Trial Outcomes & Findings for A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients (NCT NCT03066804)

Last Updated: 2021-10-11

Results Overview

To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2572 participants

Primary outcome timeframe

Baseline, week 12

Results posted on

2021-10-11

Participant Flow

A total of 2572 participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan or Individualized Medical Therapy (IMT).

Participant milestones

Participant milestones
Measure	Sacubitril/Valsartan (LCZ696) All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Overall Study STARTED	1286	1286
Overall Study COMPLETED	1235	1236
Overall Study NOT COMPLETED	51	50

Reasons for withdrawal

Reasons for withdrawal
Measure	Sacubitril/Valsartan (LCZ696) All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Overall Study Physician Decision	0	4
Overall Study Death	23	17
Overall Study Withdrawal by Subject	19	25
Overall Study Lost to Follow-up	2	0
Overall Study Adverse Event	2	3
Overall Study Technical problems	5	1

Baseline Characteristics

A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sacubitril/Valsartan (LCZ696) n=1281 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1285 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).	Total n=2566 Participants Total of all reporting groups
Age, Customized <65 years	196 Participants n=5 Participants	221 Participants n=7 Participants	417 Participants n=5 Participants
Age, Customized >=65 years	1085 Participants n=5 Participants	1064 Participants n=7 Participants	2149 Participants n=5 Participants
Sex: Female, Male Female	643 Participants n=5 Participants	658 Participants n=7 Participants	1301 Participants n=5 Participants
Sex: Female, Male Male	638 Participants n=5 Participants	627 Participants n=7 Participants	1265 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	1112 Participants n=5 Participants	1117 Participants n=7 Participants	2229 Participants n=5 Participants
Race/Ethnicity, Customized Black	11 Participants n=5 Participants	16 Participants n=7 Participants	27 Participants n=5 Participants
Race/Ethnicity, Customized Asian	56 Participants n=5 Participants	59 Participants n=7 Participants	115 Participants n=5 Participants
Race/Ethnicity, Customized Native American	39 Participants n=5 Participants	33 Participants n=7 Participants	72 Participants n=5 Participants
Race/Ethnicity, Customized Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Other	59 Participants n=5 Participants	56 Participants n=7 Participants	115 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, week 12

Population: Full Analysis Set: This outcome measure represents patients with non-missing change from baseline in log transformed NT-proBNP at Week 12. The model was fitting using change from baseline in log transformed NT-proBNP, and produced a difference in mean change from baseline in log transformed NT-proBNP, which was then transformed back to geometric mean ratio to baseline using an exponential transformation.

To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF

Outcome measures

Outcome measures
Measure	Sacubitril/Valsartan (LCZ696) n=1203 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1216 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12	0.8218 Ratio Interval 0.7955 to 0.8489	0.9828 Ratio Interval 0.9515 to 1.0151

PRIMARY outcome

Timeframe: Baseline, week 24

Population: Subset of Full Analysis Set: This outcome measure was analyzed on patients with a Baseline 6MWD from 100 meters to 450 meters.

Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002.

Outcome measures

Outcome measures
Measure	Sacubitril/Valsartan (LCZ696) n=1082 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1075 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24	9.6935 Meters Interval 5.431 to 13.9559	12.1920 Meters Interval 7.9202 to 16.4638

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.

The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

Outcome measures

Outcome measures
Measure	Sacubitril/Valsartan (LCZ696) n=1207 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1210 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24	12.3399 Scores on a scale Interval 11.3151 to 13.3647	11.8168 Scores on a scale Interval 10.7922 to 12.8415

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.

Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

Outcome measures

Outcome measures
Measure	Sacubitril/Valsartan (LCZ696) n=1207 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1210 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24	15.49 Percentage of participants	16.69 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.

Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

Outcome measures

Outcome measures
Measure	Sacubitril/Valsartan (LCZ696) n=1207 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1210 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24	67.94 Percentage of participants	65.70 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, week 24

Population: Full Analysis Set: This outcome measure represents patients with both a baseline NYHA class and NYHA class at the visit observed.

NYHA classification is a subjective physician's assessment of patient's functional capacity and symptomatic status and can change frequently over time. Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest The NYHA class change will be analyzed as a three category ordinal variable with levels: "improved", "unchanged", and "worsened", defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively.

Outcome measures

Outcome measures
Measure	Sacubitril/Valsartan (LCZ696) n=1228 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1229 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Change From Baseline in NYHA Functional Class at Week 24 Improved	23.62 Percentage of Participants	24.00 Percentage of Participants
Change From Baseline in NYHA Functional Class at Week 24 Unchanged	72.23 Percentage of Participants	71.68 Percentage of Participants
Change From Baseline in NYHA Functional Class at Week 24 Worsened	4.15 Percentage of Participants	4.31 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: Full Analysis Set: This outcome measure represents patients with non-missing change from baseline in SF-36 PCS at Week 24.

The SF-36 PCS score reflects the measure of quality of life based on the 36 questions which evaluate the person's physical, emotional, and mental status, including general health. Specifically, the SF-36 PCS score focuses on assessing the person's physical status. The score ranges from 0 to 100 with a higher score indicating a better status of physical wellbeing (range = 0 "worst"-100 "best").

