Hemodialysis, Hypertension, Left Ventricular Hypertrophy
Conditions
Keywords
Hemodialysis, Hypertension, Left ventricular hypertrophy
Brief summary
We will directly test the hypothesis that an initial strategy of lisinopril-based therapy will be more effective than atenolol-based therapy in causing regression of left ventricular hypertrophy (LVH) over one year in patients with hemodialysis hypertension despite similar degree of BP reduction.
Detailed description
This is a parallel group, active control, single-center, open-label, randomized controlled trial comparing the safety and efficacy of initial therapy with an angiotensin converting enzyme (ACE) inhibitor (lisinopril) vs. beta-blocker therapy (atenolol) each administered three times weekly after dialysis.
Interventions
DRUGLisinopril
Patients will be randomized into two groups, one that is beta blocker based, the other angiotensin converting enzyme (ACE) inhibitor (lisinopril) based. Patients who are on no medications will receive atenolol 25 mg. t.i.w. or lisinopril 10 mg. t.i.w. for one month at the end of which, dose will be titrated to twice the drug doses following monthly interval to another doubling of dose. If BP is still poorly controlled felodipine will be added. Other antihypertensive therapies will be added to control home BP to \<140/90 mm Hg.
DRUGAtenolol
Patients will be randomized into two groups, one that is beta blocker based, the other angiotensin converting enzyme (ACE) inhibitor (lisinopril) based. Patients who are on no medications will receive atenolol 25 mg. t.i.w. or lisinopril 10 mg. t.i.w. for one month at the end of which, dose will be titrated to twice the drug doses following monthly interval to another doubling of dose. If BP is still poorly controlled felodipine will be added. Other antihypertensive therapies will be added to control home BP to \<140/90 mm Hg.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients on chronic hemodialysis for \> 3 mos. 2. Compliance with hemodialysis treatments as defined by less than one missed dialysis per month 3. Hypertension as diagnosed by ambulatory blood pressure monitoring (ABPM) \>135/75 mm Hg after participation in the ultrafiltration (UF) Trial, or those on no antihypertensive medications but unwilling to do UF Trial. 4. Presence of LVH on echocardiogram defined as left ventricular mass index (LVMi) \>104 g/m2 in women and \>116 g/m2 in men. 5. Willingness to give informed consent.
Exclusion criteria
1. Vascular event (stroke, myocardial infarction or limb ischemia requiring bypass) within previous six months 2. Noncompliance with hemodialysis treatments 3. Known drug abuse 4. Chronic obstructive pulmonary disorder (COPD) requiring home oxygen 5. Congestive Heart Failure Class III or IV. 6. Body mass index \> 40 kg/m2. 7. Known contraindication to atenolol (severe heart failure, bradycardia, bronchial asthma, intolerance or allergy) or lisinopril (cough, pregnancy, intolerance or allergy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary End Point is the Regression of Left Ventricular Hypertrophy (LVH) by Echocardiographic Criteria From Baseline to 1 Year. | Baseline, 6 months, 12 months | The primary outcome of the study was the average reduction in left ventricular mass indexed for body surface area from baseline to 1 year. A mixed model was used with left ventricular mass index (LVMI) as the outcome variable. Fixed effects were indicator variables for time, treatment and their interaction. Random effect was subject and statistical inference was made using the maximum likelihood estimator. No imputation was made for missing data. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | 1 yr | Cardiovascular events were counted by subject and included the following: myocardial infarction (MI), stroke, hospitalization for congestive heart failure (CHF), hospitalized angina, arrhythmias, cardiac arrest, coronary revascularization and heart valve replacement. Adverse events reported are those during the course of 12 months of participation in the trial. All serious adverse events were adjudicated by R.A. and A.D.S. who were masked to the drug assignment at the time of adjudication. The duration of participation in the study per subject, which according to the trial design could be up to 12 months, was determined. The cardiovascular event rate was calculated by treatment group assignment. Incidence rate ratio (IRR) by treatment was then determined along with the 95% confidence intervals (95% CIs). As a post hoc analysis, we also determined the narrower definition of cardiovascular events per group that included MI, stroke, CHF, or cardiovascular death. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atenolol Atenolol: Patients will be randomized into two groups, one that is beta blocker based, the other ACE inhibitor (lisinopril) based. Patients who are on no medications will receive atenolol 25 mg. t.i.w. or lisinopril 10 mg. t.i.w. for one month at the end of which, dose will be titrated to twice the drug doses following monthly interval to another doubling of dose. If BP is still poorly controlled felodipine will be added. Other antihypertensive therapies will be added to control home BP to \<140/90 mm Hg. | 100 |
| Lisinopril Lisinopril: Patients will be randomized into two groups, one that is beta blocker based, the other ACE inhibitor (lisinopril) based. Patients who are on no medications will receive atenolol 25 mg. t.i.w. or lisinopril 10 mg. t.i.w. for one month at the end of which, dose will be titrated to twice the drug doses following monthly interval to another doubling of dose. If BP is still poorly controlled felodipine will be added. Other antihypertensive therapies will be added to control home BP to \<140/90 mm Hg. | 100 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 4 | 4 |
| Overall Study | Kidney Transplant | 3 | 1 |
| Overall Study | Lost to Follow-up | 7 | 6 |
| Overall Study | Physician Decision | 0 | 6 |
| Overall Study | Stopped by data safety monitoring board | 19 | 20 |
| Overall Study | Withdrawal by Subject | 8 | 16 |
Baseline characteristics
| Characteristic | Total | Atenolol | Lisinopril |
|---|---|---|---|
| Access type Catheter | 52 participants | 25 participants | 27 participants |
| Access type Fistula | 118 participants | 59 participants | 59 participants |
| Access type Graft | 30 participants | 16 participants | 14 participants |
| Age, Continuous | 52.7 years STANDARD_DEVIATION 12.6 | 52.5 years STANDARD_DEVIATION 11.7 | 53.1 years STANDARD_DEVIATION 13.5 |
| Albumin | 3.6 g/dL STANDARD_DEVIATION 0.5 | 3.6 g/dL STANDARD_DEVIATION 0.5 | 3.6 g/dL STANDARD_DEVIATION 0.5 |
| Alcohol Does not drink alcohol | 154 participants | 73 participants | 81 participants |
| Alcohol Drinks alcohol | 46 participants | 27 participants | 19 participants |
| Anuric | 134 participants | 68 participants | 66 participants |
| Blood flow rate | 393.4 mL/min STANDARD_DEVIATION 33.7 | 394.3 mL/min STANDARD_DEVIATION 30.9 | 392.4 mL/min STANDARD_DEVIATION 36.4 |
| Body mass index | 27.9 kg/m^2 STANDARD_DEVIATION 7.7 | 28.4 kg/m^2 STANDARD_DEVIATION 7 | 27.5 kg/m^2 STANDARD_DEVIATION 8.3 |
| Comorbid conditions Cerebrovascular disease | 33 participants | 13 participants | 20 participants |
| Comorbid conditions Coronary artery disease | 53 participants | 22 participants | 31 participants |
| Comorbid conditions Coronary revascularization | 19 participants | 4 participants | 15 participants |
| Comorbid conditions Diabetes mellitus | 86 participants | 43 participants | 43 participants |
| Comorbid conditions Hospitalized heart failure | 62 participants | 25 participants | 37 participants |
| Comorbid conditions Peripheral vascular disease | 21 participants | 10 participants | 11 participants |
| Creatinine | 10.1 mg/dL STANDARD_DEVIATION 3.6 | 10.3 mg/dL STANDARD_DEVIATION 3.5 | 10 mg/dL STANDARD_DEVIATION 3.6 |
