Trial Outcomes & Findings for Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients (NCT NCT01922089)

NCT ID: NCT01922089

Last Updated: 2015-10-15

Results Overview

Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving \> 160 mg of valsartan or \> 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 498 participants
• Primary outcome timeframe: 12 weeks
• Results posted on: 2015-10-15

Participant Flow

Participant milestones

Measure	LCZ696 Condensed Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative Up-titration to LCZ696 200 mg bid over 6 weeks
Overall Study STARTED	247	251
Overall Study Safety Set	246	251
Overall Study COMPLETED	208	221
Overall Study NOT COMPLETED	39	30

Reasons for withdrawal

Measure	LCZ696 Condensed Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative Up-titration to LCZ696 200 mg bid over 6 weeks
Overall Study Adverse Event	18	13
Overall Study Protocol Deviation	10	7
Overall Study Withdrawal by Subject	3	4
Overall Study administrative problems	4	1
Overall Study Physician Decision	2	3
Overall Study Death	2	1
Overall Study Lost to Follow-up	0	1

Baseline Characteristics

Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients

Baseline characteristics by cohort

Measure	LCZ696 Condensed n=247 Participants Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative n=251 Participants Up-titration to LCZ696 200 mg bid over 6 weeks	Total n=498 Participants Total of all reporting groups
Age, Continuous	64.2 years STANDARD_DEVIATION 11.86 • n=5 Participants	63.8 years STANDARD_DEVIATION 10.94 • n=7 Participants	64.0 years STANDARD_DEVIATION 11.39 • n=5 Participants
Sex: Female, Male Female	56 Participants n=5 Participants	50 Participants n=7 Participants	106 Participants n=5 Participants
Sex: Female, Male Male	191 Participants n=5 Participants	201 Participants n=7 Participants	392 Participants n=5 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: Full Analysis Set (FAS) consisted of all randomized patients with the exception of mis-randomized patients who had not received the study drug, but had been inadvertently randomized into the study. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)

Outcome measures

Measure	LCZ696 Condensed n=247 Participants Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative n=251 Participants Up-titration to LCZ696 200 mg bid over 6 weeks
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Angioedema Low RAAS (n=127, 124)	0 participants	1 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Angioedema ALL	0 participants	2 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Hypotension High RAAS (n=120, 127)	5 participants	7 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Hypotension Low RAAS (n=127, 124)	19 participants	14 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Hypotension ALL	24 participants	21 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Renal Dysfunction High RAAS (n=120, 127)	5 participants	9 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Renal Dysfunction Low RAAS (n=127, 124)	13 participants	10 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Renal Dysfunction ALL	18 participants	19 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Hyperkalemia High RAAS (n=120, 127)	8 participants	5 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Hyperkalemia Low RAAS (n=127, 124)	11 participants	6 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Hyperkalemia ALL	19 participants	11 participants
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Angioedema High RAAS (n=120, 127)	0 participants	1 participants

SECONDARY outcome

Timeframe: 12 weeks

Population: Evaluable patients in FAS with the exception of misrandomized patients who didn't received drug, but had been randomized into the study, excluding patients who discontinued the study prior to completion of 12 wks. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Treatment success was defined as the number of participants who achieved and maintained LCZ696 200 mg bid without any dose interruption or down-titration over 12 weeks and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)

Outcome measures

Measure	LCZ696 Condensed n=230 Participants Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative n=236 Participants Up-titration to LCZ696 200 mg bid over 6 weeks
Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) High RAAS (n=109,117)	90 participants	98 participants
Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) Low RAAS (n=121,119)	89 participants	101 participants
Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) ALL (n=230,236)	179 participants	199 participants

SECONDARY outcome

Timeframe: 12 weeks

Population: Evaluable patients in FAS with the exception of misrandomized patients who didn't received drug, but had been randomized into the study, excluding patients who discontinued the study prior to completion of 12 wks. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Tolerability was assessed as the number of participants who achieved LCZ696 200 mg bid and maintained this dose for at least 2 weeks before study completion, regardless of previous dose interruption or down-titration and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)

Outcome measures

Measure	LCZ696 Condensed n=230 Participants Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative n=236 Participants Up-titration to LCZ696 200 mg bid over 6 weeks
Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). High RAAS (n=109,117)	94 participants	103 participants
Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). Low RAAS (n=121,119)	97 participants	103 participants
Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). ALL (n=230,236)	191 participants	206 participants

Adverse Events

LCZ696 Condensed

Serious events: 21 serious events

Other events: 72 other events

Deaths: 0 deaths

LCZ696 Conservative

Serious events: 14 serious events

Other events: 52 other events

Deaths: 0 deaths

Serious adverse events

Measure	LCZ696 Condensed n=246 participants at risk Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative n=251 participants at risk Up-titration to LCZ696 200 mg bid over 6 weeks
Cardiac disorders Acute myocardial infarction	0.81% 2/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Atrial fibrillation	0.81% 2/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Cardiac failure	1.2% 3/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.80% 2/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Cardiac failure acute	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Cardiac failure chronic	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Cardiac failure congestive	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Cardiac ventricular thrombosis	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Cardiogenic shock	1.2% 3/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Coronary artery disease	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Coronary artery stenosis	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Myocardial infarction	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Tachycardia	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Ventricular fibrillation	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Cardiac disorders Ventricular tachycardia	0.81% 2/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Gastrointestinal disorders Gastritis	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
General disorders Cardiac death	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
General disorders Non-cardiac chest pain	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
General disorders Pyrexia	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Hepatobiliary disorders Hepatic cyst	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Infections and infestations Gastrointestinal infection	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Infections and infestations Infected skin ulcer	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Infections and infestations Pneumonia	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Infections and infestations Staphylococcal sepsis	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Injury, poisoning and procedural complications Ankle fracture	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Injury, poisoning and procedural complications Procedural complication	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Investigations International normalised ratio increased	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Nervous system disorders Cerebrovascular accident	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Nervous system disorders Dizziness	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Nervous system disorders Syncope	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Renal and urinary disorders Renal failure	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Renal and urinary disorders Renal failure acute	0.81% 2/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Renal and urinary disorders Renal failure chronic	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Reproductive system and breast disorders Postmenopausal haemorrhage	0.41% 1/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.00% 0/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Vascular disorders Hypotension	0.00% 0/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.

Other adverse events

Measure	LCZ696 Condensed n=246 participants at risk Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	LCZ696 Conservative n=251 participants at risk Up-titration to LCZ696 200 mg bid over 6 weeks
Cardiac disorders Cardiac failure	2.4% 6/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.40% 1/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Ear and labyrinth disorders Vertigo	2.8% 7/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	1.2% 3/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Infections and infestations Nasopharyngitis	2.4% 6/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	1.2% 3/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Metabolism and nutrition disorders Hyperkalaemia	6.5% 16/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	4.4% 11/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Metabolism and nutrition disorders Hypokalaemia	2.4% 6/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.80% 2/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Musculoskeletal and connective tissue disorders Back pain	2.0% 5/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	0.80% 2/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Nervous system disorders Dizziness	3.3% 8/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	2.4% 6/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Renal and urinary disorders Renal failure	0.81% 2/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	2.8% 7/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Renal and urinary disorders Renal impairment	4.1% 10/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	1.6% 4/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Respiratory, thoracic and mediastinal disorders Cough	0.81% 2/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	2.4% 6/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Vascular disorders Hypotension	9.8% 24/246 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.	8.4% 21/251 Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

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

Restriction type: OTHER