Post Acute Coronary Syndrome, Myocardial Ischemia
Conditions
Keywords
Post acute coronary syndrome, Acute, coronary syndrome, B-type natriuretic peptide, N-terminal, pro-B-type natriuretic peptide, myocardial infarctions
Brief summary
The purpose of this study is to test the hypothesis that the inhibition of the renin-angiotensin-aldosterone system (RAAS) with the angiotensin receptor blocker valsartan or the renin antagonist aliskiren will improve ventricular hemodynamics, as reflected by a greater reduction in levels of N-terminal proB-type natriuretic peptide (NT-proBNP) compared to placebo in subjects stabilized following acute coronary syndrome (ACS) who are determined to be at high risk due to an elevated concentration of natriuretic peptides.
Interventions
DRUGPlacebo
Placebo tablets and capsules. In order to adequately blind the study, patients were required to take a total of 1 tablet and 2 capsules during the first 4 weeks of the study. During the remainder of the study, patients were required to take 2 tablets and 2 capsules. Each dose was taken by mouth with water at approximately 8:00 AM with or without food.
DRUGAliskiren 300 mg
Following 1 week of treatment with 75 mg of aliskiren (tablets), patients in this arm were titrated up to 150 mg of aliskiren; 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study. If a patient was not up-titrated or required down-titration, the patient continued on that dose for the remainder of the study. If 2 down-titrations were required, they stopped study drug. In order to adequately blind the study, patients were required to take 1 tablet and 2 capsules during the first 4 weeks of the study and 2 tablets and 2 capsules for the remainder of the study. Each dose was taken by mouth with water at approximately 8:00 AM.
DRUGValsartan 320 mg
Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study. If a patient was not up-titrated or required down-titration, the patient continued on that dose for the remainder of the study. If 2 down-titrations were required, they stopped study drug. In order to adequately blind the study, patients were required to take 1 tablet and 2 capsules during the first 4 weeks of the study and 2 tablets and 2 capsules for the remainder of the study. Each dose was taken by mouth with water at approximately 8:00 AM.
DRUGAliskiren/valsartan 300/320 mg
Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study. Beginning with Week 4, in addition to 320 mg valsartan, patients were treated with 75 mg of aliskiren (tablets); 1 week later patients were titrated up to 150 mg of aliskiren and 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study. If a patient was not up-titrated or required down-titration, the patient continued on that dose for the remainder of the study. If 2 down-titrations were required, they stopped study drug. In order to adequately blind the study, patients were required to take 1 tablet and 2 capsules during the first 4 weeks of the study and 2 tablets and 2 capsules for the remainder of the study. Each dose was taken by mouth with water at approximately 8:00 AM.
Sponsors
The TIMI Study Group
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female outpatients 18 years old or older * Subjects who are hospitalized for ischemic chest discomfort at rest lasting at least 10 minutes and consistent with cardiac ischemia * Final diagnosis of acute coronary syndrome * Elevated concentrations of natriuretic peptide 3-10 days after admission for their qualifying acute coronary syndrome event
Exclusion criteria
* Known or suspected contraindications, including history of allergy or hypersensitivity to angiotensin receptor blockers (ARBs), renin antagonists, or to drugs with similar chemical structures. * Presence of clinically overt heart failure * Known evidence of left ventricular systolic dysfunction * Percutaneous coronary intervention (PCI) less than 24 hours before randomization. * Patients on chronic ACEI or ARB therapy for whom therapy with an ACEI or ARB is clinically required with no reasonable alternative therapy available. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 8 | Baseline to Week 8 | Blood samples for the measurement of NT-proBNP were collected, processed, and shipped to the TIMI Biomarker Core Laboratory, Boston MA for storage and analysis. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in B-type Natriuretic Peptide (BNP) at Week 8 | Baseline to Week 8 | Blood samples for the measurement of BNP were collected, processed, and shipped to the TIMI Biomarker Core Laboratory, Boston MA for storage and analysis. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline. |
| Percentage of Patients With a Cardiac Event | Baseline to Week 8 | A cardiac event was defined as at least one of the following events: Cardiovascular death, recurrent myocardial infarction (MI), or hospitalization for congestive heart failure (CHF), all to be confirmed by adjudication. |
| Percentage of Patients With a Composite Clinical-biochemical Event | Baseline to Week 8 | A composite clinical-biochemical event was defined as at least one of the following events: cardiovascular death confirmed by adjudication, recurrent MI confirmed by adjudication, hospitalization for CHF confirmed by adjudication, and/or NT-proBNP =\> 200 pg/mL. |
Countries
Belgium, Canada, Czechia, Germany, Hungary, Netherlands, Poland, Russia, Spain, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo tablets and capsules | 280 |
| Aliskiren 300 mg Following 1 week of treatment with 75 mg of aliskiren (tablets), patients in this arm were titrated up to 150 mg of aliskiren; 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study. | 271 |
| Valsartan 320 mg Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study. | 269 |
