Trial Outcomes & Findings for Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (NCT NCT01920711)

NCT ID: NCT01920711

Last Updated: 2020-09-29

Results Overview

The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association \[NYHA\] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction \[LVEF\] ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

4822 participants

Primary outcome timeframe

Total follow up time (up to 57 months)

Results posted on

2020-09-29

Participant Flow

4822 patients were randomized at 755 sites in 43 countries. 2419 participants were randomized into the LCZ696 treatment group and 2403 were randomized into the valsartan treatment group.

Participant milestones

Participant milestones
Measure	LCZ696 Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Overall Study STARTED	2419	2403
Overall Study COMPLETED	2055	2030
Overall Study NOT COMPLETED	364	373

Reasons for withdrawal

Reasons for withdrawal
Measure	LCZ696 Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Overall Study Death	347	356
Overall Study Lost to Follow-up	13	14
Overall Study Withdrawal by Subject	4	3

Baseline Characteristics

Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCZ696 n=2419 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2403 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid	Total n=4822 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	415 Participants n=93 Participants	415 Participants n=4 Participants	830 Participants n=27 Participants
Age, Categorical >=65 years	2004 Participants n=93 Participants	1988 Participants n=4 Participants	3992 Participants n=27 Participants
Sex: Female, Male Female	1247 Participants n=93 Participants	1244 Participants n=4 Participants	2491 Participants n=27 Participants
Sex: Female, Male Male	1172 Participants n=93 Participants	1159 Participants n=4 Participants	2331 Participants n=27 Participants
Race/Ethnicity, Customized Caucasian	1975 Participants n=93 Participants	1958 Participants n=4 Participants	3933 Participants n=27 Participants
Race/Ethnicity, Customized Black	52 Participants n=93 Participants	50 Participants n=4 Participants	102 Participants n=27 Participants
Race/Ethnicity, Customized Asian	297 Participants n=93 Participants	310 Participants n=4 Participants	607 Participants n=27 Participants
Race/Ethnicity, Customized Native American	28 Participants n=93 Participants	23 Participants n=4 Participants	51 Participants n=27 Participants
Race/Ethnicity, Customized Pacific Islander	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized Other	67 Participants n=93 Participants	61 Participants n=4 Participants	128 Participants n=27 Participants

PRIMARY outcome

Timeframe: Total follow up time (up to 57 months)

Population: Full Analysis Set - This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

Outcome measures

Outcome measures
Measure	LCZ696 n=2407 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2389 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. Primary Composite Events	894 Events	1009 Events
Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. Total Hospitalizations for heart failure	690 Events	797 Events
Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. Cardiovascular death	204 Events	212 Events

SECONDARY outcome

Timeframe: Baseline, 8 months

Population: Full Analysis Set-This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

The KCCQ is a validated instrument for self-assessment of quality of life and health status in heart failure (HF) patients. The clinical summary score, which is derived from the physical limitations and heart failure (HF) symptoms domains of the KCCQ is a valid measure for assessing the patient's health aspects that may be influenced by CV medications. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. Evaluation of change from baseline to month 8 in KCCQ a most sensitive, specific, and responsive health-related quality of life measure for heart failure symptoms and physical limitations.

Outcome measures

Outcome measures
Measure	LCZ696 n=2407 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2389 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ)	-1.5073 Points on a scale Standard Error 0.3709	-2.5338 Points on a scale Standard Error 0.3729

SECONDARY outcome

Timeframe: Baseline, 8 months

Population: Full Analysis Set - This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints. However, this endpoint only includes those participants who had assessments completed for both Baseline and Month 8 visits; as that is the only way a change could be calculated and analyzed.

Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a heart failure's (HF) patients' level of functionality based on the signs and symptoms of HF exhibited by the patient.

