Official Title: “Cardioprotective Benefits of Carvedilol-CR or Valsartan Added to Lisinopril”

14-week single blind, double baseline, forced-titration, cross-over comparison of the cardiac benefits of Coreg CR compared to valsartan added to existing ACE inhibition

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Subject), Active Control, Crossover Assignment, Pharmacodynamics Study

Study Primary Completion Date: April 2009

Combination drug therapy is necessary for optimal blood pressure reduction and current guidelines mandate the concomitant use of ACE inhibitors and β-blockers in most patients at significant risk for cardiovascular disease (CVD) events. There is also continuing interest in combining angiotensin receptor blockers (ARBs) with ACE inhibitors in hypertension based on the unsubstantiated belief that "more complete" renin-angiotensin system inhibition is desirable. It is more attractive physiologically to combine a long-acting β-blocker with vasodilatory actions (Coreg CR) with an ACE inhibitor because this combination addresses more directly the two fundamental hemodynamic changes needed to reduce CVD events: lowering systolic BP (afterload) and lowering heart rate; the product of the two is a reliable surrogate for reduced cardiac work. In fact, clinical trial data suggest that there is no appreciable additional BP lowering when ARBs are added to ACE inhibitors and neither class lowers heart rate. The present proposal is designed to demonstrate the superior "cardioprotection" of Coreg CR compared to ARB (valsartan) when each is added to background ACE inhibitor therapy. Principal dependent variables include ambulatory cardiac work (24-hour mean ambulatory systolic BP x heart rate) and laboratory stress responses (central systolic time-tension indices derived from arterial tonometry pre- and post-bicycle exercise).

Secondary hemodynamic variables will define changes in flow and pressure (e.g. central systolic BP and forward and reflected pressure wave estimations).

Intervention(s) in this Clinical Trial

• Drug: carvedilol
  • Coreg CR 20 mg (one week) and Coreg CR 40 mg (3 weeks).
• Drug: valsartan
  • Valsartan 160 mg (one week); valsartan 320 mg (3 weeks)

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: A
  • Valsartan 160 mg (one week); valsartan 320 mg (3 weeks)
• Active Comparator: B
  • Coreg CR 20 mg (one week) and Coreg CR 40 mg (3 weeks).

Primary Measures

• Difference in resting CTTI (cardiac work) between Coreg and valsartan.
  • Time Frame: 3 weeks, 6 weeks
    Safety Issue?: No

Inclusion Criteria:

• Subjects with residual (uncontrolled) hypertension on lisinopril monotherapy, defined as 24-hour ambulatory diastolic BP >85 mmHg.

Exclusion Criteria:

A subject meeting any of the following conditions will be excluded from the study:

• History of serious adverse effects with ACE inhibitor, Coreg, or valsartan
• Known or suspected causes of secondary hypertension (e.g., renovascular stenosis, primary hyperaldosteronism)
• Known ischemic heart disease requiring beta-blocker therapy (includes angina, prior transmural myocardial infarction, coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty or stenting within 6 months prior to study entry).
• Heart failure (NYHA Functional Class II-IV)
• Obstructive valvular heart disease or obstructive hypertrophic cardiomyopathy
• Presence of clinically significant ventricular or supraventricular arrhythmias (e.g.
• atrial fibrillation/flutter), pre-excitation syndrome, second or third degree AV block, other conduction defects necessitating the implantation of a permanent cardiac pacemaker, or sick sinus syndrome.
• Chronic kidney disease (serum creatinine >2.5 within past 6 months)
• Uncontrolled diabetes mellitus (i.e., a fasting blood glucose >200 mg/dL [>11.1 mmol/L] or hemoglobin A1c > 10%
• History of alcohol or other drug abuse within 6 months prior to enrollment
• Concomitant treatment or probable need for treatment with prohibited medications.
• NSAIDs, diabetes medications and other chronic meds are permitted if continued throughout study without dosage change.
• Any other medical condition which renders the subject unable to complete the study or which would interfere with optimal participation in the study or produce a significant risk to the subject
• Those with persistent systolic BP elevations above 179 mmHg will be discontinued from the study as will those with any significant adverse effect of medication.
• Positive pregnancy test or failure to practice adequate contraception in women of child-bearing potential
• Bronchospastic asthma requiring chronic steroid or inhaler therapy
• Any women with child-bearing potential

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: State University of New York at Buffalo

Overall Clinical Trial Officials and Contacts

Joseph L Izzo, M.D. Principal Investigator SUNY Buffalo  

Overall Contact: Peter J Osmond, M.S. 716.898.5485 pjosmond@buffalo.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00657241

Study ID Number: 111704

ClinicalTrials.gov Identifier: NCT00657241

Health Authority: United States: Institutional Review Board