Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension - Full Text View

Sponsor:	Novartis
Information provided by:	Novartis
ClinicalTrials.gov Identifier:	NCT00170950

Purpose

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.

Condition	Intervention	Phase
Hypertension	Drug: Benazepril/amlodipine 20/5 mg - Dose Level 1 from Day 1 to Month 1 Drug: Benazepril/amlodipine 40/5 mg - Dose Level 2 from Month 1 to Month 2 Drug: Benazepril/amlodipine 40/10 mg - Dose Level 3 from Month 2 to Month 3 and thereafter Drug: Benazepril/hydrochlorothiazide 20/12.5 mg - Dose Level 1 from Day 1 to Month 1 Drug: Benazepril/hydrochlorothiazide 40/12.5 mg - Dose Level 2 from Month 1 to Month 2 Drug: Benazepril/hydrochlorothiazide 40/25 mg - Dose Level 3 from Month 2 to Month 3 and thereafter	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: High Blood Pressure

Drug Information available for: Hydrochlorothiazide Benazepril hydrochloride Benazepril Amlodipine Amlodipine besylate Lotrel

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome 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.]) ] [ Designated as safety issue: No ]
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 Outcome 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.])] ] [ Designated as safety issue: No ]
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 [ 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.]) ] [ Designated as safety issue: No ]
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.

Enrollment:	11506
Study Start Date:	October 2003
Study Completion Date:	May 2008
Primary Completion Date:	January 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.	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.
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.	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

Assigned Interventions

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.

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.

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.

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.

Eligibility

Ages Eligible for Study:	55 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00170950

Locations

United States, New Jersey
Novartis Pharmaceuticals
E. Hanover, New Jersey, United States, 07936
Denmark
sites in Denmark
Denmark, Denmark
Finland
sites in Finland
Finland, Finland
Norway
sites in Norway
Norway, Norway
Sweden
sites in Sweden
Sweden, Sweden

Sponsors and Collaborators

Novartis

Investigators

Study Chair:

Novartis Pharmaceuticals

More Information

Publications:

Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 4;359(23):2417-28.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Weber MA, Bakris GL, Jamerson K, Weir M, Kjeldsen SE, Devereux RB, Velazquez EJ, Dahlöf B, Kelly RY, Hua TA, Hester A, Pitt B; ACCOMPLISH Investigators. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol. 2010 Jun 29;56(1):77-85.

Bakris GL, Sarafidis PA, Weir MR, Dahlöf B, Pitt B, Jamerson K, Velazquez EJ, Staikos-Byrne L, Kelly RY, Shi V, Chiang YT, Weber MA; ACCOMPLISH Trial investigators. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet. 2010 Apr 3;375(9721):1173-81. Epub 2010 Feb 18.

Responsible Party:	Study Diorector, Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00170950 History of Changes
Obsolete Identifiers:	NCT00097864
Other Study ID Numbers:	CCIB002I2301
Study First Received:	September 10, 2005
Results First Received:	January 13, 2011
Last Updated:	April 19, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Novartis:

cardiovascular morbidity
cardiovascular mortality
benazepril
amlodipine
high risk population

Additional relevant MeSH terms:

Hypertension
Vascular Diseases
Cardiovascular Diseases
Benazepril
Antihypertensive Agents
Hydrochlorothiazide
Amlodipine
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Diuretics

Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium Channel Blockers
Vasodilator Agents
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on February 09, 2012