CLINICAL STUDY
Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients
John M. Flack, MD, MPH*,*,
Suzanne Oparil, MD ,
J. Howard Pratt, MD ,
Barbara Roniker, MD ,
Susan Garthwaite, PhD,
Jay H. Kleiman, MD, MPA,
Yonghong Yang, PhD,
Scott L. Krause, BSN,
Diane Workman, PhD and
Elijah Saunders, MD||
* Department of Internal Medicine, Wayne State University, Detroit, Michigan, USA
Department of Medicine, University of Alabama, Birmingham, Alabama, USA
Department of Medicine, Indiana University School of Medicine and The Veterans Administration Medical Center, Indianapolis, Indiana, USA
Cardiovascular/Metabolic Diseases, Pharmacia Corporation, Skokie, Illinois, USA
|| Division of Hypertension, University of Maryland, Baltimore, Maryland, USA
Manuscript received April 30, 2002;
revised manuscript received October 17, 2002,
accepted November 19, 2002.
* Reprint requests and correspondence: Dr. John M. Flack, Department of Internal Medicine, Wayne State University School of Medicine, 4201 St. Antoine, Suite 2E, Detroit, Michigan 48201, USA.
JFlack{at}intmed.wayne.edu
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Abstract
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OBJECTIVES: The purpose of this study was to evaluate the efficacy and tolerability of monotherapy with the selective aldosterone blocker eplerenone in both black and white patients with hypertension.
BACKGROUND: Essential hypertension and cardiovascular-renal-target organ damage is more prevalent in black than white adults in the U.S.
METHODS: Black (n = 348) and white (n = 203) patients with mild-to-moderate hypertension were randomized to double-blind treatment with eplerenone 50 mg, the angiotensin II receptor antagonist losartan 50 mg, or placebo once daily. Doses were increased if blood pressure remained uncontrolled. The primary end point was change in mean diastolic blood pressure (DBP) after 16 weeks of therapy.
RESULTS: Adjusted mean changes from baseline in DBP were –5.3 ± 0.7, –10.3 ± 0.7, and –6.9 ± 0.6 mm Hg in the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean ± SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan). In black patients, DBP decreased by –4.8 ± 1.0, –10.2 ± 0.9, and –6.0 ± 0.9 mm Hg for the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean ± SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan), whereas in white patients, DBP decreased by –6.4 ± 1.0, –11.1 ± 1.1, and –8.4 ± 1.0 mm Hg, respectively (p = 0.001 eplerenone vs. placebo, p = 0.068 for eplerenone vs. losartan). For reduction of systolic blood pressure (SBP), eplerenone was superior to placebo and losartan in all patients combined and in black patients, and was superior to placebo in white patients. Eplerenone was as effective as losartan in reducing SBP and DBP in the high renin patient, but more effective than losartan in the low renin patient. Similarly, eplerenone was at least as effective as losartan in patients with differing baseline levels of aldosterone. Both eplerenone and losartan were well tolerated.
CONCLUSIONS: The antihypertensive effect of eplerenone was equal in black and white patients and was superior to losartan in black patients.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | ANCOVA | = analysis of covariance | | BP | = blood pressure | | CI | = confidence interval | | DBP | = diastolic blood pressure | | HR | = heart rate | | SAB | = selective aldosterone blocker | | SBP | = systolic blood pressure | | UA/CR | = urinary albumin/creatinine ratio |
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Hypertension and its complications cause significant and excess morbidity and mortality in the general population and particularly in black Americans (1). The age-adjusted prevalence of hypertension is 40% higher in black versus white Americans, onset is earlier, and the severity is greater (2). Furthermore, the risk of death from hypertensive heart and renal disease is approximately twofold greater in black Americans (1). The reason for these differences is unclear. However, potential explanatory factors include increased sodium sensitivity associated with low plasma renin activity and obesity, and reduced potassium intake in black patients (3,4).
