Hypertension
Conditions
Keywords
cardiovascular morbidity, cardiovascular mortality, benazepril, amlodipine, high risk population
Brief summary
A comparison study of two combination drugs, amlodipine/benazepril and benazepril/HCTZ to evaluate the effectiveness of the combination on reducing heart disease and death in a high risk hypertensive population.
Interventions
DRUGBenazepril/amlodipine 20/5 mg - Dose Level 1 from Day 1 to Month 1
Benazepril hydrochloride (HCl)/amlodipine besylate 10/5 mg capsules for oral administration once daily.
DRUGBenazepril/amlodipine 40/5 mg - Dose Level 2 from Month 1 to Month 2
Benazepril hydrochloride (HCl)/amlodipine besylate 20/5 mg capsules for oral administration once daily.
DRUGBenazepril/amlodipine 40/10 mg - Dose Level 3 from Month 2 to Month 3 and thereafter
Benazepril hydrochloride (HCl)/amlodipine besylate: 40/10 mg capsules for oral administration once daily. Patients titrated to this dose level had the possibility of subsequent free add-on antihypertensive agents after month 3 based on target blood pressure.
DRUGBenazepril/hydrochlorothiazide 20/12.5 mg - Dose Level 1 from Day 1 to Month 1
Benazepril hydrochloride (HCl)/hydrochlorothiazide (HCTZ) 20/12.5 mg capsules for oral administration once daily.
DRUGBenazepril/hydrochlorothiazide 40/12.5 mg - Dose Level 2 from Month 1 to Month 2
Benazepril hydrochloride (HCl)/hydrochlorothiazide (HCTZ) 40/12.5 mg capsules for oral administration once daily.
DRUGBenazepril/hydrochlorothiazide 40/25 mg - Dose Level 3 from Month 2 to Month 3 and thereafter
Benazepril hydrochloride (HCl)/hydrochlorothiazide (HCTZ) 40/25 mg capsules for oral administration once daily. Patients titrated to this dose level had the possibility of subsequent free add-on antihypertensive agents after month 3 based on target blood pressure.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 55 years of age. * Previously untreated or treated hypertension. * For patients \>= 60 years, evidence of at least one CV disease or target organ damage, or for patients 55-59 years evidence of at least two CV diseases or target organ damage from two different organ systems as defined in the protocol.
Exclusion criteria
* Allergy to any of the drugs administered in this trial. * Current angina pectoris (ie, no anginal event requiring NTG within 1 month prior to Visit 1). * Secondary hypertension. * Refractory hypertension defined as SBP \>= 180 mmHg and/or DBP \>= 110 mmHg unresponsive to triple-drug regimens of sympatholytics, diuretics and vasodilators. * History of symptomatic heart failure (NYHA classes II-IV) or ejection fraction \< 40%. * Myocardial infarction, coronary revascularization (CABG or PCI), unstable angina within one month of Visit 1. * Stroke or transient ischemic event (TIA) within 3 months of Visit 1. * Significant obstructive valvular cardiovascular disease or any valvular disease expected to lead to surgery during the course of the study. * Evidence of hepatic disease (AST or ALT values \>= 2 X upper limit of normal). * Impaired renal function (serum creatinine \>= 2.5 mg/dL (221 µmol/L)). * Baseline serum potassium of \> 5.2 meq/L not on potassium supplements. * History of malignancy including leukemia and lymphoma (but not basal cell skin cancer) within the last 5 years. * History of clinically significant auto immune disorders such as Systemic Lupus Erythematosus. * Significant non-cardiovascular illness or condition likely to result in death prior to trial completion, e.g., major organ transplant (life expectancy \<5 years). * Significant cardiovascular disease such as an aortic aneurysm ≥ 6 cm, likely requiring surgical intervention during the course of the study. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity or Mortality Event | For each patient, baseline to time of first CV morbidity or mortality event (or last exposure if no event occurred). (Median duration of exposure was 33.4 months. [25th to 75th percentiles: 21 to 41 months.]) | CV morbidity was defined as non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina, resuscitated sudden death, or coronary revascularization procedure. CV mortality was defined as death due to MI, stroke, coronary intervention, congestive heart failure (CHF), sudden cardiac death, or other CV causes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity Event | For each patient, baseline to time of first CV morbidity event (or last exposure if no event occurred). (Median duration of exposure was 33.4 months. [25th to 75th percentiles: 21 to 41 months.])] | Cardiovascular morbidity was defined as including any of the following events: non-fatal MI, non-fatal stroke, hospitalization for unstable angina, resuscitated sudden death, or coronary revascularization procedure (PCI or CABG). |
