Diastolic Dysfunction, Hypertension
Conditions
Keywords
Hypertension, systolic blood pressure, diastolic dysfunction, valsartan, amlodipine
Brief summary
The purpose of this study is to determine the effects of treatment with valsartan + amlodipine to a target systolic blood pressure (SBP)\<130 mmHg compared to the Joint National Commission on the Treatment of Hypertension 7 recommended target SBP of \<140 mmHg on the intrinsic diastolic properties of the myocardium in patients with hypertension and echocardiographic evidence of diastolic dysfunction.
Interventions
DRUGvalsartan
160 mg or 320 mg tablets once a day
DRUGamlodipine
5 mg or 10 mg tablets once a day
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 45 years or older * Male and female patients are eligible. Female patients must be post-menopausal for one year, surgically sterile, or using effective contraceptive methods such as a double barrier method with spermicide, an intra-uterine device, or hormonal contraceptives. Post-menopausal women on a stable dose of hormone replacement therapy (HRT) for at least three (3) months prior to the screening visit are eligible for the study. * Uncontrolled systolic hypertension on a maximum of two (2) antihypertensive medications at the time of screening. * Echocardiographic ejection fraction ≥50% and evidence of diastolic dysfunction. * Provide written informed consent to participate in the study prior to any screening or study procedures * Have the ability to communicate well and comply with all study requirements
Exclusion criteria
* Severe hypertension defined as a MSSBP \>200 mmHg and/or MSDBP \>120 mmHg. * History of a secondary cause of hypertension including but not limited to: coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing's disease, pheochromocytoma, polycystic kidney disease, etc. * Ejection fraction \<50 % * History of stroke, transient ischemic attack, myocardial infarction, coronary artery bypass graft surgery, or unstable angina pectoris within 6 months of screening * Presence of clinically significant ventricular or supraventricular arrhythmias (e.g. atrial fibrillation/flutter) * History of congestive heart failure * History of diabetes mellitus * History of renal impairment with serum creatinine \>2.0 mg/dL at screening, history of dialysis, or history of nephritic syndrome * Antihypertensive therapy with three (3) or more medications at the time of screening * Active and/or treated malignancy of any organ system within twelve (12) months of enrollment, with the exception of localized basal cell carcinoma of the skin * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\>5 mIU/ml) * Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \>40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: barrier method with spermicidal agent, an intrauterine device, hormonal contraceptives, or total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study * Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug including, but not limited to, any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active, or active inflammatory bowel syndrome within 12 months prior to Visit 1, currently active gastritis, ulcers, or gastrointestinal/rectal bleeding, or urinary tract obstruction regarded as clinically meaningful by the investigator * Pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury within 12 months prior to Visit 1 * Any serum AST or ALT elevation two (2) times the upper limit of normal Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lateral Mitral Annular Myocardial Relaxation Velocity | Baseline to 24 weeks after treatment | Change from baseline in lateral mitral annular myocardial relaxation velocity (E') at Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Ratio of Peak E Wave Velocity/Lateral Mitral Annular Myocardial Relaxation Velocity | Baseline to 24 weeks after treatment | Change from baseline in peak E-wave velocity / lateral mitral annular myocardial relaxation velocity (E/E') at Week 24 |
| Percent Change From Baseline in Vascular Stiffness | Baseline to 8 and 24 weeks after treatment | Percent change from baseline in Vascular Stiffness (measured by radial augmentation index \[AI\]) at Weeks 8 and 24 |
| Change in Left Atrial Size | Baseline to 24 weeks after treatment | Change from baseline in left atrial size at Week 24 |
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) | Baseline to 8 and 24 weeks after treatment | Change from baseline in msDBP at Weeks 8 and 24 |
| Change in Estimated Central Aortic Pressure | Baseline to 8 and 24 weeks after treatment | Change from baseline in estimated central aortic pressure at Weeks 8 and 24 |
| Change in Mean Sitting Systolic Blood Pressure (msSBP) | Baseline to 8 and 24 weeks after treatment | Change from baseline in msSBP at Weeks 8 and 24 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intensive Treatment Regimen (Valsartan + Amlodipine to target SBP \< 130 mm Hg). Patients in the intensive treatment regimen had the study medication force-titrated to the maximum tolerated dose with the goal to achieve an SBP \< 130 mm Hg.
At week 0 patients received valsartan 160 mg + amlodipine 5 mg. At week 2, patients were force-titrated to valsartan 160 mg + amlodipine 10 mg. At week 4, patients were force titrated to valsartan 320 mg + amlodipine 10 mg. At week 8, patients who reached the SBP target \< 130 mm Hg stayed on their current dose valsartan 320 mg + amlodipine 10 mg or the maximum tolerated dose as per the investigator's discretion. Patients not at SBP target \< 130 mm Hg at week 8 or any study visits thereafter received other additional antihypertensive medications. | 114 |
| Standard Treatment Regimen (Valsartan + Amlodipine to target SBP of \< 140 mmHg). Patients in the standard treatment regimen had the study medication up-titrated until the SBP goal of \< 140 mm Hg was achieved.
