Barbara Roniker

Effects of Eplerenone, Enalapril, and Eplerenone/Enalapril in Patients With Essential Hypertension and Left Ventricular Hypertrophy. The 4E-Left Ventricular Hypertrophy Study

Background—Elevated renin-angiotensin-aldosterone system activity correlates with left ventricular hypertrophy (LVH) and cardiovascular risk, but the relative contributions of angiotensin II and aldosterone remain unclear. This study compared LVH regression during treatment with the selective aldosterone blocker eplerenone, enalapril, and their combination in patients with hypertension. Methods and Results—A 9-month, double-blind, randomized study was performed in 202 patients with LVH and hypertension who received eplerenone 200 mg daily, enalapril 40 mg daily, or eplerenone 200 mg and enalapril 10 mg daily. At week 8, hydrochlorothiazide 12.5 to 25 mg and/or amlodipine 10 mg was added if diastolic blood pressure was >90 mm Hg. Change in left ventricular (LV) mass as assessed by MRI was the primary end point. Change in blood pressure, renin-angiotensin-aldosterone system hormones, albuminuria, and safety were also assessed. Eplerenone significantly reduced LV mass from baseline (−14.5±3.36 g; n=50) similarly to enalapril (−19.7±3.20 g; n=54; P =0.258), but eplerenone/enalapril (−27.2±3.39 g; n=49) was more effective than eplerenone alone (P =0.007). All treatments reduced systolic blood pressure and diastolic blood pressure from baseline (eplerenone, −23.8 and −11.9 mm Hg; enalapril, −24.7 and −13.4 mm Hg; and eplerenone/enalapril, −28.7 and −14.4 mm Hg, P =0.048, in systolic blood pressure compared with eplerenone alone). Cough was more common with enalapril than with eplerenone (P =0.033), and elevated potassium was more common with eplerenone. Conclusions—Eplerenone was as effective as enalapril in LVH regression and blood pressure control. The combination of eplerenone and enalapril was more effective in reducing LV mass and systolic blood pressure than eplerenone alone.

Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension

BACKGROUND Eplerenone, a selective aldosterone blocker (SAB) that is highly specific for the aldosterone receptor, has the potential to be efficacious in the treatment of hypertension. METHODS This 8-week, multicenter, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of eplerenone in eligible patients randomized to eplerenone 50, 100, or 400 mg once daily; eplerenone 25, 50, or 200 mg twice daily; spironolactone 50 mg twice daily; or placebo. The primary efficacy variable was the adjusted mean change in baseline to final visit for seated diastolic blood pressure (DBP). RESULTS Of 417 randomized patients, 409 were evaluated for efficacy. The adjusted mean change from baseline to final visit in seated and standing systolic blood pressure (SBP) and DBP was significantly greater (P < .05) in all eplerenone groups than in the placebo group. The adjusted mean change in 24-h ambulatory blood pressure monitoring (ABPM) measurements of SBP and DBP also documented a 24-h duration significantly greater (P < .05) than placebo in eplerenone-treated patients. For all measurements, the antihypertensive effect of eplerenone increased in a dose-response fashion. Eplerenone (100 mg) reduced BP by 75% compared with spironolactone (100 mg) and had an adverse events incidence rate similar to placebo. No antiandrogenic or progestational effects or clinically relevant safety issues were observed in eplerenone-treated patients. However, one spironolactone-treated patient reported menstrual irregularities. CONCLUSIONS Eplerenone doses of 50 to 400 mg once daily are well tolerated and effective in reducing BP in patients with mild-to-moderate hypertension during a 24-h period.

The EPHESUS trial : Eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction

The importance of aldosterone in the pathophysiology of chronic heart failure (HF) has been established in previous studies [1–4] and is emphasized by the findings of the RALES trial [5]. In this study, aldosterone blockade with spironolactone resulted in a 30% reduction in total mortality and a 35% reduction in hospitalizations for HF in patients with pre-existing chronic severe HF. Patients in the RALES trial also received standard therapy including an ACE inhibitor (if tolerated), a loop diuretic, and digoxin. While aldosterone receptor blockade has been proven beneficial in severe chronic HF due to systolic left ventricular (LV) dysfunction, its effects in patients with acute myocardial infarction (AMI) complicated by HF due to systolic left ventricular dysfunction are unknown. The pathophysiology of HF complicating AMI is complex. Factors such as the acute release of catecholamines, activation of the renin angiotensin aldosterone system, degree of ventricular remodeling, myocardial scar formation, extent of coronary artery disease, and residual ischemia may differ both quantitatively and qualitatively in patients with acute infarction compared to patients with chronic HF. Additionally, the extent of activation of cytokines, fibrinolytic balance, and activity of clotting factors may differ. Eplerenone was chosen for this study because of its demonstrated efficacy in an experimental model of AMI [6]. In clinical trials, eplerenone demonstrated efficacy similar to spironolactone in blocking aldosterone receptors, lowering blood pressure, and moderating hormonal and neurohormonal markers of HF [7,8]. However, eplerenone has significantly less affinity for androgen and progesterone receptors and should therefore be associated with a lower incidence of gynecomastia, breast pain and impotency in males, and diminished libido and menstrual irregularities in females [9–11]. While older patients suffering from refractory HF may tolerate these androgenic and progestational side effects, they may preclude widespread use of a nonspecific aldosterone antagonist in younger patients or in patients with less severe cardiac compromise. Since eplerenone is at least 100 times more specific in its affinity for aldosterone receptors than is spironolactone, if the hypothesis being tested in the EPHESUS trial proves correct, eplerenone has the potential to be used in a broad population to prevent progressive left ventricular remodeling, ventricular fibrosis, malignant arrhythmias, non-fatal AMI, and sudden cardiac death. We hypothesize that selective aldosterone receptor blockade with eplerenone will have a beneficial effect on survival and morbidity in patients with AMI complicated by HF due to systolic left ventricular dysfunction. This paper describes the background, design, and organization of a trial to test this hypothesis—the EPHESUS trial (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study).

Effects of the Selective Aldosterone Blocker Eplerenone Versus the Calcium Antagonist Amlodipine in Systolic Hypertension

Abstract—Eplerenone is a highly selective aldosterone blocker, which is under development for the treatment of hypertension and heart failure. To assess its usefulness in older patients with systolic hypertension and widened pulse pressure, we compared the effects of eplerenone with amlodipine, on clinic blood pressure (BP) and pulse pressure and in a subset of the patients, ambulatory BP, vascular compliance, and urinary albumin excretion. The study involved 269 patients ≥50 years of age who were randomly assigned to either eplerenone (50 to 200 mg daily) or amlodipine (2.5 to 10 mg daily) in a double-blind titration to effect design. After 24 weeks of therapy, reductions in clinic systolic BP were similar for both treatments (eplerenone, −20.5±1.1 mm Hg; amlodipine, −20.1±1.1 mm Hg). Reductions in clinic diastolic BP were modestly larger on amlodipine (−6.9±0.7 mm Hg) compared with eplerenone (−4.5±0.7 mm Hg) (P =0.014). Pulse pressure was also reduced similarly from baseline by the 2 treatment groups (eplerenone, −15.9 mm Hg versus amlodipine, −13.4 mm Hg, P =0.07). Changes from baseline in pulse wave velocity after 24 weeks of therapy were statistically similar for eplerenone and amlodipine. In patients with microalbuminuria at baseline (>30 mg albumin/g creatinine), eplerenone reduced the urinary albumin/creatinine ratio by 52% compared with a reduction of 10% by amlodipine (P =0.04). Thus, eplerenone was as effective as amlodipine in lowering systolic BP and pulse pressure as well as pulse wave velocity in older patients with widened pulse pressure hypertension. Furthermore, eplerenone reduced microalbuminuria to a greater extent than amlodipine in this older patient group.

Efficacy of Eplerenone Added to Renin-Angiotensin Blockade in Hypertensive Patients

The efficacy and tolerability of eplerenone, a selective aldosterone blocker, was assessed when added to existing antihypertensive therapy with an ACE inhibitor or an angiotensin II receptor blocker (ARB). Hypertensive patients (n=341) whose blood pressure (BP) was not controlled despite ACE inhibitor or ARB were randomized (double-blind) to receive 50 mg eplerenone (increasing to 100 mg if required) once daily or placebo for 8 weeks. Diastolic and systolic BP and adverse events were recorded. By study end (week 8), mean seated diastolic BP was significantly reduced from week 0 among patients receiving eplerenone/ARB (−12.7±0.81 mm Hg) compared with those receiving placebo/ARB (−9.3±0.83 mm Hg). The change in mean seated diastolic BP was −9.9±0.88 mm Hg in eplerenone/ACE inhibitor patients and −8.0±0.86 mm Hg in placebo/ACE inhibitor patients (P =NS). Systolic BP levels were also significantly lower at week 8 for eplerenone/ACE inhibitor (−13.4±1.35 mm Hg) and eplerenone/ARB (−16.0±1.37 mm Hg) patients, respectively, compared with placebo/ACE inhibitor (−7.5±1.31 mm Hg) and placebo/ARB patients (−9.2±1.41 mm Hg). Adverse events were generally nonsevere and not significantly different between eplerenone and placebo. This study demonstrated that in patients whose BP was not controlled with an ACE inhibitor or ARB, the addition of eplerenone over an 8-week period significantly lowered systolic BP in both groups and diastolic BP in ARB patients. Selective aldosterone blockade with eplerenone, therefore, may be useful add-on therapy in hypertensive patients inadequately controlled on ACE inhibitor or ARB alone.

Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients

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.

Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension

Eplerenone is a highly selective aldosterone blocking agent, which was recently approved for the treatment of hypertension and has also been shown to reduce mortality in post-myocardial infarction patients with heart failure. To assess its usefulness in patients with essential hypertension, we performed a 12-week, double-blind, placebo-controlled, parallel-arm, fixed-dose study over a range of doses using clinic and ambulatory blood pressure (BP). After single-blind placebo therapy for 3 to 4 weeks to obtain baseline measures, 400 patients were randomized to receive placebo or 1 of 4 doses of eplerenone (25, 50, 100, and 200 mg once daily). In addition, changes from baseline in serum potassium, active renin activity, and serum aldosterone were assessed. After 12 weeks of therapy, reductions in clinic BP showed a significant dose response in which 25 mg of eplerenone achieved statistical significance compared with placebo for systolic BP; maximum clinic BP reduction was achieved with the 100 mg dose. Ambulatory BP monitoring showed that all doses of eplerenone (25 to 200 mg/day) lowered BP significantly greater than placebo with a significant dose response. The 24-hour mean BP reductions ranged from 6.4/4.4 to 10.3/5.7 mm Hg on eplerenone compared with 1.3/0.8 mm Hg on placebo. One patient on placebo and 1 patient on 200 mg of eplerenone had episodes of elevated serum potassium levels (>5.5 mEq/L). Increases in serum aldosterone were related to dose but not to reductions in 24-hour BP. Side effects and withdrawal rates attributed to eplerenone were similar to those of placebo. These data show that eplerenone is an effective antihypertensive agent at doses as low as 25 mg/day. The top effective dose in stage 1 to 3 hypertension based on clinic and ambulatory BP was 100 mg once daily. The incidence of elevated serum potassium levels was not increased across doses of eplerenone in this study.

Long-Term Safety and Efficacy of the Selective Aldosterone Blocker Eplerenone in Patients with Essential Hypertension

BACKGROUND Even within the normal range, aldosterone levels are linked to end-organ toxicity and mortality in patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers does not sufficiently reduce plasma aldosterone levels. OBJECTIVE This study was conducted to assess the long-term safety profile and efficacy of the selective aldosterone blocker eplerenone. METHODS This was a multicenter, open-label, uncontrolled trial in patients with mild to moderate essential hypertension. After a 1-week washout of previous antihypertensive medications, eplerenone was initiated at 50 mg once daily; the dose was titrated to a maximum of 200 mg/d to achieve a diastolic blood pressure <90 mm Hg and a systolic blood pressure <140 mm Hg. Thereafter, another antihypertensive agent could be added and titrated once, or another agent could be substituted for eplerenone. Eplerenone treatment was continued for up to 14 months in a subset of patients. RESULTS Five hundred eighty-six patients were enrolled in the study. Their adjusted mean blood pressure (BP) at baseline was 150/96 mm Hg. The majority (80.4%) were white; 51.5% were male and 48.5% were female; 62.3% were between the ages of 45 and 64 years and 21.7% were aged >64 years. Three hundred eighty-five patients (65.7%) completed the study; 98 (16.7%) were withdrawn due to treatment failure (only 4.8% of them after month 4), and 40 (6.8%) were withdrawn due to treatment-emergent adverse events. Four hundred thirty-three of 582 (74.4%) patients in the intent-to-treat population achieved BP control during eplerenone treatment: 261 (44.8%) received eplerenone monotherapy and 172 (30.0%) received eplerenone plus another antihypertensive agent. CONCLUSIONS Eplerenone therapy was effective in the treatment of mild to moderate hypertension over a 14-month period, either as monotherapy or in combination with another antihypertensive agent. Use of eplerenone was well tolerated in the population studied.

Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy?

Since neither angiotensin‐converting enzyme inhibitors (ACE‐I) nor angiotensin II receptor blockers (ARB) can completely suppress aldosterone levels, there is a need for alternative/supplementary antihypertensive medications, such as the selective aldosterone blocker eplerenone (Inspra™). This multicenter study measured the safety and efficacy of add‐on eplerenone therapy to reduce blood pressure not controlled by ACE‐I or ARB monotherapy. An ad hoc analysis evaluated whether active plasma renin or serum aldosterone levels could predict blood pressure response to eplerenone therapy. Patients (N = 341) with a diastolic blood pressure > 95 mmHg on a fixed dose of ACE‐I or ARB were randomized to 8 weeks of double‐blind treatment with eplerenone 50 mg qd or placebo. If blood pressure remained uncontrolled following 2, 4, or 6 weeks of treatment, the eplerenone dose was increased to 100 mg qd. In a combined cohort analysis of these patients, the placebo‐adjusted change in systolic and diastolic blood pressure was −5.9/‐2.4 mmHg (p < 0.001 and p = 0.006, respectively). While adding eplerenone to an ACE‐I or ARB is safe and effective for blood pressure reduction, there was no baseline value or range of values of active plasma renin, serum aldosterone, or their ratio that predicted a favorable response to either of these drug combinations.

Eplerenone reduces proteinuria in type II diabetes mellitus: implications for aldosterone involvement in the pathogenesis of renal dysfunction

Myocardial fibrosis is found in the expadmental hypertensive heart and may be a major cause of heart failure in man. In experimental models, EndotheUn and Aldosterone were shown to act synergically in promoting myocardial fibrosis. Aim of the study was to investigate the possible relations between myocardial fibrosis as assessed by an advanced ultrasound technique (Acoustic Densitometry, AD, Agilent Technologies), and circulating levels of Endothelin and Aldostsrone in pnmary and secondary hypertension. Methods: 32 patients (21 males; mean age 50±11; BP 159±9/101±7 mmHg), including 15 with essential hypertension (EH), 7 with unilateral rano-vascular disease (RVH), 10 with pdmary aldostaronism (PA), were studied, plasma Aldosterone (Aldo), Endothelin (Endo), Renin activity, and Hydroxyprolinuda were measured and related to LV mass and function (M-mode echo), as well as to the average myocardial Integrated Backscatter (IBS; riB), obtained by AD as an estimate of myocardial fibrosis. Results: All subjects had preserved LV systolic function. In PA and RVH patients, IBS and Aldo were higher (p<0.01) than in EH (IBS: 25±5 and 24±7 vs 18±4 dB; Aldo: 1.19¢0.7, 1.18±0.5 and 0.64¢0.2 nmol/L), while Endo was increased only in PA (4.3¢-0.7 pg/ml vs 3.7±0.7 and 3.1±0.8 in RVH and EH, p<0.01), In the overall population, IBS correlated directly to Aldo (r=0.41, p<0.02), Endo (r=0.57, p<0.01), Hydroxyprolinuda (r=0.47, p<0.01), LV mass (r=0.54, p<0.0f), disease duration (r--0.35, p<0.05). In multivariate analysis, Endo, Hydroxyprolinuda, LV mass and disease duration were independently related to IBS (adjusted R2=0.87, p<0.01 for all). LV mass was directly related to hydroxyprolinuda (r--0.51, p<0.01), but not to hormonal factors. Endo was directly related to LV end-diastolic diameter (r=0.37, p<0.05) and showed a trend to increase with increasing Aldo (R---0.32, p=0.07). Conclusions: in human hypertension, myocardial fibrosis partakes of the hypertrophic process, is related to disease duration and dependent on a synergic interaction of Endo and Aldo. The clinical models of pdmary and secondary hyperaldosteronism seem more prone to such a development than essential hypertension.