Antihypertensive Effects of Drospirenone With 17-Estradiol, a Novel Hormone Treatment in Postmenopausal Women With Stage 1 Hypertension
http://www.100md.com
《循环学杂志》
the Section of Hypertension and Clinical Pharmacology (W.B.W.), Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington
the Division of Cardiology (B.P.), University of Michigan Medical School, Ann Arbor
the Division of Clinical Pharmacology (R.P.), University of Miami School of Medicine, Miami, Fla
Berlex Laboratories (V.H.), Montville, NJ.
Abstract
Background— Drospirenone (DRSP) is a novel progestin with antimineralocorticoid activity that has been developed for hormone therapy in combination with 17-estradiol (E2) in postmenopausal women. In prior studies with DRSP in postmenopausal women that were focused on relief of menopausal symptoms, DRSP/E2 yielded significant reductions in blood pressure (BP).
Methods and Results— The effects of 3 mg DRSP/1 mg E2 on clinic and 24-hour ambulatory BP as well as potassium homeostasis were evaluated in postmenopausal women with stage 1 hypertension (systolic, 140 to 159 and/or diastolic, 90 to 99 mm Hg) in a 12-week, multicenter, double-blind, randomized, placebo-controlled study. Clinic BPs were measured at baseline and at 2, 4, 6, 8, and 12 weeks of therapy, whereas potassium was measured at 2, 6, and 12 weeks of therapy. Ambulatory BP was performed in a substudy at baseline and at the end of the trial. In the intention-to-treat population of 213 women, the clinic BP was reduced significantly on DRSP/E2 (clinic BP, –14.1/–7.9 for DRSP/E2 versus –7.1/–4.3 mm Hg for placebo, P<0.0001). In the subgroup of 43 women with ambulatory BP monitoring, the 24-hour BP fell by –8.5/–4.2 mm Hg versus –1.8/–1.6 mm Hg on placebo (P=0.002/0.07). There were no significant changes from baseline in potassium levels or in the incidence of hyperkalemia (5.5 meq/L) on DRSP/E2 compared with placebo.
Conclusions— Combination therapy with DRSP/E2 significantly lowered both clinic and 24-hour systolic BP in postmenopausal women with stage 1 systolic hypertension. This characteristic may lead to benefit for cardiovascular risk reduction in this population.
Key Words: hormones hypertension blood pressure aldosterone antagonists menopause
Introduction
Postmenopausal estrogen deficiency has been associated with increases in cardiovascular risk, but clinical trials of standard formulations of hormonal therapy have not confirmed a benefit of hormone therapy in reducing cardiovascular disease in postmenopausal women.1–5 Although the reasons for these generally negative results are unclear, it is apparent that innovative, alternative strategies for hormone therapy in postmenopausal women are warranted.
Several recent experimental and clinical reports have implicated aldosterone, independent of angiotensin II, in the pathogenesis of significant cardiovascular and renal disease and have demonstrated the benefit of aldosterone blockade in reducing a variety of cardiovascular and renal end points.6–13 Drospirenone (DRSP) is a novel progestin with antialdosterone and antiandrogenic effects that, in combination with 17-estradiol (E2), has been developed for use in postmenopausal women as hormone therapy.14–16 DRSP/E2 has been shown to have significant antihypertensive effects in a short-term study of postmenopausal, hypertensive women treated with enalapril.17 When compared with other hormone therapies and oral contraceptives, DRSP yields a much greater rise in plasma aldosterone14–16 in response to the antimineralocorticoid effect of the compound.
The primary objective of the present study was to determine whether DRSP/E2 treatment has a clinically significant effect on clinic and 24-hour ambulatory blood pressure (BP) in hypertensive, postmenopausal women at doses of 3 mg DSRP and 1 mg E2. In addition, we evaluated the effects of DSRP/E2 on potassium homeostasis, because aldosterone blockade has been associated with significant increases in serum potassium values.14–16
Methods
Patient Population
Postmenopausal women (aged 45 to 80 years) were included if, in the untreated condition, their seated clinic systolic BP was 140 to 159 mm Hg and/or the diastolic BP was 90 to 99 mm Hg. Patients were excluded from the trial if they had received prior estrogen or progestin hormone therapy; had sustained a recent myocardial infarction or unstable angina; had congestive heart failure, clinically significant liver or renal disease, known secondary hypertension, a history of stroke or transient ischemic attack, venous thromboembolic disorders, or type 1 diabetes mellitus. Women whose calculated creatinine clearance was <50 mL/min or whose serum potassium was abnormal at baseline were also excluded from participation in the trial.
