Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension

Official Title: “A Prospective, Multinational, Multicenter Trial to Compare the Effects of Amlodipine/Benazepril to Benazepril and Hydrochlorothiazide Combined on the Reduction of Cardiovascular Morbidity and Mortality in Patients With High Risk Hypertension”

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.

Intervention(s) in this Clinical Trial

• Drug: Benazepril/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.
• Drug: Benazepril/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.
• Drug: Benazepril/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.
• Drug: Benazepril/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.
• Drug: Benazepril/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.
• Drug: Benazepril/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.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Benazepril/amlodipine
  • Patients were instructed to take one capsule with water in the morning, except on the morning of their next office visit. On office visit days, study medication was taken after completion of the visit evaluations. Following randomization, all patients were treated at Dose Level 1 for 4 weeks, followed by a forced titration to Dose Level 2 for a subsequent 4 week period. Thereafter, patients were titrated as needed to Dose Level 3 to achieve a target blood pressure of < 140/< 90 mm Hg. For patients with diabetes or chronic kidney disease, investigators were encouraged to use a target blood pressure of 130/80 mm Hg.
• Active Comparator: Benazepril/hydrochlorothiazide
  • Patients were instructed to take one capsule with water in the morning, except on the morning of their next office visit. On office visit days, study medication was taken after completion of the visit evaluations. Following randomization, all patients were treated at Dose Level 1 for 4 weeks, followed by a forced titration to Dose Level 2 for a subsequent 4 week period. Thereafter, patients were titrated as needed to Dose Level 3 to achieve a target blood pressure of < 140/< 90 mm Hg. For patients with diabetes or chronic kidney disease, investigators were encouraged to use a target blood pressure of 130/80 mm Hg.

Primary Measures

• Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity or Mortality Event
  • 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.])
    Safety Issue?: No

Secondary Measures

• Time-to-event Analysis of Percentage of Patients With a Composite Cardiovascular (CV) Morbidity Event
  • 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.])]
    Safety Issue?: No
• Time-to-event Analysis of Percentage of Patients With a Cardiovascular (CV) Mortality Event, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke
  • 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.])
    Safety Issue?: 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 exclusion criteria applied to the study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 55 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Novartis Industry

Overall Clinical Trial Officials and Contacts

Novartis Pharmaceuticals Study Chair Novartis Pharmaceuticals  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00170950

Study ID Number: CCIB002I2301

ClinicalTrials.gov Identifier: NCT00170950

Health Authority: United States: Food and Drug Administration