Hypertension
Conditions
Keywords
Hypertension, Cardiac hypertrophy, Angiotensin, Human
Brief summary
The renin-angiotensin-aldosterone system has been implicated in the control of structural changes of the heart and the vasculature, beyond the effects on blood pressure. This projects examines the importance of the renin-angiotensin-aldosterone system and the sympathetic nervous system in the control of cardiac and vascular structure and function in subjects with hypertension.Patients with hypertension and left ventricular hypertrophy were randomized to an angiotensin receptor blocker or a beta adrenergic receptor blocker for 48 weeks. Repeat investigations of blood pressure, structure and function of the heart and the vascular tree, and neurohormones were performed. Two control groups, consisting of normotensive subjects and of hypertensive subjects with no cardiac hypertrophy were also examined for comparison.
Detailed description
We included 115 patients with hypertension and cardiac hypertrophy, established by echocardiography. Extensive echocardiographic examinations, ultrasonography of the carotid arteries, 24h Holter registrations, 24h ambulatory blood pressure monitoring monitoring, neurohormones and blood samples for inflammation and hemostasis markers and endothelial function were done at weeks 0, 12, 24, and 48. Matched control groups (1:3, i.e. 38 normotensive subjects and 38 hypertensive subjects with no signs of hypertensive heart disease were examined at one occasion. All patients obtained irbesartan or atenolol for 12 weeks; a diuretic and a calcium antagonist was added when needed thereafter in order to obtained a blood pressure below 140/90 mm Hg. All analyses were performed central in a core laboratory.
Interventions
DRUGIrbesartan
Titrated to 300 mg od, 48 weeks.
DRUGAtenolol
Titrated to 100 mg od, 48 weeks.
Sponsors
Bristol-Myers Squibb
Sanofi
Swedish Heart Lung Foundation
Karolinska Institutet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* At least 18 ys old * Male or female with no child bearing potential * Seated blood pressure diastolic 90-115 mm Hg * Left ventricular mass above 131 g/m2 for men, above 100 g/m2 for women * Informed consent
Exclusion criteria
* Coronary artery disease, heart failure or other significant cardiac disorder * Cerebrovascular accident within the past 6 months * A seated systolic blood pressure above 200 mm Hg * Significant renal disease, collagen or vascular disease, or gastrointestinal condition * Significant allergy or intolerance to study drug * Alcohol or drug abuse * Uncontrolled diabetes mellitus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Left Ventricular Mass Index | Baseline and 48 weeks | Repeated measures multivariate analysis of variance (MANOVA) at time points 0, 12, 24, and 48 weeks. Data are presented as left ventricular mass in gram (g) indexed for body mass index (in m\^2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events | Treatment period was baseline to 48 weeks | Safety was assessed by non-directed questions, and all observed and volunteered adverse events were recorded at each study visit. Serious adverse events were defined by, and reported according to the regulations of good clinical practice (GCP). none were considered related to the study medication. |
| Left Ventricular Diastolic Function Assessed by the E/A Ratio | Baseline to 48 weeks | Changes in left ventricular diastolic function from baseline to week 48 will be evaluated as the difference in E/A ratio. Conventional pulsed wave Doppler echocardiography was used for recordings of mitral inflow in. The peak of early (E) and late (A) mitral flow velocities were measured, and the E/A-ratio was calculated. Repeated measures MANOVA at time points 0, 12, 24, and 48 weeks. Some echocardiographic recordings at some time point may be of insufficient quality or missing, and the number of observations may not always correspond to the total number of participants at all time points. |
| Blood Pressure | Baseline to 48 weeks | Difference in Diastolic Blood Pressure. Repeated measures multivariable analysis of variance (MANOVA) at time points 0, 12, 24, and 48 weeks |
| Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System | Baseline to 48 weeks | Venous plasma concentrations of angiotensin II were measured in order to study the possible associations between the activity of the renin-angiotensin-aldosteone system and changes in left ventricular mass. Further analyses of other components of the renin-angiotensin-aldosterone system and of other hormonal system (e.g. the sympathetic nervous system) have also been performed and published. Repeated measures MANOVA at time points 0, 12, 24, and 48 weeks. Data were log-transformed to avoid skewness before statistical evaluation. However, tabular data are given as mean values with 95% confidence to improve readability. |
| Effects on Carotid Artery Wall Thickness | Baseline to 48 weeks | Changes in common carotid artery intima-media thickness, assessed by ultrasonography. |
Countries
Sweden
Participant flow
Recruitment details
Multicenter Swedish study. Patients with primary hypertension and left ventricular (LV) hypertrophy.
Pre-assignment details
All participants received a placebo washout period during 4 weeks at the beginning of the study. One patient of the 115 included was during the course of the study diagnosed with Mb Conn (adrenal tumor causing endocrine secondary hypertension). This patient was excluded from all analyses. Thus, there are 114 patients included in the dataset.
