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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02554890
• Collaborator: (none)
• Enrollment: 887
• Locations: 123
• Arms: 2
• Actual Duration (Months): 26.8
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study was to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%).

Condition or Disease	Intervention/Treatment	Phase
Acute Heart Failure	Drug: sacubitril/valsartan (LCZ696); Drug: Enalapril; Drug: sacubitril/valsartan (LCZ696) matching placebo; Drug: enalapril matching placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 887 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Enalapril on Changes in NT-proBNP and Safety and Tolerability of In-hospital Initiation of LCZ696 Compared to Enalapril in HFrEF Patients Who Have Been Stabilized Following Hospitalization for Acute Decompensated Heart Failure (ADHF).
• Actual Study Start Date: Apr 29, 2016
• Actual Primary Completion Date: Jun 29, 2018
• Actual Study Completion Date: Jul 24, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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).	Drug: sacubitril/valsartan (LCZ696); sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.; Other Names: LCZ696 ; Drug: enalapril matching placebo; enalapril matching placebo tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.
Active Comparator: 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)	Drug: Enalapril; Enalapril tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.; Drug: sacubitril/valsartan (LCZ696) matching placebo; matching placebo of sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.

Outcome Measures

Primary Outcome Measures

1. N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline [Baseline, Week 4 and Week 8]

   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.

Secondary Outcome Measures

1. Number of Patients With Incidences of Symptomatic Hypotension [8 weeks of treatment]

   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.

2. Number of Patients With Incidences of Hyperkalemia [8 weeks of treatment]

   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.

3. Number of Patients With Incidences of Angioedema [8 weeks of treatment]

   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.

4. Change From Baseline in High Sensitivity Troponin (Hs-Troponin) [Baseline, Week 4/Week 8]

   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.

5. Change From Baseline in Urinary cGMP [Baseline, Week 4 and Week 8]

   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)

6. Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio [Baseline, Week 4 and Week 8]

   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).

7. Change From Baseline in BNP to NTproBNP Ratio [baseline, Week 4 and Week 8]

   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.

8. N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.

2. Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.

3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:

• SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension

• No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization

• No i.v. inotropic drugs for 24 hours prior to randomization

• No i.v. vasodilators including nitrates within last 6 hours prior to randomization

1. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of >40%.

2. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.

Key Exclusion Criteria:

1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days.

2. Enrollment in any other clinical trial involving an investigational agent or investigational device.

3. History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).

4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.

5. Requirement of treatment with both ACE inhibitor and ARB.

6. eGFR < 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.

7. Serum potassium > 5.2 mEq/L at screening.

8. Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices

9. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.

