Trial Outcomes & Findings for LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction (NCT NCT00887588)

Last Updated: 2015-08-25

Results Overview

Evaluation of NT-proBNP was performed by a central laboratory. Change from baseline in NT-proBNP was presented as a ratio where the ratio was calculated as the NT-proBNP value at 12 weeks over the NT-proBNP value at baseline. A ratio \< 1 indicates improvement.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

307 participants

Primary outcome timeframe

Baseline, 12 weeks

Results posted on

2015-08-25

Participant Flow

A total of 308 participants were randomized to the core 12 week period, but 7 participants were excluded due to major Good Clinical Practice (GCP) violation. Of the 261 participants who completed the core, 252 participants entered the extension period.

Eight participants, who completed the core, could not continue in the extension because the 36 week protocol amendment was not yet approved by health authorities; 1 participant, who completed the core, discontinued before the extension start due to an adverse event.

Participant milestones

Participant milestones
Measure	LCZ696 During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Core Period STARTED	149	152
Core Period Extension Efficacy Set	127	125
Core Period Full Analysis Set	148	146
Core Period Arterial Stiffness Set	86	94
Core Period COMPLETED	130	131
Core Period NOT COMPLETED	19	21
Extension Period STARTED	127	125
Extension Period Arterial Stiffness Set	86	94
Extension Period COMPLETED	121	120
Extension Period NOT COMPLETED	6	5

Reasons for withdrawal

Reasons for withdrawal
Measure	LCZ696 During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Core Period Death	1	1
Core Period Lost to Follow-up	3	1
Core Period Withdrawal by Subject	6	8
Core Period Adverse Event	9	11
Extension Period Adverse Event	4	4
Extension Period Death	0	1
Extension Period Protocol deviation	1	0
Extension Period Lost to Follow-up	1	0

Baseline Characteristics

LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCZ696 n=149 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=152 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.	Total n=301 Participants Total of all reporting groups
Age, Continuous	70.9 Years STANDARD_DEVIATION 9.38 • n=5 Participants	71.2 Years STANDARD_DEVIATION 8.94 • n=7 Participants	71.0 Years STANDARD_DEVIATION 9.15 • n=5 Participants
Sex: Female, Male Female	85 Participants n=5 Participants	85 Participants n=7 Participants	170 Participants n=5 Participants
Sex: Female, Male Male	64 Participants n=5 Participants	67 Participants n=7 Participants	131 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 12 weeks

Population: Participants from the full analysis set (FAS), who had both baseline and 12 week values, were included in the analysis. The FAS consisted of all randomized participants who had baseline and at least one post-baseline efficacy measurement during the double blind period.

Outcome measures

Outcome measures
Measure	LCZ696 n=134 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=132 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)	0.83 ratio: endpoint/baseline (pg/mL) Interval 0.68 to 1.01	1.08 ratio: endpoint/baseline (pg/mL) Interval 0.89 to 1.32

SECONDARY outcome

Timeframe: baseline, 36 weeks

Population: Participants from the extension efficacy set, who had both baseline and 36 week values for each parameter, were included in the analysis for that parameter. The extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

Evaluation of NT-proBNP and BNP was performed by a central laboratory. Change from baseline in NT-proBNP and in BNP was presented as a ratio where the ratio for NT-proBNP was calculated as the NT-proBNP value at 36 weeks over the NT-proBNP value at baseline, and the ratio for BNP was calculated as the BNP value at 36 weeks over the BNP value at baseline. A ratio \< 1 indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP) NT-proBNP (n=115,116)	0.78 ratio: endpoint/baseline (pg/mL) Interval 0.59 to 1.02	0.92 ratio: endpoint/baseline (pg/mL) Interval 0.7 to 1.21
Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP) BNP (n=116,113)	1.14 ratio: endpoint/baseline (pg/mL) Interval 0.88 to 1.47	0.95 ratio: endpoint/baseline (pg/mL) Interval 0.73 to 1.23

SECONDARY outcome

Timeframe: baseline, 36 weeks

Population: Participants from the extension efficacy set, who had both baseline and 36 week values, were included in the analysis for that parameter. The extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

