid loss, venous congestion, and worsening renal function in acute decompensated heart failure.

    abstract:AIMS:To investigate the relationship between decongestion, central venous pressure, and risk of worsening renal function (WRF) in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS:We studied 475 patients with ADHF, of whom 238 underwent right heart catheterization. Right atrial pressure (RAP)...

    journal_title:European journal of heart failure

    pub_type: 杂志文章,多中心研究,随机对照试验


    authors: Aronson D,Abassi Z,Allon E,Burger AJ

    更新日期:2013-06-01 00:00:00

  • Telomere length and outcomes in ischaemic heart failure: data from the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA).

    abstract:AIMS:Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart fail...

    journal_title:European journal of heart failure

    pub_type: 杂志文章,多中心研究,随机对照试验


    authors: Haver VG,Mateo Leach I,Kjekshus J,Fox JC,Wedel H,Wikstrand J,de Boer RA,van Gilst WH,McMurray JJ,van Veldhuisen DJ,van der Harst P

    更新日期:2015-03-01 00:00:00

  • Prognostic importance of exercise brain natriuretic peptide in asymptomatic degenerative mitral regurgitation.

    abstract:AIM:The exercise Doppler echocardiographic stress test can be of interest in the management of asymptomatic patients with primary mitral regurgitation (MR). The resting brain natriuretic peptide (BNP) level is a good surrogate marker of the consequences of MR and is a powerful predictor of outcome. The incremental prog...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Magne J,Mahjoub H,Pibarot P,Pirlet C,Pierard LA,Lancellotti P

    更新日期:2012-11-01 00:00:00

  • Hereditary hemochromatosis gene (HFE) mutations C282Y, H63D and S65C in patients with idiopathic dilated cardiomyopathy.

    abstract:BACKGROUND:Hereditary hemochromatosis (HH), a common autosomal recessive disease, leads to excessive iron accumulation in some organs, including the heart. It is therefore not surprising that cardiomyopathy is one of the most severe complications of HH. The HFE gene defects have been thought to contribute to idiopathic...

    journal_title:European journal of heart failure

    pub_type: 杂志文章


    authors: Hannuksela J,Leppilampi M,Peuhkurinen K,Kärkkäinen S,Saastamoinen E,Heliö T,Kaartinen M,Nieminen MS,Nieminen P,Parkkila S

    更新日期:2005-01-01 00:00:00