Study Design
The study was a multicenter (n=30 centers), double-blind, randomized, placebo-controlled, parallel-arm trial. The randomization numbers were generated in blocks of 4 by the SAS RANDO macro. The 2 treatments were allocated in a 1:1 ratio. Patients were screened and evaluated for 3 to 4 weeks to establish the baseline BPs and laboratory parameters. At randomization, patients received either placebo or DRSP 3 mg with 1 mg E2 once daily in the morning. The treatment and placebo groups were continued for 12 weeks. If the systolic BP was >160 mm Hg or the diastolic BP was >100 mm Hg on 2 consecutive occasions 1 to 3 days apart at any time during the trial, the patient was removed from the trial for safety considerations. In addition, if the patient’s serum potassium level was sustained in excess of 5.5 meq/L on 2 consecutive occasions 1 to 3 days apart, the patient was removed from the study and placed on conventional therapy.
Patients were assessed at 2-week intervals during the trial for BP, heart rate, adverse events, and concomitant medications. At 10 selected sites, 24-hour ambulatory BP monitoring was performed at baseline and at 12 weeks of therapy.
Measurements of BP and Heart Rate
The office BP was measured by mercury column sphygmomanometry in triplicate (and averaged) in the seated position at all visits after a minimum of 5 minutes of rest. These measurements were performed 22 to 26 hours after dosing with the study medication. Ambulatory BP and heart rate measurements were obtained with the SpaceLabs 90207 monitor (Spacelabs Inc) at 10 centers experienced in the use of ambulatory BP monitoring. Quality criteria used for an acceptable ambulatory BP recording included a minimum of 80% valid readings obtained within 24 hours after monitor hookup and a minimum of 2 valid readings per hour. When these criteria were not met, the patient was asked to repeat the study within 3 days. If the repeated study failed to meet the quality control criteria, the ambulatory BP data were considered nonevaluable. During the 24-hour ambulatory monitoring study, BP and heart rate were measured every 15 minutes from 6 AM to 10 PM and every 20 minutes between 10 PM and 6 AM. Monitoring hookup was initiated between 7 and 11 AM, and patients were dosed with study medication at the time of monitor hookup. Study coordinators recorded times of sleep, awakening, medication dosing, and monitor hookup in the case report forms.
Laboratory and Safety Assessments
Serum chemistry values were determined at baseline and after 2, 6, and 12 weeks of double-blind therapy. An ECG was performed at baseline and after 4 and 12 weeks of therapy. Adverse event data were obtained throughout the study by observation and indirect questioning. Each adverse event was assigned the medical term from the Hoechst Adverse Reaction Terminology System adverse event coding manual. Events of special interest in the trial included hyperkalemia, hypotension, dizziness, palpitations, syncope, and arrhythmias (including tachycardia and bradycardia). The laboratory protocol specified that all elevated serum potassium levels (5.5 meq/L) were to be checked for hemolysis and repeated within 24 hours for confirmation.
Statistical Analyses
The comparability of patients in the treatment groups was determined from the demographic data and baseline hemodynamic values. Continuous variables (age, height, BP) were analyzed with an ANOVA model with factors for treatment, pooled center, and baseline BP as covariates. Discrete variables were examined with the Cochran-Mantel-Haenszel test for general association. All analyses were conducted with SAS 8.2 software. The statistical analyses for efficacy were performed on an intent-to-treat basis, which included all patients randomized to the study with a baseline BP assessment and at least 1 postbaseline assessment during the double-blind dosing period. The last observed BP values were carried forward for dropouts. The safety analyses included all patients who received at least 1 dose of medication during the double-blind treatment phase.
The majority of study centers were small. A small center was defined as any center with <5 patients with postbaseline data in any treatment group, resulting in 5 large and 25 small centers. To avoid loss of information, small centers were pooled from largest to smallest until the pooled center had 5 patients in each treatment group. These centers were grouped into 11 pooled centers for the purpose of analysis. The pooling algorithm was predetermined before unblinding the data, and the pooling algorithm was described in the statistical analysis plan for the study. Considering the subjective nature of the pooling algorithm, albeit prespecified before completion of the study, an exploratory analysis was also performed with actual center as a fixed effect in contrast to pooled centers. This analysis did not change the probability values up to 4 decimal places for any of the comparisons between the DRSP/E2 and placebo groups. The centers in the clinical trial are rarely a random sample of all possible centers. Therefore, we were in favor of treating the actual center or pool center as a fixed effect in the model of the analysis. Analyses in a mixed model with center as a random effect also did not show any impact on probability values. An exploratory analysis with treatment-by-center effect in the model was also performed to investigate the possibility of differential effects across centers. This interaction was nonsignificant (P=0.45, and P=0.692 for pooled and actual centers, respectively), suggesting that the effect of pooled center in our model of analysis was effective in adjusting the treatment estimates for center effects.