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 child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35294
2	Novartis Investigative Site	Fort Smith	Arkansas	United States	72901
3	Novartis Investigative Site	Little Rock	Arkansas	United States	72205
4	Novartis Investigative Site	Bakersfield	California	United States	93301
5	Novartis Investigative Site	Fresno	California	United States	93701
6	Novartis Investigative Site	Long Beach	California	United States	90806
7	Novartis Investigative Site	Los Angeles	California	United States	90033
8	Novartis Investigative Site	Los Angeles	California	United States	90073
9	Novartis Investigative Site	Orange	California	United States	92868
10	Novartis Investigative Site	Pasadena	California	United States	91105
11	Novartis Investigative Site	Sacramento	California	United States	95817-1460
12	Novartis Investigative Site	San Diego	California	United States	92123
13	Novartis Investigative Site	San Marino	California	United States	91108
14	Novartis Investigative Site	San Pablo	California	United States	94806
15	Novartis Investigative Site	Stanford	California	United States	94305
16	Novartis Investigative Site	Denver	Colorado	United States
17	Novartis Investigative Site	Littleton	Colorado	United States	80120
18	Novartis Investigative Site	Bridgeport	Connecticut	United States	06610
19	Novartis Investigative Site	Hartford	Connecticut	United States	06102
20	Novartis Investigative Site	Hartford	Connecticut	United States	06105
21	Novartis Investigative Site	West Haven	Connecticut	United States	06516
22	Novartis Investigative Site	Washington	District of Columbia	United States	20422
23	Novartis Investigative Site	Atlantis	Florida	United States	33462
24	Novartis Investigative Site	Daytona Beach	Florida	United States	32117
25	Novartis Investigative Site	Fort Lauderdale	Florida	United States	33308
26	Novartis Investigative Site	Gainesville	Florida	United States	32608
27	Novartis Investigative Site	Gainesville	Florida	United States	32610
28	Novartis Investigative Site	Hollywood	Florida	United States	33021
29	Novartis Investigative Site	Jacksonville	Florida	United States	32209-6511
30	Novartis Investigative Site	Jacksonville	Florida	United States	32216
31	Novartis Investigative Site	Lakeland	Florida	United States	33805
32	Novartis Investigative Site	Sarasota	Florida	United States	34239
33	Novartis Investigative Site	Tampa	Florida	United States	33612
34	Novartis Investigative Site	Tampa	Florida	United States	34667
35	Novartis Investigative Site	Vero Beach	Florida	United States	32960
36	Novartis Investigative Site	Winter Haven	Florida	United States	33881
37	Novartis Investigative Site	Augusta	Georgia	United States	30901
38	Novartis Investigative Site	Macon	Georgia	United States	31201
39	Novartis Investigative Site	Marietta	Georgia	United States	30060
40	Novartis Investigative Site	Boise	Idaho	United States	83702
41	Novartis Investigative Site	Aurora	Illinois	United States	60504
42	Novartis Investigative Site	Elk Grove Village	Illinois	United States	60007
43	Novartis Investigative Site	Oakbrook Terrace	Illinois	United States	60181
44	Novartis Investigative Site	Park Ridge	Illinois	United States	60068
45	Novartis Investigative Site	Peoria	Illinois	United States	61606
46	Novartis Investigative Site	Peoria	Illinois	United States	61614
47	Novartis Investigative Site	Winfield	Illinois	United States	60190
48	Novartis Investigative Site	Elkhart	Indiana	United States	46514
49	Novartis Investigative Site	Indianapolis	Indiana	United States	46202
50	Novartis Investigative Site	Indianapolis	Indiana	United States	46237
51	Novartis Investigative Site	Muncie	Indiana	United States	47303-3400
52	Novartis Investigative Site	Richmond	Indiana	United States	47374
53	Novartis Investigative Site	Des Moines	Iowa	United States	50314
54	Novartis Investigative Site	Kansas City	Kansas	United States	66103
55	Novartis Investigative Site	Louisville	Kentucky	United States	40205
56	Novartis Investigative Site	Louisville	Kentucky	United States	40245
57	Novartis Investigative Site	Alexandria	Louisiana	United States	71301
58	Novartis Investigative Site	Baton Rouge	Louisiana	United States	70808
59	Novartis Investigative Site	Slidell	Louisiana	United States	70458
60	Novartis Investigative Site	Bangor	Maine	United States	04401
61	Novartis Investigative Site	Annapolis	Maryland	United States	21401
62	Novartis Investigative Site	Baltimore	Maryland	United States	21215