Outcome measures

Outcome measures
Measure	Sacubitril/Valsartan (LCZ696) n=1185 Participants All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) Comparator n=1191 Participants Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24	2.5405 Scores on a scale Interval 2.0787 to 3.0023	2.6975 Scores on a scale Interval 2.236 to 3.159

Adverse Events

Sacubitril/Valsartan (LCZ696)

Serious events: 186 serious events

Other events: 964 other events

Deaths: 23 deaths

Individualized Medical Therapy (IMT)

Serious events: 191 serious events

Other events: 832 other events

Deaths: 17 deaths

Total

Serious events: 377 serious events

Other events: 1796 other events

Deaths: 40 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

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 (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Sacubitril/Valsartan (LCZ696) n=1280 participants at risk All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) n=1284 participants at risk Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).	Total n=2564 participants at risk Total
Blood and lymphatic system disorders Anaemia	0.16% 2/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.23% 3/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.20% 5/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Blood and lymphatic system disorders Febrile neutropenia	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Blood and lymphatic system disorders Lymphadenopathy	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Acute coronary syndrome	0.31% 4/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.20% 5/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Acute myocardial infarction	0.16% 2/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.31% 4/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.23% 6/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Angina pectoris	0.62% 8/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.62% 8/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.62% 16/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Angina unstable	0.47% 6/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.55% 7/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.51% 13/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Aortic valve disease	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Aortic valve incompetence	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Atrial fibrillation	1.0% 13/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.3% 17/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.2% 30/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Atrial flutter	0.31% 4/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.16% 2/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.23% 6/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Atrial tachycardia	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Atrioventricular block complete	0.16% 2/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.23% 3/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.20% 5/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Atrioventricular block second degree	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Bradycardia	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.16% 2/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.12% 3/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiac arrest	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 2/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiac failure	1.6% 21/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.4% 31/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.0% 52/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiac failure acute	0.23% 3/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.70% 9/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.47% 12/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiac failure chronic	0.16% 2/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.12% 3/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiac failure congestive	0.16% 2/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.55% 7/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.35% 9/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiac perforation	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiogenic shock	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cor pulmonale acute	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Coronary artery disease	0.31% 4/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.20% 5/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Dressler's syndrome	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Left ventricular failure	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 2/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Mitral valve incompetence	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 2/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Myocardial infarction	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.31% 4/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.20% 5/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Myocardial ischaemia	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 2/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Pericardial effusion	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Sinus arrest	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Sinus node dysfunction	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Supraventricular tachycardia	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Congenital, familial and genetic disorders Mitochondrial myopathy	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Ear and labyrinth disorders Vertigo	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Ear and labyrinth disorders Vertigo positional	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Ear and labyrinth disorders Vestibular ataxia	0.00% 0/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.08% 1/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Eye disorders Cataract	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.16% 2/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.12% 3/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Eye disorders Eye haemorrhage	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Eye disorders Iris neovascularisation	0.08% 1/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.00% 0/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.04% 1/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).

Other adverse events
Measure	Sacubitril/Valsartan (LCZ696) n=1280 participants at risk All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi.	Individualized Medical Therapy (IMT) n=1284 participants at risk Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).	Total n=2564 participants at risk Total
Investigations Urine albumin/creatinine ratio increased	12.3% 157/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	7.6% 97/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	9.9% 254/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Investigations Urine protein/creatinine ratio increased	5.2% 66/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	5.1% 65/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	5.1% 131/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Metabolism and nutrition disorders Hyperkalaemia	11.6% 148/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	10.7% 138/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	11.2% 286/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Musculoskeletal and connective tissue disorders Arthralgia	2.7% 35/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.6% 21/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.2% 56/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Musculoskeletal and connective tissue disorders Back pain	2.1% 27/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.0% 26/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.1% 53/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Nervous system disorders Dizziness	5.5% 70/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	4.9% 63/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	5.2% 133/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Nervous system disorders Headache	1.4% 18/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.3% 30/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.9% 48/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Renal and urinary disorders Haematuria	11.3% 145/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	8.1% 104/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	9.7% 249/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Renal and urinary disorders Microalbuminuria	2.0% 26/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.5% 19/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.8% 45/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Renal and urinary disorders Proteinuria	9.5% 121/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	6.5% 84/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	8.0% 205/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Renal and urinary disorders Renal failure	3.8% 49/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.0% 38/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.4% 87/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Renal and urinary disorders Renal impairment	11.6% 148/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	8.6% 110/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	10.1% 258/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Respiratory, thoracic and mediastinal disorders Cough	3.2% 41/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.9% 25/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.6% 66/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.7% 47/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.6% 46/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.6% 93/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Skin and subcutaneous tissue disorders Pruritus	2.1% 27/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.78% 10/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.4% 37/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Vascular disorders Hypertension	3.3% 42/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	6.3% 81/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	4.8% 123/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Vascular disorders Hypotension	13.8% 176/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	5.4% 69/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	9.6% 245/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Blood and lymphatic system disorders Anaemia	1.3% 17/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.2% 28/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.8% 45/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Atrial fibrillation	3.4% 44/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.3% 43/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.4% 87/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Cardiac disorders Cardiac failure	2.7% 34/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.3% 43/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.0% 77/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Gastrointestinal disorders Diarrhoea	3.4% 43/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.3% 42/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.3% 85/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
General disorders Fatigue	3.0% 38/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.6% 21/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.3% 59/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
General disorders Oedema peripheral	3.4% 43/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.7% 35/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.0% 78/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Infections and infestations Bronchitis	2.3% 29/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.7% 35/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.5% 64/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Infections and infestations Influenza	2.6% 33/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.8% 23/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.2% 56/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Infections and infestations Nasopharyngitis	2.7% 35/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	4.7% 60/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.7% 95/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Infections and infestations Urinary tract infection	3.8% 49/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	2.7% 35/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	3.3% 84/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Investigations Blood creatinine increased	2.1% 27/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.7% 22/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.9% 49/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Investigations Blood potassium increased	2.0% 26/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	0.78% 10/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	1.4% 36/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Investigations Glomerular filtration rate decreased	10.7% 137/1280 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	11.7% 150/1284 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).	11.2% 287/2564 • Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set \[2572\], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).