The primary efficacy end point of the trial was the mean change from baseline at week 12 in clinic BP for DSRP/E2 and placebo. Secondary analyses included the changes from baseline in the 24-hour systolic and diastolic BPs and heart rate, as well as other ambulatory monitoring parameters such as daytime mean and nighttime mean values. In addition, mean changes from baseline were examined for serum potassium. The incidence of hyperkalemia (defined as plasma potassium 5.5 meq/L) was tabulated.
Treatment groups were compared with respect to the change from baseline in clinic BP with a 2-way ANCOVA, with terms for treatment, pooled center, and baseline measures as covariates in the model. Before implementing the final ANCOVA model, the assumption of homogeneity of treatment covariate slopes was tested with an ANCOVA model that included terms for baseline, treatment, and treatment-by-baseline interaction.
Adverse events were coded and summarized by treatment group and tabulated by treatment group and body system. Clinical laboratory data were summarized by treatment group. For each parameter, the treatments were compared with respect to the mean change from baseline by ANCOVA. Shifts in baseline laboratory values were compared between treatment groups.
The planned sample size of 268 subjects (ie, 134 subjects per treatment group) provided at least 80% power to detect a difference of 4 mm Hg between active treatment and placebo groups in the change from baseline in office cuff systolic BP with a 2-sample t test of the null hypothesis at the 0.05 level of significance. The estimated sample SD of 11 mm Hg used in the calculation was obtained from the results of a previous study.17 The sample size calculation was based on an assumed dropout rate of 10%.
Results
Patient Characteristics and Dosing of Drugs
There were 213 patients randomized into the 2 treatment arms, with similar demographics and baseline clinic and ambulatory BP values (Table 1). The percentage of patients who withdrew from the study was 16 (14.4%) in the placebo group and 10 (9.8%) in the DSRP/E2 group. The main reasons for withdrawal after randomization were adverse events and treatment failure. Other reasons included loss to follow-up, protocol violations, or patient withdrawal of consent. No patient was withdrawn because of hyperkalemia.
Clinic BP
The adjusted mean changes in BP in the clinic setting are shown in Table 2 and Figure 1. After 2 weeks of therapy, the reductions in systolic BP were significantly greater on DRSP/E2 compared with placebo. Significant reductions in diastolic BP occurred after 4 weeks of DRSP/E2 therapy compared with placebo (Figure 1). At the end of the study, the mean reductions in clinic BP in the DSRP/E2 group averaged –14.1/–7.9 mm Hg, whereas the respective reductions for the placebo group were –7.1/–4.3 mm Hg (P<0.001 for both systolic and diastolic BP). DRSP/E2 also significantly lowered pulse pressure compared with placebo by –3.5 mm Hg (P=0.007). The changes from baseline in heart rate were similar for DRSP/E2 and placebo (Table 2).
Ambulatory BP
The mean changes from baseline in 24-hour ambulatory systolic and diastolic BPs from the substudy are shown in Table 2. Significant reductions from baseline in mean 24-hour systolic BP (P=0.002) were observed in the DRSP/E2 treatment group compared with placebo. The reductions in ambulatory systolic BP occurred primarily during the daytime. As noted in Table 2, DRSP/E2 induced significant reductions in both daytime systolic and diastolic BPs compared with placebo, but there were no significant changes from baseline in nighttime BP. As shown in Figure 2, DRSP/E2 induced sustained reductions in systolic BP throughout the 24-hour period compared with baseline and with placebo treatment. Lesser but significant daytime effects were observed with changes from baseline in the hourly diastolic BP (Figure 2). The largest reductions in diastolic BP were observed during hours 4 to 8 and hours 17 to 21 after dosing.
Adverse Events
Because of the antimineralocorticoid effects of DRSP, changes in serum potassium were closely monitored. There were no patients in the DRSP/E2 group who developed a serum potassium value >5.5 meq/L. In the placebo group, 4 patients (3.6%) had a transient serum potassium value >5.5 meq/ L (P=0.122 for DRSP/E2 versus placebo). The patterns of changes from baseline in serum potassium were quite similar for DRSP/E2 and placebo (Figure 3). The mean maximal change from baseline in the DRSP/E2 group was 0.24±0.38 meq/L versus 0.16±0.43 meq/L for the placebo group and was not significant (P=0.18).
There were no deaths during the course of the study. One patient randomized to DRSP/E2 sustained an acute myocardial infarction. The incidence of minor, clinically nonsignificant ECG abnormalities was identical for patients randomized to DRSP/E2 (22%) and placebo (22%). There were no significant differences in the number of patients with selected cardiovascular events (arrhythmia, bradycardia, dizziness, palpitations, syncope) on DRSP/E2 versus placebo. The overall incidence of these adverse events was 7/102 (6.9%) of patients taking DRSP/E2 versus 3/111 (2.7%) of patients taking placebo. Dizziness was the most common event (4% of DRSP patients versus 2% of the placebo patients).