63	Novartis Investigative Site	Boston	Massachusetts	United States	02215
64	Novartis Investigative Site	Boston	Massachusetts	United States
65	Novartis Investigative Site	Ann Arbor	Michigan	United States	48106
66	Novartis Investigative Site	Bay City	Michigan	United States	48708
67	Novartis Investigative Site	Detroit	Michigan	United States	48201
68	Novartis Investigative Site	Maplewood	Minnesota	United States	55109
69	Novartis Investigative Site	Minneapolis	Minnesota	United States	55417
70	Novartis Investigative Site	Saint Paul	Minnesota	United States	55101
71	Novartis Investigative Site	Saint Paul	Minnesota	United States	55102
72	Novartis Investigative Site	Hattiesburg	Mississippi	United States	39401
73	Novartis Investigative Site	Jackson	Mississippi	United States	39216
74	Novartis Investigative Site	Kansas City	Missouri	United States	64108
75	Novartis Investigative Site	Omaha	Nebraska	United States	68198
76	Novartis Investigative Site	Reno	Nevada	United States	89502
77	Novartis Investigative Site	Camden	New Jersey	United States	08103-3117
78	Novartis Investigative Site	Elmer	New Jersey	United States	08318
79	Novartis Investigative Site	Haddon Heights	New Jersey	United States	08035
80	Novartis Investigative Site	Newark	New Jersey	United States	07102
81	Novartis Investigative Site	Bronx	New York	United States	10461
82	Novartis Investigative Site	Bronx	New York	United States	10467-2490
83	Novartis Investigative Site	Brooklyn	New York	United States	11215
84	Novartis Investigative Site	Buffalo	New York	United States	14215
85	Novartis Investigative Site	Johnson City	New York	United States	13790
86	Novartis Investigative Site	Manhasset	New York	United States	11030
87	Novartis Investigative Site	New York	New York	United States	10016
88	Novartis Investigative Site	New York	New York	United States	10029
89	Novartis Investigative Site	New York	New York	United States	10032
90	Novartis Investigative Site	Poughkeepsie	New York	United States	12601
91	Novartis Investigative Site	Rochester	New York	United States	14621
92	Novartis Investigative Site	Staten Island	New York	United States	10310
93	Novartis Investigative Site	Chapel Hill	North Carolina	United States	27599
94	Novartis Investigative Site	Greenville	North Carolina	United States	27834
95	Novartis Investigative Site	Winston-Salem	North Carolina	United States	27157
96	Novartis Investigative Site	Grand Forks	North Dakota	United States	58201
97	Novartis Investigative Site	Cincinnati	Ohio	United States	45220
98	Novartis Investigative Site	Toledo	Ohio	United States	43608
99	Novartis Investigative Site	Oklahoma City	Oklahoma	United States	73122
100	Novartis Investigative Site	Tulsa	Oklahoma	United States	74104
101	Novartis Investigative Site	Abington	Pennsylvania	United States	19001
102	Novartis Investigative Site	Camp Hill	Pennsylvania	United States	17011
103	Novartis Investigative Site	Natrona Heights	Pennsylvania	United States	15065
104	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19102 2293
105	Novartis Investigative Site	Providence	Rhode Island	United States	02903
106	Novartis Investigative Site	Charleston	South Carolina	United States	29403
107	Novartis Investigative Site	Greenville	South Carolina	United States	29615
108	Novartis Investigative Site	Rapid City	South Dakota	United States	57701
109	Novartis Investigative Site	Nashville	Tennessee	United States	37203
110	Novartis Investigative Site	Nashville	Tennessee	United States	37212
111	Novartis Investigative Site	Dallas	Texas	United States	75204
112	Novartis Investigative Site	Dallas	Texas	United States	75390
113	Novartis Investigative Site	Houston	Texas	United States	77030
114	Novartis Investigative Site	Plano	Texas	United States	75093
115	Novartis Investigative Site	San Antonio	Texas	United States	78229
116	Novartis Investigative Site	White River Junction	Vermont	United States	05009
117	Novartis Investigative Site	Charlottesville	Virginia	United States	22908
118	Novartis Investigative Site	Lynchburg	Virginia	United States	24501
119	Novartis Investigative Site	Richmond	Virginia	United States	23298
120	Novartis Investigative Site	Virginia Beach	Virginia	United States	23454
121	Novartis Investigative Site	Clarksburg	West Virginia	United States	26301
122	Novartis Investigative Site	Madison	Wisconsin	United States	53792-1615
123	Novartis Investigative Site	Wausau	Wisconsin	United States	54401

