Trial Outcomes & Findings for Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode. (NCT NCT02554890)

Last Updated: 2021-01-05

Results Overview

To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction \[LVEF\] ≤ 40%) between week 4 and 8. Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

887 participants

Primary outcome timeframe

Baseline, Week 4 and Week 8

Results posted on

2021-01-05

Participant Flow

A total of 964 patients were screened for the study. Of these, 887 patients were randomized, 444 to enalapril and 443 to sacubitril/valsartan, and 875 randomized patients were treated.

Patients were randomized 1:1 to sacubitril/valsartan or enalapril. At the end of the 8-week treatment period, all patients had a 36-hour washout from study treatment prior to starting the open-label extension to ensure that the blinding of the core study was maintained.

Participant milestones

Participant milestones
Measure	Enalapril Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Double-blind STARTED	444	443
Double-blind Treated Patients	436	439
Double-blind COMPLETED	348	352
Double-blind NOT COMPLETED	96	91
Open-label STARTED	0	887
Open-label COMPLETED	0	835
Open-label NOT COMPLETED	0	52

Reasons for withdrawal

Reasons for withdrawal
Measure	Enalapril Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Double-blind Adverse Event	45	51
Double-blind Death	6	4
Double-blind Protocol Violation	1	1
Double-blind Physician Decision	4	3
Double-blind Subject/Guardian decision	21	16
Double-blind Lost to Follow-up	7	5
Double-blind Technical problems	1	0
Double-blind Withdrawal by Subject	5	6
Double-blind Noncompliance with study treatment	6	5
Open-label Adverse Event	0	30
Open-label Death	0	1
Open-label Physician Decision	0	1
Open-label Subject/Guardian decision	0	11
Open-label Lost to Follow-up	0	7
Open-label Technical problems	0	1
Open-label Withdrawal by Subject	0	1

Baseline Characteristics

Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).	Total n=881 Participants Total of all reporting groups
Age, Customized <65 years	232 Participants n=5 Participants	253 Participants n=7 Participants	485 Participants n=5 Participants
Age, Customized ≥65 years	209 Participants n=5 Participants	187 Participants n=7 Participants	396 Participants n=5 Participants
Age, Customized < 75 years	363 Participants n=5 Participants	370 Participants n=7 Participants	733 Participants n=5 Participants
Age, Customized ≥75 years	78 Participants n=5 Participants	70 Participants n=7 Participants	148 Participants n=5 Participants
Sex: Female, Male Female	133 Participants n=5 Participants	113 Participants n=7 Participants	246 Participants n=5 Participants
Sex: Female, Male Male	308 Participants n=5 Participants	327 Participants n=7 Participants	635 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	41 Participants n=5 Participants	34 Participants n=7 Participants	75 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	399 Participants n=5 Participants	405 Participants n=7 Participants	804 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 4 and Week 8

Population: Full analysis set (FAS): consisted of all randomized patients with the exception for those patients who had not been qualified for randomization and had not received study treatment, but had been inadvertently randomized into the study.

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline	0.7466 pg/ml Interval 0.6842 to 0.8147	0.5333 pg/ml Interval 0.489 to 0.5816

SECONDARY outcome

Timeframe: 8 weeks of treatment

Population: FAS

Examine the effect of LCZ696 vs. enalapril on incidence of symptomatic hypotension during 8 weeks of treatment Hypotension is low blood pressure. Patients with hypotension may experience symptoms when their blood pressure drops, compared to the patient's normal values. Symptoms of hypotension can include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache.

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Number of Patients With Incidences of Symptomatic Hypotension	56 participants	66 participants

SECONDARY outcome

Timeframe: 8 weeks of treatment

Population: FAS

Hyperkalemia is defined as Potassium level \>5.5 mEq/L. Hyperkalemia is the medical term that describes a potassium level in your blood that's higher than normal. Potassium is a chemical that is critical to the function of nerve and muscle cells, including those in your heart.