Discussion
Principal Findings
DRSP (3 mg) with E2 (1 mg), a new hormonal treatment with selective aldosterone-blocking properties, was effective in reducing clinic and 24-hour BPs in postmenopausal women with stage 1 hypertension. Twenty-four-hour ambulatory BP may yield a more reliable antihypertensive assessment owing to the lack of observer bias, the substantially increased number of values taken over the dosing interval, and the enhanced statistical reproducibility of ambulatory BP compared with clinical BP measurements.18–20 Another important finding in this trial was the lack of evidence for clinically significant increases in mean serum potassium values with DRSP/E2 in this population of older women with stage I hypertension. Furthermore, no patient developed hyperkalemia while taking DRSP/E2.
Clinic and Ambulatory BP
DRSP/E2 lowered both the clinic and daytime ambulatory BPs significantly compared with placebo; the levels of ambulatory BP reductions observed in our study are comparable to many other antihypertensive agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers,21 and the recently approved selective aldosterone blocker eplerenone.11 In fact, in prior work with eplerenone,11 the mean reduction from baseline in 24-hour BP was 7/4 mm Hg for the 50-mg dose, a value similar to that which was observed with 3 mg DRSP in the present study (Table 2 and Figure 2). Additionally, Preston et al17 reported that after just 2 weeks of therapy, DRSP/E2 lowered 24-hour ambulatory BP by 9/5 mm Hg when the drug was added to enalapril in 12 postmenopausal women. These reductions in BP were associated with increases in aldosterone of 3 ng/dL (40% above baseline),11 attesting to DRSP’s effect in blocking the mineralocorticoid receptor.
It is noteworthy that the reductions from baseline in the clinic BP versus reductions in the daytime ambulatory BP were somewhat dissimilar for DRSP/E2 (Table 2). This is often the case in antihypertensive therapy trials, because typically the mean reduction in ambulatory BPs in clinical trials is 40% less than the average reduction in clinic BP.18 This phenomenon is due in part to both observer bias and regression to the mean.18–20 The reductions in nighttime BPs were not significantly greater on DRSP/E2 compared with placebo (Table 2). This is likely to be due to the relatively normal baseline nighttime BP levels observed in this mildly hypertensive population rather than a loss of effect at the end of the dosing period (Table 1). Changes in BP during sleep on antihypertensive agents are quite dependent on the baseline level of nocturnal pressure,22 and when baseline values are in the range of 125/73 mm Hg, as was the case in this population (Table 1), small declines in sleep BP would be expected during the treatment period. Although the intention-to-treat population was smaller than the planned randomization, the estimates of changes from baseline in BP were larger than expected, and the statistical power for these changes was quite high at 99%.
Safety and Tolerability and Laboratory Assessments
DRSP/E2 was well tolerated in this 213-patient trial, with adverse-event profiles similar to those of placebo. Most important, laboratory assessment did not show any clinically significant changes in serum potassium (Figure 3). Additionally, specific adverse events such as syncope, cardiac arrhythmias, or ECG changes were not observed with DRSP/E2, a finding that supports its potential advantage in clinical practice in postmenopausal women with hypertension.
Conclusions
Our study demonstrates that DRSP/E2, a new hormone therapy with mineralocorticoid receptor-blocking activity, was effective in reducing ambulatory systolic and diastolic BPs at doses of 3 mg/1 mg daily. The drug was well tolerated, with no evidence of subjective or objective adverse events. These findings are clinically relevant, because hormone therapy for postmenopausal women has been under scrutiny because of its potential for increasing cardiovascular thrombotic events.1–5 Because reductions in systolic BP have significant implications for older individuals with hypertension,23–25 especially for the reduction of stroke and congestive heart failure, DRSP/E2 may have an advantage for the treatment of menopausal symptoms in older women. In future antihypertensive studies with DRSP/E2, it will be of interest to study the effects of E2 alone as well as to compare this unique progestin to more conventional progestins that lack antimineralocorticoid effects.
Acknowledgments
This work was supported in part by Berlex Laboratories, Inc (Montvale, NJ), the Catherine and Patrick Donaghue Medical Research Foundation (Hartford, Conn), and the University of Connecticut Clinical Trials Unit (Farmington, Conn).
Disclosure
This study was funded by a grant from Berlex Laboratories, Montvale, NJ, the manufacturer of drospirenone, with 17-estradiol. The current work was done in an unrestricted, independent manner with full access provided to all data. The sponsor was entitled to comment on manuscripts, and the authors might have considered these comments, but the rights to publication resided contractually with the investigators. Dr White has received research grants from Berlex Laboratories, Astra-Zeneca, Boehringer-Ingelheim, and Pfizer and has received honoraria to serve on advisory boards of Berlex and Boehringer Ingelheim during the past 4 years. Dr Pitt has received honoraria from and been a consultant to Berlex Laboratories during the past 4 years. Dr Preston has received research grants from Berlex Laboratories and has served as a paid consultant to Berlex Laboratories during the past 4 years. Dr Hanes is a full-time employee in research and development at Berlex Laboratories, Inc.