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 5, 2017
• Statistical Analysis Plan - Aug 20, 2018

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Publications

• Morrow DA, Velazquez EJ, DeVore AD, Desai AS, Duffy CI, Ambrosy AP, Gurmu Y, McCague K, Rocha R, Braunwald E. Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial. Circulation. 2019 May 7;139(19):2285-2288. doi: 10.1161/CIRCULATIONAHA.118.039331.
• Morrow DA, Velazquez EJ, DeVore AD, Prescott MF, Duffy CI, Gurmu Y, McCague K, Rocha R, Braunwald E. Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial. Eur Heart J. 2019 Oct 21;40(40):3345-3352. doi: 10.1093/eurheartj/ehz240.
• Velazquez EJ, Morrow DA, DeVore AD, Ambrosy AP, Duffy CI, McCague K, Hernandez AF, Rocha RA, Braunwald E. Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Am Heart J. 2018 Apr;198:145-151. doi: 10.1016/j.ahj.2018.01.004. Epub 2018 Jan 10.
• Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11. Erratum in: N Engl J Med. 2019 Mar 14;380(11):1090.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02554890
• Other Study ID Numbers: CLCZ696BUS01
• First Posted: Sep 18, 2015
• Last Update Posted: Jan 5, 2021
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Novartis Pharmaceuticals: Acute; Heart Failure; reduced ejection fraction; NTproBNP; Heart failure with reduced ejection fraction (HFREF)
• Additional relevant MeSH terms: Heart Failure; Valsartan; Enalapril; Enalaprilat; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Period Title: Double-blind
STARTED	444	443
Treated Patients	436	439
COMPLETED	348	352
NOT COMPLETED	96	91
Period Title: Double-blind
STARTED	0	887
COMPLETED	0	835
NOT COMPLETED	0	52

Baseline Characteristics

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)	Total
Arm/Group Description	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)	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 of all reporting groups
Overall Participants	441	440	881
Age, Customized (Number) [Number]
<65 years	232 52.6%	253 57.5%	485 55.1%
≥65 years	209 47.4%	187 42.5%	396 44.9%
< 75 years	363 82.3%	370 84.1%	733 83.2%
≥75 years	78 17.7%	70 15.9%	148 16.8%
Sex: Female, Male (Count of Participants)
Female	133 30.2%	113 25.7%	246 27.9%
Male	308 69.8%	327 74.3%	635 72.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	41 9.3%	34 7.7%	75 8.5%
Not Hispanic or Latino	399 90.5%	405 92%	804 91.3%
Unknown or Not Reported	1 0.2%	1 0.2%	2 0.2%

Outcome Measures

1. Primary Outcome

Title	N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline
Description	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.
Time Frame	Baseline, Week 4 and Week 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Geometric Mean (95% Confidence Interval) [pg/ml]	0.7466	0.5333

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan (LCZ696)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	ANCOVA model for a log-scaled response with treatment group as a class variable and biomarker baseline value in logarithmic scale as a continuous covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	expon. back transformed from LS means
	Estimated Value	0.7143
	Confidence Interval	(2-Sided) 95%; 0.6315 to 0.8080
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio: Sacubitril/ Valsartan vs. Enalapril

2. Secondary Outcome

Title	Number of Patients With Incidences of Symptomatic Hypotension
Description	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.
Time Frame	8 weeks of treatment

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Number [participants]	56 12.7%	66 15%

3. Secondary Outcome

Title	Number of Patients With Incidences of Hyperkalemia
Description	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.
Time Frame	8 weeks of treatment

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Number [Participants]	41 9.3%	51 11.6%

4. Secondary Outcome

Title	Number of Patients With Incidences of Angioedema
Description	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.
Time Frame	8 weeks of treatment

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Number [Participants]	11 2.5%	1 0.2%

5. Secondary Outcome

Title	Change From Baseline in High Sensitivity Troponin (Hs-Troponin)
Description	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.
Time Frame	Baseline, Week 4/Week 8

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Geometric Mean (95% Confidence Interval) [Ratio]	0.7477	0.6345

