Hypertension in Hemodialysis Patients
Hypertension in Hemodialysis Patients
The Hypertension in Hemodialysis Patients Treated with Atenolol or Lisinopril (HDPAL) was a randomized, open-label, parallel group, active control, single-center trial that compared the safety and efficacy of ACE-inhibitor-based therapy with β-blocker-based treatment, each administered three times weekly after dialysis. The study was conducted between August 2005 and September 2013 at four dialysis units affiliated with Indiana University. Recruitment and data collection were performed by the principal investigator, coordinators and technicians. An independent data and safety monitoring board reviewed the safety data and the study progress on an annual basis. The study was approved by the Institutional Review Board of Indiana University and the Research and Development Committee of the Roudebush VA Medical Center, Indianapolis, and all subjects gave written informed consent. The principal investigator (R.A.) takes full responsibility to the fidelity of this report.
Patients 18 years or older who had end-stage renal disease treated with chronic hemodialysis dialyzed three times a week (TIW) for at least 3 months with hypertension and left-ventricular hypertrophy were subjects for this study. Patients were excluded if they had ongoing atrial fibrillation, body mass index of ≥40 kg/m, history of missing one or more hemodialysis treatments in the previous month, known drug abuse, severe chronic obstructive airway disease, stroke or myocardial infarction within the previous 6 months or known contraindication to atenolol or lisinopril.
Randomization Subjects were randomized in a 1:1 ratio to either atenolol or lisinopril using concealed opaque envelopes, using a random permuted block design. A permuted block design was chosen to avoid imbalance in assignment to the study drugs over time. Random sequence was generated by a statistician using a computer program and study technicians opened these envelopes after confirming eligibility with the principal investigator. Given that atenolol predictably slows heart rate, it would be easy to guess the assigned drug. Furthermore, a double-blind trial is more resource intensive and costly; therefore, an open-label trial design was chosen. Technicians performing echocardiograms were masked to the treatment assignment.
Diagnosis of hypertension Subjects were asked to monitor their home BP following a mid-week dialysis for 4 days (as described in the Supplementary data). If patients were treated with antihypertensive medications, these medications were tapered and home BP obtained every week up to a maximum of 3 weeks. If home BP increased to ≥160/100 mmHg during this washout period, further tapering of antihypertensive medications was stopped and 44-h interdialytic ambulatory BP monitoring was performed. A diagnosis of hypertension was made if the 44-h interdialytic ambulatory BP monitoring was ≥135 mmHg systolic or ≥85 mmHg diastolic. After one subject had a stroke shortly after washout, the protocol was amended such that washout was required only if the treated home BP was <150/90 mmHg or the ambulatory BP remained normal after tapering antihypertensive medications.
To evaluate the comparative effectiveness of the two drug regimens in controlling hypertension, interdialytic ambulatory BP monitoring was performed at 3 months, 6 months and at the end of the study.
Diagnosis of left ventricular hypertrophy Echocardiographic determination of chamber diameters is sensitive to volume changes. Accordingly, echocardiograms were performed immediately following dialysis (as detailed in the Supplementary data). Left ventricular hypertrophy was defined as echocardiographic left ventricular mass index (LVMI) of ≥104 g/m in women and ≥116 g/m in men. We recognized that cardiac magnetic resonance imaging is less susceptible to volume fluxes and can more accurately detect change in left ventricular mass, but, at the time of initiation of the study, this technique was not available to us.
Drug dosing and titration Target home BP was 140/90 mmHg or less. Initial study drug dose selection was based on baseline ambulatory BP. If 44- h interdialytic ambulatory BP was 135–154/85–94 mmHg, study drugs were started at the lower dose and titrated upwards using the following protocol. Subjects received atenolol 25 mg TIW or lisinopril 10 mg TIW, and the dose was doubled every 2–4 weeks up to a maximum dose of 100 mg TIW for atenolol and 40 mg TIW for lisinopril. If BP control was not possible felodipine or amlodipine 10 mg QD (once daily) was added, followed by other antihypertensive therapies in the following order: doxazosin, minoxidil and guanfacine. If ambulatory BP was ≥155 mmHg systolic or ≥95 mmHg diastolic patients, the maximum dose of the drug was used: for lisinopril 40 mg TIW after dialysis or for atenolol 100 mg TIW after dialysis.