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the Division of Cardiology (B.P.), University of Michigan Medical School, Ann Arbor
the Division of Clinical Pharmacology (R.P.), University of Miami School of Medicine, Miami, Fla
Berlex Laboratories (V.H.), Montville, NJ.
Abstract
Background— Drospirenone (DRSP) is a novel progestin with antimineralocorticoid activity that has been developed for hormone therapy in combination with 17-estradiol (E2) in postmenopausal women. In prior studies with DRSP in postmenopausal women that were focused on relief of menopausal symptoms, DRSP/E2 yielded significant reductions in blood pressure (BP).
Methods and Results— The effects of 3 mg DRSP/1 mg E2 on clinic and 24-hour ambulatory BP as well as potassium homeostasis were evaluated in postmenopausal women with stage 1 hypertension (systolic, 140 to 159 and/or diastolic, 90 to 99 mm Hg) in a 12-week, multicenter, double-blind, randomized, placebo-controlled study. Clinic BPs were measured at baseline and at 2, 4, 6, 8, and 12 weeks of therapy, whereas potassium was measured at 2, 6, and 12 weeks of therapy. Ambulatory BP was performed in a substudy at baseline and at the end of the trial. In the intention-to-treat population of 213 women, the clinic BP was reduced significantly on DRSP/E2 (clinic BP, –14.1/–7.9 for DRSP/E2 versus –7.1/–4.3 mm Hg for placebo, P<0.0001). In the subgroup of 43 women with ambulatory BP monitoring, the 24-hour BP fell by –8.5/–4.2 mm Hg versus –1.8/–1.6 mm Hg on placebo (P=0.002/0.07). There were no significant changes from baseline in potassium levels or in the incidence of hyperkalemia (5.5 meq/L) on DRSP/E2 compared with placebo.
Conclusions— Combination therapy with DRSP/E2 significantly lowered both clinic and 24-hour systolic BP in postmenopausal women with stage 1 systolic hypertension. This characteristic may lead to benefit for cardiovascular risk reduction in this population.
Key Words: hormones hypertension blood pressure aldosterone antagonists menopause
Introduction
Postmenopausal estrogen deficiency has been associated with increases in cardiovascular risk, but clinical trials of standard formulations of hormonal therapy have not confirmed a benefit of hormone therapy in reducing cardiovascular disease in postmenopausal women.1–5 Although the reasons for these generally negative results are unclear, it is apparent that innovative, alternative strategies for hormone therapy in postmenopausal women are warranted.
Several recent experimental and clinical reports have implicated aldosterone, independent of angiotensin II, in the pathogenesis of significant cardiovascular and renal disease and have demonstrated the benefit of aldosterone blockade in reducing a variety of cardiovascular and renal end points.6–13 Drospirenone (DRSP) is a novel progestin with antialdosterone and antiandrogenic effects that, in combination with 17-estradiol (E2), has been developed for use in postmenopausal women as hormone therapy.14–16 DRSP/E2 has been shown to have significant antihypertensive effects in a short-term study of postmenopausal, hypertensive women treated with enalapril.17 When compared with other hormone therapies and oral contraceptives, DRSP yields a much greater rise in plasma aldosterone14–16 in response to the antimineralocorticoid effect of the compound.
The primary objective of the present study was to determine whether DRSP/E2 treatment has a clinically significant effect on clinic and 24-hour ambulatory blood pressure (BP) in hypertensive, postmenopausal women at doses of 3 mg DSRP and 1 mg E2. In addition, we evaluated the effects of DSRP/E2 on potassium homeostasis, because aldosterone blockade has been associated with significant increases in serum potassium values.14–16
Methods
Patient Population
Postmenopausal women (aged 45 to 80 years) were included if, in the untreated condition, their seated clinic systolic BP was 140 to 159 mm Hg and/or the diastolic BP was 90 to 99 mm Hg. Patients were excluded from the trial if they had received prior estrogen or progestin hormone therapy; had sustained a recent myocardial infarction or unstable angina; had congestive heart failure, clinically significant liver or renal disease, known secondary hypertension, a history of stroke or transient ischemic attack, venous thromboembolic disorders, or type 1 diabetes mellitus. Women whose calculated creatinine clearance was <50 mL/min or whose serum potassium was abnormal at baseline were also excluded from participation in the trial.