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan (LCZ696)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	exponentially back transformed from LS m
	Estimated Value	0.8487
	Confidence Interval	(2-Sided) 95%; 0.7694 to 0.9361
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio: Sacubitril/ Valsartan vs. Enalapril

6. Secondary Outcome

Title	Change From Baseline in Urinary cGMP
Description	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)
Time Frame	Baseline, Week 4 and Week 8

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Geometric Mean (95% Confidence Interval) [Ratio]	0.9641	1.5895

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan (LCZ696)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	expon. back transformed from LS means
	Estimated Value	1.6487
	Confidence Interval	(2-Sided) 95%; 1.4559 to 1.8669
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio: Sacubitril/ Valsartan vs. Enalapril

7. Secondary Outcome

Title	Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio
Description	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).
Time Frame	Baseline, Week 4 and Week 8

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Geometric Mean (95% Confidence Interval) [Ratio]	0.8258	1.1714

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan (LCZ696)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	expon. back transformed from LS means
	Estimated Value	1.4186
	Confidence Interval	(2-Sided) 95%; 1.3248 to 1.5190
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio: Sacubitril/ Valsartan vs. Enalapril

8. Secondary Outcome

Title	Change From Baseline in BNP to NTproBNP Ratio
Description	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.
Time Frame	baseline, Week 4 and Week 8

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Geometric Mean (95% Confidence Interval) [Ratio]	0.9174	1.3527

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan (LCZ696)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	expon. back transformed from LS means
	Estimated Value	1.4745
	Confidence Interval	(2-Sided) 95%; 1.3752 to 1.5810
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio: Sacubitril/ Valsartan vs. Enalapril

9. Secondary Outcome

Title	N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8
Description	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.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Enalapril	Sacubitril/Valsartan (LCZ696)
Arm/Group Description	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)	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).
Measure Participants	441	440
Geometric Mean (95% Confidence Interval) [pg/ml]	0.6443	0.4596

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Sacubitril/Valsartan (LCZ696)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	ANCOVA model for a log-scaled response with treatment group as a class variable and biomarker baseline value in logarithmic scale as a continuous covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	expon. back transformed from LS means
	Estimated Value	0.7133
	Confidence Interval	(2-Sided) 95%; 0.6171 to 0.8245
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric Mean Ratio: Sacubitril/Valsartan vs. Enalapril

