PARASAIL: Description of Tolerability of LCZ696 (Sacubitril / Valsartan) in Heart Failure With Reduced Ejection Fraction (HFrEF) Treated in Real Life Setting

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02690974
• Collaborator: (none)
• Enrollment: 302
• Locations: 32
• Arm: 1
• Actual Duration (Months): 20.7
• Patients Per Site: 9.4
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The primary purpose of the study was to describe the tolerability of treatment with the optimal dose of LCZ696 (97 mg sacubitril / 103 mg valsartan bid), over six (6) months, in patients with heart failure with reduced ejection fraction (HFrEF) in Canada.

The study was also to describe the overall tolerability, effectiveness and safety of LCZ696 for the management of HFrEF over 12 months of treatment, as well as describe the patterns of LCZ696 up and down dose titrations occurring during the management of patients with HFrEF.

Condition or Disease	Intervention/Treatment	Phase
Hearth Failure With Reduced Ejection Fraction (HFrEF)	Drug: LCZ696 (sacubitril/valsartan)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 302 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Prospective, Multi-center, Open lAbel, Post-appRovAl Study AImed at Characterizing the Use of LCZ696 at 97 mg Sacubitril / 103 mg Valsartan Bid in Patients With HFrEF
• Actual Study Start Date: Mar 8, 2016
• Actual Primary Completion Date: Jun 7, 2017
• Actual Study Completion Date: Nov 29, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: LCZ696 (sacubitril / valsartan) All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.	Drug: LCZ696 (sacubitril/valsartan); All patients were treated with the LCZ696 (sacubitril and valsartan) tablets

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants on LCZ696 200 mg Bid at Month 6 [Month 6]

   The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 6. Only descriptive analysis done.

Secondary Outcome Measures

1. Percentage of Participants on LCZ696 200 mg Bid at Month 12 [Month 12]

   The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 12. Only descriptive analysis done.

2. Percentage of Participants Requiring Down-titration From LCZ696 200 mg [Month 12]

   The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the percentage of patients on LCZ696 200mg requiring down-titration. Only descriptive analysis done.

3. Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment [Month 12]

   The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the number of down-titration during the 12 months treatment period. Dow-titration schemes considered for the analysis are 200 mg to 100 mg; 100 mg to 50 mg; and 50 mg to 0 mg (i.e. treatment discontinuation). The down-titration scheme of 50mg to 0 mg was taken in account in this analysis to ensure to reflect all actual changes in dose. Only descriptive analysis done.

4. Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12 [Baseline, Month 6 and Month 12]

   The impact of LCZ696 on functional exercise capacity was measured by the Six Minute Walk Test at 6 and 12 months. The 6MWT measures the distance an individual is able to walf over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. Only descriptive analysis done.

5. Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg [Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12]

   To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.

6. Median Time to Reach LCZ696 200 mg [Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12]

   To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.

7. Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time [Baseline, Month 6 and Month 12]

   To describe the adherence to guideline recommended dosing of beta-blockers and MRAs at 6 and 12 months of treatment of LCZ696. Only descriptive analysis done.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. Age ≥ 18 years and ≤ 80 years.

3. Males or females.

4. Diagnosis of Heart Failure NYHA class II-III.

5. Diagnosis of Heart Failure with reduced Ejection Fraction (LVEF =< 40%) and NYHA class II or III.

6. Stable on any dose of ACEI or ARB prior to enrolment in the study

7. Stable on any dose of a beta-blocker prior to enrolment in the study.

8. Eligible for treatment with LCZ696 as per Canadian product monograph.

9. Treated as an outpatient.

10. Signed an informed consent agreeing to participate in the study.

Key Exclusion Criteria:

1. Symptomatic hypotension and/or a SBP < 100 mmHg at baseline visit.

2. Estimated GFR < 30 mL/min/1.73m^2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at baseline visit.

3. Known history of angioedema related to previous ACEI or ARBs therapy, or history of hereditary or idiopathic angioedema.

4. Requirement of concomitant treatment with both ACEIs and ARBs.

5. Concurrent participation in other clinical trials or receiving other investigational drugs within 30 days of enrollment.

6. Hypersensitivity to the active substances, sacubitril or valsartan, or to any of the excipients.

7. Concomitant use of aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR <60ml/min/1.73m^2).

8. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.

9. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

11. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception methods are described in the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Edmonton	Alberta	Canada	T5H 3V9
2	Novartis Investigative Site	New Westminster	British Columbia	Canada	V3L 3W4
3	Novartis Investigative Site	Vancouver	British Columbia	Canada	V6Z 1Y6
4	Novartis Investigative Site	Winnipeg	Manitoba	Canada	R2H 2A6
5	Novartis Investigative Site	Moncton	New Brunswick	Canada	E1C 2Z3
6	Novartis Investigative Site	Moncton	New Brunswick	Canada	E1G 1A7
7	Novartis Investigative Site	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
8	Novartis Investigative Site	Burlington	Ontario	Canada	L7M 4Y1
9	Novartis Investigative Site	Cambridge	Ontario	Canada	N1R 6V6
10	Novartis Investigative Site	London	Ontario	Canada	N6A 5A5
11	Novartis Investigative Site	Mississauga	Ontario	Canada	L5K 2L3
12	Novartis Investigative Site	Newmarket	Ontario	Canada	L3Y 2P6
13	Novartis Investigative Site	Newmarket	Ontario	Canada	L3Y 8C3
14	Novartis Investigative Site	Ottawa	Ontario	Canada	K1Y 4W7
15	Novartis Investigative Site	Peterborough	Ontario	Canada	K9J 0B2
16	Novartis Investigative Site	Sarnia	Ontario	Canada	N7T 4X3
17	Novartis Investigative Site	Scarborough	Ontario	Canada	M1E 5E9
18	Novartis Investigative Site	Scarborough	Ontario	Canada	M1P 2V5
19	Novartis Investigative Site	Sudbury	Ontario	Canada	P3E 3B8
20	Novartis Investigative Site	Sudbury	Ontario	Canada	P3E 5M9
21	Novartis Investigative Site	Toronto	Ontario	Canada	M6R 1B5
22	Novartis Investigative Site	Waterloo	Ontario	Canada	N2T 0C1
23	Novartis Investigative Site	Weston	Ontario	Canada	M9N 1W4
24	Novartis Investigative Site	Greenfield Park	Quebec	Canada	J4V 2G8
25	Novartis Investigative Site	Joliette	Quebec	Canada	J6E 6J2
26	Novartis Investigative Site	Montreal	Quebec	Canada	H1T 3Y7
27	Novartis Investigative Site	St-Jean-sur-Richelieu	Quebec	Canada	J3A 1J2
28	Novartis Investigative Site	Terrebonne	Quebec	Canada	J6V 2H2
29	Novartis Investigative Site	Brossard		Canada	J4Z 2K9
30	Novartis Investigative Site	Hamilton		Canada	L8L 0A9
31	Novartis Investigative Site	Quebec		Canada	GIV 4G5
32	Novartis Investigative Site	St-Lambert		Canada	J4P 2J2

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 4, 2017
• Study Protocol - Sep 12, 2016

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02690974
• Other Study ID Numbers: CLCZ696BCA02
• First Posted: Feb 24, 2016
• Last Update Posted: Jun 7, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: HFrEF,; ACEi,; ACE inhibitor,; ARBs,; systolic heart failure,; chronic heart failure,; CHF,; reduced EF,; Ejection Fraction
• Additional relevant MeSH terms: Heart Failure; Valsartan; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	This study was conducted in 32 study centers in Canada
Pre-assignment Detail	Approximately 300 patients with HFrEF were planned for enrolling into the study. A total of 302 patients received at least one dose of LCZ696 and were included in the Full Analysis Set (FAS). The analysis of the primary endpoint was based on the FAS.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Period Title: Overall Study
STARTED	302
COMPLETED	262
NOT COMPLETED	40

Baseline Characteristics

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Overall Participants	302
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.47 (10.7659)
Sex: Female, Male (Count of Participants)
Female	62 20.5%
Male	240 79.5%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	271 89.7%
Black	8 2.6%
Asian	15 5%
Native American	4 1.3%
Unknown or Not Reported	4 1.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants on LCZ696 200 mg Bid at Month 6
Description	The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 6. Only descriptive analysis done.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	302
Number (95% Confidence Interval) [Percentage of Participants]	64.6 21.4%

2. Secondary Outcome

Title	Percentage of Participants on LCZ696 200 mg Bid at Month 12
Description	The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 12. Only descriptive analysis done.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	302
Number (95% Confidence Interval) [Percentage of Participants]	62.3 20.6%

3. Secondary Outcome

Title	Percentage of Participants Requiring Down-titration From LCZ696 200 mg
Description	The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the percentage of patients on LCZ696 200mg requiring down-titration. Only descriptive analysis done.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	302
Number (95% Confidence Interval) [Percentage of Participants]	11.92 3.9%

4. Secondary Outcome

Title	Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment
Description	The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the number of down-titration during the 12 months treatment period. Dow-titration schemes considered for the analysis are 200 mg to 100 mg; 100 mg to 50 mg; and 50 mg to 0 mg (i.e. treatment discontinuation). The down-titration scheme of 50mg to 0 mg was taken in account in this analysis to ensure to reflect all actual changes in dose. Only descriptive analysis done.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	302
200 mg dose level	188 62.3%
100 mg dose level	44 14.6%
50 mg dose level	28 9.3%

5. Secondary Outcome

Title	Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12
Description	The impact of LCZ696 on functional exercise capacity was measured by the Six Minute Walk Test at 6 and 12 months. The 6MWT measures the distance an individual is able to walf over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. Only descriptive analysis done.
Time Frame	Baseline, Month 6 and Month 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	279
Value at Baseline (Day 1)	392.62 (139.3277)
Change from Baseline at Month 6	11.99 (67.5725)
Change from Baseline at Month 12	8.19 (71.3619)