However, following the protocol amendment, study medications were generally used in maximum doses at initiation along with amlodipine and other drugs. Off-study ACE inhibitors, angiotensin receptor blockers and β-blockers were forbidden. Dry weight was adjusted based on the clinical assessment of volume status. At least monthly titration of antihypertensive drugs was based on home BP measurements.
An interim history, concomitant medication list and adverse events related or unrelated to the study were monitored at each monthly visit. Tolerance to BP reduction was assessed by interdialytic symptoms during the course of the trial at monthly intervals. Study duration was 12 months.
Other measurements Quality of life was measured by the kidney disease quality of life tool at the beginning and end of the trial. Postdialysis weights were monitored at least monthly.
The primary outcome was between group differences in change from baseline (CFB) to 12 months in LVMI.
The study was powered to detect between treatment difference of 11 g/m in LVMI over 1 year using 83 hypertensive ESRD patients with left ventricular hypertrophy per group with a power of 80% at a 0.05 two-sided significance level. Assuming a 15% drop out, a total of 100 patients per group were recruited.
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 (which was the case for each subject) regardless of the availability of a postbaseline echocardiogram. A mixed model was used with 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.
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. Adverse events reported are those during the course of 12 months of participation in the trial. All serious adverse events were jointly 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 myocardial infarction, stroke, congestive heart failure or cardiovascular death. At the request of the data safety and monitoring board, we also calculated the hospitalization rates by treatment and their confidence intervals.
All analyses were conducted using Stata version 11.2 (Stata Corp., College Station, TX, USA). The P values reported are two-sided and taken to be significant at <0.05.
The funding source had no input in the decision to submit the manuscript for publication. R.A. was responsible for the decision to submit the manuscript. All authors had full access to data at all times.
Materials and Methods
The Hypertension in Hemodialysis Patients Treated with Atenolol or Lisinopril (HDPAL) was a randomized, open-label, parallel group, active control, single-center trial that compared the safety and efficacy of ACE-inhibitor-based therapy with β-blocker-based treatment, each administered three times weekly after dialysis. The study was conducted between August 2005 and September 2013 at four dialysis units affiliated with Indiana University. Recruitment and data collection were performed by the principal investigator, coordinators and technicians. An independent data and safety monitoring board reviewed the safety data and the study progress on an annual basis. The study was approved by the Institutional Review Board of Indiana University and the Research and Development Committee of the Roudebush VA Medical Center, Indianapolis, and all subjects gave written informed consent. The principal investigator (R.A.) takes full responsibility to the fidelity of this report.
Participants
Patients 18 years or older who had end-stage renal disease treated with chronic hemodialysis dialyzed three times a week (TIW) for at least 3 months with hypertension and left-ventricular hypertrophy were subjects for this study. Patients were excluded if they had ongoing atrial fibrillation, body mass index of ≥40 kg/m, history of missing one or more hemodialysis treatments in the previous month, known drug abuse, severe chronic obstructive airway disease, stroke or myocardial infarction within the previous 6 months or known contraindication to atenolol or lisinopril.
Study Design
Randomization Subjects were randomized in a 1:1 ratio to either atenolol or lisinopril using concealed opaque envelopes, using a random permuted block design. A permuted block design was chosen to avoid imbalance in assignment to the study drugs over time. Random sequence was generated by a statistician using a computer program and study technicians opened these envelopes after confirming eligibility with the principal investigator. Given that atenolol predictably slows heart rate, it would be easy to guess the assigned drug. Furthermore, a double-blind trial is more resource intensive and costly; therefore, an open-label trial design was chosen. Technicians performing echocardiograms were masked to the treatment assignment.
