Drug Trials Snapshot: ENTRESTO

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The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race, and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.enter content

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Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the ENTRESTO Prescribing Information for complete information.

ENTRESTO (sacubitril/valsartan)
(en-TRESS-toh)
Novartis Pharmaceuticals Corporation
Approval date: July 7, 2015

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ENTRESTO is a drug to be taken in conjunction with other heart failure therapies for the long-term treatment of chronic heart failure. This is a condition in which the heart is weak and cannot pump enough blood to meet the body’s needs.

ENTRESTO should not be taken with any drug that belongs to certain classes of medication called ACE inhibitors and angiotensin receptor blockers. This is because ENTRESTO itself contains an angiotensin receptor blocker.

How is this drug used?

ENTRESTO is a tablet that is taken by mouth two times daily.

What are the benefits of this drug?

ENTRESTO reduced the risk of death related to the heart and blood vessels as well as hospitalization related to heart failure.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes the primary endpoint. The primary endpoint was a composite that measured the first event of either cardiovascular death or hospitalization for heart failure. Six patients were incorrectly randomized and were not treated, and 37 patients were enrolled at medical centers where problems were found with the conduct of the trial.  These 43 patients were not included in the analyses.

Table 2. Primary Endpoint, Its Components, and All-cause Mortality

	ENTRESTO N=4187 n (%)	Enalapril N=4212 n (%)	Hazard Ratio (95% CI)	p-value
Primary composite endpoint of cardiovascular death or heart failure hospitalization	914 (22)	1117 (27)	0.80 (0.73, 0.87)	<>
Cardiovascular death as first event	377 (9)	459 (11)
Heart failure hospitalization as first event	537 (13)	658 (16)
Number of Subjects with events*
Cardiovascular death **	558 (13)	693 (17)	0.80 (0.71, 0.89)
Heart failure hospitalizations	537 (13)	658 (16)	0.79 (0.71, 0.89)
All-cause mortality	711 (17)	835 (20)	0.84 (0.76, 0.93)	0.0009

*Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity
**Includes subjects who had heart failure hospitalization prior to death
Source: ENTRESTO Prescribing Information Section 14, Table 2

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race, and age.

• Sex: ENTRESTO worked similarly in men and women.
• Race: ENTRESTO worked similarly in all races studied.
• Age: ENTRESTO worked similarly in all age groups studied.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table below summarizes the primary endpoint results by subgroup. Results were generally similar in sex, age, and race subgroups.

Table 3. Subgroup Analysis of Primary Endpoint

Subgroup	ENTRESTO		Enalapril		Hazard Ratio	95% CI
	n (%)	Total N	n (%)	Total N		LL		UL
Overall Response/All patients	914 (22)	4187	1117 (27)	4212	0.80	0.73		0.87
Sex
Male	756 (23)	3308	902 (28)	3259	0.80	0.73	0.89
Female	158 (18)	879	215 (23)	953	0.76	0.62	0.94
Age Group
>=18 - <65>	431 (20)	2111	556 (26)	2168	0.77	0.68	0.88
>=65 years	483 (23)	2076	561 (27)	2044	0.82	0.73	0.93
>=75 years	208 (27)	784	232 (30)	779	0.86	0.72	1.04
Race
White	598 (22)	2763	717 (26)	2781	0.81	0.73	0.90
Black or African American	58 (27)	213	72 (34)	215	0.81	0.57	1.14
Asian	179 (24)	759	204 (27)	750	0.85	0.70	1.04
American Indian or Alaska Native	15 (18)	84	22 (25)	88	0.68	0.35	1.31
Other	64 (17)	368	102 (27)	378	0.63	0.46	0.86

Source: Company Clinical Trial Data and adapted from ENTRESTO Prescribing Information Section 14, Figure 4

What are the possible side effects?

The most common side effects were low blood pressure, high blood potassium levels, cough, dizziness, and poor function of the kidneys.

ENTRESTO can harm or cause death to an unborn baby and should not be taken by pregnant women.

ENTRESTO may cause an allergic reaction called angioedema. This usually appears as swelling of the face, lips, tongue, and throat. The reaction may lead to trouble breathing and death.

What are the possible side effects?

The table below summarizes side effects. The trial included 2 “run-in” periods where patients had to show they could tolerate enalapril (first run-in) and ENTRESTO (second run-in) well enough to continue into the randomized phase of the trial.  Twelve percent (12%) of patients dropped out of the “run-in” phases because of side effects; therefore, the adverse reaction rates shown below are lower than would be expected in practice. The population represented is any patient who received at least one dose of ENTRESTO or enalapril during the randomized phase of the trial.

Table 4. Adverse Reactions Reported in ≥5% of Patients Treated with ENTRESTO (double-blind period)

	ENTRESTO (n = 4203) %	Enalapril (n = 4229) %
Hypotension	18	12
Hyperkalemia	12	14
Cough	9	13
Dizziness	6	5
Renal failure/acute renal failure	5	5

Source: ENTRESTO Prescribing Information Section 6, Table 1

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race, and age.

• Sex:  The risk of side effects appeared to be similar in men and women.
• Race:  There was an increased risk of an allergic reaction called angioedema in black patients.
• Age: The risk of low blood pressure was higher in patients 65 years and older.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes angioedema by subgroup. Angioedema occurred more often with ENTRESTO than with enalapril in all groups, and was more common in Blacks.