Evaluation of cGMP was performed by a central laboratory. Change from baseline in cGMP was presented as a ratio where the ratio was calculated as the cGMP value at 36 weeks over the cGMP value at baseline. A ratio \< 1 indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=56 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=54 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP)	0.90 ratio: endpoint/baseline (nmol/L) Interval 0.78 to 1.03	0.85 ratio: endpoint/baseline (nmol/L) Interval 0.73 to 0.99

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension LVE diastolic diameter (n=98,107)	-0.23 cm Standard Error 0.051	-0.19 cm Standard Error 0.051
Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension LVE systolic diameter (n=98,107)	-0.12 cm Standard Error 0.044	-0.11 cm Standard Error 0.044
Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension Septal end diastolic thickness (n=98,106)	0.01 cm Standard Error 0.020	0.01 cm Standard Error 0.020
Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension Post. LV wall end diastolic thickness (n=99,107)	0.00 cm Standard Error 0.015	0.01 cm Standard Error 0.015
Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension Relative wall thickness (n=98,107)	0.02 cm Standard Error 0.008	0.02 cm Standard Error 0.008
Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension Left atrial dimension (n=99,108)	-0.21 cm Standard Error 0.043	-0.12 cm Standard Error 0.042

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume LVE diastolic volume (n=94,111)	-12.66 ml Standard Error 2.094	-14.31 ml Standard Error 2.027
Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume LVE systolic volume (n=95,111)	-8.49 ml Standard Error 1.251	-9.64 ml Standard Error 1.215
Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume LV stroke volume (n=94,111)	-4.34 ml Standard Error 1.448	-4.63 ml Standard Error 1.400
Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume Left atrial volume (n=96,112)	-8.08 ml Standard Error 2.133	-2.38 ml Standard Error 2.057

SECONDARY outcome

Timeframe: Baseline, 36 weeks

Population: Participants from the extension efficacy set, who had both baseline and 36 week values, were included in the analysis. The extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=94 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=111 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction	2.62 Percent ejection fraction Standard Error 0.778	2.90 Percent ejection fraction Standard Error 0.755

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=97 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=106 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: Left Ventricular Mass	-11.26 grams (g) Standard Error 4.145	-8.00 grams (g) Standard Error 4.106

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=91 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=100 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index	-3.95 g/m^2 Standard Error 2.249	-1.94 g/m^2 Standard Error 2.283

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=90 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=106 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index	-4.02 ml/m^2 Standard Error 1.260	-0.88 ml/m^2 Standard Error 1.237

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus E wave velocity (n=100,112)	-0.60 cm/s Standard Error 2.947	4.12 cm/s Standard Error 2.897
Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus A wave velocity (n=60,68)	-0.39 cm/s Standard Error 4.199	0.59 cm/s Standard Error 4.265
Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus e' at septal mitral annulus (n=79,98)	1.00 cm/s Standard Error 0.266	0.98 cm/s Standard Error 0.260
Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus e' at lateral mitral annulus (n=84,96)	0.71 cm/s Standard Error 0.307	0.95 cm/s Standard Error 0.296

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A ratio \< 1 indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio E to A velocity (n=60,68)	0.01 ratio Standard Error 0.080	0.07 ratio Standard Error 0.081
Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio E/e' (n=83,95)	-1.18 ratio Standard Error 0.561	-0.75 ratio Standard Error 0.543

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=35 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=42 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change in Echocardiography Parameters: Isovolumic Relaxation Time	0.01 ms Standard Error 0.002	0.01 ms Standard Error 0.002

SECONDARY outcome

Timeframe: Baseline, 36 weeks

A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=35 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=42 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity	-0.05 m/s Standard Error 0.081	0.00 m/s Standard Error 0.079

SECONDARY outcome

Timeframe: baseline, 36 weeks

Population: Participants from the extension efficacy set, who had both baseline and 36 week values for each domain, were included in the analysis for that domain. The extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

