Cardioprotective Benefits of Carvedilol-CR or Valsartan Added to Lisinopril

NCT00657241 | Completed Phase 3 Results DMC

• 1 other identifier: 111704
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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

Conditions

Hypertension

Keywords

cardiac work; carvedilol CR; valsartan; tonometry

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Heart Rate (Beats/Min)

  End of each treatment period (4 weeks on ARB or beta-blocker)

• Stroke Volume (SV)

  End of each treatment period (4 weeks on ARB or beta-blocker)

• Cardiac Output

  End of each 4-week treatment period (valsartan vs. carvedilol CR)

• Systemic Vascular Resistance

  End of each treatment period (4 weeks of valsartan or carvedilol CR)

• Central Systolic Blood Pressure

  End of each treatment period (4 weeks of valsartan or carvedilol CR)

Study Arms (2)

(A) ARB first, beta-blocker second

ACTIVE COMPARATOR

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; Drug: Valsartan

(B) Beta-blocker first, ARB second

ACTIVE COMPARATOR

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; Drug: Valsartan

Interventions

Carvedilol CR DRUG

Also known as: Coreg CR

(A) ARB first, beta-blocker second; (B) Beta-blocker first, ARB second

Valsartan DRUG

Also known as: Diovan

(A) ARB first, beta-blocker second; (B) Beta-blocker first, ARB second

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• State University of New York at Buffalo: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Erie County Medical Center

Buffalo, New York, 14215, United States

Location

Related Publications (1)

• 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.

  PMID: 23107894 DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Carvedilol; Valsartan

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring; Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Limitations and Caveats

Short duration of trial may miss long-term effects. Statistical powering for primary outcome may preclude secondary analyses.

Results Point of Contact

• Title: Joseph L. Izzo Jr. M.D.
• Organization: SUNYBuffalo

jizzo@buffalo.edu

716-898-5625

Study Officials

• Joseph L Izzo, M.D.

  SUNY Buffalo

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Drugs names omitted on patient bottles
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Run-in period with lisinopril is followed by random entry into valsartan followed by carvedilol CR or carvedilol CR followed by valsartan

Study Record Dates

• First Submitted: April 9, 2008
• First Posted: April 14, 2008
• Study Start: April 1, 2008
• Primary Completion: April 1, 2010
• Study Completion: April 1, 2010
• Last Updated: May 27, 2022
• Results First Posted: May 27, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)