| Dialysate flow rate | 770.4 mL/min STANDARD_DEVIATION 73 | 779.6 mL/min STANDARD_DEVIATION 61.9 | 761.3 mL/min STANDARD_DEVIATION 82 |
| Dialysis duration Delivered dialysis duration | 222 minutes STANDARD_DEVIATION 34.2 | 224.1 minutes STANDARD_DEVIATION 34.7 | 219.8 minutes STANDARD_DEVIATION 33.7 |
| Dialysis duration Prescribed dialysis duration | 239.4 minutes STANDARD_DEVIATION 22.7 | 239.4 minutes STANDARD_DEVIATION 19 | 239.4 minutes STANDARD_DEVIATION 25.9 |
| Dialysis vintage | 4.1 years STANDARD_DEVIATION 4.3 | 4.2 years STANDARD_DEVIATION 4.4 | 3.9 years STANDARD_DEVIATION 4.2 |
| Education | 12 years STANDARD_DEVIATION 2 | 12 years STANDARD_DEVIATION 2 | 12 years STANDARD_DEVIATION 2 |
| Employed Not working | 137 participants | 67 participants | 70 participants |
| Employed Retired | 45 participants | 22 participants | 23 participants |
| Employed Working | 18 participants | 11 participants | 7 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 199 Participants | 99 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Etiology of chronic kidney disease Diabetes mellitus | 56 participants | 29 participants | 27 participants |
| Etiology of chronic kidney disease Glomerulonephritis | 9 participants | 4 participants | 5 participants |
| Etiology of chronic kidney disease Hypertension | 100 participants | 54 participants | 46 participants |
| Etiology of chronic kidney disease Other etiologies | 34 participants | 13 participants | 21 participants |
| Etiology of chronic kidney disease Polycystic kidney disease | 1 participants | 0 participants | 1 participants |
| Height | 67.9 inches STANDARD_DEVIATION 3.9 | 68.3 inches STANDARD_DEVIATION 4.1 | 67.6 inches STANDARD_DEVIATION 3.7 |
| Hemoglobin | 11.3 g/dL STANDARD_DEVIATION 1.3 | 11.3 g/dL STANDARD_DEVIATION 1.2 | 11.3 g/dL STANDARD_DEVIATION 1.4 |
| Income < $25,000 | 164 participants | 84 participants | 80 participants |
| Income >= $25,000 | 17 participants | 10 participants | 7 participants |
| Income Refused | 19 participants | 6 participants | 13 participants |
| Marital status Divorced/separated | 33 participants | 18 participants | 15 participants |
| Marital status Married | 42 participants | 23 participants | 19 participants |
| Marital status Single | 109 participants | 53 participants | 56 participants |
| Marital status Widowed | 16 participants | 6 participants | 10 participants |
| Race/Ethnicity, Customized Blacks | 172 participants | 86 participants | 86 participants |
| Race/Ethnicity, Customized Non-blacks | 28 participants | 14 participants | 14 participants |
| Region of Enrollment United States | 200 participants | 100 participants | 100 participants |
| Sex: Female, Male Female | 69 Participants | 27 Participants | 42 Participants |
| Sex: Female, Male Male | 131 Participants | 73 Participants | 58 Participants |
| Smoking Current smoker | 86 participants | 43 participants | 43 participants |
| Smoking Non-smoker | 114 participants | 57 participants | 57 participants |
| Urea reduction ratio | 75 % STANDARD_DEVIATION 8 | 74 % STANDARD_DEVIATION 8 | 76 % STANDARD_DEVIATION 8 |
| Weight | 83 kg STANDARD_DEVIATION 23.1 | 85.1 kg STANDARD_DEVIATION 21.7 | 80.9 kg STANDARD_DEVIATION 24.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 100 | 29 / 100 |
| serious Total, serious adverse events | 58 / 100 | 70 / 100 |
Outcome results
Primary
The Primary End Point is the Regression of Left Ventricular Hypertrophy (LVH) by Echocardiographic Criteria From Baseline to 1 Year.
The primary outcome of the study was the average reduction in left ventricular mass indexed for body surface area from baseline to 1 year. A mixed model was used with left ventricular mass index (LVMI) as the outcome variable. Fixed effects were indicator variables for time, treatment and their interaction. Random effect was subject and statistical inference was made using the maximum likelihood estimator. No imputation was made for missing data.