The KCCQ is a self-administered questionnaire. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and quality of life, each with different Likert scale wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A positive change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Physical limitation (n=117,114)	9.27 score on a scale Standard Error 2.528	9.88 score on a scale Standard Error 2.516
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Symptom stability (n=118,116)	6.43 score on a scale Standard Error 3.171	7.94 score on a scale Standard Error 3.167
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Symptom frequency (n=118,116)	10.38 score on a scale Standard Error 2.582	9.16 score on a scale Standard Error 2.577
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Symptom burden (n=118,116)	9.23 score on a scale Standard Error 2.528	9.45 score on a scale Standard Error 2.527
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Total symptom score (n=118,116)	9.83 score on a scale Standard Error 2.386	9.32 score on a scale Standard Error 2.384
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Self efficacy (n=118,116)	11.24 score on a scale Standard Error 2.427	8.77 score on a scale Standard Error 2.419
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Quality of life (n=118,116)	13.13 score on a scale Standard Error 2.706	12.50 score on a scale Standard Error 2.702
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Social limitation (n=113,107)	9.99 score on a scale Standard Error 2.878	11.04 score on a scale Standard Error 2.936
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores Overall summary score (n=118,116)	11.25 score on a scale Standard Error 2.185	11.31 score on a scale Standard Error 2.183

SECONDARY outcome

Timeframe: 36 weeks

Population: Extension efficacy set: the extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

The clinical composite assessment is defined as follows: Improved = a) participant improved (markedly or moderately) in the global assessment of disease activity with no worsening of NYHA functional class and no major adverse cardiovascular event or b) participant improved in NYHA functional class with no worsening (markedly or moderately) in the global assessment of disease activity and no major adverse cardiovascular event. Worsened = participant worsened (markedly or moderately) in the global assessment of disease activity or in NYHA functional class or experienced a major adverse cardiovascular event. Unchanged = participant does not meet the definition for improved or worsened.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened Improved	41.7 Percentage of participants	32.8 Percentage of participants
Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened Unchanged	45.7 Percentage of participants	53.6 Percentage of participants
Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened Worsened	12.6 Percentage of participants	13.6 Percentage of participants

SECONDARY outcome

Timeframe: baseline, 36 weeks

Population: Extension efficacy set: the extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

The NYHA Functional Classification classifies patients' heart failure according to the severity of their symptoms. The classification is as follows: Class I: no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath); Class II: slight limitation to physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation or dyspnea; Class III: marked limitation of physical activity, comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea; Class IV: unable to carry on any physical activity without discomfort, symptoms of heart failure at rest, if any physical activity is undertaken, discomfort increases.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Baseline, Class I	0.8 Percentage of participants	0.8 Percentage of participants
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Baseline, Class II	78.7 Percentage of participants	81.6 Percentage of participants
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Baseline, Class III	20.5 Percentage of participants	17.6 Percentage of participants
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Baseline, Class IV	0 Percentage of participants	0 Percentage of participants
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Week 36, Class I	12.6 Percentage of participants	7.2 Percentage of participants
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Week 36, Class II	74.0 Percentage of participants	78.4 Percentage of participants
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Week 36, Class III	13.4 Percentage of participants	14.4 Percentage of participants
Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV Week 36, Class IV	0 Percentage of participants	0 Percentage of participants

SECONDARY outcome

Timeframe: baseline, 36 weeks

eGFR was calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=126 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=123 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)	-3.68 mL/min/1.73m^2 Standard Error 1.493	-7.14 mL/min/1.73m^2 Standard Error 1.517

SECONDARY outcome

Timeframe: baseline, 36 weeks

Population: Extension efficacy set: the extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

Evaluation of serum creatinine was performed by central laboratory. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Serum Creatinine	5.82 µmol/L Standard Error 2.136	10.65 µmol/L Standard Error 2.183

SECONDARY outcome

Timeframe: baseline, 36 weeks

Evaluation of albumin/creatinine was performed by central laboratory. A ratio \< 1 indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=100 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=101 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Albumin/Creatinine Ratio	1.19 ratio Interval 0.85 to 1.66	0.74 ratio Interval 0.52 to 1.06

SECONDARY outcome

Timeframe: baseline, 36 weeks

Population: Participants from the arterial stiffness set, who had values for both baseline and week 36, were analyzed. The arterial stiffness set included randomized participants who participated in the arterial stiffness sub-study.