Study Design
The study was a multicenter (n=30 centers), double-blind, randomized, placebo-controlled, parallel-arm trial. The randomization numbers were generated in blocks of 4 by the SAS RANDO macro. The 2 treatments were allocated in a 1:1 ratio. Patients were screened and evaluated for 3 to 4 weeks to establish the baseline BPs and laboratory parameters. At randomization, patients received either placebo or DRSP 3 mg with 1 mg E2 once daily in the morning. The treatment and placebo groups were continued for 12 weeks. If the systolic BP was >160 mm Hg or the diastolic BP was >100 mm Hg on 2 consecutive occasions 1 to 3 days apart at any time during the trial, the patient was removed from the trial for safety considerations. In addition, if the patient’s serum potassium level was sustained in excess of 5.5 meq/L on 2 consecutive occasions 1 to 3 days apart, the patient was removed from the study and placed on conventional therapy.
Patients were assessed at 2-week intervals during the trial for BP, heart rate, adverse events, and concomitant medications. At 10 selected sites, 24-hour ambulatory BP monitoring was performed at baseline and at 12 weeks of therapy.
Measurements of BP and Heart Rate
The office BP was measured by mercury column sphygmomanometry in triplicate (and averaged) in the seated position at all visits after a minimum of 5 minutes of rest. These measurements were performed 22 to 26 hours after dosing with the study medication. Ambulatory BP and heart rate measurements were obtained with the SpaceLabs 90207 monitor (Spacelabs Inc) at 10 centers experienced in the use of ambulatory BP monitoring. Quality criteria used for an acceptable ambulatory BP recording included a minimum of 80% valid readings obtained within 24 hours after monitor hookup and a minimum of 2 valid readings per hour. When these criteria were not met, the patient was asked to repeat the study within 3 days. If the repeated study failed to meet the quality control criteria, the ambulatory BP data were considered nonevaluable. During the 24-hour ambulatory monitoring study, BP and heart rate were measured every 15 minutes from 6 AM to 10 PM and every 20 minutes between 10 PM and 6 AM. Monitoring hookup was initiated between 7 and 11 AM, and patients were dosed with study medication at the time of monitor hookup. Study coordinators recorded times of sleep, awakening, medication dosing, and monitor hookup in the case report forms.
Laboratory and Safety Assessments
Serum chemistry values were determined at baseline and after 2, 6, and 12 weeks of double-blind therapy. An ECG was performed at baseline and after 4 and 12 weeks of therapy. Adverse event data were obtained throughout the study by observation and indirect questioning. Each adverse event was assigned the medical term from the Hoechst Adverse Reaction Terminology System adverse event coding manual. Events of special interest in the trial included hyperkalemia, hypotension, dizziness, palpitations, syncope, and arrhythmias (including tachycardia and bradycardia). The laboratory protocol specified that all elevated serum potassium levels (5.5 meq/L) were to be checked for hemolysis and repeated within 24 hours for confirmation.
Statistical Analyses
The comparability of patients in the treatment groups was determined from the demographic data and baseline hemodynamic values. Continuous variables (age, height, BP) were analyzed with an ANOVA model with factors for treatment, pooled center, and baseline BP as covariates. Discrete variables were examined with the Cochran-Mantel-Haenszel test for general association. All analyses were conducted with SAS 8.2 software. The statistical analyses for efficacy were performed on an intent-to-treat basis, which included all patients randomized to the study with a baseline BP assessment and at least 1 postbaseline assessment during the double-blind dosing period. The last observed BP values were carried forward for dropouts. The safety analyses included all patients who received at least 1 dose of medication during the double-blind treatment phase.
The majority of study centers were small. A small center was defined as any center with <5 patients with postbaseline data in any treatment group, resulting in 5 large and 25 small centers. To avoid loss of information, small centers were pooled from largest to smallest until the pooled center had 5 patients in each treatment group. These centers were grouped into 11 pooled centers for the purpose of analysis. The pooling algorithm was predetermined before unblinding the data, and the pooling algorithm was described in the statistical analysis plan for the study. Considering the subjective nature of the pooling algorithm, albeit prespecified before completion of the study, an exploratory analysis was also performed with actual center as a fixed effect in contrast to pooled centers. This analysis did not change the probability values up to 4 decimal places for any of the comparisons between the DRSP/E2 and placebo groups. The centers in the clinical trial are rarely a random sample of all possible centers. Therefore, we were in favor of treating the actual center or pool center as a fixed effect in the model of the analysis. Analyses in a mixed model with center as a random effect also did not show any impact on probability values. An exploratory analysis with treatment-by-center effect in the model was also performed to investigate the possibility of differential effects across centers. This interaction was nonsignificant (P=0.45, and P=0.692 for pooled and actual centers, respectively), suggesting that the effect of pooled center in our model of analysis was effective in adjusting the treatment estimates for center effects.
The primary efficacy end point of the trial was the mean change from baseline at week 12 in clinic BP for DSRP/E2 and placebo. Secondary analyses included the changes from baseline in the 24-hour systolic and diastolic BPs and heart rate, as well as other ambulatory monitoring parameters such as daytime mean and nighttime mean values. In addition, mean changes from baseline were examined for serum potassium. The incidence of hyperkalemia (defined as plasma potassium 5.5 meq/L) was tabulated.
