Research article
Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension

https://doi.org/10.1016/j.jash.2008.05.005Get rights and content

Abstract

Resistant hypertension is defined as uncontrolled hypertension despite intensive treatment with at least three antihypertensive agents, one of which ideally should be a diuretic. To determine the efficacy and safety of the selective aldosterone antagonist eplerenone in this population, we studied patients with resistant hypertension (clinic blood pressure [BP] >140 mm Hg systolic or >90 mm Hg diastolic on maximal doses of more than three antihypertensive agents, including a loop or thiazide diuretic). At baseline and after 12 weeks of eplerenone therapy (50 to 100 mg daily titrated to effect), patients underwent clinic and 24-hour BP measurements, serum potassium, plasma renin activity, and serum aldosterone measurements. Patients (n = 52) completing the trial averaged 62 ± 10 years of age, were overweight (mean body mass index, 32.1 ± 5.5 kg/m2), and had variable renal function (glomerular filtration rate, 106 ± 38 mL/minute); 70% were men and 74% were non-Black. The mean number of antihypertensive agents at baseline was 3.7 ± 0.8 (range, three to seven drugs) to achieve a clinic BP of 150.5/84.1 mm Hg. The mean serum aldosterone was 12.9 ± 7.6 ng/mL and plasma renin activity was 2.3 ± 2.7 ng/mL/hour. After eplerenone, the change from baseline in the clinic BP was −17.6/−7.9 mm Hg (P < .0001 for both systolic blood pressure [SBP] and diastolic blood pressure [DBP]) and in 24-hour BP was −12.2/−6.0 mm Hg (P < .0001 for both). The number of antihypertensive drugs decreased to 3.3 ± 0.9 (range, one to seven agents). Plasma potassium increased by 0.30 ± 0.45 mEq/L (P < .001), but there were only three instances in two patients of mild hyperkalemia (potassium >5.5 mEq/L, but <6.0 mEq/L), despite all patients being on a background therapy that included an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Reductions in clinic and ambulatory BP were related to baseline clinic and ambulatory BP values (r2 > 0.3 for both SBP and DBP, P < .0001), weakly related to baseline serum aldosterone (r = −0.30; P = .05), and unrelated to plasma renin activity, age, gender, or race. In conclusion, eplerenone demonstrated substantial efficacy in treatment-resistant hypertension and was well-tolerated with modest changes in plasma potassium. Serum aldosterone and plasma renin activity did not predict BP responses to eplerenone in this population.

Introduction

Resistant hypertension, defined as uncontrolled hypertension despite treatment with three antihypertensive agents, is a common problem in clinical medicine and results in referrals from primary care physicians to hypertension specialists on a regular basis.1, 2 Recently, there have been observations that aldosterone blockade with spironolactone or amiloride is an effective strategy for reducing both systolic blood pressure (SBP) and diastolic blood pressure (DBP) when added to existing antihypertensive regimens in patients with resistant hypertension.3, 4 Furthermore, the addition of aldosterone antagonists has led to reductions in the overall number of antihypertensive medications. Despite these benefits, an important limiting factor for long-term utility of spironolactone has been its poor tolerability, especially in male patients at higher doses. The incidence of gynecomastia with concomitant sexual dysfunction in men increases to 10% to 30% with daily doses of 25 mg and higher.5, 6

Eplerenone is a highly selective aldosterone blocker with minimal sex hormone receptor activity.7 Eplerenone has a high degree of selectivity for the aldosterone receptor and a low binding affinity for progesterone (<1%) and androgen receptors (0.1%).7 Consequently, eplerenone is associated with a favorable tolerability profile with rates of gynecomastia, impotence, and menstrual cycle abnormalities similar to that of placebo.8, 9, 10, 11, 12 Because eplerenone has been shown to be an effective and well-tolerated agent when combined with renin-angiotensin blocking agents or diuretics when inadequate blood pressure (BP) control was observed,9, 10, 11 we hypothesized that it might be effective in patients with resistant hypertension who are taking these agents. To objectively evaluate the impact of eplerenone in this group of patients, we used ambulatory BP monitoring to evaluate the patient's response to therapy.13, 14 Because ambulatory BP monitoring removes all of the observer bias seen in antihypertensive drug trials and much of the “placebo” effect that is observed based on clinic measurements,14 we performed this trial with a prospective, open-label, blinded endpoint design as previously described.15

Section snippets

Study Design

The study was a prospective, open-label, two-center (Alabama and Connecticut) blinded endpoint (ambulatory BP measurements) clinical trial. After a screening visit, patients entered a 10- to 14-day run-in period to determine baseline BP stability. Ambulatory BP monitoring was used to establish the presence of true resistant hypertension (eg, vs. controlled hypertension and white-coat effect phenomenon). The screening period was followed by a 12-week, open-label treatment period in which

Patient Enrollment and Disposition

A total of 67 patients were screened for the study, of which 52 patients met all of the inclusion criteria and were initiated on eplerenone therapy. All patients who entered the eplerenone treatment phase of the study completed the trial. The two reasons for screening failures not qualifying for continuation in the study were out-of-range clinic BP values (n = 10) or ambulatory BP values (n = 5).

Baseline Characteristics of the Study Population

The baseline characteristics of the study population are shown in the Table. The mean age of the

Principal Findings

Results from this trial in patients with uncontrolled hypertension despite taking nearly four antihypertensive drugs demonstrated that eplerenone, a highly selective aldosterone antagonist, substantially and significantly lowered both clinic and ambulatory BP (Figure 1). Furthermore, the addition of eplerenone to a regimen of standard antihypertensive therapy that included a diuretic, renin-angiotensin blocking agent and in two-thirds of patients, a calcium antagonist, led to normalization of

Conclusions

This is the first study that has evaluated the effects of the selective aldosterone receptor blocking agent, eplerenone, in patients with resistant or difficult-to-control hypertension. Data derived from both clinic and ambulatory BP monitoring demonstrate that highly significant reductions in BP occurred with eplerenone and that the drug was very well tolerated. BP control rates were as high as 60% based on clinic BP values and 40% based on ambulatory BP values. These findings support the use

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      A 50-patient study of eplerenone for the treatment of RH showed substantial BP lowering and was well tolerated. Interestingly, serum aldosterone and plasma renin activity did not predict BP responses to eplerenone in this study.35 A substudy of PATHWAY-2 assessed whether amiloride could be used as an alternative to spironolactone.

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    This article was supported by Pfizer, Inc (IIR no. 2004-0619) and by an unrestricted, investigator-initiated research Grant from University of Connecticut Health Center Clinical Trials Unit, Farmington, Connecticut.

    Dr. Calhoun has served as a consultant to Novartis and is a member of the Pfizer speaker's bureau. Dr. White has served as a consultant to Pfizer on the topic of cardiovascular effects of arthritis therapies.

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