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Number of Patients With Incidences of Hyperkalemia	41 Participants	51 Participants

SECONDARY outcome

Timeframe: 8 weeks of treatment

Population: FAS

Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines. Severe cases may be associated with difficulty in breathing.

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Number of Patients With Incidences of Angioedema	11 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline, Week 4/Week 8

Population: FAS

time-averaged (Weeks 4 and 8) change from baseline in hs-troponin T. hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions.

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Change From Baseline in High Sensitivity Troponin (Hs-Troponin)	0.7477 Ratio Interval 0.6979 to 0.801	0.6345 Ratio Interval 0.592 to 0.6801

SECONDARY outcome

Timeframe: Baseline, Week 4 and Week 8

Population: FAS

Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP. Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide)

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Change From Baseline in Urinary cGMP	0.9641 Ratio Interval 0.8832 to 1.0524	1.5895 Ratio Interval 1.4554 to 1.7359

SECONDARY outcome

Timeframe: Baseline, Week 4 and Week 8

Population: FAS

Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP to urinary creatinine ratio. Urinary cGMP to urinary creatinine ratio is how much urinary cGMP (which reflects natriuretic peptide activity) compared to a compound in the urine called creatinine (which helps your doctor evaluate how well your kidneys are functioning).

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio	0.8258 Ratio Interval 0.787 to 0.8665	1.1714 Ratio Interval 1.116 to 1.2296

SECONDARY outcome

Timeframe: baseline, Week 4 and Week 8

Population: FAS

Time-averaged (Weeks 4 and 8) change from baseline in BNP to NT-proBNP ratio. BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
Change From Baseline in BNP to NTproBNP Ratio	0.9174 Ratio Interval 0.8728 to 0.9642	1.3527 Ratio Interval 1.2882 to 1.4204

SECONDARY outcome

Timeframe: Baseline, Week 8

BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure. Plasma NT-proBNP (pg/mL) values were Week 8 visit.

Outcome measures

Outcome measures
Measure	Enalapril n=441 Participants Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)	Sacubitril/Valsartan (LCZ696) n=440 Participants Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8	0.6443 pg/ml Interval 0.5815 to 0.741	0.4596 pg/ml Interval 0.415 to 0.5089

Adverse Events

Double Blind Phase Enalapril

Serious events: 132 serious events

Other events: 139 other events

Deaths: 15 deaths

Double Blind Phase Sacubitril/Valsartan

Serious events: 117 serious events

Other events: 153 other events

Deaths: 10 deaths

Open-Label Phase Sacubitril/Valsartan

Serious events: 104 serious events

Other events: 65 other events

Deaths: 6 deaths

Pooled Phase Sacubitril/Valsartan

Serious events: 191 serious events

Other events: 199 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Double Blind Phase Enalapril n=436 participants at risk Patients who received Enalapril in the double-blind phase.	Double Blind Phase Sacubitril/Valsartan n=439 participants at risk Patients who received Sacubitril/Valsartan in the double-blind phase.	Open-Label Phase Sacubitril/Valsartan n=828 participants at risk All patients who received sacubitril/valsartan in the open-label phase.	Pooled Phase Sacubitril/Valsartan n=851 participants at risk All patients who received a dose of sacubitril/valsartan either in the double-blind phase or open-label phase.
Investigations Blood creatinine increased	4.4% 19/436 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	6.8% 30/439 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	0.85% 7/828 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	4.2% 36/851 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.
Metabolism and nutrition disorders Hyperkalaemia	8.9% 39/436 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	10.7% 47/439 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	1.3% 11/828 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	6.7% 57/851 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.
Nervous system disorders Dizziness	7.6% 33/436 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	8.7% 38/439 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	2.1% 17/828 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	6.5% 55/851 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.
Renal and urinary disorders Acute kidney injury	5.3% 23/436 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	5.2% 23/439 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	0.36% 3/828 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	2.8% 24/851 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.
Vascular disorders Hypotension	14.9% 65/436 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	16.2% 71/439 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	4.0% 33/828 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.	11.4% 97/851 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 85 days. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 85 days. Data reported on the safety population.

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