6. Secondary Outcome

Title	Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg
Description	To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.
Time Frame	Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	302
50- 100 mg bid level	21.44 (23.1799)
100- 200 mg bid level	27.37 (28.5601)
50- 200 mg bid level	46.61 (36.9439)

7. Secondary Outcome

Title	Median Time to Reach LCZ696 200 mg
Description	To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.
Time Frame	Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	302
Median (95% Confidence Interval) [Days]	37.00

8. Secondary Outcome

Title	Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time
Description	To describe the adherence to guideline recommended dosing of beta-blockers and MRAs at 6 and 12 months of treatment of LCZ696. Only descriptive analysis done.
Time Frame	Baseline, Month 6 and Month 12

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set (FAS), which consisted of all participants with an observed value, was considered.

Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
Measure Participants	302
Baseline	298 98.7%
Month 6	272 90.1%
Month 12	261 86.4%

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 1 year.
Arm/Group Title	LCZ696 (Sacubitril / Valsartan)
Arm/Group Description	All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.
All Cause Mortality
	LCZ696 (Sacubitril / Valsartan)
	Affected / at Risk (%)	# Events
Total	9/302 (3%)
Serious Adverse Events
	LCZ696 (Sacubitril / Valsartan)
	Affected / at Risk (%)	# Events
Total	47/302 (15.6%)
Blood and lymphatic system disorders
Anaemia	1/302 (0.3%)
Cardiac disorders
Acute myocardial infarction	3/302 (1%)
Angina pectoris	1/302 (0.3%)
Atrial fibrillation	1/302 (0.3%)
Atrial tachycardia	1/302 (0.3%)
Bradyarrhythmia	1/302 (0.3%)
Cardiac arrest	3/302 (1%)
Cardiac failure	3/302 (1%)
Cardiac failure acute	1/302 (0.3%)
Cardiac failure congestive	13/302 (4.3%)
Congestive cardiomyopathy	1/302 (0.3%)
Nodal arrhythmia	1/302 (0.3%)
Ventricular tachycardia	3/302 (1%)
Gastrointestinal disorders
Gastrooesophageal reflux disease	1/302 (0.3%)
Volvulus	1/302 (0.3%)
General disorders
Death	3/302 (1%)
Multiple organ dysfunction syndrome	1/302 (0.3%)
Sudden death	1/302 (0.3%)
Hepatobiliary disorders
Cholecystitis chronic	1/302 (0.3%)
Infections and infestations
Bacteraemia	1/302 (0.3%)
Bronchitis	1/302 (0.3%)
Diverticulitis	1/302 (0.3%)
Gastroenteritis	2/302 (0.7%)
Infective exacerbation of bronchiectasis	1/302 (0.3%)
Osteomyelitis	1/302 (0.3%)
Pneumococcal sepsis	1/302 (0.3%)
Pneumonia	6/302 (2%)
Postoperative wound infection	1/302 (0.3%)
Injury, poisoning and procedural complications
Post procedural complication	1/302 (0.3%)
Investigations
Brain natriuretic peptide increased	1/302 (0.3%)
White blood cell count increased	1/302 (0.3%)
Metabolism and nutrition disorders
Dehydration	2/302 (0.7%)
Fluid overload	1/302 (0.3%)
Hyponatraemia	2/302 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	1/302 (0.3%)
Squamous cell carcinoma	1/302 (0.3%)
Tongue neoplasm malignant stage unspecified	1/302 (0.3%)
Nervous system disorders
Cerebrovascular accident	1/302 (0.3%)
Intracranial mass	1/302 (0.3%)
Ischaemic stroke	1/302 (0.3%)
Presyncope	1/302 (0.3%)
Product Issues
Device malfunction	1/302 (0.3%)
Psychiatric disorders
Adjustment disorder	1/302 (0.3%)
Delirium	1/302 (0.3%)
Suicidal ideation	1/302 (0.3%)
Renal and urinary disorders
Acute kidney injury	2/302 (0.7%)
Renal failure	1/302 (0.3%)
Respiratory, thoracic and mediastinal disorders
Laryngeal mass	1/302 (0.3%)
Pleural effusion	1/302 (0.3%)
Pulmonary oedema	1/302 (0.3%)
Vascular disorders
Orthostatic hypotension	1/302 (0.3%)
Peripheral ischaemia	1/302 (0.3%)
Other (Not Including Serious) Adverse Events
	LCZ696 (Sacubitril / Valsartan)
	Affected / at Risk (%)	# Events
Total	98/302 (32.5%)
Gastrointestinal disorders
Diarrhoea	18/302 (6%)
General disorders
Fatigue	19/302 (6.3%)
Nervous system disorders
Dizziness	45/302 (14.9%)
Respiratory, thoracic and mediastinal disorders
Cough	20/302 (6.6%)
Vascular disorders
Hypotension	31/302 (10.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.