Outcome measures

Outcome measures
Measure	LCZ696 n=2407 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2389 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class Improved (n=2316, 2302)	347 Number of Participants	289 Number of Participants
Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class Unchanged (n=2316, 2302)	1767 Number of Participants	1792 Number of Participants
Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class Worsened (n=2316, 2302)	202 Number of Participants	221 Number of Participants

SECONDARY outcome

Timeframe: Randomization to total follow-up time (up to 57 months)

Population: Full Analysis Set -This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

Analyis of composite renal endpoint defined as renal death, or reaching ESRD, or ≥50% decline in eGFR relative to baseline, using Cox's proportional hazards model.

Outcome measures

Outcome measures
Measure	LCZ696 n=2407 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2389 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
Participants With First Occurrence of a Composite Renal Endpoint Composite renal endpoint	33 Participants	64 Participants
Participants With First Occurrence of a Composite Renal Endpoint Renal Death	1 Participants	1 Participants
Participants With First Occurrence of a Composite Renal Endpoint Reaching ESRD	7 Participants	12 Participants
Participants With First Occurrence of a Composite Renal Endpoint >=50% decline in eGFR from baseline	27 Participants	60 Participants

SECONDARY outcome

Timeframe: Randomization to total follow up time (up to 57 months)

Population: Full Analysis Set -This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.

Analysis for all-cause mortality using Cox's proportional hazards model.

Outcome measures

Outcome measures
Measure	LCZ696 n=2407 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2389 Participants Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid
All-cause Mortality	342 Participants	349 Participants

Adverse Events

LCZ696

Serious events: 1424 serious events

Other events: 2005 other events

Deaths: 347 deaths

Valsartan

Serious events: 1416 serious events

Other events: 1995 other events

Deaths: 357 deaths

All Patients

Serious events: 2840 serious events

Other events: 4000 other events

Deaths: 704 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	LCZ696 n=2419 participants at risk Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2402 participants at risk Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid	All Patients n=4821 participants at risk Total patients
Cardiac disorders Arrhythmia	0.17% 4/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.17% 4/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.17% 8/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Acquired haemophilia	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Anaemia	2.8% 68/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.8% 67/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.8% 135/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Anaemia macrocytic	0.08% 2/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.06% 3/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Anaemia megaloblastic	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Anaemia vitamin B12 deficiency	0.08% 2/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 2/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Autoimmune haemolytic anaemia	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Blood loss anaemia	0.08% 2/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.29% 7/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.19% 9/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Coagulopathy	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.08% 2/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.06% 3/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Hypercoagulation	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Hypersplenism	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Immune thrombocytopenic purpura	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Iron deficiency anaemia	0.21% 5/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.25% 6/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.23% 11/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Leukocytosis	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.25% 6/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.15% 7/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Leukopenia	0.08% 2/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 2/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.08% 2/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 2/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Lymphadenopathy mediastinal	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Microcytic anaemia	0.12% 3/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.08% 4/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Nephrogenic anaemia	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Neutropenia	0.08% 2/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.06% 3/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Normochromic normocytic anaemia	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Pancytopenia	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.12% 3/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.08% 4/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Splenic infarction	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Splenitis	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Thrombocytopenia	0.25% 6/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.15% 7/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Thrombocytosis	0.04% 1/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.00% 0/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Acute coronary syndrome	0.45% 11/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.54% 13/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.50% 24/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Acute left ventricular failure	0.58% 14/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.62% 15/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.60% 29/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Acute myocardial infarction	2.5% 60/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.2% 54/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.4% 114/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Adams-Stokes syndrome	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Angina pectoris	1.7% 42/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.1% 50/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	1.9% 92/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Angina unstable	2.1% 50/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	1.8% 43/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	1.9% 93/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Aortic valve disease	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Aortic valve incompetence	0.08% 2/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.08% 2/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.08% 4/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Aortic valve stenosis	0.17% 4/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.12% 3/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.15% 7/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Arrhythmia supraventricular	0.00% 0/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.04% 1/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.02% 1/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Arteriosclerosis coronary artery	0.17% 4/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.17% 4/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	0.17% 8/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Atrial fibrillation	6.7% 162/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	6.0% 145/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	6.4% 307/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.

