SILVHIA: Irbesartan and Atenolol in Hypertensive Heart Disease

• Sponsor: Karolinska Institutet (Other)
• Overall Status: Completed
• CT.gov ID: NCT00389168
• Collaborator: Bristol-Myers Squibb (Industry), Sanofi (Industry), Swedish Heart Lung Foundation (Other)
• Enrollment: 115
• Location: 1
• Arms: 2
• Duration (Months): 24
• Patients Per Site Per Month: 4.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Irbesartan; Drug: Atenolol	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind Evaluation of the Effects of Irbesartan and Atenolol on Cardiovascular Structure and Function in Subjects With Hypertension and Left Ventricular Hypertrophy
• Study Start Date: Apr 1, 1995
• Actual Primary Completion Date: Apr 1, 1997
• Actual Study Completion Date: Apr 1, 1997

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Irbesartan Irbesartan per os titrated to 300 mg od, 48 weeks	Drug: Irbesartan; Titrated to 300 mg od, 48 weeks.; Other Names: Aprovel
Active Comparator: Atenolol Atenolol per os titrated to 100 mg od, 48 weeks	Drug: Atenolol; Titrated to 100 mg od, 48 weeks.; Other Names: Tenormin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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

4. 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.

5. Effects on Carotid Artery Wall Thickness [Baseline to 48 weeks]

   Changes in common carotid artery intima-media thickness, assessed by ultrasonography.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Karolinska Institutet, Daprtment of Clinical Sciences, Danderyd Hospital, Cardiovascular Research Laboratory	Stockholm		Sweden	SE-182 88

Sponsors and Collaborators

• Karolinska Institutet
• Bristol-Myers Squibb
• Sanofi
• Swedish Heart Lung Foundation

Investigators

• Study Chair: Thomas Kahan, MD, PhD, Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, SE-182 88 Stockholm, Sweden

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thomas Kahan, Professor, Principal investigator and Study Chair, Karolinska Institutet
• ClinicalTrials.gov Identifier: NCT00389168
• Other Study ID Numbers: CV131-052
• First Posted: Oct 18, 2006
• Last Update Posted: May 5, 2015
• Last Verified: May 1, 2015

• Keywords provided by Thomas Kahan, Professor, Principal investigator and Study Chair, Karolinska Institutet: Hypertension; Cardiac hypertrophy; Angiotensin; Human
• Additional relevant MeSH terms: Hypertension; Atenolol; Irbesartan

Study Results

Participant Flow

Recruitment Details	Multicenter Swedish study. Patients with primary hypertension and left ventricular (LV) hypertrophy.
Pre-assignment Detail	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.

Arm/Group Title	Irbesartan	Atenolol
Arm/Group Description	A double blind study with parallel group treatment with irbesartan or atenolol; addition of hydrochlorothiazide (HCTZ) and felodipine when needed to achieve < 140/90 mm Hg	A double blind study with parallel group treatment with irbesartan or atenolol; addition of hydrochlorothiazide (HCTZ) and felodipine when needed to achieve < 140/90 mm Hg
Period Title: Overall Study
STARTED	56	58
COMPLETED	47	53
NOT COMPLETED	9	5

Baseline Characteristics

Arm/Group Title	Atenolol	Irbesartan	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	58	56	114
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	51 87.9%	49 87.5%	100 87.7%
>=65 years	7 12.1%	7 12.5%	14 12.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54 (10)	54 (8)	54 (9)
Sex: Female, Male (Count of Participants)
Female	18 31%	20 35.7%	38 33.3%
Male	40 69%	36 64.3%	76 66.7%
Region of Enrollment (participants) [Number]
Sweden	58 100%	56 100%	114 100%

Outcome Measures

1. Secondary Outcome

Title	Number of Participants With Serious Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atenolol	Irbesartan
Arm/Group Description	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	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
Measure Participants	58	56
Number [Participants]	5 8.6%	5 8.9%

2. Primary Outcome

Title	Changes in Left Ventricular Mass Index
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Atenolol	Irbesartan
Arm/Group Description	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	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
Measure Participants	50	44
12 weeks	-1	-9
24 weeks	-6	-14
48 weeks	-14	-26

3. Secondary Outcome

Title	Left Ventricular Diastolic Function Assessed by the E/A Ratio
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atenolol	Irbesartan
Arm/Group Description	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	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
Measure Participants	50	45
Week 12	0.18 (0.23)	0.10 (0.22)
Week 24	0.16 (0.28)	0.04 (0.18)
Week 48	0.13 (0.24)	0.10 (0.21)

4. Secondary Outcome

Title	Blood Pressure
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atenolol	Irbesartan
Arm/Group Description	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	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
Measure Participants	53	47
Mean (95% Confidence Interval) [mm Hg]	-16.3	-18.8

5. Secondary Outcome

Title	Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atenolol	Irbesartan
Arm/Group Description	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	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
Measure Participants	53	46
Weel 12	-1.0	3.0
Week 24	-0.8	3.3
Week 48	-0.2	10.0

6. Secondary Outcome

Title	Effects on Carotid Artery Wall Thickness
Description	Changes in common carotid artery intima-media thickness, assessed by ultrasonography.
Time Frame	Baseline to 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atenolol	Irbesartan
Arm/Group Description	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	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
Measure Participants	56	52
Mean (Standard Deviation) [mm]	0.03 (0.12)	-0.01 (0.10)

Adverse Events

Time Frame	The entire duration of study: that is 4-6 weeks of single-blinded placebo run-in, 48 weeks of double-blinded medication, and 4 weeks following completion of the study.
Adverse Event Reporting Description	Defied and reported according to study protocol.
Arm/Group Title	Irbesratan		Atenolol
Arm/Group Description	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		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
All Cause Mortality
	Irbesratan		Atenolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Irbesratan		Atenolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/56 (8.9%)		5/58 (8.6%)
Cardiac disorders
inadequate blood pressure reduction	2/56 (3.6%)	2	0/58 (0%)	0
Social circumstances
events were not documented specifically in the records available	3/56 (5.4%)	3	5/58 (8.6%)	5
Other (Not Including Serious) Adverse Events
	Irbesratan		Atenolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/56 (0%)		0/58 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.