Hearth Failure With Reduced Ejection Fraction (HFrEF)
Conditions
Keywords
HFrEF,, ACEi,, ACE inhibitor,, ARBs,, systolic heart failure,, chronic heart failure,, CHF,, reduced EF,, Ejection Fraction
Brief summary
The primary purpose of the study was to describe the tolerability of treatment with the optimal dose of LCZ696 (97 mg sacubitril / 103 mg valsartan bid), over six (6) months, in patients with heart failure with reduced ejection fraction (HFrEF) in Canada. The study was also to describe the overall tolerability, effectiveness and safety of LCZ696 for the management of HFrEF over 12 months of treatment, as well as describe the patterns of LCZ696 up and down dose titrations occurring during the management of patients with HFrEF.
Interventions
All patients were treated with the LCZ696 (sacubitril and valsartan) tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Written informed consent must be obtained before any assessment is performed. 2. Age ≥ 18 years and ≤ 80 years. 3. Males or females. 4. Diagnosis of Heart Failure NYHA class II-III. 5. Diagnosis of Heart Failure with reduced Ejection Fraction (LVEF =\< 40%) and NYHA class II or III. 6. Stable on any dose of ACEI or ARB prior to enrolment in the study 7. Stable on any dose of a beta-blocker prior to enrolment in the study. 8. Eligible for treatment with LCZ696 as per Canadian product monograph. 9. Treated as an outpatient. 10. Signed an informed consent agreeing to participate in the study. Key
Exclusion criteria
1. Symptomatic hypotension and/or a SBP \< 100 mmHg at baseline visit. 2. Estimated GFR \< 30 mL/min/1.73m\^2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at baseline visit. 3. Known history of angioedema related to previous ACEI or ARBs therapy, or history of hereditary or idiopathic angioedema. 4. Requirement of concomitant treatment with both ACEIs and ARBs. 5. Concurrent participation in other clinical trials or receiving other investigational drugs within 30 days of enrollment. 6. Hypersensitivity to the active substances, sacubitril or valsartan, or to any of the excipients. 7. Concomitant use of aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR \<60ml/min/1.73m\^2). 8. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes. 9. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. 10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. 11. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception methods are described in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants on LCZ696 200 mg Bid at Month 6 | Month 6 | The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 6. Only descriptive analysis done. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Requiring Down-titration From LCZ696 200 mg | Month 12 | The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the percentage of patients on LCZ696 200mg requiring down-titration. Only descriptive analysis done. |
| Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment | Month 12 | The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the number of down-titration during the 12 months treatment period. Dow-titration schemes considered for the analysis are 200 mg to 100 mg; 100 mg to 50 mg; and 50 mg to 0 mg (i.e. treatment discontinuation). The down-titration scheme of 50mg to 0 mg was taken in account in this analysis to ensure to reflect all actual changes in dose. Only descriptive analysis done. |
| Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12 | Baseline, Month 6 and Month 12 | The impact of LCZ696 on functional exercise capacity was measured by the Six Minute Walk Test at 6 and 12 months. The 6MWT measures the distance an individual is able to walf over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. Only descriptive analysis done. |
| Percentage of Participants on LCZ696 200 mg Bid at Month 12 | Month 12 | The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 12. Only descriptive analysis done. |
| Median Time to Reach LCZ696 200 mg | Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12 | To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done. |
| Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time | Baseline, Month 6 and Month 12 | To describe the adherence to guideline recommended dosing of beta-blockers and MRAs at 6 and 12 months of treatment of LCZ696. Only descriptive analysis done. |
| Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg | Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12 | To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done. |
Countries
Canada
Participant flow
Recruitment details
This study was conducted in 32 study centers in Canada
Pre-assignment details
Approximately 300 patients with HFrEF were planned for enrolling into the study. A total of 302 patients received at least one dose of LCZ696 and were included in the Full Analysis Set (FAS). The analysis of the primary endpoint was based on the FAS.