At week 0 patients received valsartan 160 mg + amlodipine 5 mg. At week 2 patients were up-titrated to valsartan 160 mg + amlodipine 10 mg only if they were not at SBP target \< 140 mm Hg. At week 4 patients were up-titrated to valsartan 320 mg + amlodipine 10 mg only if they were not at SBP target \< 140 mm Hg. Patients not at SBP target \< 140 mm Hg by Week 8 or at any study visit thereafter received additional antihypertensive medications. | 114 |
| Total | 228 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Patient withdrew consent | 7 | 6 |
| Overall Study | Protocol Deviation | 3 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Intensive Treatment Regimen | Standard Treatment Regimen |
|---|---|---|---|
| Age Continuous | 59.6 years STANDARD_DEVIATION 9.74 | 60.2 years STANDARD_DEVIATION 10.03 | 58.9 years STANDARD_DEVIATION 9.45 |
| Sex: Female, Male Female | 115 Participants | 61 Participants | 54 Participants |
| Sex: Female, Male Male | 113 Participants | 53 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 49 / 114 | 41 / 114 |
| serious Total, serious adverse events | 3 / 114 | 3 / 114 |
Outcome results
Primary
Change in Lateral Mitral Annular Myocardial Relaxation Velocity
Change from baseline in lateral mitral annular myocardial relaxation velocity (E') at Week 24
Time frame: Baseline to 24 weeks after treatment
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive Treatment Regimen | Change in Lateral Mitral Annular Myocardial Relaxation Velocity | 1.544 cm/s | Standard Deviation 1.3946 |
| Standard Treatment Regimen | Change in Lateral Mitral Annular Myocardial Relaxation Velocity | 1.476 cm/s | Standard Deviation 1.5985 |
Secondary
Change in Estimated Central Aortic Pressure
Change from baseline in estimated central aortic pressure at Weeks 8 and 24
Time frame: Baseline to 8 and 24 weeks after treatment
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intensive Treatment Regimen | Change in Estimated Central Aortic Pressure | Week 24 | -17.71 mm Hg | Standard Deviation 14.635 |
| Intensive Treatment Regimen | Change in Estimated Central Aortic Pressure | Week 8 | -16.30 mm Hg | Standard Deviation 12.483 |
| Standard Treatment Regimen | Change in Estimated Central Aortic Pressure | Week 24 | -14.76 mm Hg | Standard Deviation 12.689 |
| Standard Treatment Regimen | Change in Estimated Central Aortic Pressure | Week 8 | -14.68 mm Hg | Standard Deviation 12.751 |
Secondary
Change in Left Atrial Size
Change from baseline in left atrial size at Week 24
Time frame: Baseline to 24 weeks after treatment
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive Treatment Regimen | Change in Left Atrial Size | -0.127 cm | Standard Deviation 0.3082 |
| Standard Treatment Regimen | Change in Left Atrial Size | -0.104 cm | Standard Deviation 0.2845 |
Secondary
Change in Mean Sitting Diastolic Blood Pressure (msDBP)
Change from baseline in msDBP at Weeks 8 and 24
Time frame: Baseline to 8 and 24 weeks after treatment
Population: Intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intensive Treatment Regimen | Change in Mean Sitting Diastolic Blood Pressure (msDBP) | Week 8 | -12.77 mm Hg | Standard Deviation 10.118 |
| Intensive Treatment Regimen | Change in Mean Sitting Diastolic Blood Pressure (msDBP) | Week 24 | -15.21 mm Hg | Standard Deviation 10.147 |
| Standard Treatment Regimen | Change in Mean Sitting Diastolic Blood Pressure (msDBP) | Week 8 | -12.62 mm Hg | Standard Deviation 10.475 |
| Standard Treatment Regimen | Change in Mean Sitting Diastolic Blood Pressure (msDBP) | Week 24 | -14.08 mm Hg | Standard Deviation 11.163 |
Secondary
Change in Mean Sitting Systolic Blood Pressure (msSBP)
Change from baseline in msSBP at Weeks 8 and 24
Time frame: Baseline to 8 and 24 weeks after treatment
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intensive Treatment Regimen | Change in Mean Sitting Systolic Blood Pressure (msSBP) | Week 8 | -25.74 mm Hg | Standard Deviation 16.112 |
| Intensive Treatment Regimen | Change in Mean Sitting Systolic Blood Pressure (msSBP) | Week 24 | -30.37 mm Hg | Standard Deviation 18.745 |
| Standard Treatment Regimen | Change in Mean Sitting Systolic Blood Pressure (msSBP) | Week 8 | -22.31 mm Hg | Standard Deviation 16.014 |
| Standard Treatment Regimen | Change in Mean Sitting Systolic Blood Pressure (msSBP) | Week 24 | -25.06 mm Hg | Standard Deviation 17.074 |
Secondary
Change in Ratio of Peak E Wave Velocity/Lateral Mitral Annular Myocardial Relaxation Velocity
Change from baseline in peak E-wave velocity / lateral mitral annular myocardial relaxation velocity (E/E') at Week 24
Time frame: Baseline to 24 weeks after treatment
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive Treatment Regimen | Change in Ratio of Peak E Wave Velocity/Lateral Mitral Annular Myocardial Relaxation Velocity | -0.951 ratio | Standard Deviation 2.1729 |
| Standard Treatment Regimen | Change in Ratio of Peak E Wave Velocity/Lateral Mitral Annular Myocardial Relaxation Velocity | -0.680 ratio | Standard Deviation 2.0714 |
Secondary
Percent Change From Baseline in Vascular Stiffness
Percent change from baseline in Vascular Stiffness (measured by radial augmentation index \[AI\]) at Weeks 8 and 24
Time frame: Baseline to 8 and 24 weeks after treatment
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intensive Treatment Regimen | Percent Change From Baseline in Vascular Stiffness | Week 8 | -7.89 percentage of change in mean AI | Standard Deviation 9.645 |
| Intensive Treatment Regimen | Percent Change From Baseline in Vascular Stiffness | Week 24 | -6.07 percentage of change in mean AI | Standard Deviation 10.582 |
| Standard Treatment Regimen | Percent Change From Baseline in Vascular Stiffness | Week 8 | -7.32 percentage of change in mean AI | Standard Deviation 11.97 |
| Standard Treatment Regimen | Percent Change From Baseline in Vascular Stiffness | Week 24 | -5.63 percentage of change in mean AI | Standard Deviation 11.367 |