HypertensionPhase 3NCT00657241
Cardioprotective Benefits of Carvedilol-CR or Valsartan Added to Lisinopril
A Phase 3 study testing Carvedilol CR and Valsartan in people with Hypertension, run by State University of New York at Buffalo at 1 site in United States.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Hypertension
- What is being tested?
- Carvedilol CR and Valsartan
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2008to Apr 2010
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects with residual (uncontrolled) hypertension on lisinopril monotherapy, defined as 24-hour ambulatory diastolic BP >85 mmHg.
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
Read the 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).
- Conditions
- Hypertension
- Being tested
- Carvedilol CR, Valsartan
- Keywords
- cardiac work, carvedilol CR, valsartan, tonometry
- Medical subject headings
- Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Carvedilol CRDrug
Also called Coreg CR
ValsartanDrug
Also called Diovan
| Study group | Role | What they receive |
|---|---|---|
| (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) Receives: 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). Receives: Drug: Carvedilol CR; Drug: Valsartan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: End of each treatment period (4 weeks on ARB or beta-blocker)
Secondary outcomes (5)
Heart Rate (Beats/Min)
Hemodynamic variable (cardiac rate)
Measured: 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
Measured: 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)
Measured: 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]
Measured: 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.
Measured: End of each treatment period (4 weeks of valsartan or carvedilol CR)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2008 (estimated)
- Study startApr 2008
- Primary completionApr 2010
- Study completionApr 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HypertensionStudies of the same condition, open and under way.
- More trials run by State University of New York at BuffaloThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- 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 blind
- Who is masked
- Participant
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- State University of New York at Buffalo
- Sponsor type
- University, hospital or other
- Collaborators
- GlaxoSmithKline
- Responsible party
- Principal investigator, JOSEPH IZZO, State University of New York at Buffalo
- Investigators
- Joseph L Izzo, M.D., Principal investigator, SUNY Buffalo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00657241
- Sponsor's protocol ID
- 111704
- Status last verified
- May 2022
- First submitted
- 9 Apr 2008
- Last updated
- 27 May 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 23107894
Study at a glance
From the registry record, last updated by the sponsor on 27 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cardioprotective Benefits of Carvedilol-CR or Valsartan Added to Lisinopril
- ClinicalTrials.gov ID
- NCT00657241
- Acronym / sponsor ID
- 111704
- Conditions
- Hypertension
- Keywords
- cardiac work, carvedilol CR, valsartan, tonometry
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- State University of New York at BuffaloUniversity, hospital or other
- Collaborators
- GlaxoSmithKline
- Study start
- Apr 2008
- Primary completion
- Apr 2010 (actual)
- Study completion
- Apr 2010 (actual)
- First posted
- 14 Apr 2008 (estimated)
- Results
- Posted 27 May 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Run-in period with lisinopril is followed by random entry into valsartan followed by carvedilol CR or carvedilol CR followed by valsartan
| Arm | Type | Receives |
|---|---|---|
| (A) ARB first, beta-blocker second | Active comparator | Drug: Carvedilol CR, Drug: ValsartanValsartan 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) |
| (B) Beta-blocker first, ARB second | Active comparator | Drug: Carvedilol CR, Drug: Valsartancarvedilol 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). |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Subjects with residual (uncontrolled) hypertension on lisinopril monotherapy, defined as 24-hour ambulatory diastolic BP >85 mmHg.
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Carvedilol CRAlso: Coreg CR | Drug | (A) ARB first, beta-blocker second, (B) Beta-blocker first, ARB second |
| ValsartanAlso: Diovan | Drug | (A) ARB first, beta-blocker second, (B) Beta-blocker first, ARB second |
Primary outcome
Difference in Resting CTTI Between Carvedilol CR (Beta-blocker) and Valsartan (ARB) in Combination With Lisinopril.
Time frame: End of each treatment period (4 weeks on ARB or beta-blocker)
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.
5 secondary outcomes
Heart Rate (Beats/Min)
Time frame: End of each treatment period (4 weeks on ARB or beta-blocker)
Stroke Volume (SV)
Time frame: End of each treatment period (4 weeks on ARB or beta-blocker)
Cardiac Output
Time frame: End of each 4-week treatment period (valsartan vs. carvedilol CR)
Systemic Vascular Resistance
Time frame: End of each treatment period (4 weeks of valsartan or carvedilol CR)
Central Systolic Blood Pressure
Time frame: End of each treatment period (4 weeks of valsartan or carvedilol CR)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 May 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 23107894Izzo 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joseph L Izzo, M.D. principal investigator
SUNY Buffalo
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Carvedilol CR and Valsartan in people with Hypertension, run by State University of New York at Buffalo at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 May 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 May 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in Resting CTTI Between Carvedilol CR (Beta-blocker) and Valsartan (ARB) in Combination With Lisinopril. (time frame: End of each treatment period (4 weeks on ARB or beta-blocker)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00657241, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 May 2022.