The Effects of Systolic Blood Pressure Lowering on Diastolic Function Using Valsartan + Amlodipine in Patients With Hypertension and Diastolic Dysfunction

A Multi-center, Prospective, Randomized, Open-label Study With Blinded Outcome Evaluation to Evaluate the Effects of Systolic Blood Pressure Lowering to Different Targets (Less Than 130 mmHg vs. Less Than 140 mmHg) on Diastolic Function Using Valsartan + Amlodipine in Patients With Hypertension and Diastolic Dysfunction

The purpose of this study is to determine the effects of treatment with valsartan + amlodipine to a target systolic blood pressure (SBP)<130 mmHg compared to the Joint National Commission on the Treatment of Hypertension 7 recommended target SBP of <140 mmHg on the intrinsic diastolic properties of the myocardium in patients with hypertension and echocardiographic evidence of diastolic dysfunction.

Study Overview

• Status: Completed
• Conditions: Hypertension; Diastolic Dysfunction
• Intervention / Treatment: Drug: valsartan; Drug: amlodipine

• Study Type: Interventional
• Enrollment (Actual): 229
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • USA, New Jersey, United States
      • Novartis Investigative Sites

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 45 years or older
• Male and female patients are eligible. Female patients must be post-menopausal for one year, surgically sterile, or using effective contraceptive methods such as a double barrier method with spermicide, an intra-uterine device, or hormonal contraceptives. Post-menopausal women on a stable dose of hormone replacement therapy (HRT) for at least three (3) months prior to the screening visit are eligible for the study.
• Uncontrolled systolic hypertension on a maximum of two (2) antihypertensive medications at the time of screening.
• Echocardiographic ejection fraction ≥50% and evidence of diastolic dysfunction.
• Provide written informed consent to participate in the study prior to any screening or study procedures
• Have the ability to communicate well and comply with all study requirements

Exclusion Criteria:

• Severe hypertension defined as a MSSBP >200 mmHg and/or MSDBP >120 mmHg.
• History of a secondary cause of hypertension including but not limited to: coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing's disease, pheochromocytoma, polycystic kidney disease, etc.
• Ejection fraction <50 %
• History of stroke, transient ischemic attack, myocardial infarction, coronary artery bypass graft surgery, or unstable angina pectoris within 6 months of screening
• Presence of clinically significant ventricular or supraventricular arrhythmias (e.g. atrial fibrillation/flutter)
• History of congestive heart failure
• History of diabetes mellitus
• History of renal impairment with serum creatinine >2.0 mg/dL at screening, history of dialysis, or history of nephritic syndrome
• Antihypertensive therapy with three (3) or more medications at the time of screening
• Active and/or treated malignancy of any organ system within twelve (12) months of enrollment, with the exception of localized basal cell carcinoma of the skin
• 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 (>5 mIU/ml)
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: barrier method with spermicidal agent, an intrauterine device, hormonal contraceptives, or total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug including, but not limited to, any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active, or active inflammatory bowel syndrome within 12 months prior to Visit 1, currently active gastritis, ulcers, or gastrointestinal/rectal bleeding, or urinary tract obstruction regarded as clinically meaningful by the investigator
• Pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury within 12 months prior to Visit 1
• Any serum AST or ALT elevation two (2) times the upper limit of normal

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard treatment regimen; (Valsartan + Amlodipine to target SBP of < 140 mmHg)	Drug: valsartan; 160 mg or 320 mg tablets once a day; Other Names: Diovan; Drug: amlodipine; 5 mg or 10 mg tablets once a day; Other Names: Norvasc
Experimental: Intensive treatment regimen; (Valsartan + Amlodipine to target SBP < 130 mm Hg)	Drug: valsartan; 160 mg or 320 mg tablets once a day; Other Names: Diovan; Drug: amlodipine; 5 mg or 10 mg tablets once a day; Other Names: Norvasc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Lateral Mitral Annular Myocardial Relaxation Velocity	Change from baseline in lateral mitral annular myocardial relaxation velocity (E') at Week 24	Baseline to 24 weeks after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Left Atrial Size	Change from baseline in left atrial size at Week 24	Baseline to 24 weeks after treatment
Change in Ratio of Peak E Wave Velocity/Lateral Mitral Annular Myocardial Relaxation Velocity	Change from baseline in peak E-wave velocity / lateral mitral annular myocardial relaxation velocity (E/E') at Week 24	Baseline to 24 weeks after treatment
Percent Change From Baseline in Vascular Stiffness	Percent change from baseline in Vascular Stiffness (measured by radial augmentation index [AI]) at Weeks 8 and 24	Baseline to 8 and 24 weeks after treatment
Change in Mean Sitting Systolic Blood Pressure (msSBP)	Change from baseline in msSBP at Weeks 8 and 24	Baseline to 8 and 24 weeks after treatment
Change in Mean Sitting Diastolic Blood Pressure (msDBP)	Change from baseline in msDBP at Weeks 8 and 24	Baseline to 8 and 24 weeks after treatment
Change in Estimated Central Aortic Pressure	Change from baseline in estimated central aortic pressure at Weeks 8 and 24	Baseline to 8 and 24 weeks after treatment

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Solomon SD, Verma A, Desai A, Hassanein A, Izzo J, Oparil S, Lacourciere Y, Lee J, Seifu Y, Hilkert RJ, Rocha R, Pitt B; Exforge Intensive Control of Hypertension to Evaluate Efficacy in Diastolic Dysfunction Investigators. Effect of intensive versus standard blood pressure lowering on diastolic function in patients with uncontrolled hypertension and diastolic dysfunction. Hypertension. 2010 Feb;55(2):241-8. doi: 10.1161/HYPERTENSIONAHA.109.138529. Epub 2009 Dec 7.

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): January 1, 2008
• Study Completion (Actual): January 1, 2008

Study Registration Dates

• First Submitted: August 30, 2007
• First Submitted That Met QC Criteria: August 30, 2007
• First Posted (Estimate): August 31, 2007

Study Record Updates

• Last Update Posted (Estimate): April 23, 2012
• Last Update Submitted That Met QC Criteria: April 19, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: Hypertension; amlodipine; diastolic dysfunction; systolic blood pressure; valsartan
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Heart Murmurs; Hypertension; Systolic Murmurs; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Amlodipine; Valsartan
• Other Study ID Numbers: CVAA489AUS01