Safety and Efficacy of Valsartan vs Atenolol and Hydrochlorothiazide Combination on Blood Flow in Hypertensive Patients

Study Overview
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Brief Summary
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This study evaluated the effect of valsartan on small vessel blood flow in patients with mild-to-moderate hypertension in direct comparison to atenolol and hydrochlorothiazide.

Official Title
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A Randomized, Open-label, Multicenter, Cross-over Trial to Evaluate the Efficacy of a 20 Week Treatment of Valsartan 320 mg Versus Atenolol 100 mg in Combination With Hydrochlorothiazide on Microcirculation in Hypertensive Patients

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Atenolol
* Drug: Hydrochlorothiazide (HCTZ))
* Drug: Valsartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian; male or female outpatients and age between 40-65 years of age, inclusive. At Visit 2 all patients must have a mean sitting diastolic blood pressure (msSBP) of ≥ 90 mmHg and < 110 mmHg. Exclusion Criteria: If a single reading for arterial hypertension in msSBP > 180 mmHg or msDBP > 110 mmHg at any visit after randomization. Inability to discontinue all prior antihypertensive medications safely for a period of 2 weeks prior to randomization. Known history of hypotensive symptoms or orthostatic hypotension. Concomitant use of statins or statin intake during the four weeks prior to Visit 1. Known Keith-Wagener grade III or IV hypertensive retinopathy. A history of heart failure (NYHA II-IV).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valsartan followed by atenolol + hydrochlorothiazide (HCTZ)<br>After a 2-week washout period, patients were treated with valsartan for 20 weeks followed by one week in which it was tapered off. Patients received valsartan 160 mg for 4 weeks, followed by valsartan 320 mg for 16 weeks. The valsartan dose was then tapered off to 80 mg for one week. Patients took valsartan film coated tablets orally once a day (od) in the morning. After a second 2-week washout period, patients were treated with atenolol plus HCTZ for 20 weeks. Patients received atenolol 100 mg for 20 weeks. Patients took atenolol tablets orally once a day (od) in the morning. Patients received HCTZ 12.5 mg for 4 weeks starting at the beginning of the 5th week and then received 25 mg for 12 weeks. Patients took HCTZ tablets orally once a day (od) in the morning. | Drug: Atenolol<br>* 100 mg tablets orally once a day (od) in the morning.<br>Drug: Hydrochlorothiazide (HCTZ))<br>* 12.5 or 25 mg tablets orally once a day (od) in the morning.<br>Drug: Valsartan<br>* 80 mg, 160 mg, or 320 mg tablets orally once a day in the morning<br>|
| Experimental: Atenolol + hydrochlorothiazide (HCTZ) followed by valsartan<br>After a 2-week washout period, patients were treated with atenolol plus HCTZ for 20 weeks followed by one week in which atenolol was tapered off and HCTZ was discontinued. Patients received atenolol 100 mg for 20 weeks. Patients took atenolol tablets orally once a day (od) in the morning. Patients received HCTZ 12.5 mg for 4 weeks starting at the beginning of the 5th week and then received 25 mg for 12 weeks. Patients took HCTZ tablets orally once a day (od) in the morning. After a second 2-week washout period, patients were treated with valsartan for 20 weeks. Patients received valsartan 160 mg for 4 weeks, followed by valsartan 320 mg for 16 weeks. Patients took valsartan film coated tablets orally once a day (od) in the morning. | Drug: Atenolol<br>* 100 mg tablets orally once a day (od) in the morning.<br>Drug: Hydrochlorothiazide (HCTZ))<br>* 12.5 or 25 mg tablets orally once a day (od) in the morning.<br>Drug: Valsartan<br>* 80 mg, 160 mg, or 320 mg tablets orally once a day in the morning<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Mean Post-treatment Microcirculation at Acetylcholine (ACH) Injected Sites Compared to NaCl Injected Sites | 10 µl of acetylcholine (ACH) at 3 concentrations (10-7, 10-8, 10-9 M) was injected intra-dermally at 3 sites on the forearms. NaCl was injected at 2 sites on the forearms. Microcirculation was measured using laser doppler velocimetry before and 12 times in the 30 minutes following injection. The mean difference of the 12 post-injection measurements to the pre-injection measurement was calculated. Means for the 3 ACH and the 2 NaCl sites were calculated and compared. Microcirculation was measured in perfusion units which is an arbitrary measure specific to each laser doppler scanner. | At end of each treatment period (Week 21 and Week 43) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Mean Post-treatment Microcirculation at Acetylcholine (ACH) Plus L-NMMA Injected Sites Compared to NaCl Injected Sites | 10 µl of acetylcholine (ACH) at 3 concentrations (10-7, 10-8, 10-9 M) plus 10 µl L-NMMA (10-6 M) was injected intra-dermally at 3 sites on the forearms. NaCl was injected at 2 sites. Microcirculation was measured using laser doppler velocimetry before and 12 times in the 30 minutes following injection. The mean difference of the 12 post-injection measurements to the pre-injection measurement was calculated. Means for the 3 ACH and the 2 NaCl sites were calculated and compared. Microcirculation was measured in perfusion units which is an arbitrary measure specific to each laser doppler scanner. | At end of each treatment period (Week 21 and Week 43) | 
| Difference in Mean Post-treatment Microcirculation at a Sodium Nitroprusside Injected Site Compared to NaCl Injected Sites | 10 µl of sodium nitroprusside at a concentration of 10-7 M was injected intra-dermally at 1 site on the forearms. NaCl was injected at 2 sites on the forearms. Microcirculation was measured using laser doppler velocimetry before and 12 times in the 30 minutes following injection. The mean difference of the 12 post-injection measurements to the pre-injection measurement was calculated. A mean for the 2 NaCl sites was calculated and compared to the sodium nitroprusside mean. Microcirculation was measured in perfusion units which is an arbitrary measure specific to each laser doppler scanner. | At end of each treatment period (Week 21 and Week 43) | 
| Mean Post-treatment Microcirculation at NaCl Injected Sites | 10 µl of NaCl was injected intra-dermally at 2 sites on the forearms. Microcirculation was measured using laser doppler velocimetry before and 12 times in the 30 minutes following injection. The mean difference of the 12 post-injection measurements to the pre-injection measurement was calculated. A mean for the 2 NaCl sites was calculated. Microcirculation was measured in perfusion units which is an arbitrary measure specific to each laser doppler scanner. | At end of each treatment period (Week 21 and Week 43) | 
| Arterial Pressure Waveform Augmentation Index at the End of Treatment | Using applanation tonometry, the arterial pulse form measured at the wrist was analyzed using computerized pulse wave analysis. The arterial pressure waveform has two components; the first is the forward traveling wave when the left ventricle contracts and the second is the reflected wave returning from the periphery. The augmentation index is the ratio of the first and second systolic peaks and is used as a surrogate measure of arterial stiffness. | At end of each treatment period (Week 21 and Week 43) | 
| Arterial Pressure Waveform Pulse Wave Velocity at the End of Treatment | Using applanation tonometry, the arterial pulse form measured at the wrist was analyzed using computerized pulse wave analysis. The arterial pressure waveform has two components; the first is the forward traveling wave when the left ventricle contracts and the second is the reflected wave returning from the periphery. Pulse wave velocity is the speed of the forward traveling wave and can be used as a measure of arterial stiffness since the more rigid the wall of the artery, the faster the wave moves. | At end of each treatment period (Week 21 and Week 43) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulse wave analysis, hypertension, valsartan, atenolol, hydrochlorothiazide, microcirculation, arterial compliance