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	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.
Arm/Group Title	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan		Pooled Phase Sacubitril/Valsartan
Arm/Group Description	Patients who received Enalapril in the double-blind phase.		Patients who received Sacubitril/Valsartan in the double-blind phase.		All patients who received sacubitril/valsartan in the open-label phase.		All patients who received a dose of sacubitril/valsartan either in the double-blind phase or open-label phase.
All Cause Mortality
	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan		Pooled Phase Sacubitril/Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/436 (3.4%)		10/439 (2.3%)		6/828 (0.7%)		16/851 (1.9%)
Serious Adverse Events
	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan		Pooled Phase Sacubitril/Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/436 (30.3%)		117/439 (26.7%)		104/828 (12.6%)		191/851 (22.4%)
Blood and lymphatic system disorders
Anaemia	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Coagulopathy	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Leukocytosis	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Thrombocytopenia	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Cardiac disorders
Acute left ventricular failure	4/436 (0.9%)		4/439 (0.9%)		2/828 (0.2%)		5/851 (0.6%)
Acute myocardial infarction	2/436 (0.5%)		2/439 (0.5%)		2/828 (0.2%)		4/851 (0.5%)
Angina pectoris	3/436 (0.7%)		1/439 (0.2%)		4/828 (0.5%)		5/851 (0.6%)
Angina unstable	0/436 (0%)		2/439 (0.5%)		2/828 (0.2%)		4/851 (0.5%)
Atrial fibrillation	3/436 (0.7%)		4/439 (0.9%)		5/828 (0.6%)		9/851 (1.1%)
Atrial flutter	1/436 (0.2%)		2/439 (0.5%)		0/828 (0%)		2/851 (0.2%)
Atrial thrombosis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Bradycardia	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Cardiac arrest	4/436 (0.9%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Cardiac failure	15/436 (3.4%)		7/439 (1.6%)		14/828 (1.7%)		19/851 (2.2%)
Cardiac failure acute	11/436 (2.5%)		8/439 (1.8%)		10/828 (1.2%)		18/851 (2.1%)
Cardiac failure chronic	0/436 (0%)		1/439 (0.2%)		2/828 (0.2%)		3/851 (0.4%)
Cardiac failure congestive	29/436 (6.7%)		16/439 (3.6%)		13/828 (1.6%)		27/851 (3.2%)
Cardiac sarcoidosis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Cardiac ventricular thrombosis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Cardiogenic shock	3/436 (0.7%)		3/439 (0.7%)		2/828 (0.2%)		5/851 (0.6%)
Cardiomyopathy	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Congestive cardiomyopathy	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Coronary artery stenosis	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Ischaemic cardiomyopathy	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Left ventricular failure	8/436 (1.8%)		3/439 (0.7%)		3/828 (0.4%)		6/851 (0.7%)
Long QT syndrome	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Myocardial infarction	2/436 (0.5%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Pericardial effusion	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Pulseless electrical activity	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Right ventricular failure	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Sinus arrest	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Sinus tachycardia	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Supraventricular tachycardia	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Systolic dysfunction	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Tachycardia	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Ventricular arrhythmia	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Ventricular extrasystoles	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Ventricular fibrillation	0/436 (0%)		0/439 (0%)		2/828 (0.2%)		2/851 (0.2%)
Ventricular tachycardia	7/436 (1.6%)		5/439 (1.1%)		6/828 (0.7%)		11/851 (1.3%)
Eye disorders
Retinal detachment	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Gastrointestinal disorders
Abdominal distension	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Abdominal hernia	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Abdominal pain upper	1/436 (0.2%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Diarrhoea	2/436 (0.5%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Gastric disorder	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Gastric ulcer	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Gastric ulcer haemorrhage	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Gastrointestinal haemorrhage	3/436 (0.7%)		0/439 (0%)		2/828 (0.2%)		2/851 (0.2%)
Lower gastrointestinal haemorrhage	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Megacolon	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Nausea	0/436 (0%)		0/439 (0%)		3/828 (0.4%)		3/851 (0.4%)
Retroperitoneal haematoma	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Upper gastrointestinal haemorrhage	0/436 (0%)		1/439 (0.2%)		1/828 (0.1%)		2/851 (0.2%)
Vomiting	0/436 (0%)		0/439 (0%)		3/828 (0.4%)		3/851 (0.4%)
General disorders
Asthenia	1/436 (0.2%)		2/439 (0.5%)		2/828 (0.2%)		4/851 (0.5%)
Death	0/436 (0%)		3/439 (0.7%)		2/828 (0.2%)		5/851 (0.6%)
Hypothermia	0/436 (0%)		1/439 (0.2%)		1/828 (0.1%)		2/851 (0.2%)
Multiple organ dysfunction syndrome	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Non-cardiac chest pain	3/436 (0.7%)		3/439 (0.7%)		2/828 (0.2%)		5/851 (0.6%)
