Irbesartan and Atenolol in Hypertensive Heart Disease - Full Text View

Purpose

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	Intervention	Phase
Hypertension	Drug: Irbesartan Drug: Atenolol	Phase 2 Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:

Drug Information available for: Atenolol Irbesartan

U.S. FDA Resources

Further study details as provided by Karolinska Institutet:

Primary Outcome Measures:

Changes in Left Ventricular Mass Index [ Time Frame: Baseline and 48 weeks ] [ Designated as safety issue: No ]
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:

Number of Participants With Serious Adverse Events [ Time Frame: Treatment period was baseline to 48 weeks ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
Changes in common carotid artery intima-media thickness, assessed by ultrasonography.


Enrollment:	115
Study Start Date:	April 1995
Study Completion Date:	April 1997
Primary Completion Date:	April 1997 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Irbesartan Irbesartan per os titrated to 300 mg od, 48 weeks	Drug: Irbesartan Titrated to 300 mg od, 48 weeks. Other Name: Aprovel
Active Comparator: Atenolol Atenolol per os titrated to 100 mg od, 48 weeks	Drug: Atenolol Titrated to 100 mg od, 48 weeks. Other Name: Tenormin

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.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00389168

Locations


Sweden
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

More Information

Publications:

Malmqvist K, Kahan T, Edner M, Held C, Hägg A, Lind L, Müller-Brunotte R, Nyström F, Ohman KP, Osbakken MD, Ostergern J. Regression of left ventricular hypertrophy in human hypertension with irbesartan. J Hypertens. 2001 Jun;19(6):1167-76.

Nyström F, Malmqvist K, Ohman KP, Kahan T. Nurse-recorded and ambulatory blood pressure predicts treatment-induced reduction of left ventricular hypertrophy equally well in hypertension: results from the Swedish irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA) study. J Hypertens. 2002 Aug;20(8):1527-33.

Malmqvist K, Kahan T, Edner M, Bergfeldt L. Comparison of actions of irbesartan versus atenolol on cardiac repolarization in hypertensive left ventricular hypertrophy: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation Versus Atenolol (SILVHIA). Am J Cardiol. 2002 Nov 15;90(10):1107-12.

Malmqvist K, Ohman KP, Lind L, Nyström F, Kahan T. Long-term effects of irbesartan and atenolol on the renin-angiotensin-aldosterone system in human primary hypertension: the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA). J Cardiovasc Pharmacol. 2003 Dec;42(6):719-26.

Müller-Brunotte R, Kahan T, Malmqvist K, Ring M, Edner M. Tissue velocity echocardiography shows early improvement in diastolic function with irbesartan and atenolol therapy in patients with hypertensive left ventricular hypertrophy. Results form the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA). Am J Hypertens. 2006 Sep;19(9):927-36.

Mörtsell D, Malmqvist K, Held C, Kahan T. Irbesartan reduces common carotid artery intima-media thickness in hypertensive patients when compared with atenolol: the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) study. J Intern Med. 2007 May;261(5):472-9.

Malmqvist K, Kahan T, Edner M, Bergfeldt L. Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study. J Hum Hypertens. 2007 Dec;21(12):956-65. Epub 2007 Jul 19.

Müller-Brunotte R, Kahan T, López B, Edner M, González A, Díez J, Malmqvist K. Myocardial fibrosis and diastolic dysfunction in patients with hypertension: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA). J Hypertens. 2007 Sep;25(9):1958-66.

Kurland L, Hallberg P, Melhus H, Liljedahl U, Hashemi N, Syvänen AC, Lind L, Kahan T. The relationship between the plasma concentration of irbesartan and the antihypertensive response is disclosed by an angiotensin II type 1 receptor polymorphism: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) Trial. Am J Hypertens. 2008 Jul;21(7):836-9. doi: 10.1038/ajh.2008.190. Epub 2008 May 8.

Liljedahl S, Kahan T, Lind L, Arnlöv J. The effects of antihypertensive treatment on the doppler-derived myocardial performance index in patients with hypertensive left ventricular hypertrophy: results from the Swedish irbesartan in left ventricular hypertrophy investigation versus atenolol (SILVHIA). Echocardiography. 2009 Aug;26(7):753-8. doi: 10.1111/j.1540-8175.2008.00886.x. Epub .

Müller-Brunotte R, Kahan T, Malmqvist K, Edner M; Swedish ibesartan left ventricular hypertrophy investigation vs atenolol (SILVHIA). Blood pressure and left ventricular geometric pattern determine diastolic function in hypertensive myocardial hypertrophy. J Hum Hypertens. 2003 Dec;17(12):841-9.

Müller-Brunotte R, Edner M, Malmqvist K, Kahan T. Irbesartan and atenolol improve diastolic function in patients with hypertensive left ventricular hypertrophy. J Hypertens. 2005 Mar;23(3):633-40.

Jekell A, Malmqvist K, Wallén NH, Mörtsell D, Kahan T. Markers of inflammation, endothelial activation, and arterial stiffness in hypertensive heart disease and the effects of treatment: results from the SILVHIA study. J Cardiovasc Pharmacol. 2013 Dec;62(6):559-66. doi: 10.1097/FJC.0000000000000017.

Kurland L, Liljedahl U, Karlsson J, Kahan T, Malmqvist K, Melhus H, Syvänen AC, Lind L. Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial. Am J Hypertens. 2004 Jan;17(1):8-13.


Responsible Party:	Thomas Kahan, Professor, Principal investigator and Study Chair, Karolinska Institutet
ClinicalTrials.gov Identifier:	NCT00389168 History of Changes
Other Study ID Numbers:	CV131-052
Study First Received:	October 17, 2006
Results First Received:	August 19, 2012
Last Updated:	May 3, 2015
Health Authority:	Sweden: Regional Ethical Review Board

Keywords provided by Karolinska Institutet:


Hypertension Cardiac hypertrophy Angiotensin Human

Additional relevant MeSH terms:


Hypertension Vascular Diseases Cardiovascular Diseases Irbesartan Atenolol Antihypertensive Agents Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Antagonists Molecular Mechanisms of Pharmacological Action Anti-Arrhythmia Agents	Sympatholytics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Adrenergic beta-1 Receptor Antagonists Adrenergic beta-Antagonists Adrenergic Antagonists Adrenergic Agents Neurotransmitter Agents

ClinicalTrials.gov processed this record on September 30, 2016

Irbesartan and Atenolol in Hypertensive Heart Disease (SILVHIA)