Participants by arm
| Arm | Count |
|---|---|
| Atenolol A double blind study with parallel group treatment with irbesartan or atenolol; addition of HCTZ and felodipine when needed to achieve \< 140/90 mm Hg | 58 |
| Irbesartan A double blind study with parallel group treatment with irbesartan or atenolol; addition of HCTZ and felodipine when needed to achieve \< 140/90 mm Hg | 56 |
| Total | 114 |
Baseline characteristics
| Characteristic | Irbesartan | Atenolol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 7 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants | 51 Participants | 100 Participants |
| Age, Continuous | 54 years STANDARD_DEVIATION 8 | 54 years STANDARD_DEVIATION 10 | 54 years STANDARD_DEVIATION 9 |
| Region of Enrollment Sweden | 56 participants | 58 participants | 114 participants |
| Sex: Female, Male Female | 20 Participants | 18 Participants | 38 Participants |
| Sex: Female, Male Male | 36 Participants | 40 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 56 | 0 / 58 |
| serious Total, serious adverse events | 5 / 56 | 5 / 58 |
Outcome results
Primary
Changes in Left Ventricular Mass Index
Repeated measures multivariate analysis of variance (MANOVA) at time points 0, 12, 24, and 48 weeks. Data are presented as left ventricular mass in gram (g) indexed for body mass index (in m\^2).
Time frame: Baseline and 48 weeks
Population: Data on echocardiography is not always available at all time points and for all participants. This is reflected by the number of observations, which sometimes are less than the number of participants.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Atenolol | Changes in Left Ventricular Mass Index | 12 weeks | -1 g/m^2 |
| Atenolol | Changes in Left Ventricular Mass Index | 24 weeks | -6 g/m^2 |
| Atenolol | Changes in Left Ventricular Mass Index | 48 weeks | -14 g/m^2 |
| Irbesartan | Changes in Left Ventricular Mass Index | 12 weeks | -9 g/m^2 |
| Irbesartan | Changes in Left Ventricular Mass Index | 24 weeks | -14 g/m^2 |
| Irbesartan | Changes in Left Ventricular Mass Index | 48 weeks | -26 g/m^2 |
Secondary
Blood Pressure
Difference in Diastolic Blood Pressure. Repeated measures multivariable analysis of variance (MANOVA) at time points 0, 12, 24, and 48 weeks
Time frame: Baseline to 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Atenolol | Blood Pressure | -16.3 mm Hg |
| Irbesartan | Blood Pressure | -18.8 mm Hg |
Secondary
Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System
Venous plasma concentrations of angiotensin II were measured in order to study the possible associations between the activity of the renin-angiotensin-aldosteone system and changes in left ventricular mass. Further analyses of other components of the renin-angiotensin-aldosterone system and of other hormonal system (e.g. the sympathetic nervous system) have also been performed and published. Repeated measures MANOVA at time points 0, 12, 24, and 48 weeks. Data were log-transformed to avoid skewness before statistical evaluation. However, tabular data are given as mean values with 95% confidence to improve readability.
Time frame: Baseline to 48 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Atenolol | Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System | Weel 12 | -1.0 pmol/L |
| Atenolol | Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System | Week 24 | -0.8 pmol/L |
| Atenolol | Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System | Week 48 | -0.2 pmol/L |
| Irbesartan | Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System | Weel 12 | 3.0 pmol/L |
| Irbesartan | Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System | Week 24 | 3.3 pmol/L |
| Irbesartan | Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System | Week 48 | 10.0 pmol/L |
Secondary
Effects on Carotid Artery Wall Thickness
Changes in common carotid artery intima-media thickness, assessed by ultrasonography.
Time frame: Baseline to 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atenolol | Effects on Carotid Artery Wall Thickness | 0.03 mm | Standard Deviation 0.12 |
| Irbesartan | Effects on Carotid Artery Wall Thickness | -0.01 mm | Standard Deviation 0.1 |
Secondary
Left Ventricular Diastolic Function Assessed by the E/A Ratio
Changes in left ventricular diastolic function from baseline to week 48 will be evaluated as the difference in E/A ratio. Conventional pulsed wave Doppler echocardiography was used for recordings of mitral inflow in. The peak of early (E) and late (A) mitral flow velocities were measured, and the E/A-ratio was calculated. Repeated measures MANOVA at time points 0, 12, 24, and 48 weeks. Some echocardiographic recordings at some time point may be of insufficient quality or missing, and the number of observations may not always correspond to the total number of participants at all time points.
Time frame: Baseline to 48 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atenolol | Left Ventricular Diastolic Function Assessed by the E/A Ratio | Week 12 | 0.18 ratio | Standard Deviation 0.23 |
| Atenolol | Left Ventricular Diastolic Function Assessed by the E/A Ratio | Week 24 | 0.16 ratio | Standard Deviation 0.28 |
| Atenolol | Left Ventricular Diastolic Function Assessed by the E/A Ratio | Week 48 | 0.13 ratio | Standard Deviation 0.24 |
| Irbesartan | Left Ventricular Diastolic Function Assessed by the E/A Ratio | Week 12 | 0.10 ratio | Standard Deviation 0.22 |
| Irbesartan | Left Ventricular Diastolic Function Assessed by the E/A Ratio | Week 24 | 0.04 ratio | Standard Deviation 0.18 |
| Irbesartan | Left Ventricular Diastolic Function Assessed by the E/A Ratio | Week 48 | 0.10 ratio | Standard Deviation 0.21 |
Secondary
Number of Participants With Serious Adverse Events
Safety was assessed by non-directed questions, and all observed and volunteered adverse events were recorded at each study visit. Serious adverse events were defined by, and reported according to the regulations of good clinical practice (GCP). none were considered related to the study medication.
Time frame: Treatment period was baseline to 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atenolol | Number of Participants With Serious Adverse Events | 5 Participants |
| Irbesartan | Number of Participants With Serious Adverse Events | 5 Participants |