Hypertension
Conditions
Keywords
cardiac work, carvedilol CR, valsartan, tonometry
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).
Interventions
DRUGCarvedilol CR
DRUGValsartan
Sponsors
GlaxoSmithKline
State University of New York at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Drugs names omitted on patient bottles
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
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Resting CTTI Between Carvedilol CR (Beta-blocker) and Valsartan (ARB) in Combination With Lisinopril. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart Rate (Beats/Min) | End of each treatment period (4 weeks on ARB or beta-blocker) | Hemodynamic variable (cardiac rate) |
| Stroke Volume (SV) | End of each treatment period (4 weeks on ARB or beta-blocker) | Hemodynamic variable (volume pumped per heart beat) in mL per beat. Clinically, SV is reported simply as mL |
| Cardiac Output | End of each 4-week treatment period (valsartan vs. carvedilol CR) | Hemodynamic variable representing whole-body blood flow (the product of heart rate and stroke volume) |
| Systemic Vascular Resistance | End of each treatment period (4 weeks of valsartan or carvedilol CR) | Hemodynamic variable measured as mean arterial pressure (mmHg) / cardiac output (L/min) \*80 in units of dyne-sec-cm\[-5\] |
| Central Systolic Blood Pressure | End of each treatment period (4 weeks of valsartan or carvedilol CR) | 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. |
Countries
United States
Participant flow
Recruitment details
Study subjects were recruited by advertisement or from the practice of the PI
Pre-assignment details
Prior antihypertensive medications were discontinued and subjects entered a 3-week run-in taking lisinopril 40 mg daily
Participants by arm
| Arm | Count |
|---|---|
| ARB First Lisinopril 40 mg daily plus valsartan 160 mg daily (one week) then valsartan 320 mg daily (3 weeks) followed by lisinopril 40 mg daily plus carvedilol CR 20 mg daily (1 week) then carvedilol CR 40 mg daily (3 weeks) | 15 |
| Beta-blocker First Lisinopril 40 mg daily plus carvedilol CR 20 mg daily (1 week) then carvedilol CR 40 mg daily (3 weeks) followed by lisinopril 40 mg daily plus valsartan 160 mg daily (one week) then valsartan 320 mg daily (3 weeks) | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Beta-blocker First | ARB First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 14 Participants | 27 Participants |
| Age, Continuous | 56 years STANDARD_DEVIATION 9.5 | 56 years STANDARD_DEVIATION 9.5 | 56 years STANDARD_DEVIATION 9.5 |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 16 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
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.
Time frame: End of each treatment period (4 weeks on ARB or beta-blocker)
Population: Analysis groups are different from treatment arms, which reflect the sequence of administration of the comparators, valsartan or carvedilol CR, which are received by all participants. CTTI comparisons made at end of each 4-week treatment period; study powered to detect an 8% difference in CTTI by paired t-test at p \< 0.05, power 0.8.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol CR | Difference in Resting CTTI Between Carvedilol CR (Beta-blocker) and Valsartan (ARB) in Combination With Lisinopril. | 2447 CTTI units (mmHg*beats/min) | Standard Deviation 547 |
| Valsartan | Difference in Resting CTTI Between Carvedilol CR (Beta-blocker) and Valsartan (ARB) in Combination With Lisinopril. | 2500 CTTI units (mmHg*beats/min) | Standard Deviation 561 |
Comparison: Statistical analysis performed on treatment groups (valsartan or carvedilol CR) at end of treatment period (4 weeks), not on the randomization arms in the crossover design (which controlled for carryover effects of the prior treatment arm).p-value: <0.05t-test, 2 sided
Secondary
Cardiac Output
Hemodynamic variable representing whole-body blood flow (the product of heart rate and stroke volume)
Time frame: End of each 4-week treatment period (valsartan vs. carvedilol CR)
Population: 4-week treatment period (valsartan vs. carvedilol CR); comparison by paired t-test
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol CR | Cardiac Output | 5.7 L/min | Standard Deviation 1.4 |
| Valsartan | Cardiac Output | 5.1 L/min | Standard Deviation 1.1 |
Comparison: Statistical analysis performed on treatment groups (valsartan or carvedilol CR) at end of treatment period (4 weeks), not on the randomization arms in the crossover design (which controlled for carryover effects of the prior treatment arm).p-value: 0.05t-test, 2 sided
Secondary
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.
Time frame: End of each treatment period (4 weeks of valsartan or carvedilol CR)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol CR | Central Systolic Blood Pressure | 130 mmHg | Standard Deviation 22 |
| Valsartan | Central Systolic Blood Pressure | 141 mmHg | Standard Deviation 25 |
Comparison: Statistical analysis performed on treatment groups (valsartan or carvedilol CR) at end of treatment period (4 weeks), not on the randomization arms in the crossover design (which controlled for carryover effects of the prior treatment arm).p-value: 0.05t-test, 2 sided
Secondary
Heart Rate (Beats/Min)
Hemodynamic variable (cardiac rate)
Time frame: End of each treatment period (4 weeks on ARB or beta-blocker)
Population: These analysis groups reflect the main study aim of direct comparison of ARB to beta-blocker with respect to cardiac work (CTTI). The analysis groups are not the same as the cross-over arms that represent sequence of drug administration (i.e. ARB first or beta-blocker first).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol CR | Heart Rate (Beats/Min) | 75 beats per minute | Standard Deviation 17 |
| Valsartan | Heart Rate (Beats/Min) | 68 beats per minute | Standard Deviation 14 |
Secondary
Stroke Volume (SV)
Hemodynamic variable (volume pumped per heart beat) in mL per beat. Clinically, SV is reported simply as mL
Time frame: End of each treatment period (4 weeks on ARB or beta-blocker)
Population: Mean of (intra-individual) SV values after 4 weeks of valsartan or carvedilol CR
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol CR | Stroke Volume (SV) | 77 mL or mL/beat | Standard Deviation 17 |
| Valsartan | Stroke Volume (SV) | 76 mL or mL/beat | Standard Deviation 15 |
Comparison: Statistical analysis performed on treatment groups (valsartan or carvedilol CR) at end of treatment period (4 weeks), not on the randomization arms in the crossover design (which controlled for carryover effects of the prior treatment arm).p-value: 0.05t-test, 2 sided
Secondary
Systemic Vascular Resistance
Hemodynamic variable measured as mean arterial pressure (mmHg) / cardiac output (L/min) \*80 in units of dyne-sec-cm\[-5\]
Time frame: End of each treatment period (4 weeks of valsartan or carvedilol CR)
Population: Valsartan vs. carvedilol CR at end of 4-week treatment period; comparison by paired t-test
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carvedilol CR | Systemic Vascular Resistance | 1407 dyne sec cm-5 | Standard Deviation 378 |
| Valsartan | Systemic Vascular Resistance | 1591 dyne sec cm-5 | Standard Deviation 410 |
Comparison: Statistical analysis performed on treatment groups (valsartan or carvedilol CR) at end of treatment period (4 weeks), not on the randomization arms in the crossover design (which controlled for carryover effects of the prior treatment arm).p-value: 0.05t-test, 2 sided