Diagnosis of hypertension Subjects were asked to monitor their home BP following a mid-week dialysis for 4 days (as described in the Supplementary data). If patients were treated with antihypertensive medications, these medications were tapered and home BP obtained every week up to a maximum of 3 weeks. If home BP increased to ≥160/100 mmHg during this washout period, further tapering of antihypertensive medications was stopped and 44-h interdialytic ambulatory BP monitoring was performed. A diagnosis of hypertension was made if the 44-h interdialytic ambulatory BP monitoring was ≥135 mmHg systolic or ≥85 mmHg diastolic. After one subject had a stroke shortly after washout, the protocol was amended such that washout was required only if the treated home BP was <150/90 mmHg or the ambulatory BP remained normal after tapering antihypertensive medications.
To evaluate the comparative effectiveness of the two drug regimens in controlling hypertension, interdialytic ambulatory BP monitoring was performed at 3 months, 6 months and at the end of the study.
Diagnosis of left ventricular hypertrophy Echocardiographic determination of chamber diameters is sensitive to volume changes. Accordingly, echocardiograms were performed immediately following dialysis (as detailed in the Supplementary data). Left ventricular hypertrophy was defined as echocardiographic left ventricular mass index (LVMI) of ≥104 g/m in women and ≥116 g/m in men. We recognized that cardiac magnetic resonance imaging is less susceptible to volume fluxes and can more accurately detect change in left ventricular mass, but, at the time of initiation of the study, this technique was not available to us.
Drug dosing and titration Target home BP was 140/90 mmHg or less. Initial study drug dose selection was based on baseline ambulatory BP. If 44- h interdialytic ambulatory BP was 135–154/85–94 mmHg, study drugs were started at the lower dose and titrated upwards using the following protocol. Subjects received atenolol 25 mg TIW or lisinopril 10 mg TIW, and the dose was doubled every 2–4 weeks up to a maximum dose of 100 mg TIW for atenolol and 40 mg TIW for lisinopril. If BP control was not possible felodipine or amlodipine 10 mg QD (once daily) was added, followed by other antihypertensive therapies in the following order: doxazosin, minoxidil and guanfacine. If ambulatory BP was ≥155 mmHg systolic or ≥95 mmHg diastolic patients, the maximum dose of the drug was used: for lisinopril 40 mg TIW after dialysis or for atenolol 100 mg TIW after dialysis.
However, following the protocol amendment, study medications were generally used in maximum doses at initiation along with amlodipine and other drugs. Off-study ACE inhibitors, angiotensin receptor blockers and β-blockers were forbidden. Dry weight was adjusted based on the clinical assessment of volume status. At least monthly titration of antihypertensive drugs was based on home BP measurements.
An interim history, concomitant medication list and adverse events related or unrelated to the study were monitored at each monthly visit. Tolerance to BP reduction was assessed by interdialytic symptoms during the course of the trial at monthly intervals. Study duration was 12 months.
Other measurements Quality of life was measured by the kidney disease quality of life tool at the beginning and end of the trial. Postdialysis weights were monitored at least monthly.
Outcome
The primary outcome was between group differences in change from baseline (CFB) to 12 months in LVMI.
Statistical Analysis
The study was powered to detect between treatment difference of 11 g/m in LVMI over 1 year using 83 hypertensive ESRD patients with left ventricular hypertrophy per group with a power of 80% at a 0.05 two-sided significance level. Assuming a 15% drop out, a total of 100 patients per group were recruited.
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 (which was the case for each subject) regardless of the availability of a postbaseline echocardiogram. A mixed model was used with 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.
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. Adverse events reported are those during the course of 12 months of participation in the trial. All serious adverse events were jointly 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 myocardial infarction, stroke, congestive heart failure or cardiovascular death. At the request of the data safety and monitoring board, we also calculated the hospitalization rates by treatment and their confidence intervals.
All analyses were conducted using Stata version 11.2 (Stata Corp., College Station, TX, USA). The P values reported are two-sided and taken to be significant at <0.05.
The funding source had no input in the decision to submit the manuscript for publication. R.A. was responsible for the decision to submit the manuscript. All authors had full access to data at all times.