eplerenone and Hypokalemia

Primary aldosteronism with a prevalence of 8 % of hypertension and 20 % of pharmacologically resistant hypertension is the most common secondary cause of hypertension. Yet, the diagnosis is missed in the vast majority of patients. Current clinical practice guidelines recommend screening for primary aldosteronism in patients with sustained elevation of blood pressure (BP) ≥150/100 mmHg if possible prior to initiation of antihypertensive therapy, and in patients with resistant hypertension, spontaneous or diuretic-induced hypokalemia, adrenal incidentaloma, obstructive sleep apnea, a family history of early onset of hypertension or cerebrovascular accident

Topics: Adrenalectomy; Eplerenone; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Laparoscopy; Mass Screening; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Prevalence; Spironolactone

The identification of primary aldosteronism as a common cause of resistant hypertension is a significant advance in our ability to care for patients with hypertension. Primary aldosteronism is common, and when unrecognized is associated with an increased incidence of adverse cardiovascular outcomes. Identification of primary aldosteronism is based on use of the plasma aldosterone level, plasma renin activity, and the aldosterone:renin ratio. Differentiation between unilateral and bilateral autonomous adrenal aldosterone production then guides further therapy, with use of mineralocorticoid-receptor blockers for patients with bilateral autonomous adrenal aldosterone production and laparoscopic adrenalectomy for patients with unilateral autonomous aldosterone production. In this review, we discuss in detail the pathogenesis of primary aldosteronism-induced hypertension and potassium disorders, the evaluation of the patient with suspected primary aldosteronism, and the management of primary aldosteronism, both through medications and surgery.

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Adenoma; Aldosterone; Eplerenone; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Mineralocorticoid Receptor Antagonists; Renin; Spironolactone

Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as "Conn-Trias" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary.

Topics: Adrenal Cortex Neoplasms; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adrenocortical Adenoma; Aldosterone; Antihypertensive Agents; Diagnosis, Differential; Eplerenone; Hyperaldosteronism; Hypertension; Hypokalemia; Magnetic Resonance Imaging; Mass Screening; Renin; Spironolactone; Tomography, X-Ray Computed

Aldosterone plays a pivotal role in sodium and water homeostasis, in particular in patients with heart failure or high blood pressure. These medications, when used on top of a standard therapy, improve the outcome of patients with heart failure and are also effective in lowering blood pressure of hypertensive patients. The major risk associated with the use of these antagonists is hyperkalemia, which can be prevented in avoiding their prescription in patients with impaired renal function. Eplerenone has the advantage, compared with spironolactone, to be better tolerated in terms of "hormonal" adverse effects.

Topics: Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Hypertension; Hypokalemia; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain.. In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone.

Topics: Dose-Response Relationship, Drug; Eplerenone; Europe; Female; Follow-Up Studies; Heart Failure, Systolic; Humans; Hypokalemia; Male; Mineralocorticoid Receptor Antagonists; Prognosis; Spironolactone; Survival Rate; Time Factors; Treatment Outcome

Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8±0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient.

Topics: Adolescent; Adult; Amiloride; Blood Pressure; Body Weight; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Eplerenone; Female; Gitelman Syndrome; Glomerular Filtration Rate; Heart Rate; Humans; Hypokalemia; Indomethacin; Male; Middle Aged; Potassium; Renin; Spironolactone; Treatment Outcome; Young Adult

The aim of this prospective, randomised, open-label, blinded-end point study was to compare the efficacy and safety of eplerenone versus spironolactone in patients with bilateral idiopathic hyperaldosteronism (IHA). After a 2-week washout period, 34 patients with IHA were assigned to receive either spironolactone 25 mg b.i.d. (n = 17) or eplerenone 25 mg b.i.d. (n = 17) for 24 weeks. If the patients' blood pressure (BP) was not < 140/90 mmHg, the doses were gradually increased up to 400 mg for spironolactone and 200 mg for eplerenone. If the patients' BP remained uncontrolled, a daily dose of hydrochlorothiazide 12.5 mg was added at week 16. The primary outcome was the percentage of patients with BP < 140/90 mmHg at 16 weeks (i.e., with aldosterone antagonist monotherapy). The patients' BP was normalised in 13 out of 17 (76.5%) and 14 out of 17 (82.4%) patients in the spironolactone and eplerenone groups, respectively (p = 1.00). Systolic BP decreased more rapidly with eplerenone. Serum potassium levels were normalised (> 3.5 mmol/l) in all patients at 4 weeks. Mild hyperkalaemia was observed in two patients receiving 400 mg of spironolactone and in three patients receiving 150 mg of eplerenone. Two patients presented with bilateral painful gynaecomastia at the end of week 16 while receiving 400 mg of spironolactone. Switching spironolactone to 150 mg of eplerenone daily resulted in resolution of gynaecomastia and also maintained BP control. At the end of the study, 19 patients were on eplerenone and 15 were on spironolactone. However, this did not affect the primary end point, because the switch from spironolactone to eplerenone (in two patients) occurred at the end of week 16. It was concluded that eplerenone was as effective as spironolactone in reducing BP in patients with IHA. The risk of mild hyperkalaemia was similar with both drugs.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Eplerenone; Female; Gynecomastia; Humans; Hyperaldosteronism; Hyperkalemia; Hypertension; Hypokalemia; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Prospective Studies; Spironolactone; Time Factors; Treatment Outcome

Primary aldosteronism (PA) is associated with a higher rate of cardiovascular events than essential hypertension. Although adrenalectomy has been reported to reduce carotid intima-media thickness (IMT) in patients with PA, the effects of the selective aldosterone blocker, eplerenone, on vascular damage in these patients remains unclear. To evaluate the effects of eplerenone on vascular status in PA patients, we sequentially measured carotid IMT (using computer software to calculate an average IMT for accurate and reproducible evaluation) in 22 patients including 8 patients treated by unilateral adrenalectomy and 14 patients treated with eplerenone for 12 months. Patients who underwent adrenalectomy showed significant reductions in aldosterone concentration (from 345 ± 176 pg/mL to 67 ± 34 pg/mL; P<0.01) and IMT (from 0.67 ± 0.07 mm to 0.63 ± 0.09 mm; P<0.05) 6 months after surgery. Patients treated with eplerenone showed significant reductions in IMT from baseline (0.75 ± 0.10 mm) to 6 (0.71 ± 0.11 mm; P<0.05) and 12 (0.65 ± 0.09 mm; P<0.01) months, although plasma aldosterone level increased significantly, from 141 ± 105 pg/mL to 207 ± 98 pg/mL (P<0.05). Eplerenone treatment of patients with PA reduces blood pressure, increases serum potassium level, and improves vascular status. Carotid IMT may be a useful marker for evaluating the effectiveness of eplerenone in patients with PA.

Topics: Adrenalectomy; Adult; Aged; Aldosterone; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Drug Monitoring; Eplerenone; Female; Follow-Up Studies; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Japan; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Reproducibility of Results; Risk; Spironolactone

Spironolactone, which is a potent mineralocorticoid receptor antagonist, represents the first line medical treatment of primary aldosteronism (PA). As spironolactone is also an antagonist of the androgen and progesterone receptor, it may present side effects, especially in male patients. In case of intolerance to spironolactone, amiloride may be used to control hypokaliemia and we suggest that eplerenone, which is a more selective but less powerful antagonist of the mineralocorticoid receptor, be used in case of intolerance to spironolactone and insufficient control of hypertension by amiloride. Specific calcic inhibitors and thiazide diuretics may be used as second or third line therapy. Medical treatment of bilateral forms of PA seem to be as efficient as surgical treatment of lateralized PA for the control of hypertension and the prevention of cardiovascular and renal morbidities. This allows to propose medical treatment of PA to patients with lateralized forms of PA who refuse surgery or to patients with PA who do not want to be explored by adrenal venous sampling to determine whether they have a bilateral or lateralized form.

Topics: Eplerenone; Female; France; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

Topics: Aldosterone; Eplerenone; Gynecomastia; Humans; Hyperaldosteronism; Hypertension; Hypokalemia; Meta-Analysis as Topic; Mineralocorticoid Receptor Antagonists; Spironolactone

A 47-year-old woman presented with hypokalemia (2.4 mmol/L). She also had hypomagnesemia, hypocalciuria, and hyperreninemic hyperaldosteronism. Sequence analysis revealed a compound heterozygous mutation, R655C and R955Q, in the SLC12A3 gene. These findings were compatible with Gitelman's syndrome (GS). Eplerenone, a selective aldosterone blocker, in combination with oral potassium chloride improved serum potassium level (3.6 mmol/L) with no apparent adverse effect. Although eplerenone has an advantage over spironolactone for its selective affinity for the aldosterone receptor, the efficacy and safety of eplerenone for GS is little understood. Our observation suggests that eplerenone is a useful treatment option for GS.

Topics: Base Sequence; DNA Mutational Analysis; Eplerenone; Female; Gitelman Syndrome; Humans; Hypokalemia; Middle Aged; Mineralocorticoid Receptor Antagonists; Mutation, Missense; Potassium; Receptors, Drug; Solute Carrier Family 12, Member 3; Spironolactone; Symporters; Treatment Outcome

The Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial demonstrated that selective aldosterone blockade with eplerenone significantly reduced total mortality by 15%, combined cardiovascular (CV) mortality/CV hospitalization by 13%, CV mortality by 17% and sudden cardiac death by 21%, vs. placebo when added to standard care in patients with left ventricular systolic dysfunction (LVSD) and signs of congestive heart failure (CHF) following acute myocardial infarction (AMI). We retrospectively evaluated the effect of eplerenone vs. placebo in a subset of 1483 diabetic patients with LVSD and signs of CHF following AMI.. Diabetic status was determined from medical histories at screening. Analyses were based on time to first occurrence of an event. Results were based on a Cox's proportional hazards regression model stratified by region with treatment, subgroup and treatment-by-subgroup interaction as factors. The 95% confidence intervals for the risk ratios were based on the Wald's test.. Treatment with eplerenone in diabetic patients with CHF following AMI reduced the risk of the primary endpoint, a composite of CV mortality or CV hospitalization, by 17% (p = 0.031). The absolute risk reduction of the primary endpoint was greater in the diabetic cohort (5.1%) than in the non-diabetic cohort (3%). Hyperkalaemia occurred more often with eplerenone than with placebo (5.6 vs. 3%, p = 0.015). Among the diabetic cohorts, the prespecified endpoint of 'any CV disorder' occurred in 28% of the eplerenone group and 35% of the placebo group (p = 0.007).. Eplerenone treatment may reduce adverse CV events in diabetic patients with LVSD and signs of CHF following AMI.

Topics: Aged; Clinical Trials as Topic; Diabetes Complications; Eplerenone; Female; Heart Failure; Humans; Hyperkalemia; Hyperuricemia; Hypokalemia; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Retrospective Studies; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Death, Sudden, Cardiac; Eplerenone; Humans; Hypokalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left