Cardioprotective Benefits of Carvedilol-CR or Valsartan Added to Lisinopril

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Carvedilol CR
* Drug: Valsartan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Run-in period with lisinopril is followed by random entry into valsartan followed by carvedilol CR or carvedilol CR followed by valsartan
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: (A) ARB first, beta-blocker second<br>Valsartan 160 mg daily (one week) and valsartan 320 mg daily (3 weeks) followed by carvedilol CR 20 mg daily (one week) and carvedilol CR 40 mg daily (3 weeks) | Drug: Carvedilol CR<br> <br> * Other names: Coreg CR;Drug: Valsartan<br> <br> * Other names: Diovan;|
| Active Comparator: (B) Beta-blocker first, ARB second<br>carvedilol CR 20 mg daily (one week) and carvedilol CR 40 mg daily (3 weeks) followed by valsartan 160 mg daily (1 week) and valsartan 320 mg daily (3 weeks). | Drug: Carvedilol CR<br> <br> * Other names: Coreg CR;Drug: Valsartan<br> <br> * Other names: Diovan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Resting CTTI Between Carvedilol CR (Beta-blocker) and Valsartan (ARB) in Combination With Lisinopril. | Cardiac time-tension index (CTTI) is a refined version of the rate-pressure product (RPP, historically systolic [S] BP x heart rate) reported by the SphygmoCor pulse wave analysis system used in this trial. CTTI is preferable to RPP because the latter overestimates the contribution of systolic BP to cardiac work (the formula intrinsically assumes maximum SBP throughout the entire heart period [RR interval]). In contrast, CTTI represents cardiac work during the actual systolic time interval (STI, the period of active contraction, which is about 320 ms, inversely related to HR). Thus, CTTI = [mean systolic BP during STI, mmHg] x [STI/RR] x [HR, beats/min] and is expressed as CTTI units or as mmHg*beats/min. Mean resting CTTI for SBP 150, HR 60 = about 2500 units (corresponding RPP = 9000 units). In this crossover study, the principal dependent variable is the mean within-subjects difference in supine CTTI between valsartan and carvedilol CR after 4 weeks of each treatment. | End of each treatment period (4 weeks on ARB or beta-blocker) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate (Beats/Min) | Hemodynamic variable (cardiac rate) | End of each treatment period (4 weeks on ARB or beta-blocker) | 
| Stroke Volume (SV) | Hemodynamic variable (volume pumped per heart beat) in mL per beat. Clinically, SV is reported simply as mL | End of each treatment period (4 weeks on ARB or beta-blocker) | 
| Cardiac Output | Hemodynamic variable representing whole-body blood flow (the product of heart rate and stroke volume) | End of each 4-week treatment period (valsartan vs. carvedilol CR) | 
| Systemic Vascular Resistance | Hemodynamic variable measured as mean arterial pressure (mmHg) / cardiac output (L/min) *80 in units of dyne-sec-cm[-5] | End of each treatment period (4 weeks of valsartan or carvedilol CR) | 
| Central Systolic Blood Pressure | Aortic SBP derived non-invasively from radial arterial tonometry, pulse wave analysis, and a generalized transfer function algorithm within the SphygmoCor device. Aortic SBP is different from brachial SBP and is variably lower than brachial SBP due to pulse wave transmission differences between individuals. It is expressed in mmHg. | End of each treatment period (4 weeks of valsartan or carvedilol CR) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiac work, carvedilol CR, valsartan, tonometry