Pain	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Sudden cardiac death	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Hepatobiliary disorders
Cardiac cirrhosis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Cholangitis	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Cholecystitis	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Cholelithiasis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Hepatic cirrhosis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Hepatic failure	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Hepatic function abnormal	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Liver injury	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Immune system disorders
Sarcoidosis	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Infections and infestations
Bacteraemia	1/436 (0.2%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Bronchitis	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Cellulitis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Clostridium difficile colitis	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Clostridium difficile infection	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Corona virus infection	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Diverticulitis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Gastroenteritis	1/436 (0.2%)		2/439 (0.5%)		0/828 (0%)		2/851 (0.2%)
Gastroenteritis viral	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Herpes zoster	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Infection	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Influenza	2/436 (0.5%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Kidney infection	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Osteomyelitis	2/436 (0.5%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Pneumonia	8/436 (1.8%)		4/439 (0.9%)		1/828 (0.1%)		4/851 (0.5%)
Pseudomembranous colitis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Respiratory tract infection viral	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Sepsis	1/436 (0.2%)		3/439 (0.7%)		2/828 (0.2%)		5/851 (0.6%)
Septic shock	1/436 (0.2%)		0/439 (0%)		2/828 (0.2%)		2/851 (0.2%)
Upper respiratory tract infection	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Urinary tract infection	0/436 (0%)		3/439 (0.7%)		1/828 (0.1%)		4/851 (0.5%)
Injury, poisoning and procedural complications
Contusion	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Fall	2/436 (0.5%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Gun shot wound	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Head injury	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Joint injury	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Laceration	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Rib fracture	0/436 (0%)		1/439 (0.2%)		1/828 (0.1%)		2/851 (0.2%)
Road traffic accident	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Subarachnoid haematoma	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Subdural haematoma	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Thoracic vertebral fracture	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Investigations
Anticoagulation drug level above therapeutic	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Blood creatinine increased	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Ejection fraction decreased	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Glomerular filtration rate decreased	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Heart rate decreased	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Heart rate increased	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Oxygen saturation decreased	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Transaminases increased	0/436 (0%)		1/439 (0.2%)		1/828 (0.1%)		2/851 (0.2%)
Troponin increased	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Metabolism and nutrition disorders
Dehydration	1/436 (0.2%)		3/439 (0.7%)		1/828 (0.1%)		4/851 (0.5%)
Diabetes mellitus	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Failure to thrive	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Fluid overload	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Gout	0/436 (0%)		2/439 (0.5%)		0/828 (0%)		2/851 (0.2%)
Hypercalcaemia	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Hyperglycaemia	1/436 (0.2%)		1/439 (0.2%)		2/828 (0.2%)		3/851 (0.4%)
Hyperkalaemia	2/436 (0.5%)		10/439 (2.3%)		4/828 (0.5%)		13/851 (1.5%)
Hypoglycaemia	1/436 (0.2%)		2/439 (0.5%)		2/828 (0.2%)		4/851 (0.5%)
Hypokalaemia	2/436 (0.5%)		1/439 (0.2%)		1/828 (0.1%)		2/851 (0.2%)
Hyponatraemia	3/436 (0.7%)		2/439 (0.5%)		2/828 (0.2%)		4/851 (0.5%)
Hypovolaemia	2/436 (0.5%)		1/439 (0.2%)		2/828 (0.2%)		3/851 (0.4%)
Ketosis	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Lactic acidosis	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Type 1 diabetes mellitus	1/436 (0.2%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/436 (0.2%)		1/439 (0.2%)		2/828 (0.2%)		3/851 (0.4%)
Back pain	0/436 (0%)		1/439 (0.2%)		1/828 (0.1%)		2/851 (0.2%)
Joint effusion	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Joint swelling	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Rhabdomyolysis	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Adenocarcinoma of colon	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Basal cell carcinoma	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Plasma cell myeloma	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Nervous system disorders