Time frame: Baseline, 6 months, 12 months
Population: The primary outcome of the study was the average reduction in left ventricular mass indexed for body surface area from baseline to 1 year. The analysis was performed by intention to treat, if the patient received at least one dose of the randomized drug regardless of the availability of a post-baseline echocardiogram.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atenolol | The Primary End Point is the Regression of Left Ventricular Hypertrophy (LVH) by Echocardiographic Criteria From Baseline to 1 Year. | LVMI Change from baseline, 6 months | -8.4 g/m^2 | Standard Deviation 5.1 |
| Atenolol | The Primary End Point is the Regression of Left Ventricular Hypertrophy (LVH) by Echocardiographic Criteria From Baseline to 1 Year. | LVMI Change from baseline, 12 months | -21.5 g/m^2 | Standard Deviation 5.7 |
| Lisinopril | The Primary End Point is the Regression of Left Ventricular Hypertrophy (LVH) by Echocardiographic Criteria From Baseline to 1 Year. | LVMI Change from baseline, 6 months | -3.4 g/m^2 | Standard Deviation 5.5 |
| Lisinopril | The Primary End Point is the Regression of Left Ventricular Hypertrophy (LVH) by Echocardiographic Criteria From Baseline to 1 Year. | LVMI Change from baseline, 12 months | -15.1 g/m^2 | Standard Deviation 6.2 |
Other Pre-specified
Serious Adverse Events and Cardiovascular Events That Led to Trial Termination
Cardiovascular events were counted by subject and included the following: myocardial infarction (MI), stroke, hospitalization for congestive heart failure (CHF), hospitalized angina, arrhythmias, cardiac arrest, coronary revascularization and heart valve replacement. Adverse events reported are those during the course of 12 months of participation in the trial. All serious adverse events were adjudicated by R.A. and A.D.S. who were masked to the drug assignment at the time of adjudication. The duration of participation in the study per subject, which according to the trial design could be up to 12 months, was determined. The cardiovascular event rate was calculated by treatment group assignment. Incidence rate ratio (IRR) by treatment was then determined along with the 95% confidence intervals (95% CIs). As a post hoc analysis, we also determined the narrower definition of cardiovascular events per group that included MI, stroke, CHF, or cardiovascular death.
Time frame: 1 yr
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atenolol | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, cardiovasular events | 24.6 events/100 patient-years |
| Atenolol | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, combined MI, stroke, CHF, CV death | 13.5 events/100 patient-years |
| Atenolol | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, congest heart failure | 6.2 events/100 patient-years |
| Atenolol | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, all-cause hospitalizations | 89.9 events/100 patient-years |
| Lisinopril | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, all-cause hospitalizations | 144.3 events/100 patient-years |
| Lisinopril | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, cardiovasular events | 58 events/100 patient-years |
| Lisinopril | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, congest heart failure | 20.2 events/100 patient-years |
| Lisinopril | Serious Adverse Events and Cardiovascular Events That Led to Trial Termination | Incidence rate, combined MI, stroke, CHF, CV death | 31 events/100 patient-years |
Comparison: Cardiovascular events were counted by subject and included the following: myocardial infarction, stroke, hospitalization for congestive heart failure, hospitalized angina, arrhythmias, cardiac arrest, coronary revascularization and heart valve replacement. The duration of participation in the study per subject, which according to the trial design could be up to 12 months, was determined. Incidence rate ratio (IRR) by treatment was then determined along with the 95%confidence intervals (95% CIs).p-value: 0.00195% CI: [1.36, 4.23]Mixed Models Analysis
Comparison: As a post hoc analysis, we determined the narrower definition of cardiovascular events per group that included myocardial infarction, stroke, congestive heart failure or cardiovascular death. The duration of participation in the study per subject, which according to the trial design could be up to 12 months, was determined. Incidence rate ratio (IRR) by treatment was then determined along with the 95%confidence intervals (95% CIs).p-value: 0.0295% CI: [1.07, 5.21]Mixed Models Analysis
Comparison: Hospitalization for congestive heart failure between groups was analyzed. The duration of participation in the study per subject, which according to the trial design could be up to 12 months, was determined. Incidence rate ratio (IRR) by treatment was then determined along with the 95%confidence intervals.p-value: 0.0295% CI: [1.08, 10.99]Mixed Models Analysis
Comparison: All-cause hospitalizations between groups were analyzed. The duration of participation in the study per subject, which according to the trial design could be up to 12 months, was determined. Incidence rate ratio (IRR) by treatment was then determined along with the 95%confidence intervals.p-value: 0.00295% CI: [1.18, 2.19]Mixed Models Analysis