Treatment groups were compared with respect to the change from baseline in clinic BP with a 2-way ANCOVA, with terms for treatment, pooled center, and baseline measures as covariates in the model. Before implementing the final ANCOVA model, the assumption of homogeneity of treatment covariate slopes was tested with an ANCOVA model that included terms for baseline, treatment, and treatment-by-baseline interaction.
Adverse events were coded and summarized by treatment group and tabulated by treatment group and body system. Clinical laboratory data were summarized by treatment group. For each parameter, the treatments were compared with respect to the mean change from baseline by ANCOVA. Shifts in baseline laboratory values were compared between treatment groups.
The planned sample size of 268 subjects (ie, 134 subjects per treatment group) provided at least 80% power to detect a difference of 4 mm Hg between active treatment and placebo groups in the change from baseline in office cuff systolic BP with a 2-sample t test of the null hypothesis at the 0.05 level of significance. The estimated sample SD of 11 mm Hg used in the calculation was obtained from the results of a previous study.17 The sample size calculation was based on an assumed dropout rate of 10%.
Results
Patient Characteristics and Dosing of Drugs
There were 213 patients randomized into the 2 treatment arms, with similar demographics and baseline clinic and ambulatory BP values (Table 1). The percentage of patients who withdrew from the study was 16 (14.4%) in the placebo group and 10 (9.8%) in the DSRP/E2 group. The main reasons for withdrawal after randomization were adverse events and treatment failure. Other reasons included loss to follow-up, protocol violations, or patient withdrawal of consent. No patient was withdrawn because of hyperkalemia.
Clinic BP
The adjusted mean changes in BP in the clinic setting are shown in Table 2 and Figure 1. After 2 weeks of therapy, the reductions in systolic BP were significantly greater on DRSP/E2 compared with placebo. Significant reductions in diastolic BP occurred after 4 weeks of DRSP/E2 therapy compared with placebo (Figure 1). At the end of the study, the mean reductions in clinic BP in the DSRP/E2 group averaged –14.1/–7.9 mm Hg, whereas the respective reductions for the placebo group were –7.1/–4.3 mm Hg (P<0.001 for both systolic and diastolic BP). DRSP/E2 also significantly lowered pulse pressure compared with placebo by –3.5 mm Hg (P=0.007). The changes from baseline in heart rate were similar for DRSP/E2 and placebo (Table 2).
Ambulatory BP
The mean changes from baseline in 24-hour ambulatory systolic and diastolic BPs from the substudy are shown in Table 2. Significant reductions from baseline in mean 24-hour systolic BP (P=0.002) were observed in the DRSP/E2 treatment group compared with placebo. The reductions in ambulatory systolic BP occurred primarily during the daytime. As noted in Table 2, DRSP/E2 induced significant reductions in both daytime systolic and diastolic BPs compared with placebo, but there were no significant changes from baseline in nighttime BP. As shown in Figure 2, DRSP/E2 induced sustained reductions in systolic BP throughout the 24-hour period compared with baseline and with placebo treatment. Lesser but significant daytime effects were observed with changes from baseline in the hourly diastolic BP (Figure 2). The largest reductions in diastolic BP were observed during hours 4 to 8 and hours 17 to 21 after dosing.
Adverse Events
Because of the antimineralocorticoid effects of DRSP, changes in serum potassium were closely monitored. There were no patients in the DRSP/E2 group who developed a serum potassium value >5.5 meq/L. In the placebo group, 4 patients (3.6%) had a transient serum potassium value >5.5 meq/ L (P=0.122 for DRSP/E2 versus placebo). The patterns of changes from baseline in serum potassium were quite similar for DRSP/E2 and placebo (Figure 3). The mean maximal change from baseline in the DRSP/E2 group was 0.24±0.38 meq/L versus 0.16±0.43 meq/L for the placebo group and was not significant (P=0.18).
There were no deaths during the course of the study. One patient randomized to DRSP/E2 sustained an acute myocardial infarction. The incidence of minor, clinically nonsignificant ECG abnormalities was identical for patients randomized to DRSP/E2 (22%) and placebo (22%). There were no significant differences in the number of patients with selected cardiovascular events (arrhythmia, bradycardia, dizziness, palpitations, syncope) on DRSP/E2 versus placebo. The overall incidence of these adverse events was 7/102 (6.9%) of patients taking DRSP/E2 versus 3/111 (2.7%) of patients taking placebo. Dizziness was the most common event (4% of DRSP patients versus 2% of the placebo patients).