| Time-to-event Analysis of Percentage of Patients With a Cardiovascular (CV) Mortality Event, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke | For each patient, baseline to time of first CV mortality event, MI (non-fatal), or stroke (non-fatal) (or last exposure if no event occurred). (Median duration of exposure was 33.4 months. [25th to 75th percentiles: 21 to 41 months.]) | CV mortality was defined as death due to sudden cardiac death, fatal MI, fatal stroke, coronary intervention, congestive heart failure (CHF), or other CV causes. |
Countries
Denmark, Finland, Norway, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Benazepril/Amlodipine Benazepril hydrochloride (HCl)/amlodipine besylate: 20/5 mg (Dose Level 1 from Day 1 to Month 1), 40/5 mg (Dose Level 2 from Month 1 to Month 2), and 40/10 mg (Dose Level 3 from Month 2 to Month 3 and thereafter) capsules for oral administration once daily | 5,744 |
| Benazepril/Hydrochlorothiazide Benazepril hydrochloride (HCl)/hydrochlorothiazide (HCTZ): 20/12.5 mg (Dose Level 1 from Day 1 to Month 1), 40/12.5 mg (Dose Level 2 from Month 1 to Month 2), and 40/25 mg (Dose Level 3 from Month 2 to Month 3 and thereafter) capsules for oral administration once daily | 5,761 |
| Total | 11,505 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 236 | 274 |
| Overall Study | Lost to Follow-up | 134 | 115 |
| Overall Study | Missing | 2 | 1 |
| Overall Study | Termination Data Not Recorded | 17 | 22 |
| Overall Study | Withdrawal by Subject | 496 | 498 |
Baseline characteristics
| Characteristic | Benazepril/Amlodipine | Benazepril/Hydrochlorothiazide | Total |
|---|---|---|---|
| Age, Continuous | 68.4 Years STANDARD_DEVIATION 6.86 | 68.3 Years STANDARD_DEVIATION 6.86 | 68.4 Years STANDARD_DEVIATION 6.86 |
| Sex: Female, Male Female | 2296 Participants | 2246 Participants | 4542 Participants |
| Sex: Female, Male Male | 3448 Participants | 3515 Participants | 6963 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3,077 / 5,740 | 2,663 / 5,757 |
| serious Total, serious adverse events | 1,844 / 5,740 | 2,026 / 5,757 |
Outcome results
Primary
Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity or Mortality Event
CV morbidity was defined as non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina, resuscitated sudden death, or coronary revascularization procedure. CV mortality was defined as death due to MI, stroke, coronary intervention, congestive heart failure (CHF), sudden cardiac death, or other CV causes.
Time frame: For each patient, baseline to time of first CV morbidity or mortality event (or last exposure if no event occurred). (Median duration of exposure was 33.4 months. [25th to 75th percentiles: 21 to 41 months.])
Population: Intent-to-treat population: All randomized patients by assigned treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Benazepril/Amlodipine | Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity or Mortality Event | 9.6 Percentage of Patients with an event |
| Benazepril/Hydrochlorothiazide | Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity or Mortality Event | 11.8 Percentage of Patients with an event |
Secondary
Time-to-event Analysis of Percentage of Patients With a Cardiovascular (CV) Mortality Event, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke
CV mortality was defined as death due to sudden cardiac death, fatal MI, fatal stroke, coronary intervention, congestive heart failure (CHF), or other CV causes.
Time frame: For each patient, baseline to time of first CV mortality event, MI (non-fatal), or stroke (non-fatal) (or last exposure if no event occurred). (Median duration of exposure was 33.4 months. [25th to 75th percentiles: 21 to 41 months.])
Population: Intent-to-treat population: All randomized patients by assigned treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Benazepril/Amlodipine | Time-to-event Analysis of Percentage of Patients With a Cardiovascular (CV) Mortality Event, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke | 5.0 Percentage of Patients with an Event |
| Benazepril/Hydrochlorothiazide | Time-to-event Analysis of Percentage of Patients With a Cardiovascular (CV) Mortality Event, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke | 6.3 Percentage of Patients with an Event |
Secondary
Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity Event
Cardiovascular morbidity was defined as including any of the following events: non-fatal MI, non-fatal stroke, hospitalization for unstable angina, resuscitated sudden death, or coronary revascularization procedure (PCI or CABG).
Time frame: For each patient, baseline to time of first CV morbidity event (or last exposure if no event occurred). (Median duration of exposure was 33.4 months. [25th to 75th percentiles: 21 to 41 months.])]
Population: Intent-to-treat population: All randomized patients by assigned treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Benazepril/Amlodipine | Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity Event | 8.6 Percentage of Patients with an Event |
| Benazepril/Hydrochlorothiazide | Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity Event | 10.3 Percentage of Patients with an Event |