Blood pressure (BP) control preserves target-organ function and minimizes risk for adverse clinical events (5). The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure established the relatively conservative BP goal of <140/90 mm Hg for most patients, and the more stringent goals of  130/85 mm Hg for persons with diabetes mellitus and <125/75 mm Hg for patients with proteinuria in excess of 1 g/day (5). However, only about 25% and 24% of black and white hypertensive patients, respectively, achieve BP <140/90 mm Hg (2). At present, only 50% to 60% of all patients can reach diastolic blood pressure (DBP) goals with monotherapy (6), although responsiveness may be influenced by race, age, pretreatment BP, geography, and kidney function (7–11). For example, more white men than black men  60 years reached the suggested DBP goal when treated with an angiotensin-converting enzyme (ACE) inhibitor (85% vs. 50%, respectively) (9). Lesser BP responses in black patients compared with white patients have also been observed with losartan, an angiotensin II receptor antagonist (12). Although it is likely that racial differences in BP responses are confounded, at least in part, by such factors as the pretreatment BP level and the degree of kidney dysfunction, it is important to determine both the absolute and relative BP-lowering responses of black and white patients.
Aldosterone receptor antagonists are logical therapeutic options for the treatment of hypertension given that aldosterone has a critical role in sodium homeostasis and plasma volume regulation, and in mediating target-organ injury. Spironolactone, a nonselective aldosterone blocker, lowers BP in patients with essential hypertension and reduces morbidity and mortality in patients with severe heart failure (13,14). However, chronic spironolactone use is limited owing to its interactions with progesterone and androgen receptors which can result in gynecomastia, breast tenderness, menstrual abnormalities, and impotence (13–15).
Eplerenone, the first selective aldosterone blocker (SAB), is being developed for the treatment of hypertension and congestive heart failure. Studies in hypertensive animal models showed that eplerenone reduces both myocardial necrosis and renal arteriopathy (16). Due to highly selective receptor binding, it is expected that eplerenone will be more tolerable than spironolactone. We conducted a randomized, double-blind study to determine the efficacy and tolerability of monotherapy with eplerenone compared with losartan and placebo in black and white patients with mild-to-moderate hypertension.
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Methods
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Study population.
Men and women 18 years old with mild-to-moderate hypertension were eligible for inclusion if their systolic blood pressure (SBP) was <180 mm Hg and DBP was 95 to 109 mm Hg without medication. Only patients self-identified as black or white were included. Patients on one or two antihypertensive medications were eligible only if their BP was <140/90 mm Hg. Patients were excluded if they had known secondary hypertension, insulin-dependent diabetes mellitus, hepatic disease, or elevated serum creatinine level; evidence of alcohol or drug abuse; could not be withdrawn from antihypertensives; or regularly used corticosteroids. Patients with a history of New York Heart Association functional class II to IV congestive heart failure, myocardial infarction, coronary revascularization, stroke, or transient ischemic attack within the past six months, current unstable angina, or any serious medical condition were also excluded. The protocol was approved by the institutional review board at each study site. All patients provided written informed consent.
Study design.
This was a randomized, double-blind, placebo- and active-controlled, placebo run-in, parallel group trial conducted at eight centers in South Africa and 42 centers in the U.S. between January 4, 2000 and January 19, 2001. The study population was stratified at a 2:1 ratio of black to white patients. The primary study end point was the mean change in DBP from baseline to the final visit. Secondary end points were the mean change from baseline to the final visit for SBP and DBP within and between racial groups; improvement in urinary protein excretion as measured by changes in the urinary albumin/creatinine ratio (UA/CR); and the effect of eplerenone in selected subpopulations, including women, obese patients, patients with SBP 160 mm Hg, elderly patients, and patients with microalbuminuria. Exploratory analyses assessed the rate of response to therapy and the relationships between BP changes and baseline active renin or aldosterone levels.
Study procedures.
At a screening visit, patients underwent a complete physical examination, including medical history, 12-lead electrocardiogram, heart rate (HR) and BP (by cuff sphygmomanometer), and laboratory testing. Patients successfully withdrawn from antihypertensive medication, without arrhythmia requiring treatment, without clinically significant laboratory abnormality, and with a serum potassium level of 3.5 to 5.0 mmol/l, were entered into a two- to four-week, single-blind, placebo run-in period.
At the end of the placebo run-in period, eligible patients (mean cuff DBP 95 mm Hg and <110 mm Hg and a mean cuff SBP <180 mm Hg, negative urine and serum pregnancy tests, medication compliance during placebo run-in) were randomized (stratified by race) to treatment with eplerenone, losartan, or matching placebo. Treatment was initiated with daily doses of eplerenone 50 mg, losartan 50 mg, or matching placebo administered in the morning. If DBP was 90 mm Hg or SBP was 140 mm Hg at weeks 4, 8, or 12, the dose was increased to 100 mg/day of eplerenone or losartan. If BP remained 140/90 mm Hg, the dose was increased to eplerenone 200 mg/day or continued at losartan 100 mg/day, the maximal recommended dose. Patients were withdrawn from the study for the following reasons: if DBP was 95 mm Hg or SBP was 150 mm Hg after week 12 at the highest dose of study drug; if DBP was 110 mm Hg or SBP was 180 mm Hg at two consecutive visits taking place 1 to 3 days apart; if symptomatic hypotension (lightheadedness, dizziness, or syncope) occurred; or if serum potassium level was >5.5 mmol/l on two consecutive measurements done 1 to 3 days apart.
Randomized patients were assessed every two weeks for HR, BP, serum potassium level, and adverse events. Active renin and serum aldosterone quantitation was performed at week 0 and final visit. To do so, blood samples were collected by direct venipuncture from patients in the seated position, and plasma was separated by centrifugation. Levels of active renin and aldosterone were determined by radioimmunoassay using kits from Nichols Institute Diagnostics and Abbott Laboratories, respectively. Hematologic and biochemical analysis and urinalysis were performed at week 0 and the final visit. A first morning voided spot urine specimen was used for assessment of UA/CR at week 0 and the final visit.
Statistical analysis.
A priori power calculations determined the sample size of black and white patients that was required to detect a 4.5 mm Hg difference in DBP from baseline between eplerenone and placebo with power of 99%, 97%, and 80%, respectively, in all patients, black patients, and white patients. The study also had a power of 90% for all patients and 75% for black patients to show a 3 mm Hg difference in DBP between the eplerenone and losartan groups.
Analyses were performed in all patients combined, within, and between racial groups. All randomized patients with a baseline BP assessment and 1 post-baseline assessment were included in the intent-to-treat analysis. Missing values were imputed using the last observation carried forward method.
Baseline factors for treatment groups were compared using one-way analysis of variance for continuous variables or Pearson chi-square tests for categorical variables. The BP measurement obtained on the last visit of the placebo run-in period was the baseline value, and the last BP measurement during the 16-week treatment period was the final value. BP data were analyzed using two-way analysis of covariance (ANCOVA) with the baseline measurement as the covariate and treatment and center as factors. Analyses of BP differences between racial groups used a similar model, adding race as a factor. The significance of response rates was determined using the Cochrane-Mantel-Haenszel test. The ANCOVA analysis was used in exploratory analyses. Results for treatment effect comparisons in all patients and in black and white patients, including mean changes from baseline in SBP/DBP at week 16 end point as well as weekly changes, are based on adjusted means (adjusted for baseline value, treatment, and center) from the ANCOVA model. The results from the subgroup analysis (based on the tertile of baseline aldosterone and active renin) are derived from the raw mean changes and two-sample test between the raw mean changes within each subgroup. In the safety analysis, the incidences of adverse events are summarized and compared using Fisher exact test. A two-tailed p value of <0.05 was considered statistically significant.
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Results
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Patient characteristics.
A total of 551 patients were randomized to study treatment, and 352 completed 16 weeks of treatment. Of these, 16 patients (4 placebo, 8 eplerenone, and 4 losartan) had no post-baseline assessment; therefore, 535 patients were included in the cohort for efficacy analysis (Table 1). Compliance, determined by patient diary and counting of patients’ returned medication by study personnel at each clinic visit, was 90.5% in the placebo group, 91.5% in the eplerenone group, and 88.6% to 89.1% in the losartan group. No significant differences were observed between the three randomized treatment groups for baseline demographic or clinical characteristics (Table 2). As expected, however, there was a difference in active renin concentration between black and white patients (data not shown). Thus, in black (n = 243) versus white (n = 156) patients, active renin was 10.3 mU/l versus 13.8 mU/l, respectively (p < 0.001). Serum aldosterone was similar in black and white patients (6.8 vs. 7.4 ng/dl, respectively, p = 0.25).
Efficacy.
Mean changes in DBP and SBP from baseline to final visit (week 16) were significantly greater with eplerenone treatment than with placebo or losartan treatment in all patients combined (p < 0.001) and in black patients (p 0.001) (Table 3). Among white patients, adjusted mean changes in DBP and SBP were significantly greater with eplerenone treatment than with placebo (p = 0.001), but not significantly different between eplerenone and losartan, although the change in DBP approached significance (p = 0.068) (Table 3). Significant differences in DBP between eplerenone and placebo or losartan were observed by week 4 in black patients and were maintained for the study duration (Fig. 1). Response rates (defined as the percentage of patients with DBP <90 mm Hg or with DBP 90 mm Hg but 10 mm Hg below baseline) for placebo, eplerenone, and losartan were 41.2%, 64.5%, and 48.3%, respectively (p < 0.001 for eplerenone vs. placebo, p = 0.003 for eplerenone vs. losartan).
The change from baseline in the UA/CR was determined in a partial patient sample (n = 118, 132, and 133 for placebo, eplerenone, and losartan, respectively). This analysis covered a smaller population because urine samples were not available for a number of patients at baseline and/or the final visit. The calculated mean percent change was 5.2% (95% confidence interval [CI] –8.4 to 20.8) for placebo, –21.6% (95% CI –31.3 to –10.7) for eplerenone, and –18.2% (95% CI –28.3 to –6.7) for losartan, indicating improvement from both treatments compared with placebo (p = 0.003 for eplerenone vs. placebo). There was no difference in UA/CR change between the eplerenone and losartan groups (p = 0.652).
Analysis of special patient populations.
Subgroup analysis failed to show any significant differences in efficacy for eplerenone in women, men, and patients with baseline SBP 160 mm Hg (Table 4). Eplerenone was also effective in both obese and nonobese patients (data not shown). Eplerenone was more effective than losartan in lowering SBP and DBP in the moderate and low renin patient, and was as effective as losartan in the high renin patient (Fig. 2). Similarly, eplerenone was more effective in reducing SBP than losartan in patients with low and high aldosterone levels, and was more effective in reducing DBP in patients with low aldosterone levels (Fig. 3). Eplerenone was similar to losartan in antihypertensive effect at all other baseline aldosterone levels.
Tolerability.
Six (3.3%) patients in the placebo and eplerenone groups and eight (4.3%) in the losartan group discontinued study medication for adverse events. Adverse events were reported by 85, 89, and 81 patients in the placebo, eplerenone, and losartan groups, respectively (Table 5). Most frequently reported events included headache, respiratory system disorders, and gastrointestinal disorders. No significant differences in the incidence of adverse events were noted between eplerenone and placebo or losartan (Table 5). No patient in the eplerenone treatment group reported impotence, gynecomastia, or breast tenderness; two patients reported menstrual disorder; and two reported decreased libido (Table 5).
Vital signs and laboratory values were very similar among patients treated with placebo, eplerenone, and losartan. No significant differences versus baseline in adjusted mean HR were observed between treatment groups for all patients. No clinically significant differences between eplerenone and placebo or losartan were observed for liver function tests, serum creatinine, or blood urea nitrogen. At the final visit, mean changes in serum uric acid levels were 2.4 ± 4.6, 13.0 ± 4.3, and –15.1 ± 3.6 µmol/l for the placebo, eplerenone, and losartan groups, respectively (p < 0.001 for eplerenone vs. losartan); all changes were within the normal range. Similarly, changes in serum potassium at study end were –0.01 ± 0.03, +0.09 ± 0.03, and +0.03 ± 0.03 mmol/l in the placebo, eplerenone, and losartan groups, respectively (p < 0.001 for eplerenone vs. placebo, p = 0.003 for eplerenone vs. losartan). A serum potassium level >5.5 mmol/l was observed for three, four, and three patients in the placebo, eplerenone, and losartan groups, respectively. One eplerenone-treated patient was withdrawn due to an elevated potassium level.
More patients discontinued therapy in the placebo and losartan groups than in the eplerenone group, primarily because of treatment failure (p = 0.0001 for eplerenone vs. placebo, p < 0.001 for eplerenone vs. losartan [Table 1]). Treatment failure was lowered significantly in black eplerenone-treated patients compared with placebo (12/115 [10.4%] vs. 29/113 [25.7%], respectively [p = 0.003]) and trended towards a decrease in white patients treated with eplerenone (8/67 [11.9%] vs. 16/68 [23.5%], eplerenone vs. placebo [p = 0.078]).
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Discussion
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This study demonstrated that eplerenone treatment significantly reduced DBP and SBP compared with placebo in both black and white patients with mild-to-moderate hypertension. Eplerenone monotherapy was more effective than losartan monotherapy for all patients combined and in black patients, and was comparable to losartan in white patients. It should be pointed out that use of the term "all patients combined" in this analysis is influenced by the preponderantly black population (63% black vs. 37% white); thus, the increased efficacy seen in blacks influenced the improved efficacy seen in "all patients combined." Nevertheless, within both racial groups, the estimated mean change in DBP and SBP consistently rank-ordered eplerenone > losartan > placebo.
Previous studies have suggested that racial differences in response to hypertension therapy are drug-class specific. Monotherapy with angiotensin II receptor antagonists lower BP less in black than in white patients (12,17); these findings were confirmed by our study. Similarly, black hypertensive patients do not respond as well as white patients to lower doses of ACE inhibitor or beta-blocker monotherapy, although uptitration to higher doses of ACE inhibitors either eliminates or narrows any racial difference in BP-lowering efficacy (18–20). However, black patients have been found to respond better to thiazide diuretics and calcium channel blockers than white patients (7,9,19). In this study, antihypertensive treatment with monotherapy using eplerenone, the SAB, is similarly effective in both black and white patients.
Predicting the most effective hypertension monotherapy in a given patient can be challenging. A crossover study rotating treatment among an ACE inhibitor, a beta-blocker, a calcium channel blocker, and a diuretic indicated that patients respond either to the first two drugs or to the latter two (21). Another study predicted medication response based on age-race subgroup or renin profile (9). Our exploratory analyses suggest that many patient populations respond consistently to eplerenone (black patients, white patients, men, women, obese patients, nonobese patients, patients with SBP 160 mm Hg, and patients with low renin activity), which may increase the likelihood of treatment success. Indeed, observation of overall treatment failure was 11.0% with eplerenone, compared with 24.9% and 22.9% with placebo and losartan, respectively (Table 1).
A recent study demonstrated that the majority of patients with uncontrolled BP have SBP levels higher than goal (22). In this present study, the maximal decrease in SBP (–22.8 mm Hg) was demonstrated in eplerenone-treated patients with SBP 160 mm Hg (Table 4). Therefore, eplerenone treatment may be a highly effective therapeutic option for patients with prominent SBP elevations.
An important goal of hypertensive therapy is to prevent complications, including kidney and cardiovascular damage. Inhibiting the actions of either angiotensin II or aldosterone protects against target organ damage in rat models of hypertension (16,23,24). The UA/CR reflects the degree of albuminuria, which is predictive of both renal damage (25) and cardiovascular events (26). Both eplerenone and losartan significantly reduced the UA/CR relative to placebo, and therefore may reduce the risk for complications of hypertension.
No significant differences in adverse events incidence or type were observed between eplerenone or losartan or placebo. A non-significant trend towards increased respiratory disorders was observed in patients treated with eplerenone (Table 5). The reported incidence of gynecomastia, breast pain, menstrual abnormalities, impotence, and decreased libido with eplerenone was low and comparable to losartan and placebo. These adverse events have been reported much more frequently with spironolactone treatment >50 mg/day for 23 months (13–15). Further, no clinically relevant differences in laboratory test results were observed between eplerenone and placebo. Small increases in serum uric acid and serum potassium concentration in the eplerenone group were within the normal range and without clinical consequence.
This study indicates that eplerenone, a novel antihypertensive agent, significantly reduces DBP and SBP in both black and white patients and is well tolerated. Eplerenone appears to effectively lower BP across a broad spectrum of patients, including those with low active renin levels and, therefore, may protect patients from hypertension-related target-organ damage (Appendix).
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APPENDIX
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The following investigators participated in this trial (020). South Africa: Bloemfontein: P. Jordaan. Capetown: L. Burgess, B. Rayner. Durban: S. Cassim. Johannesburg: G. Norton, Y. Veriava. Pretoria: R. Sommers. Western Cape: M. Middle. United States: M. Debruin, J. Earl, J. Fialkow, D. Harper, G. Hilliard, K. Hinchey, E. Klainer, M. Lester, D. Pate, A. Patron, M. Peshimam, J. Rohlf, J. Rosen, W. Smith, T. Stone, D. Sugimoto. Atlanta, GA: J. Martin, Jr. Baltimore, MD: E. Saunders. Birmingham, AL: S. Oparil; Charleston, SC: H. Resnick. Chicago, IL: J. Kopin, J. Villamizar. Cincinnati, OH: W. Cox, R. Wolff. Cleveland, OH: J. Wright, Jr. Columbia, SC: S. Rosansky. Coral Gables, FL: R. Sievers. Detroit, MI: J. Flack. Eugene, OR: P. Taggert. Houston, TX: C. McKeever. Indianapolis, IN: J. Pratt. Jackson, MS: M. Wofford. Jacksonville, FL: M. Koren. Kansas City, MO: S. Prohaska. Milwaukee, WI: C. Grim. New Orleans, LA: J. Angelo, K. Ferdinand, M. Gomez, D. Smith. Oakland, CA: H. Watson. Spring Valley, CA: R. Lipetz. Washington, DC: D. Harper. Winston-Salem, NC: T. Littlejohn.
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Footnotes
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Supported by a grant from Pharmacia Corporation, Skokie, Illinois.
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M. Bochud, J. Nussberger, P. Bovet, M. R. Maillard, R. C. Elston, F. Paccaud, C. Shamlaye, and M. Burnier
Plasma Aldosterone Is Independently Associated With the Metabolic Syndrome
Hypertension,
August 1, 2006;
48(2):
239 - 245.
[Abstract]
[Full Text]
[PDF]
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K. Nagata, K. Obata, J. Xu, S. Ichihara, A. Noda, H. Kimata, T. Kato, H. Izawa, T. Murohara, and M. Yokota
Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats
Hypertension,
April 1, 2006;
47(4):
656 - 664.
[Abstract]
[Full Text]
[PDF]
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C. Saha, G. J. Eckert, W. T. Ambrosius, T.-Y. Chun, M. A. Wagner, Q. Zhao, and J. H. Pratt
Improvement in Blood Pressure With Inhibition of the Epithelial Sodium Channel in Blacks With Hypertension
Hypertension,
September 1, 2005;
46(3):
481 - 487.
[Abstract]
[Full Text]
[PDF]
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C. E. Grim, A. W. Cowley Jr, P. Hamet, D. Gaudet, M. L. Kaldunski, J. M. Kotchen, S. Krishnaswami, Z. Pausova, R. Roman, J. Tremblay, et al.
Hyperaldosteronism and Hypertension: Ethnic Differences
Hypertension,
April 1, 2005;
45(4):
766 - 772.
[Abstract]
[Full Text]
[PDF]
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S J Lee and A Kavanaugh
A need for greater reporting of socioeconomic status and race in clinical trials
Ann Rheum Dis,
December 1, 2004;
63(12):
1700 - 1701.
[Full Text]
[PDF]
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L. M. Brewster, G. A. van Montfrans, and J. Kleijnen
Systematic Review: Antihypertensive Drug Therapy in Black Patients
Ann Intern Med,
October 19, 2004;
141(8):
614 - 627.
[Abstract]
[Full Text]
[PDF]
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D. G. Levy, R. Rocha, and J. W. Funder
Distinguishing the Antihypertensive and Electrolyte Effects of Eplerenone
J. Clin. Endocrinol. Metab.,
June 1, 2004;
89(6):
2736 - 2740.
[Abstract]
[Full Text]
[PDF]
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D. H. Endemann, R. M. Touyz, M. Iglarz, C. Savoia, and E. L. Schiffrin
Eplerenone Prevents Salt-Induced Vascular Remodeling and Cardiac Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats
Hypertension,
June 1, 2004;
43(6):
1252 - 1257.
[Abstract]
[Full Text]
[PDF]
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R. S. Vasan, J. C. Evans, E. J. Benjamin, D. Levy, M. G. Larson, J. Sundstrom, J. M. Murabito, F. Sam, W. S. Colucci, and P. W. F. Wilson
Relations of Serum Aldosterone to Cardiac Structure: Gender-Related Differences in the Framingham Heart Study
Hypertension,
May 1, 2004;
43(5):
957 - 962.
[Abstract]
[Full Text]
[PDF]
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F. K Shieh, E. Kotlyar, and F. Sam
Aldosterone and cardiovascular remodelling: focus on myocardial failure
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2004;
5(1):
3 - 13.
[Abstract]
[PDF]
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L. G. Futterman and L. Lemberg
The Resurrection of Spironolactone on Its Golden Anniversary
Am. J. Crit. Care.,
March 1, 2004;
13(2):
162 - 165.
[Full Text]
[PDF]
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A. D Struthers and T. M MacDonald
Review of aldosterone- and angiotensin II-induced target organ damage and prevention
Cardiovasc Res,
March 1, 2004;
61(4):
663 - 670.
[Abstract]
[Full Text]
[PDF]
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L. M. Humma and P. L. Adenekan
Response to renin-angiotensin system antagonists in hypertensive black subjects
J. Am. Coll. Cardiol.,
September 17, 2003;
42(6):
1141 - 1141.
[Full Text]
[PDF]
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B. Pitt, C. T Stier Jr, and S. Rajagopalan
Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2003;
4(3):
164 - 168.
[Abstract]
[PDF]
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J. W. Funder
Aldosterone Resurgens--Letter from EPHESUS
J. Clin. Endocrinol. Metab.,
June 1, 2003;
88(6):
2373 - 2375.
[Full Text]
[PDF]
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O. Ben-Yehuda
Hypertension, angiotensin II, aldosterone, and race
J. Am. Coll. Cardiol.,
April 2, 2003;
41(7):
1156 - 1158.
[Full Text]
[PDF]
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Abstract
Methods