Aphasia	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Cerebellar infarction	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Cerebral infarction	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Cerebrovascular accident	3/436 (0.7%)		4/439 (0.9%)		1/828 (0.1%)		5/851 (0.6%)
Dizziness	0/436 (0%)		1/439 (0.2%)		4/828 (0.5%)		5/851 (0.6%)
Encephalopathy	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Ischaemic stroke	0/436 (0%)		3/439 (0.7%)		0/828 (0%)		3/851 (0.4%)
Loss of consciousness	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Presyncope	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Syncope	2/436 (0.5%)		5/439 (1.1%)		4/828 (0.5%)		9/851 (1.1%)
Transient ischaemic attack	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Vascular headache	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Product Issues
Lead dislodgement	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Psychiatric disorders
Anxiety	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Confusional state	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Hallucination	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Major depression	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Mental status changes	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Substance abuse	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Suicidal ideation	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Renal and urinary disorders
Acute kidney injury	15/436 (3.4%)		16/439 (3.6%)		5/828 (0.6%)		21/851 (2.5%)
Azotaemia	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Chronic kidney disease	0/436 (0%)		4/439 (0.9%)		1/828 (0.1%)		5/851 (0.6%)
Haematuria	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Renal failure	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Renal impairment	0/436 (0%)		3/439 (0.7%)		2/828 (0.2%)		5/851 (0.6%)
Renal infarct	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Urinary retention	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Acute respiratory failure	3/436 (0.7%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Asthma	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Bronchiectasis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Chronic obstructive pulmonary disease	3/436 (0.7%)		3/439 (0.7%)		2/828 (0.2%)		5/851 (0.6%)
Cough	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Dyspnoea	2/436 (0.5%)		4/439 (0.9%)		8/828 (1%)		12/851 (1.4%)
Haemoptysis	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Hypoxia	2/436 (0.5%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Interstitial lung disease	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Organising pneumonia	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Orthopnoea	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Pleurisy	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Pleuritic pain	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Pneumonia aspiration	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Pneumothorax	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Pulmonary embolism	1/436 (0.2%)		3/439 (0.7%)		0/828 (0%)		3/851 (0.4%)
Pulmonary infarction	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Pulmonary ossification	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Respiratory failure	3/436 (0.7%)		1/439 (0.2%)		3/828 (0.4%)		4/851 (0.5%)
Skin and subcutaneous tissue disorders
Angioedema	5/436 (1.1%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Vascular disorders
Accelerated hypertension	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Arterial haemorrhage	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Circulatory collapse	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Deep vein thrombosis	0/436 (0%)		2/439 (0.5%)		0/828 (0%)		2/851 (0.2%)
Extremity necrosis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Haematoma	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Hypertensive crisis	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Hypoperfusion	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Hypotension	17/436 (3.9%)		11/439 (2.5%)		12/828 (1.4%)		21/851 (2.5%)
Orthostatic hypotension	0/436 (0%)		3/439 (0.7%)		0/828 (0%)		3/851 (0.4%)
Peripheral arterial occlusive disease	1/436 (0.2%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Peripheral ischaemia	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Peripheral vascular disorder	0/436 (0%)		0/439 (0%)		1/828 (0.1%)		1/851 (0.1%)
Shock	0/436 (0%)		1/439 (0.2%)		0/828 (0%)		1/851 (0.1%)
Shock haemorrhagic	1/436 (0.2%)		0/439 (0%)		0/828 (0%)		0/851 (0%)
Other (Not Including Serious) Adverse Events
	Double Blind Phase Enalapril		Double Blind Phase Sacubitril/Valsartan		Open-Label Phase Sacubitril/Valsartan		Pooled Phase Sacubitril/Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	139/436 (31.9%)		153/439 (34.9%)		65/828 (7.9%)		199/851 (23.4%)
Investigations
Blood creatinine increased	19/436 (4.4%)		30/439 (6.8%)		7/828 (0.8%)		36/851 (4.2%)
Metabolism and nutrition disorders
Hyperkalaemia	39/436 (8.9%)		47/439 (10.7%)		11/828 (1.3%)		57/851 (6.7%)
Nervous system disorders
Dizziness	33/436 (7.6%)		38/439 (8.7%)		17/828 (2.1%)		55/851 (6.5%)
Renal and urinary disorders
Acute kidney injury	23/436 (5.3%)		23/439 (5.2%)		3/828 (0.4%)		24/851 (2.8%)
Vascular disorders
Hypotension	65/436 (14.9%)		71/439 (16.2%)		33/828 (4%)		97/851 (11.4%)

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.