Clinical trial NCT00389168: Irbesartan and Atenolol in Hypertensive Heart Disease
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hypertension
Keywords: Hypertension
Cardiac hypertrophy
Angiotensin
Human
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Sanofi
name: Swedish Heart Lung Foundation
First posted: 2006-10-18
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Changes in Left Ventricular Mass Index
timeFrame: Baseline and 48 weeks
Secondary outcomes:
measure: Number of Participants With Serious Adverse Events
timeFrame: Treatment period was baseline to 48 weeks
measure: Left Ventricular Diastolic Function Assessed by the E/A Ratio
timeFrame: Baseline to 48 weeks
measure: Blood Pressure
timeFrame: Baseline to 48 weeks
measure: Changes of Venous Plasma Angiotensin II as a Marker of the Renin-Angiotensin-Aldosterone System
timeFrame: Baseline to 48 weeks
measure: Effects on Carotid Artery Wall Thickness
timeFrame: Baseline to 48 weeks
Other outcomes:
Locations:
city: Stockholm
country: Sweden
facility: Karolinska Institutet, Daprtment of Clinical Sciences, Danderyd Hospital, Cardiovascular Research Laboratory
Study officials:
affiliation: Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, SE-182 88 Stockholm, Sweden
name: Thomas Kahan, MD, PhD
role: STUDY_CHAIR
References:
citation: Malmqvist K, Kahan T, Edner M, Held C, Hagg A, Lind L, Muller-Brunotte R, Nystrom 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. doi: 10.1097/00004872-200106000-00023.
citation: Nystrom 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. doi: 10.1097/00004872-200208000-00015.
citation: 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. doi: 10.1016/s0002-9149(02)02777-7.
citation: Malmqvist K, Ohman KP, Lind L, Nystrom 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. doi: 10.1097/00005344-200312000-00005.
citation: Muller-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. doi: 10.1016/j.amjhyper.2006.02.009.
citation: Mortsell 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. doi: 10.1111/j.1365-2796.2007.01775.x.
citation: 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. doi: 10.1038/sj.jhh.1002250. Epub 2007 Jul 19.
citation: Muller-Brunotte R, Kahan T, Lopez B, Edner M, Gonzalez A, Diez 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. doi: 10.1097/HJH.0b013e3282170ada.
citation: Kurland L, Hallberg P, Melhus H, Liljedahl U, Hashemi N, Syvanen 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.
citation: Liljedahl S, Kahan T, Lind L, Arnlov 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.
citation: Muller-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. doi: 10.1038/sj.jhh.1001622.
citation: Muller-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. doi: 10.1097/01.hjh.0000160222.17092.b8.
citation: Jekell A, Malmqvist K, Wallen NH, Mortsell 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.
citation: Kurland L, Liljedahl U, Karlsson J, Kahan T, Malmqvist K, Melhus H, Syvanen 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. doi: 10.1016/j.amjhyper.2003.09.009.