Table 6. Subgroup Analysis of Angioedema in Safety Population*

Subgroup	ENTRESTO (N=4203) n(%)		Enalapril (N=4229)		Relative Risk	95% CI
	n (%)	Total, m	n (%)	Total, m		LL	UL
Any Angioedema	19 (<1)	4203	10 (<1)	4229	1.91	0.89	4.11
Sex
Male	12 (<1)	3316	8 (<1)	3270	1.48	0.61	3.61
Female	7 (1)	887	2 (<1)	959	3.78	0.79	18.17
Age Group
>=18 - <65	12 (1)	2120	6 (<1)	2174	2.05	0.77	5.45
>=65 years	7 (<1)	2083	4 (<1)	2055	1.73	0.51	5.89
>=75 years	1 (<1)	786	2 (<1)	783	0.50	0.05	5.48
Race
White	10 (<1)	2777	5 <1)	2796	2.01	0.69	5.88
Black or African American	5 (2)	213	1 (<1)	214	5.02	0.59	42.64
Asian	3 (<1)	757	2 (<1)	750	1.49	0.25	8.87
American Indian or Alaska Native	0	84	0	88	NE**	NE**	NE**
Other	1 (<1)	372	2 (1)	381	0.51	0.05	5.61

*Safety population=any patient who received at least one dose of study drug.
**NE=not evaluable
Source: Company Clinical Trial Data

The figure below summarizes hyperkalemia by subgroup. The frequency of hyperkalemia was similar among sex, race, and age.

Figure 4. Subgroup Analysis of Hyperkalemia (Safety Population)

Source: FDA Review

The figure below summarizes hypotension by subgroup. Hypotension was observed more in patients 65 years and older.

Figure 5. Hypotension by Subgroup (Safety Population)

Source: FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved ENTRESTO based on evidence from a clinical trial that enrolled 8442 patients with chronic heart failure. The trial was conducted in the United States, Canada, Western and Central Europe, Latin America and Asia. The same trial was used to assess the benefits and the side effects of the drug.

The figure below summarizes how many men and women were enrolled in the clinical trial.

Figure 1. Baseline Demographics by Sex

Source: Company Clinical Trial Data

The figure and table below summarize how many patients by race were enrolled in the clinical trial.

Figure 2. Baseline Demographics by Race

*Other: all other races combined
Source: Company Clinical Trial Data

Table 1. Baseline Demographics by Race

Race	Number of Patients	Percentage of Patients
White	5579	66
Asian	1510	18
Other	753	9
Black or African American	428	5
American Indian or Alaska Native	172	2

Source: Company Clinical Trial Data

Figure 3. Baseline Demographics by Age

Source: Company Clinical Trial Data

Who participated in the trials?

The table below summarizes baseline demographics for the randomized population.

Table 7. Baseline Demographics (Randomized Population)

	Treatment Groups
Demographic Parameters	ENTRESTO (N=4209) n (%)	Enalapril (N=4233) n (%)	Total (N=8442) n (%)
Sex
Male	3321 (79)	3274 (77)	6595 (78)
Female	888 (21)	959 (23)	1847 (22)
Age (years)
Mean (SD)	64 (11.5)	64 (11.2)	64 (11.4)
Median	64	64	64
(Min, Max)	18, 96	21, 96	18, 96
Age group
18 to <65	2122 (50)	2177 (51)	4299 (51)
>=65	2087 (50)	2056 (49)	4142 (49)
>=75	786 (19)	783 (19)	1569 (19)
Race
White	2780 (66)	2799 (66)	5579 (66)
Black or African American	213 (5)	215 (5)	428 (5)
American Indian or Alaskan native	84 (2)	88 (2)	172 (2)
Asian	760 (18)	750 (18)	1510 (18)
Other	372 (9)	381 (9)	753 (9)
Ethnicity
Hispanic or Latino	777 (18)	778 (18)	1555 (18)
Not Hispanic or Latino	3432 (82)	3455 (82)	6887 (82)
Region
United States	225 (5)	209 (5)	434 (5)
Canada	85 (2)	83 (2)	168 (2)
Central Europe	1398 (33)	1439 (34)	2837 (34)
Western Europe	1029 (24)	1028 (24)	2057 (24)
Asia/Pacific/Other	746 (18)	742 (18)	1488 (18)
Latin America	726 (17)	732 (17)	1458 (17)

Source: Company Clinical Trial Data

How were the trials designed?

There was one trial that evaluated the benefits and side effects of ENTRESTO. In the trial, patients with heart failure were randomly assigned to receive either ENTRESTO or an approved drug called enalapril. Neither the patients nor the health care providers knew which treatment was being given until after the trial was complete. Patients in the trial were taking other drugs for heart failure.

The trial compared patients taking ENTRESTO to patients taking enalapril by measuring the numbers of patients who died from any cause related to the heart or blood vessels or were hospitalized for heart failure.

How were the trials designed?

One multinational, randomized, double-blind trial was conducted comparing ENTRESTO and enalapril in 8442 adult patients with symptomatic chronic heart failure (New York Heart Association [NYHA] class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤40%). Patients had to have been on an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for at least four weeks and on maximally tolerated doses of beta-blockers. The trial included 2 “run-in” periods where patients had to show they could tolerate enalapril (first run-in) and ENTRESTO (second run-in) well enough to continue into the randomized phase of the trial.

The primary endpoint was the first event for the composite of cardiovascular death or hospitalization for heart failure.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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