Discussion
Principal Findings
DRSP (3 mg) with E2 (1 mg), a new hormonal treatment with selective aldosterone-blocking properties, was effective in reducing clinic and 24-hour BPs in postmenopausal women with stage 1 hypertension. Twenty-four-hour ambulatory BP may yield a more reliable antihypertensive assessment owing to the lack of observer bias, the substantially increased number of values taken over the dosing interval, and the enhanced statistical reproducibility of ambulatory BP compared with clinical BP measurements.18–20 Another important finding in this trial was the lack of evidence for clinically significant increases in mean serum potassium values with DRSP/E2 in this population of older women with stage I hypertension. Furthermore, no patient developed hyperkalemia while taking DRSP/E2.
Clinic and Ambulatory BP
DRSP/E2 lowered both the clinic and daytime ambulatory BPs significantly compared with placebo; the levels of ambulatory BP reductions observed in our study are comparable to many other antihypertensive agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers,21 and the recently approved selective aldosterone blocker eplerenone.11 In fact, in prior work with eplerenone,11 the mean reduction from baseline in 24-hour BP was 7/4 mm Hg for the 50-mg dose, a value similar to that which was observed with 3 mg DRSP in the present study (Table 2 and Figure 2). Additionally, Preston et al17 reported that after just 2 weeks of therapy, DRSP/E2 lowered 24-hour ambulatory BP by 9/5 mm Hg when the drug was added to enalapril in 12 postmenopausal women. These reductions in BP were associated with increases in aldosterone of 3 ng/dL (40% above baseline),11 attesting to DRSP’s effect in blocking the mineralocorticoid receptor.
It is noteworthy that the reductions from baseline in the clinic BP versus reductions in the daytime ambulatory BP were somewhat dissimilar for DRSP/E2 (Table 2). This is often the case in antihypertensive therapy trials, because typically the mean reduction in ambulatory BPs in clinical trials is 40% less than the average reduction in clinic BP.18 This phenomenon is due in part to both observer bias and regression to the mean.18–20 The reductions in nighttime BPs were not significantly greater on DRSP/E2 compared with placebo (Table 2). This is likely to be due to the relatively normal baseline nighttime BP levels observed in this mildly hypertensive population rather than a loss of effect at the end of the dosing period (Table 1). Changes in BP during sleep on antihypertensive agents are quite dependent on the baseline level of nocturnal pressure,22 and when baseline values are in the range of 125/73 mm Hg, as was the case in this population (Table 1), small declines in sleep BP would be expected during the treatment period. Although the intention-to-treat population was smaller than the planned randomization, the estimates of changes from baseline in BP were larger than expected, and the statistical power for these changes was quite high at 99%.
Safety and Tolerability and Laboratory Assessments
DRSP/E2 was well tolerated in this 213-patient trial, with adverse-event profiles similar to those of placebo. Most important, laboratory assessment did not show any clinically significant changes in serum potassium (Figure 3). Additionally, specific adverse events such as syncope, cardiac arrhythmias, or ECG changes were not observed with DRSP/E2, a finding that supports its potential advantage in clinical practice in postmenopausal women with hypertension.
Conclusions
Our study demonstrates that DRSP/E2, a new hormone therapy with mineralocorticoid receptor-blocking activity, was effective in reducing ambulatory systolic and diastolic BPs at doses of 3 mg/1 mg daily. The drug was well tolerated, with no evidence of subjective or objective adverse events. These findings are clinically relevant, because hormone therapy for postmenopausal women has been under scrutiny because of its potential for increasing cardiovascular thrombotic events.1–5 Because reductions in systolic BP have significant implications for older individuals with hypertension,23–25 especially for the reduction of stroke and congestive heart failure, DRSP/E2 may have an advantage for the treatment of menopausal symptoms in older women. In future antihypertensive studies with DRSP/E2, it will be of interest to study the effects of E2 alone as well as to compare this unique progestin to more conventional progestins that lack antimineralocorticoid effects.
Acknowledgments
This work was supported in part by Berlex Laboratories, Inc (Montvale, NJ), the Catherine and Patrick Donaghue Medical Research Foundation (Hartford, Conn), and the University of Connecticut Clinical Trials Unit (Farmington, Conn).
Disclosure
This study was funded by a grant from Berlex Laboratories, Montvale, NJ, the manufacturer of drospirenone, with 17-estradiol. The current work was done in an unrestricted, independent manner with full access provided to all data. The sponsor was entitled to comment on manuscripts, and the authors might have considered these comments, but the rights to publication resided contractually with the investigators. Dr White has received research grants from Berlex Laboratories, Astra-Zeneca, Boehringer-Ingelheim, and Pfizer and has received honoraria to serve on advisory boards of Berlex and Boehringer Ingelheim during the past 4 years. Dr Pitt has received honoraria from and been a consultant to Berlex Laboratories during the past 4 years. Dr Preston has received research grants from Berlex Laboratories and has served as a paid consultant to Berlex Laboratories during the past 4 years. Dr Hanes is a full-time employee in research and development at Berlex Laboratories, Inc.
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