Other adverse events
Measure	LCZ696 n=2419 participants at risk Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid	Valsartan n=2402 participants at risk Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid	All Patients n=4821 participants at risk Total patients
Gastrointestinal disorders Diarrhoea	7.3% 177/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.5% 180/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.4% 357/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Blood and lymphatic system disorders Anaemia	6.9% 166/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	8.9% 214/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.9% 380/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Angina pectoris	3.6% 87/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.4% 82/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.5% 169/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Atrial fibrillation	10.3% 248/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	10.0% 239/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	10.1% 487/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Bradycardia	2.2% 53/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.5% 85/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.9% 138/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Cardiac failure	9.3% 225/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	11.2% 269/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	10.2% 494/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Cardiac disorders Palpitations	2.6% 62/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.3% 56/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.4% 118/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Ear and labyrinth disorders Vertigo	3.2% 77/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.5% 60/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.8% 137/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Eye disorders Cataract	3.5% 84/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.9% 70/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.2% 154/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Gastrointestinal disorders Abdominal pain	2.2% 53/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.2% 54/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.2% 107/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Gastrointestinal disorders Constipation	4.1% 100/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.6% 86/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.9% 186/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Gastrointestinal disorders Nausea	3.8% 93/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.6% 87/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.7% 180/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Gastrointestinal disorders Vomiting	2.9% 70/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.4% 58/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.7% 128/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
General disorders Asthenia	2.5% 60/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.4% 58/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.4% 118/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
General disorders Fatigue	4.1% 98/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.5% 107/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.3% 205/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
General disorders Non-cardiac chest pain	4.1% 98/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.8% 92/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.9% 190/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
General disorders Oedema peripheral	6.9% 166/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.6% 183/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.2% 349/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
General disorders Pyrexia	2.4% 59/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.2% 54/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.3% 113/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Bronchitis	7.3% 177/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	8.2% 197/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.8% 374/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Cellulitis	2.5% 61/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	1.7% 41/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.1% 102/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Influenza	4.5% 110/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.5% 109/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.5% 219/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Nasopharyngitis	8.6% 207/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.4% 177/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	8.0% 384/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Pneumonia	4.1% 100/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.0% 97/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.1% 197/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Respiratory tract infection	2.0% 48/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.5% 60/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.2% 108/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Upper respiratory tract infection	6.0% 145/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	5.8% 139/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	5.9% 284/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Infections and infestations Urinary tract infection	10.0% 243/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	11.2% 268/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	10.6% 511/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Injury, poisoning and procedural complications Contusion	2.4% 57/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.0% 72/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.7% 129/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Injury, poisoning and procedural complications Fall	4.4% 106/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.7% 90/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.1% 196/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Investigations Blood creatinine increased	2.6% 63/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.7% 65/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.7% 128/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Investigations Glomerular filtration rate decreased	3.5% 85/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.9% 93/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.7% 178/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Investigations Weight decreased	2.9% 71/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.4% 82/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.2% 153/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Metabolism and nutrition disorders Diabetes mellitus	2.1% 52/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.6% 62/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.4% 114/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Metabolism and nutrition disorders Gout	3.1% 76/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.7% 88/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.4% 164/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Metabolism and nutrition disorders Hyperkalaemia	9.8% 238/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	12.4% 298/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	11.1% 536/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Metabolism and nutrition disorders Hyperuricaemia	2.6% 62/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	3.1% 75/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.8% 137/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Metabolism and nutrition disorders Hypokalaemia	4.5% 110/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.2% 100/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	4.4% 210/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Musculoskeletal and connective tissue disorders Arthralgia	6.3% 152/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	6.4% 153/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	6.3% 305/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Musculoskeletal and connective tissue disorders Back pain	6.2% 149/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	7.1% 170/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	6.6% 319/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Musculoskeletal and connective tissue disorders Muscle spasms	1.5% 36/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.0% 49/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	1.8% 85/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	2.6% 63/2419 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.4% 58/2402 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.	2.5% 121/4821 • 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. 5 years. Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. Safety set included all randomized patients minus 1 patient who did not receive study drug: 4821 patients.