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 (Sacubitril / Valsartan) All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable. | 302 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 16 |
| Overall Study | Death | 9 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Non-compliance with study treatment | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Protocol-defined stopping criteria | 1 |
| Overall Study | Protocol Deviation | 1 |
| Overall Study | Subject/guardian decision | 4 |
| Overall Study | Withdrawal of Informed Consent | 3 |
Baseline characteristics
| Characteristic | LCZ696 (Sacubitril / Valsartan) |
|---|---|
| Age, Continuous | 64.47 Years STANDARD_DEVIATION 10.7659 |
| Race/Ethnicity, Customized Asian | 15 Participants |
| Race/Ethnicity, Customized Black | 8 Participants |
| Race/Ethnicity, Customized Caucasian | 271 Participants |
| Race/Ethnicity, Customized Native American | 4 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 4 Participants |
| Sex: Female, Male Female | 62 Participants |
| Sex: Female, Male Male | 240 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 302 |
| other Total, other adverse events | 98 / 302 |
| serious Total, serious adverse events | 47 / 302 |
Outcome results
Primary
Percentage of Participants on LCZ696 200 mg Bid at Month 6
The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 6. Only descriptive analysis done.
Time frame: Month 6
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants on LCZ696 200 mg Bid at Month 6 | 64.6 Percentage of Participants |
Secondary
Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12
The impact of LCZ696 on functional exercise capacity was measured by the Six Minute Walk Test at 6 and 12 months. The 6MWT measures the distance an individual is able to walf over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. Only descriptive analysis done.
Time frame: Baseline, Month 6 and Month 12
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12 | Value at Baseline (Day 1) | 392.62 Meter (m) | Standard Deviation 139.3277 |
| LCZ696 (Sacubitril / Valsartan) | Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12 | Change from Baseline at Month 6 | 11.99 Meter (m) | Standard Deviation 67.5725 |
| LCZ696 (Sacubitril / Valsartan) | Change From Baseline in the Six Minute Walk Test (6MWT) at Month 6 and Month 12 | Change from Baseline at Month 12 | 8.19 Meter (m) | Standard Deviation 71.3619 |
Secondary
Median Time to Reach LCZ696 200 mg
To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.
Time frame: Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Median Time to Reach LCZ696 200 mg | 37.00 Days |
Secondary
Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time
To describe the adherence to guideline recommended dosing of beta-blockers and MRAs at 6 and 12 months of treatment of LCZ696. Only descriptive analysis done.
Time frame: Baseline, Month 6 and Month 12
Population: The Safety Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time | Baseline | 298 Participants |
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time | Month 6 | 272 Participants |
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants on Guideline Recommended Dose of Beta-blockers and MRAs Over Time | Month 12 | 261 Participants |
Secondary
Percentage of Participants on LCZ696 200 mg Bid at Month 12
The tolerability of LCZ696 was defined as the percentage of patients on LCZ696 at the dose of 97 mg sacubitril / 103 mg valsartan twice daily (bid) who did not experience down titration or treatment discontinuation because of adverse events while on this dose at month 12. Only descriptive analysis done.
Time frame: Month 12
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants on LCZ696 200 mg Bid at Month 12 | 62.3 Percentage of Participants |
Secondary
Percentage of Participants Requiring Down-titration From LCZ696 200 mg
The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the percentage of patients on LCZ696 200mg requiring down-titration. Only descriptive analysis done.
Time frame: Month 12
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants Requiring Down-titration From LCZ696 200 mg | 11.92 Percentage of Participants |
Secondary
Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment
The impact of the titration scheme on the tolerability of patients maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid was defined as the number of down-titration during the 12 months treatment period. Dow-titration schemes considered for the analysis are 200 mg to 100 mg; 100 mg to 50 mg; and 50 mg to 0 mg (i.e. treatment discontinuation). The down-titration scheme of 50mg to 0 mg was taken in account in this analysis to ensure to reflect all actual changes in dose. Only descriptive analysis done.
Time frame: Month 12
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment | 200 mg dose level | 188 Participants |
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment | 100 mg dose level | 44 Participants |
| LCZ696 (Sacubitril / Valsartan) | Percentage of Participants With Down-titration Changes From LCZ696 200 mg During 12 Months of Treatment | 50 mg dose level | 28 Participants |
Secondary
Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg
To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan bid and 49 mg sacubitril / 51 mg valsartan bid) of LCZ696. Only descriptive analysis done.
Time frame: Baseline, Week 2, Week 4, Month 3, Month 6 and Month 12
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 (Sacubitril / Valsartan) | Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg | 50- 100 mg bid level | 21.44 Days | Standard Deviation 23.1799 |
| LCZ696 (Sacubitril / Valsartan) | Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg | 100- 200 mg bid level | 27.37 Days | Standard Deviation 28.5601 |
| LCZ696 (Sacubitril / Valsartan) | Time to Each Up-titration to LCZ696 100 mg and LCZ696 200 mg | 50- 200 mg bid level | 46.61 Days | Standard Deviation 36.9439 |