| Aliskiren/Valsartan 300/320 mg Following 1 week of treatment with 80 mg of valsartan (capsules), patients in this arm were titrated up to 160 mg of valsartan; 1 week later they were titrated up to 320 mg valsartan for the remainder of the study. Beginning with Week 4, in addition to 320 mg valsartan, patients were treated with 75 mg of aliskiren (tablets); 1 week later patients were titrated up to 150 mg of aliskiren and 1 week later they were titrated up to 300 mg aliskiren for the remainder of the study. | 281 |
| Total | 1,101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 2 | 2 | 2 | 4 |
| Overall Study | Administrative problems | 8 | 9 | 2 | 4 |
| Overall Study | Adverse Event | 27 | 37 | 25 | 33 |
| Overall Study | Death | 2 | 4 | 4 | 2 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 | 2 | 2 |
| Overall Study | Missing | 0 | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 2 | 3 | 1 |
| Overall Study | Subject no longer requires study drug | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 15 | 16 | 17 |
Baseline characteristics
| Characteristic | Placebo | Aliskiren 300 mg | Valsartan 320 mg | Aliskiren/Valsartan 300/320 mg | Total |
|---|---|---|---|---|---|
| Age Continuous | 63 years STANDARD_DEVIATION 11.8 | 63 years STANDARD_DEVIATION 11.7 | 64 years STANDARD_DEVIATION 11.6 | 63 years STANDARD_DEVIATION 11.1 | 63 years STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 103 Participants | 86 Participants | 72 Participants | 87 Participants | 348 Participants |
| Sex: Female, Male Male | 177 Participants | 185 Participants | 197 Participants | 194 Participants | 753 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 64 / 278 | 61 / 264 | 51 / 268 | 57 / 279 |
| serious Total, serious adverse events | 26 / 278 | 39 / 264 | 33 / 268 | 46 / 279 |
Outcome results
Primary
Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 8
Blood samples for the measurement of NT-proBNP were collected, processed, and shipped to the TIMI Biomarker Core Laboratory, Boston MA for storage and analysis. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline.
Time frame: Baseline to Week 8
Population: Full analysis set: All patients who were correctly randomized. Missing baseline values were not imputed. The last post-baseline biomarker measurement collected was used for analysis. In the aliskiren treated group, 4 patients never received study drug but were included in the full analysis set but were not included in any efficacy analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 8 | 0.582 pg/mL |
| Aliskiren 300 mg | Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 8 | 0.563 pg/mL |
| Valsartan 320 mg | Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 8 | 0.614 pg/mL |
| Aliskiren/Valsartan 300/320 mg | Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 8 | 0.635 pg/mL |
Secondary
Change From Baseline in B-type Natriuretic Peptide (BNP) at Week 8
Blood samples for the measurement of BNP were collected, processed, and shipped to the TIMI Biomarker Core Laboratory, Boston MA for storage and analysis. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline.
Time frame: Baseline to Week 8
Population: Full analysis set: All patients who were correctly randomized. Missing baseline values were not imputed. The last post-baseline biomarker measurement collected was used for analysis. In the aliskiren treated group, 4 patients never received study drug but were included in the full analysis set but were not included in any efficacy analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in B-type Natriuretic Peptide (BNP) at Week 8 | 0.642 pg/mL |
| Aliskiren 300 mg | Change From Baseline in B-type Natriuretic Peptide (BNP) at Week 8 | 0.597 pg/mL |
| Valsartan 320 mg | Change From Baseline in B-type Natriuretic Peptide (BNP) at Week 8 | 0.670 pg/mL |
| Aliskiren/Valsartan 300/320 mg | Change From Baseline in B-type Natriuretic Peptide (BNP) at Week 8 | 0.682 pg/mL |
Secondary
Percentage of Patients With a Cardiac Event
A cardiac event was defined as at least one of the following events: Cardiovascular death, recurrent myocardial infarction (MI), or hospitalization for congestive heart failure (CHF), all to be confirmed by adjudication.
Time frame: Baseline to Week 8
Population: Full analysis set: All patients who were correctly randomized. Missing baseline values were not imputed. The last post-baseline biomarker measurement collected was used for analysis. In the aliskiren treated group, 4 patients never received study drug but were included in the full analysis set but were not included in any efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With a Cardiac Event | 2.9 Percentage of patients |
| Aliskiren 300 mg | Percentage of Patients With a Cardiac Event | 4.9 Percentage of patients |
| Valsartan 320 mg | Percentage of Patients With a Cardiac Event | 4.9 Percentage of patients |
| Aliskiren/Valsartan 300/320 mg | Percentage of Patients With a Cardiac Event | 4.0 Percentage of patients |
Secondary
Percentage of Patients With a Composite Clinical-biochemical Event
A composite clinical-biochemical event was defined as at least one of the following events: cardiovascular death confirmed by adjudication, recurrent MI confirmed by adjudication, hospitalization for CHF confirmed by adjudication, and/or NT-proBNP =\> 200 pg/mL.
Time frame: Baseline to Week 8
Population: Full analysis set: All patients who were correctly randomized. Missing baseline values were not imputed. The last post-baseline biomarker measurement collected was used for analysis. In the aliskiren treated group, 4 patients never received study drug but were included in the full analysis set but were not included in any efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With a Composite Clinical-biochemical Event | 79.5 Percentage of patients |
| Aliskiren 300 mg | Percentage of Patients With a Composite Clinical-biochemical Event | 73.5 Percentage of patients |
| Valsartan 320 mg | Percentage of Patients With a Composite Clinical-biochemical Event | 77.2 Percentage of patients |
| Aliskiren/Valsartan 300/320 mg | Percentage of Patients With a Composite Clinical-biochemical Event | 75.2 Percentage of patients |