A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=86 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=94 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure Brachial SBP(n=36,44)	-1.27 mmHg Standard Error 3.935	1.47 mmHg Standard Error 3.670
Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure Brachial DBP (n=36,44)	1.68 mmHg Standard Error 2.279	0.79 mmHg Standard Error 2.165
Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure Central augmentation pressure (n=36,44)	-0.21 mmHg Standard Error 1.824	-0.24 mmHg Standard Error 1.705
Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure Central pressure at T1-DP (n=36,44)	-1.92 mmHg Standard Error 2.071	0.02 mmHg Standard Error 1.941
Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure Central SBP (n=36,44)	-0.71 mmHg Standard Error 3.856	0.86 mmHg Standard Error 3.594
Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure Central DBP (n=36,44)	1.40 mmHg Standard Error 2.319	0.24 mmHg Standard Error 2.204
Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure Central mean pressure (n=36,44)	0.84 mmHg Standard Error 2.565	-0.13 mmHg Standard Error 2.436

SECONDARY outcome

Timeframe: baseline, 36 weeks

Outcome measures

Outcome measures
Measure	LCZ696 n=36 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=43 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Arterial Stiffness Parameters: Heart Rate Correct Cen Aug/Pulse Ht	-0.74 Percent Standard Error 2.392	-2.16 Percent Standard Error 2.250

SECONDARY outcome

Timeframe: baseline, 36 weeks

Outcome measures

Outcome measures
Measure	LCZ696 n=36 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=44 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Arterial Stiffness Parameters: Heart Rate	-0.64 bpm Standard Error 2.026	-1.32 bpm Standard Error 1.905

SECONDARY outcome

Timeframe: baseline, 36 weeks

Outcome measures

Outcome measures
Measure	LCZ696 n=32 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=42 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Arterial Stiffness Parameters: Pulse Wave Velocity	-0.44 cm/s Standard Error 0.731	-0.74 cm/s Standard Error 0.631

SECONDARY outcome

Timeframe: baseline, 36 weeks

Population: Extension efficacy set: The extension efficacy set included all randomized participants who had baseline and at least one post-baseline efficacy measurement during the extension period.

Sitting blood pressure and sitting pulse pressure were assessed. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	LCZ696 n=125 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=127 Participants During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP) mean SBP	-7.47 mmHg Standard Error 1.909	-2.18 mmHg Standard Error 1.936
Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP) mean DBP	-5.28 mmHg Standard Error 1.188	-1.39 mmHg Standard Error 1.204
Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP) Pulse pressure	-2.24 mmHg Standard Error 1.482	-1.17 mmHg Standard Error 1.497

