Trial Outcomes & Findings for Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI (NCT NCT02924727)

Last Updated: 2023-06-22

Results Overview

A confirmed composite endpoint includes cardiovascular (CV) death, heart failure (HF) hospitalization, or outpatient heart failure

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

5669 participants

Primary outcome timeframe

From randomization to first occurrence (up to approximately 43 months)

Results posted on

2023-06-22

Participant Flow

A total of 5669 patients were randomized in a 1:1 ratio to the sacubitril/valsartan treatment group and the ramipril treatment group at 493 sites in 41 countries. A total of 8 patients were mis-randomized, 4 from each treatment group. One of the mis-randomized patients of the ramipril group died. The Full analysis set (FAS) was comprised of 5661 patients.

Participant milestones

Participant milestones
Measure	LCZ696 (Sacubitril/Valsartan) Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Overall Study STARTED	2834	2835
Overall Study Full Analysis Set (FAS)	2830	2831
Overall Study Safety Set (SAF)	2820	2816
Overall Study COMPLETED	2605	2576
Overall Study NOT COMPLETED	229	259

Reasons for withdrawal

Reasons for withdrawal
Measure	LCZ696 (Sacubitril/Valsartan) Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Overall Study Withdrawal by Subject	2	4
Overall Study Lost to Follow-up	2	5
Overall Study Death	221	247
Overall Study Mis-randomized (one mis-randomized patient in the Ramipril group also died)	4	3

Baseline Characteristics

Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCZ696 (Sacubitril/Valsartan) n=2830 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2831 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.	Total n=5661 Participants Total of all reporting groups
Age, Customized <65 years	1386 Participants n=5 Participants	1451 Participants n=7 Participants	2837 Participants n=5 Participants
Age, Customized ≥65 years	1444 Participants n=5 Participants	1380 Participants n=7 Participants	2824 Participants n=5 Participants
Age, Customized <75 years	2286 Participants n=5 Participants	2324 Participants n=7 Participants	4610 Participants n=5 Participants
Age, Customized ≥75 years	544 Participants n=5 Participants	507 Participants n=7 Participants	1051 Participants n=5 Participants
Sex: Female, Male Female	663 Participants n=5 Participants	700 Participants n=7 Participants	1363 Participants n=5 Participants
Sex: Female, Male Male	2167 Participants n=5 Participants	2131 Participants n=7 Participants	4298 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	2125 Participants n=5 Participants	2138 Participants n=7 Participants	4263 Participants n=5 Participants
Race/Ethnicity, Customized Black	35 Participants n=5 Participants	40 Participants n=7 Participants	75 Participants n=5 Participants
Race/Ethnicity, Customized Asian	475 Participants n=5 Participants	478 Participants n=7 Participants	953 Participants n=5 Participants
Race/Ethnicity, Customized Native American	45 Participants n=5 Participants	45 Participants n=7 Participants	90 Participants n=5 Participants
Race/Ethnicity, Customized Pacific Islander	0 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	22 Participants n=5 Participants	21 Participants n=7 Participants	43 Participants n=5 Participants
Race/Ethnicity, Customized Other	128 Participants n=5 Participants	105 Participants n=7 Participants	233 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to first occurrence (up to approximately 43 months)

Population: Full Analysis Set

A confirmed composite endpoint includes cardiovascular (CV) death, heart failure (HF) hospitalization, or outpatient heart failure

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=2830 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2831 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint Primary Composite	338 Count of Participants	373 Count of Participants
Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint Cardiovascular (CV) Death	168 Count of Participants	191 Count of Participants
Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint First Heart Failure (HF) Hospitalization	170 Count of Participants	195 Count of Participants
Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint First Outpatient Heart Failure (HF)	39 Count of Participants	57 Count of Participants

SECONDARY outcome

Timeframe: Time from randomization to first occurrence (up to approximately 43 months)

Population: Full Analysis Set

A confirmed composite endpoint for this outcome measure includes cardiovascular death or heart failure hospitalization.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=2830 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2831 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Number of Participants With a Confirmed Composite of CV Death or HF Hospitalization	308 Participants	335 Participants

SECONDARY outcome

Timeframe: Time from randomization to first occurrence (approximately up to 43 months)

Population: Full Analysis Set

A confirmed composite endpoint includes first occurrence of heart failure hospitalization or outpatient heart failure

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=2830 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2831 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Number of Participants With a Confirmed Composite of HF Hospitalization or Outpatient HF	201 Participants	237 Participants

SECONDARY outcome

Timeframe: Time from randomization to first occurrence (approximately up to 43 months)

Population: Full Analysis Set

A confirmed composite endpoint for this outcome measure includes cardiovascular death, non-fatal spontaneous myocardial infarction or non-fatal stroke

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=2830 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2831 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Number of Participants With a Confirmed Composite of CV Death, Non-fatal Spontaneous Myocardial Infarction or Non-fatal Stroke	315 Participants	349 Participants

SECONDARY outcome

Timeframe: Time from randomization to end of study (approximately up to 43 months)

Population: Full Analysis Set

A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, non-fatal spontaneous MI hospitalization, and non-fatal stroke hospitalization

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=2830 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2831 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Total Number of Confirmed Composite Endpoints	416 Events	455 Events

SECONDARY outcome

Timeframe: Time from randomization to death (approximately up to 43 months)

Population: Full Analysis Set

All-cause mortality defined as deaths related to Cardiovascular (CV) and non-CV events for patients in the Full Analysis Set up to a cut-off date of 31-Dec-2020.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=2830 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2831 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
All-cause Mortality for Full Analysis Set (FAS)	213 Participants	242 Participants

POST_HOC outcome

Timeframe: Pre-treatment: Up to 5 days before Day 1. On-treatment and post-treatment safety follow up: up to 4 years

Population: All subjects to whom study treatment was assigned by randomization, regardless of whether or not treatment was administered

Pre-treatment deaths were collected from randomization to the day before first dose of study medication, for a maximum duration of 5 days. On-treatment and post-treatment safety follow-up deaths were collected from first dose of study medication to 30 days after the last dose of study medication. All deaths refer to the sum of pre-treatment, on-treatment and post-treatment safety follow-up deaths.

Outcome measures

Outcome measures
Measure	LCZ696 (Sacubitril/Valsartan) n=2834 Participants Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients were required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from Ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.	Ramipril n=2835 Participants Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients were required to take a total of two pills, (one capsule from the Ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to Ramipril who were previously treated with ACE inhibitors, receiving the last dose of that agent during the last 36 hours prior to randomization immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
All Collected Deaths All deaths	221 Participants	247 Participants
All Collected Deaths pre-treatment deaths	1 Participants	3 Participants
All Collected Deaths On-treatment deaths and extended safety follow-up	220 Participants	244 Participants

Adverse Events

LCZ696 Pre-treatment

Serious events: 0 serious events

Other events: 0 other events

Deaths: 1 deaths

Ramipril Pre-treatment

Serious events: 0 serious events

Other events: 0 other events

Deaths: 3 deaths

LCZ696

Serious events: 1146 serious events

Other events: 1769 other events

Deaths: 220 deaths

Ramipril

Serious events: 1126 serious events

Other events: 1770 other events

Deaths: 244 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER