Hypertension
Conditions
Keywords
hypertension, postmenopausal, valsartan, amlodipine, hydrochlorothiazide
Brief summary
The purpose of this study is compare treatment with valsartan with the possible addition of a diuretic, hydrochlorothiazide, on high blood pressure with the drug amlodipine with the possible addition of a diuretic, hydrochlorothiazide. In particular, the effect of treatment on the stiffness of the blood vessels will be studied.
Interventions
DRUGValsartan 320 mg
Patients received 160 mg valsartan for 4 weeks. Patients were then up-titrated to receive either 320 mg valsartan for the following 8 weeks.
DRUGAmlodipine 10 mg
Patients received 5 mg amlodipine for four weeks. Patients were then up-titrated to receive 10 mg amlodipine for the following 8 weeks.
DRUGHydrochlorothiazide
At Week 12, patients who did not meet target Blood Pressure for both Systolic Blood Pressure \< 140 mmHg and Diastolic Blood Pressure \< 90 mmHg were eligible to receive 12.5 mg open-label Hydrochlorothiazide for the following 26 weeks.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
50 Years to 75 Years
Inclusion criteria
* Postmenopausal women * Mild to moderate hypertension * Statin therapy or LDL≤ 4.1 mmol/L
Exclusion criteria
* Severe hypertension * LDL \> 4.1 mmol/L if not taking anti-hyperlipidemic medication * Certain hormonal therapy * History of stroke, myocardial infarction, heart failure, chest pain, abnormal heart rhythm * Liver, kidney, or pancreas disease * Diabetes * Raynaud's disease or any other significant peripheral vascular disease * Allergy to certain medications used to treat high blood pressure Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 38 in the Carotid-femoral Pulse Wave Velocity (PWV) | Baseline and Week 38 | PWV was determined from transcutaneous Doppler flow recordings and the foot-to-foot method triggered by the simultaneous ECG. Two simultaneous Doppler flow tracings were taken at the left common carotid and the right femoral artery in the groin with a linear array probe. The time delay (t) was measured between R wave of the ECG and the base of the flow waves recorded at these points, and averaged over 10 beats. The distance (D) traveled by the pulse wave was measured over body surface as the distance from the suprasternal notch to the carotid artery. PWV was calculated as PWV=D/t. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Endpoint (Week 38) | Week 38 | Cutaneous blood flow was continuously recorded by a laser Doppler flowmeter. The laser Doppler flow probe was applied on the volar part of the right forearm with a plastic holder 10 cm proximal to the wrist. All measurements were made with a pressure cuff on the arm and inflated 20 mmHg above systolic BP and maintained for 2 min then rapidly deflated. All measurements were made in a quiet room with a patient in the supine position. The maximal reactive hyperemia was measured after cuff deflation, which allows measurement of the right forearm postischemic skin reactive hyperemia (SRH). |
| Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at Week 12 | Baseline and Week 12 | Endothelial function will be assessed using high-resolution duplex ultrasound with wall tracking to measure FMD of the brachial artery during reactive hyperemia. FMD of the brachial artery in response to reactive hyperemia in the distal forearm (and glyceryl trinitrate as a non-endothelium dependent control) will be measured from B-mode ultrasound images using a standard 7 MHz linear array transducer and HDI 5000 system with edge detection. |
| Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at End-point (Week 38) | Baseline and Week 38 | Endothelial function will be assessed using high-resolution duplex ultrasound with wall tracking to measure FMD of the brachial artery during reactive hyperemia. FMD of the brachial artery in response to reactive hyperemia in the distal forearm (and glyceryl trinitrate as a non-endothelium dependent control) will be measured from B-mode ultrasound images using a standard 7 MHz linear array transducer and HDI 5000 system with edge detection. |
| Changes in Mean Left Carotid Distensibility at Week 12 | Baseline and Week 12 | For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure. |
| Changes in Mean Left Carotid Distensibility at Week 38 | Baseline and Week 38 | For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure. |
| Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Week 12 | Baseline and Week 12 | Cutaneous blood flow was continuously recorded by a laser Doppler flowmeter. The laser Doppler flow probe was applied on the volar part of the right forearm with a plastic holder 10 cm proximal to the wrist. All measurements were made with a pressure cuff on the arm and inflated 20 mmHg above systolic BP and maintained for 2 min then rapidly deflated. All measurements were made in a quiet room with a patient in the supine position. The maximal reactive hyperemia was measured after cuff deflation, which allows measurement of the right forearm postischemic skin reactive hyperemia (SRH). |
| Changes in Mean Right Carotid Distensibility at Week 38 | Baseline and Week 38 | For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure. |
| Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 12 | Baseline and Week 12 | The calculation of spontaneous baroflex sensitivity was obtained by the sequence method. Baroflex sequences are defined by at least three consecutive beats in which the systolic blood pressure and the RR interval of the following beat either both increased or decreased. The slope of each individual sequence is computed and the mean slope is determined as the average of all slopes within a given period of time and taken as the gain of the cardiac baroflex (BRSs). |
| Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 38 | Baseline and Week 38 | The calculation of spontaneous baroflex sensitivity was obtained by the sequence method. Baroflex sequences are defined by at least three consecutive beats in which the systolic blood pressure and the RR interval of the following beat either both increased or decreased. The slope of each individual sequence is computed and the mean slope is determined as the average of all slopes within a given period of time and taken as the gain of the cardiac baroflex (BRSs). |
| Change in Left Ventricular Mass Index (LVMI) and Diastolic Function Using Echocardiography From Baseline to Week 38 | Baseline and Week 38 | — |
| Changes in Central Blood Pressure, Evaluated by Applanation Tonometry From Baseline at Weeks 12 and 38 | Baseline, Week 12 and Week 38 | Central Blood Pressure was measured via applanation tonometry recordings of the common carotid artery and from brachial oscillometric recordings. The Simultaneously obtained carotid artery pressure and standard brachial artery blood pressure are computed to obtain the central systolic pressure. |
| Changes in Mean Right Carotid Distensibility at Week 12 | Baseline and Week 12 | For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure. |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Valsartan 320 mg Double-blind study medication consisted of valsartan 160 mg capsules for oral administration. Open-label HCTZ 12.5 mg (orally administered) was electively prescribed at week 12. | 63 |
| Amlodipine 10 mg Amlodipine, orally administered, was provided as 5 mg capsules. Open-label HCTZ 12.5 mg (orally administered) was electively prescribed at week 12. | 62 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 8 |
| Overall Study | Condition no longer required study drug | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Patient withdrew consent | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 2 |
Baseline characteristics
| Characteristic | Valsartan 320 mg | Amlodipine 10 mg | Total |
|---|---|---|---|
| Age Continuous | 62.3 years STANDARD_DEVIATION 5.76 | 60.4 years STANDARD_DEVIATION 5.08 | 61.4 years STANDARD_DEVIATION 5.5 |
| Sex: Female, Male Female | 63 Participants | 62 Participants | 125 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 63 | 51 / 62 |
| serious Total, serious adverse events | 2 / 63 | 2 / 62 |
Outcome results
Primary
Change From Baseline to Week 38 in the Carotid-femoral Pulse Wave Velocity (PWV)
PWV was determined from transcutaneous Doppler flow recordings and the foot-to-foot method triggered by the simultaneous ECG. Two simultaneous Doppler flow tracings were taken at the left common carotid and the right femoral artery in the groin with a linear array probe. The time delay (t) was measured between R wave of the ECG and the base of the flow waves recorded at these points, and averaged over 10 beats. The distance (D) traveled by the pulse wave was measured over body surface as the distance from the suprasternal notch to the carotid artery. PWV was calculated as PWV=D/t.
Time frame: Baseline and Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Change From Baseline to Week 38 in the Carotid-femoral Pulse Wave Velocity (PWV) | -1.9 m/s | Standard Error 0.29 |
| Amlodipine 10 mg | Change From Baseline to Week 38 in the Carotid-femoral Pulse Wave Velocity (PWV) | -1.7 m/s | Standard Error 0.3 |
Secondary
Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at End-point (Week 38)
Endothelial function will be assessed using high-resolution duplex ultrasound with wall tracking to measure FMD of the brachial artery during reactive hyperemia. FMD of the brachial artery in response to reactive hyperemia in the distal forearm (and glyceryl trinitrate as a non-endothelium dependent control) will be measured from B-mode ultrasound images using a standard 7 MHz linear array transducer and HDI 5000 system with edge detection.
Time frame: Baseline and Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at End-point (Week 38) | -8.1 percent | Standard Error 0.53 |
| Amlodipine 10 mg | Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at End-point (Week 38) | -8.2 percent | Standard Error 0.56 |
Secondary
Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at Week 12
Endothelial function will be assessed using high-resolution duplex ultrasound with wall tracking to measure FMD of the brachial artery during reactive hyperemia. FMD of the brachial artery in response to reactive hyperemia in the distal forearm (and glyceryl trinitrate as a non-endothelium dependent control) will be measured from B-mode ultrasound images using a standard 7 MHz linear array transducer and HDI 5000 system with edge detection.
Time frame: Baseline and Week 12
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at Week 12 | -8.7 percent | Standard Error 0.35 |
| Amlodipine 10 mg | Change From Baseline for Endothelial Function Measured by Brachial Artery Flow-mediated Vasodilatation (FMD) Using the Brachial Artery Reactivity Test (BART) at Week 12 | -8.6 percent | Standard Error 0.38 |
Secondary
Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Endpoint (Week 38)
Cutaneous blood flow was continuously recorded by a laser Doppler flowmeter. The laser Doppler flow probe was applied on the volar part of the right forearm with a plastic holder 10 cm proximal to the wrist. All measurements were made with a pressure cuff on the arm and inflated 20 mmHg above systolic BP and maintained for 2 min then rapidly deflated. All measurements were made in a quiet room with a patient in the supine position. The maximal reactive hyperemia was measured after cuff deflation, which allows measurement of the right forearm postischemic skin reactive hyperemia (SRH).
Time frame: Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Endpoint (Week 38) | -9.7 Perfusion units | Standard Error 13.73 |
| Amlodipine 10 mg | Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Endpoint (Week 38) | -94.6 Perfusion units | Standard Error 14.2 |
Secondary
Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Week 12
Cutaneous blood flow was continuously recorded by a laser Doppler flowmeter. The laser Doppler flow probe was applied on the volar part of the right forearm with a plastic holder 10 cm proximal to the wrist. All measurements were made with a pressure cuff on the arm and inflated 20 mmHg above systolic BP and maintained for 2 min then rapidly deflated. All measurements were made in a quiet room with a patient in the supine position. The maximal reactive hyperemia was measured after cuff deflation, which allows measurement of the right forearm postischemic skin reactive hyperemia (SRH).
Time frame: Baseline and Week 12
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Week 12 | 25.4 Perfusion units | Standard Error 14.88 |
| Amlodipine 10 mg | Change From Baseline in Post-ischemic Forearm Skin Reactive Hyperemia at Week 12 | -105.6 Perfusion units | Standard Error 15.31 |
Secondary
Change in Left Ventricular Mass Index (LVMI) and Diastolic Function Using Echocardiography From Baseline to Week 38
Time frame: Baseline and Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Change in Left Ventricular Mass Index (LVMI) and Diastolic Function Using Echocardiography From Baseline to Week 38 | -4.8 percent | Standard Error 2.43 |
| Amlodipine 10 mg | Change in Left Ventricular Mass Index (LVMI) and Diastolic Function Using Echocardiography From Baseline to Week 38 | -6.2 percent | Standard Error 2.13 |
Secondary
Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 12
The calculation of spontaneous baroflex sensitivity was obtained by the sequence method. Baroflex sequences are defined by at least three consecutive beats in which the systolic blood pressure and the RR interval of the following beat either both increased or decreased. The slope of each individual sequence is computed and the mean slope is determined as the average of all slopes within a given period of time and taken as the gain of the cardiac baroflex (BRSs).
Time frame: Baseline and Week 12
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 12 | 1.5 EP | Standard Error 1.71 |
| Amlodipine 10 mg | Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 12 | -1.5 EP | Standard Error 1.78 |
Secondary
Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 38
The calculation of spontaneous baroflex sensitivity was obtained by the sequence method. Baroflex sequences are defined by at least three consecutive beats in which the systolic blood pressure and the RR interval of the following beat either both increased or decreased. The slope of each individual sequence is computed and the mean slope is determined as the average of all slopes within a given period of time and taken as the gain of the cardiac baroflex (BRSs).
Time frame: Baseline and Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 38 | -2.0 EP | Standard Error 1.38 |
| Amlodipine 10 mg | Changes in Baroreflex Sensitivity as it Relates to Changes in Carotid Distensibility From Baseline to Week 38 | 0.1 EP | Standard Error 1.44 |
Secondary
Changes in Central Blood Pressure, Evaluated by Applanation Tonometry From Baseline at Weeks 12 and 38
Central Blood Pressure was measured via applanation tonometry recordings of the common carotid artery and from brachial oscillometric recordings. The Simultaneously obtained carotid artery pressure and standard brachial artery blood pressure are computed to obtain the central systolic pressure.
Time frame: Baseline, Week 12 and Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan 320 mg | Changes in Central Blood Pressure, Evaluated by Applanation Tonometry From Baseline at Weeks 12 and 38 | Week 12 | -9.1 mm Hg | Standard Error 1.06 |
| Valsartan 320 mg | Changes in Central Blood Pressure, Evaluated by Applanation Tonometry From Baseline at Weeks 12 and 38 | Week 36 | -11.1 mm Hg | Standard Error 1.07 |
| Amlodipine 10 mg | Changes in Central Blood Pressure, Evaluated by Applanation Tonometry From Baseline at Weeks 12 and 38 | Week 12 | -14.2 mm Hg | Standard Error 1.1 |
| Amlodipine 10 mg | Changes in Central Blood Pressure, Evaluated by Applanation Tonometry From Baseline at Weeks 12 and 38 | Week 36 | -13.9 mm Hg | Standard Error 1.12 |
Secondary
Changes in Mean Left Carotid Distensibility at Week 12
For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure.
Time frame: Baseline and Week 12
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Changes in Mean Left Carotid Distensibility at Week 12 | 0.0 percent | Standard Error 0.14 |
| Amlodipine 10 mg | Changes in Mean Left Carotid Distensibility at Week 12 | 0.0 percent | Standard Error 0.15 |
Secondary
Changes in Mean Left Carotid Distensibility at Week 38
For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure.
Time frame: Baseline and Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Changes in Mean Left Carotid Distensibility at Week 38 | 0.0 percent | Standard Error 0.16 |
| Amlodipine 10 mg | Changes in Mean Left Carotid Distensibility at Week 38 | 0.1 percent | Standard Error 0.16 |
Secondary
Changes in Mean Right Carotid Distensibility at Week 12
For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure.
Time frame: Baseline and Week 12
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Changes in Mean Right Carotid Distensibility at Week 12 | -0.4 percent | Standard Error 0.16 |
| Amlodipine 10 mg | Changes in Mean Right Carotid Distensibility at Week 12 | 0.1 percent | Standard Error 0.17 |
Secondary
Changes in Mean Right Carotid Distensibility at Week 38
For carotid distensibility, the left and right bulbs and common carotid arteries are measured using tissue Doppler imaging with the linear array probe. Absolute diameter and diameter changes over the cardiac cycles will be recorded. Distensibility of each bulb will be calculated for three consecutive heart cycles and averaged and corrected for blood pressure.
Time frame: Baseline and Week 38
Population: Intent-to-treat. The intent to treat population is defined as those who provide a baseline measure and at least one post-baseline measurement (not necessarily an endpoint measure)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan 320 mg | Changes in Mean Right Carotid Distensibility at Week 38 | -0.2 percent | Standard Error 0.17 |
| Amlodipine 10 mg | Changes in Mean Right Carotid Distensibility at Week 38 | 0.0 percent | Standard Error 0.17 |