Adverse Events

LCZ696

Serious events: 22 serious events

Other events: 79 other events

Deaths: 0 deaths

Valsartan

Serious events: 30 serious events

Other events: 92 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	LCZ696 n=149 participants at risk During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=152 participants at risk During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Blood and lymphatic system disorders Anaemia	1.3% 2/149	0.66% 1/152
Cardiac disorders Acute myocardial infarction	0.67% 1/149	0.00% 0/152
Cardiac disorders Angina pectoris	0.67% 1/149	1.3% 2/152
Cardiac disorders Angina unstable	2.0% 3/149	0.66% 1/152
Cardiac disorders Atrial fibrillation	0.67% 1/149	0.66% 1/152
Cardiac disorders Atrioventricular block complete	0.00% 0/149	0.66% 1/152
Cardiac disorders Bradyarrhythmia	0.67% 1/149	0.00% 0/152
Cardiac disorders Bradycardia	0.67% 1/149	0.00% 0/152
Cardiac disorders Cardiac failure	2.0% 3/149	1.3% 2/152
Cardiac disorders Cardiac failure acute	0.67% 1/149	2.0% 3/152
Cardiac disorders Cardiac failure congestive	0.00% 0/149	0.66% 1/152
Cardiac disorders Cardio-respiratory arrest	0.00% 0/149	0.66% 1/152
Cardiac disorders Cardiogenic shock	0.00% 0/149	0.66% 1/152
Cardiac disorders Coronary artery stenosis	0.00% 0/149	0.66% 1/152
Cardiac disorders Myocardial infarction	0.67% 1/149	0.00% 0/152
Cardiac disorders Palpitations	0.67% 1/149	0.00% 0/152
Cardiac disorders Sick sinus syndrome	0.00% 0/149	0.66% 1/152
Cardiac disorders Tachyarrhythmia	0.00% 0/149	0.66% 1/152
Ear and labyrinth disorders Vertigo	0.67% 1/149	0.00% 0/152
Gastrointestinal disorders Ascites	0.67% 1/149	0.00% 0/152
Gastrointestinal disorders Diarrhoea	0.67% 1/149	0.00% 0/152
Gastrointestinal disorders Diarrhoea haemorrhagic	0.00% 0/149	0.66% 1/152
Gastrointestinal disorders Duodenal ulcer	0.67% 1/149	0.00% 0/152
Gastrointestinal disorders Gastric haemorrhage	0.00% 0/149	1.3% 2/152
Gastrointestinal disorders Gastritis	0.00% 0/149	0.66% 1/152
Gastrointestinal disorders Gastritis erosive	0.00% 0/149	0.66% 1/152
Gastrointestinal disorders Ileus	0.00% 0/149	0.66% 1/152
Gastrointestinal disorders Melaena	0.00% 0/149	0.66% 1/152
General disorders Asthenia	1.3% 2/149	0.00% 0/152
General disorders Chest discomfort	0.67% 1/149	0.00% 0/152
General disorders Device malfunction	0.00% 0/149	0.66% 1/152
General disorders Non-cardiac chest pain	0.67% 1/149	0.66% 1/152
General disorders Oedema peripheral	0.67% 1/149	0.00% 0/152
General disorders Pyrexia	0.00% 0/149	1.3% 2/152
Hepatobiliary disorders Cholelithiasis	0.67% 1/149	0.00% 0/152
Infections and infestations Appendicitis	0.00% 0/149	0.66% 1/152
Infections and infestations Bacterial sepsis	0.00% 0/149	0.66% 1/152
Infections and infestations Bronchitis	0.00% 0/149	0.66% 1/152
Infections and infestations Endocarditis	0.67% 1/149	0.00% 0/152
Infections and infestations Gastroenteritis	0.67% 1/149	0.00% 0/152
Infections and infestations Pneumonia	0.67% 1/149	0.66% 1/152
Infections and infestations Postoperative wound infection	0.67% 1/149	0.00% 0/152
Infections and infestations Sepsis	0.00% 0/149	0.66% 1/152
Infections and infestations Urinary tract infection	0.00% 0/149	1.3% 2/152
Injury, poisoning and procedural complications Humerus fracture	0.67% 1/149	0.00% 0/152
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/149	0.66% 1/152
Injury, poisoning and procedural complications Spinal fracture	0.67% 1/149	0.00% 0/152
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.00% 0/149	0.66% 1/152
Metabolism and nutrition disorders Hyperglycaemia	0.67% 1/149	0.00% 0/152
Metabolism and nutrition disorders Hyperkalaemia	1.3% 2/149	0.66% 1/152
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/149	0.66% 1/152
Musculoskeletal and connective tissue disorders Muscular weakness	0.67% 1/149	0.00% 0/152
Musculoskeletal and connective tissue disorders Osteoarthritis	0.67% 1/149	0.00% 0/152
Musculoskeletal and connective tissue disorders Osteonecrosis	0.00% 0/149	0.66% 1/152
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adrenal carcinoma	0.00% 0/149	0.66% 1/152
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.67% 1/149	0.00% 0/152
Nervous system disorders Carotid artery stenosis	0.00% 0/149	0.66% 1/152
Nervous system disorders Cerebrovascular insufficiency	0.00% 0/149	0.66% 1/152
Nervous system disorders Syncope	0.00% 0/149	0.66% 1/152
Nervous system disorders Transient ischaemic attack	0.00% 0/149	0.66% 1/152
Renal and urinary disorders Hyperuricosuria	0.00% 0/149	0.66% 1/152
Renal and urinary disorders Renal colic	0.00% 0/149	0.66% 1/152
Renal and urinary disorders Renal failure	0.00% 0/149	0.66% 1/152
Renal and urinary disorders Renal failure acute	1.3% 2/149	0.66% 1/152
Renal and urinary disorders Urinary retention	0.67% 1/149	0.00% 0/152
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.00% 0/149	0.66% 1/152
Respiratory, thoracic and mediastinal disorders Bronchiectasis	0.67% 1/149	0.00% 0/152
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.3% 2/149	2.6% 4/152
Respiratory, thoracic and mediastinal disorders Productive cough	0.00% 0/149	2.0% 3/152
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/149	0.66% 1/152
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/149	1.3% 2/152
Skin and subcutaneous tissue disorders Angioedema	0.67% 1/149	0.00% 0/152
Vascular disorders Arterial thrombosis limb	0.00% 0/149	0.66% 1/152
Vascular disorders Femoral arterial stenosis	0.00% 0/149	0.66% 1/152
Vascular disorders Hypotension	1.3% 2/149	0.66% 1/152
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/149	0.66% 1/152
Vascular disorders Peripheral embolism	0.00% 0/149	0.66% 1/152

