Clinical trial NCT00657241: Cardioprotective Benefits of Carvedilol-CR or Valsartan Added to Lisinopril
Official title: Cardioprotective Benefits of Carvedilol-CR or Valsartan Added to Lisinopril
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypertension
Keywords: cardiac work
carvedilol CR
valsartan
tonometry
Lead sponsor: State University of New York at Buffalo
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2008-04-14
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Run-in period with lisinopril is followed by random entry into valsartan followed by carvedilol CR or carvedilol CR followed by valsartan
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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 (carvedilol 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 carvedilol 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).

Eligibility criteria: 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

Primary outcomes:
measure: Difference in Resting CTTI Between Carvedilol CR (Beta-blocker) and Valsartan (ARB) in Combination With Lisinopril.
timeFrame: End of each treatment period (4 weeks on ARB or beta-blocker)
Secondary outcomes:
measure: Heart Rate (Beats/Min)
timeFrame: End of each treatment period (4 weeks on ARB or beta-blocker)
measure: Stroke Volume (SV)
timeFrame: End of each treatment period (4 weeks on ARB or beta-blocker)
measure: Cardiac Output
timeFrame: End of each 4-week treatment period (valsartan vs. carvedilol CR)
measure: Systemic Vascular Resistance
timeFrame: End of each treatment period (4 weeks of valsartan or carvedilol CR)
measure: Central Systolic Blood Pressure
timeFrame: End of each treatment period (4 weeks of valsartan or carvedilol CR)
Other outcomes:
Locations:
city: Buffalo
country: United States
facility: Erie County Medical Center
state: New York
Study officials:
affiliation: SUNY Buffalo
name: Joseph L Izzo, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Izzo JL Jr, Yedlapati SH, Faheem SM, Younus U, Osmond PJ. Differences in mean and variability of heart rate and ambulatory rate-pressure product when valsartan or carvedilol is added to lisinopril. J Am Soc Hypertens. 2012 Nov-Dec;6(6):399-404. doi: 10.1016/j.jash.2012.08.007. Epub 2012 Oct 26.