Other adverse events

Other adverse events
Measure	LCZ696 n=149 participants at risk During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.	Valsartan n=152 participants at risk During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Blood and lymphatic system disorders Anaemia	1.3% 2/149	3.3% 5/152
Cardiac disorders Angina pectoris	2.7% 4/149	1.3% 2/152
Cardiac disorders Atrial fibrillation	1.3% 2/149	5.3% 8/152
Cardiac disorders Bradycardia	0.00% 0/149	2.6% 4/152
Cardiac disorders Cardiac failure	2.0% 3/149	2.6% 4/152
Cardiac disorders Cardiac failure chronic	0.67% 1/149	2.6% 4/152
Cardiac disorders Palpitations	3.4% 5/149	3.3% 5/152
Ear and labyrinth disorders Vertigo	3.4% 5/149	0.66% 1/152
Eye disorders Cataract	2.0% 3/149	0.66% 1/152
Gastrointestinal disorders Abdominal pain	2.0% 3/149	2.0% 3/152
Gastrointestinal disorders Constipation	1.3% 2/149	3.3% 5/152
Gastrointestinal disorders Diarrhoea	6.0% 9/149	2.6% 4/152
Gastrointestinal disorders Dyspepsia	2.7% 4/149	1.3% 2/152
Gastrointestinal disorders Nausea	2.0% 3/149	2.6% 4/152
General disorders Asthenia	4.7% 7/149	6.6% 10/152
General disorders Fatigue	2.0% 3/149	3.9% 6/152
General disorders Non-cardiac chest pain	2.0% 3/149	0.00% 0/152
General disorders Oedema peripheral	2.7% 4/149	5.9% 9/152
General disorders Pyrexia	2.7% 4/149	0.00% 0/152
Infections and infestations Bronchitis	4.0% 6/149	1.3% 2/152
Infections and infestations Gastroenteritis	2.7% 4/149	0.66% 1/152
Infections and infestations Influenza	2.7% 4/149	3.3% 5/152
Infections and infestations Nasopharyngitis	2.0% 3/149	3.3% 5/152
Infections and infestations Respiratory tract infection	0.67% 1/149	2.6% 4/152
Infections and infestations Upper respiratory tract infection	2.0% 3/149	0.66% 1/152
Infections and infestations Urinary tract infection	4.0% 6/149	5.9% 9/152
Metabolism and nutrition disorders Dyslipidaemia	2.0% 3/149	0.00% 0/152
Metabolism and nutrition disorders Gout	0.00% 0/149	2.6% 4/152
Metabolism and nutrition disorders Hyperkalaemia	6.7% 10/149	5.3% 8/152
Metabolism and nutrition disorders Hypokalaemia	2.0% 3/149	0.66% 1/152
Musculoskeletal and connective tissue disorders Arthralgia	3.4% 5/149	1.3% 2/152
Musculoskeletal and connective tissue disorders Back pain	3.4% 5/149	2.6% 4/152
Musculoskeletal and connective tissue disorders Pain in extremity	3.4% 5/149	1.3% 2/152
Nervous system disorders Dizziness	7.4% 11/149	4.6% 7/152
Nervous system disorders Headache	2.0% 3/149	2.6% 4/152
Psychiatric disorders Insomnia	0.67% 1/149	2.6% 4/152
Renal and urinary disorders Renal impairment	0.67% 1/149	3.3% 5/152
Respiratory, thoracic and mediastinal disorders Cough	6.0% 9/149	5.3% 8/152
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.7% 4/149	7.2% 11/152
Skin and subcutaneous tissue disorders Pruritus	1.3% 2/149	3.3% 5/152
Vascular disorders Hypertension	2.0% 3/149	3.9% 6/152
Vascular disorders Hypotension	12.8% 19/149	9.2% 14/152
Vascular disorders Orthostatic hypotension	1.3% 2/149	3.3% 5/152

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER