Showing papers on "Spironolactone published in 2018"

Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association.

Abstract: Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the "white-coat effect" (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment).

Abstract: The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5–50 mg QD) or clonidine (0.1–0.3 mg BID). The primary end point was BP control during office ( P =1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01643434.

Female pattern hair loss: a pilot study investigating combination therapy with low-dose oral minoxidil and spironolactone

Abstract: Background Minoxidil and spironolactone are oral antihypertensives known to stimulate hair growth. Objective To report on a case series of women with pattern hair loss (PHL) treated with once daily minoxidil 0.25 mg and spironolactone 25 mg. Methods Women newly diagnosed with a Sinclair stage 2–5 PHL were scored for hair shedding and hair density before and after 12 months of treatment with oral minoxidil 0.25 mg and spironolactone 25 mg. Results A total of 100 women were included in this observational pilot study. Mean age was 48.44 years (range 18–80). Mean hair loss severity at baseline was Sinclair 2.79 (range 2–5). Mean hair shedding score at baseline was 4.82. Mean duration of diagnosis was 6.5 years (range 0.5–30). Mean reduction in hair loss severity score was 0.85 at 6 months and 1.3 at 12 months. Mean reduction in hair shedding score was 2.3 at 6 months and 2.6 at 12 months. Mean change in blood pressure was −4.52 mmHg systolic and −6.48 mmHg diastolic. Side effects were seen in eight women but were generally mild. No patients developed hyperkalemia or any other blood test abnormality. Six of these women continued treatment, and two women who developed urticaria discontinued treatment. Limitations Prospective, uncontrolled, open-label observational study. Discussion Once daily capsules containing minoxidil 0.25 mg and spironolactone 25 mg appear to be safe and effective in the treatment of FPHL. Placebo-controlled studies to investigate this further are warranted.

Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial

Abstract: Aims Decisive evidence on the optimal diuretic agent, dosing schedule, and administration route is lacking in acute heart failure (AHF) with congestion. The Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial is designed to test the hypothesis that the carbonic anhydrase inhibitor acetazolamide, a potent inhibitor of proximal tubular sodium reabsorption, improves decongestion when combined with loop diuretic therapy in AHF, potentially leading to better clinical outcomes. Methods The ADVOR trial is set up as a multicentre, randomized, double-blind, placebo-controlled study, aiming to recruit 519 patients with AHF and clinically evident volume overload. All study participants receive high-dose intravenous loop diuretics as background therapy and are randomized towards intravenous acetazolamide at a dose of 500 mg once daily vs. placebo, stratified according to including study centre and ejection fraction ( 3.5 L during the first 30-48 h of decongestive treatment. Secondary endpoints include all-cause mortality or heart failure readmission after 3 months, length of hospital stay for the index admission, and longitudinal changes in the EuroQol-5 dimensions questionnaire. Conclusion ADVOR will investigate if acetazolamide combined with loop diuretic therapy improves decongestion in AHF with volume overload.

Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial

Abstract: Objectives This study assessed the relationship between atrial fibrillation (AF) and outcomes in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, to evaluate whether AF modified the treatment response to spironolactone and whether spironolactone influenced post-randomization AF. Background AF is common in heart failure with preserved ejection fraction (HFpEF) and likely contributes to increased risk of adverse outcomes. Methods A total 1,765 patients enrolled in TOPCAT trial in North and South America were divided into 3 groups: no known AF, history of AF without AF at enrollment, and AF found on the electrocardiogram (ECG) at enrollment. We assessed outcomes and treatment response to spironolactone in all groups, and the association between post-randomization AF and outcomes in patients free of AF at baseline. The primary outcome of the TOPCAT trial was a composite of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. Results A total of 760 patients (43%) had a history of AF (18%) or AF on ECG at enrollment (25%). The highest adjusted risk was associated with AF at enrollment (primary outcome, hazard ratio: 1.34; 95% confidence interval: 1.09 to 1.65; p = 0.006; and an increased early risk of secondary outcomes). Neither history of AF nor AF at enrollment modified the beneficial treatment effect of spironolactone. Post-randomization AF, which occurred in 6.3% of patients, was not influenced by spironolactone treatment, but was associated with an increased early risk of the primary outcome (hazard ratio: 2.32; 95% confidence interval: 1.59 to 3.40; p Conclusions AF at enrollment was associated with increased cardiovascular risk in HFpEF patients in the TOPCAT study. Post-randomization AF, which was associated with an increased risk of morbidity and mortality, was not influenced by spironolactone. (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302).

Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial

Abstract: Background: Myocardial fibrosis is characterized by excessive cross‐linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross‐linking and/or deposition. Methods and results: We investigated 381 HFpEF patients from the multicentre, randomized, placebo‐controlled Aldo‐DHF trial with measures of the E:e' ratio. The ratio of serum carboxy‐terminal telopeptide of collagen type I to serum matrix metalloproteinase‐1 (CITP:MMP‐1, an inverse index of myocardial collagen cross‐linking) and serum carboxy‐terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1‐year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP‐1 and PICP tertiles at baseline. While CITP:MMP‐1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP‐1 levels, this ratio was significantly reduced in the remaining spironolactone‐treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP‐1 levels but was reduced in the remaining spironolactone‐treated patients. Conclusions: A biochemical phenotype of high collagen cross‐linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross‐linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients.

Elevated Potassium Levels in Patients With Congestive Heart Failure: Occurrence, Risk Factors, and Clinical Outcomes: A Danish Population-Based Cohort Study

Abstract: Background Data on the true burden of hyperkalemia in patients with heart failure (HF) in a real‐world setting are limited. Methods and Results Incidence rates of hyperkalemia (first blood test with a potassium level >5.0 mmol/L) in primary or hospital care were assessed in a population‐based cohort of patients with incident HF diagnoses in northern Denmark from 2000 to 2012. Risk factors and clinical outcomes were compared in patients with HF with versus without hyperkalemia. Of 31 649 patients with HF, 39% experienced hyperkalemia (mean follow‐up, 2.2 years). Risks of experiencing a second, third, or fourth event were 43%, 54%, and 60%, respectively. Among patients with HF with stage 3A, 3B, 4, or 5 kidney dysfunction, 26%, 35%, 44%, and 48% experienced hyperkalemia within the first year. Important hyperkalemia risk factors included chronic kidney disease (prevalence ratio, 1.46; 95% confidence interval [CI], 1.43−1.49), diabetes mellitus (prevalence ratio, 1.38; 95% CI, 1.32−1.45), and spironolactone use (prevalence ratio, 1.48; 95% CI, 1.42−1.54). In patients with HF who developed hyperkalemia, 53% had any acute‐care hospitalization 6 months before the hyperkalemia event, increasing to 74% 6 months after hyperkalemia (before‐after risk ratio, 1.41; 95% CI, 1.38−1.44). Compared with matched patients with HF without hyperkalemia, adjusted 6‐month hazard ratios in patients with hyperkalemia were 2.75‐fold (95% CI, 2.65–2.85) higher for acute‐care hospitalization and 3.39‐fold (95% CI, 3.19–3.61) higher for death. Conclusions Almost 4 in 10 patients with HF develop hyperkalemia, and many patients have recurrent hyperkalemia episodes. Hyperkalemia risk is strongly associated with degree of reduced kidney function and use of spironolactone. Hyperkalemia is associated with severe clinical outcomes and death in HF.

Aldosterone and mineralocorticoid receptors in regulation of the cardiovascular system and pathological remodelling of the heart and arteries.

Abstract: In the review we discuss the role of mineralocorticoid receptors (MRs) in regulation and pathological remodelling of the cardiovascular system and the therapeutic potential of pharmacological targeting of MRs in cardiovascular diseases. MRs are expressed in organs involved in cardiovascular homeostasis: brain, heart, kidneys and vessels. The excessive activation of MRs has deleterious effects on the cardiovascular system through sympatho-excitation, elevated salt appetite, and renal retention of salt with consequent positive sodium balance, fibrosis and remodelling of the heart and arteries, and with propensity for atrial and ventricular arrhythmias. Hence, it provides basis for a common pathophysiological milieu of hypertension and heart failure. Furthermore, MR-mediated changes in the cardiovascular system are potentiated by renin-angiotensin system and activation of angiotensin type 1 receptors. Due to low selectivity, MRs bind both aldosterone and GCs - cortisol in humans and corticosterone in laboratory rodents. The binding of GCs to MRs is determined by availability of tissue specific 11β-hydroxysteroid dehydrogenase of type 1 (11β-HSD1) or type 2 (11β-HSD2). 11β-HSD1 metabolizes GCs to either active or inactive metabolites depending on the presence of special cofactors, whereas 11β-HSD2 transforms GCs only into inactive metabolites allowing for selective stimulation of MRs by aldosterone. 11β-HSD2 is expressed in the vascular wall, renal epithelium and some groups of cardiovascular neurons in the brain. In contrast, cardiac expression of 11β-HSD2 is low, thus, both aldosterone and GCs interact with cardiac MRs. The importance of MRs in the cardiovascular pathology is reflected in clinical guidelines that recommend use of MR blockers, spironolactone and eplerenone, in the treatment of heart failure, myocardial infarction and hypertension. Furthermore, new MR blockers and selective inhibitors of 11β-HSD1 have been developed and are currently tested in clinical trials.

Derangements in adrenergic-adipokine signalling establish a neurohormonal basis for obesity-related heart failure with a preserved ejection fraction.

Abstract: Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta2 -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis.

Long-Term Effects of Spironolactone on Kidney Function and Hyperkalemia-Associated Hospitalization in Patients with Chronic Kidney Disease.

Abstract: Background: Spironolactone, a non-selective mineralocorticoid receptor antagonist, can protect against cardiac fibrosis and left ventricular dysfunction, and improve endothelial dysfunction and proteinuria. However, the safety and effects of spironolactone on patient-centered cardiovascular and renal endpoints remain unclear. Methods: We identified predialysis stage 3–4 chronic kidney disease (CKD) patients between 2000 and 2013 from the Longitudinal Health Insurance Database 2005 (LHID 2005). The outcomes of interest were end-stage renal disease (ESRD), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), hyperkalemia-associated hospitalization (HKAH), all-cause mortality and cardiovascular mortality. The Fine and Gray sub-distribution hazards approach was adopted to adjust for the competing risk of death. Results: After the propensity score matching, 693 patients with stage 3–4 CKD were spironolactone users and 1386 were nonusers. During the follow-up period, spironolactone users had a lower incidence rate for ESRD than spironolactone non-users (39.2 vs. 53.69 per 1000 person-years) and a higher incidence rate for HKAH (54.79 vs. 18.57 per 1000 person-years). The adjusted hazard ratios for ESRD of spironolactone users versus non-users were 0.66 (95% CI, 0.51–0.84; p value < 0.001) and 3.17 (95% CI, 2.41–4.17; p value < 0.001) for HKAH. A dose-response relationship was found between spironolactone use and risk of ESRD and HKAH. There were no statistical differences in MACE, HHF, all-cause mortality and cardiovascular mortality between spironolactone users and non-users. Conclusion: Spironolactone represented a promising treatment option to retard CKD progression to ESRD amongst stage 3–4 CKD patients, but strategic treatments to prevent hyperkalemia should be enforced.

Pharmacological treatments for heart failure with preserved ejection fraction-a systematic review and indirect comparison.

Abstract: Pharmacological interventions for heart failure with preserved ejection fraction (HFpEF) have failed to reduce mortality and hospitalization. Evidence for mineralocorticoid antagonists (MRAs), β-adrenoceptor blockers (β-blockers), and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs)-to reduce clinical outcomes in HFpEF remains unclear. We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov for randomized controlled trials (RCTs) assessing pharmacological treatments in HFpEF diagnosed according the recommendations of the European Society of Cardiology (ESC) 2016 guidelines from inception to August, 2017. The study outcomes were mortality, hospitalization, changes in indexes of cardiac structure and function, biomarkers, and indexes of functional capacity-quality of life (QoL) assessment and 6-min walk distance test (6-MWD). The random-effects models were used to estimate pooled relative risks (RRs) for the binary outcomes and standardized mean differences for continuous outcomes, with 95% CI. A network meta-analysis using a random-effects model was employed to estimate the comparative efficacy of treatments. We included data from 15 RCTs comprising 5930 patients. There was no significant effect seen with all treatments compared with placebo and comparative efficacy of any two treatments on all outcomes assessed. However, mineralocorticoid antagonist spironolactone demonstrated a trend towards reducing mortality compared with placebo (RR 0.92; 95% CI 0.79-1.08), sildenafil (0.14; 0.01-2.78), perindopril (0.87; 0.59-1.28), and eplerenone (0.91; 0.25-3.33). Similar trends in treatment effect were observed with spironolactone on surrogate outcomes while eplerenone demonstrated a trend of superior effect in reduction of hospitalizations compared with all other drug treatment. No drug treatment demonstrated statistically significant improvement in clinical and surrogate outcomes in HFpEF diagnosed according to the ESC 2016 guideline. Spironolactone and eplerenone showed clinically relevant reduction in mortality and hospitalization respectively compared with other drug treatments. Further trials with MRAs are warranted to confirm treatment effects in HFpEF.

Perturbations in serum chloride homeostasis in heart failure with preserved ejection fraction: insights from TOPCAT.

Abstract: AIMS Prior cohorts demonstrating the importance of serum chloride levels in heart failure either excluded or had partial representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between serum chloride concentration and outcomes in HFpEF. METHODS AND RESULTS We included participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) who met the following criteria: met inclusion by the natriuretic peptide stratum, had recorded serum chloride levels, and were from the Americas (n = 942). Multivariable Cox proportional hazards models tested the association of serum chloride with clinical outcomes, and mixed effects modelling tested the association of spironolactone or loop diuretic on serial serum chloride levels. The median serum chloride level was 102 [25th-75th percentile 100-105 mmol/L (range 84-114 mmol/L)]. After multivariable adjustment, every standard deviation decrease in serum chloride (4.05 mmol/L) was associated with ∼50% increased risk for cardiovascular death [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.11-2.06, P = 0.008] and ∼30% increased risk for all-cause death (HR 1.29, 95% CI 1.02-1.62, P = 0.04), but not with the primary composite endpoint or heart failure hospitalization (P > 0.3 for both). There were no significant interactions between spironolactone use and the serum chloride-risk relationship (P > 0.1) for each endpoint. Spironolactone was not (P = 0.33) but loop diuretic use was associated with lower serial serum chloride levels (P < 0.001). CONCLUSION Lower serum chloride was independently associated with increased risk of cardiovascular and all-cause death in HFpEF. Loop diuretic use, but not spironolactone, lead to a decrease in serum chloride levels over time.

Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction.

Abstract: Background: Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction. M...

Racial Differences in Characteristics and Outcomes of Patients With Heart Failure and Preserved Ejection Fraction in the Treatment of Preserved Cardiac Function Heart Failure Trial.

Abstract: Background:Black patients have been shown to have different baseline characteristics and outcomes compared with nonblack patients in cohort studies. However, few studies have focused on heart failu...

Association between hypo- and hyperkalemia and outcome in acute heart failure patients: the role of medications

Abstract: The interaction between chronic medications on admission and the association between serum potassium level and outcome in patients with acute heart failure (AHF) are unknown. Observational intercontinental study of patients admitted with AHF. 15954 patients were included from 12 cohorts in 4 continents. Main outcome was 90-day mortality. Clinical presentation (medication use, hemodynamics, comorbidities), demographic, echocardiographic, and biochemical data on admission were recorded prospectively in each cohort, with prospective adjudication of outcomes. Positive and negative linear relationships between 90-day mortality and sK+ above 4.5 mmol/L (hyperkalemia) and below 3.5 mmol/L (hypo-kalemia) were observed. Hazard ratio for death was 1.46 [1.34–1.58] for hyperkalemia and 1.22 [1.06–1.40] for hypokalemia. In a fully adjusted model, only hyperkalemia remained associated with mortality (HR 1.03 [1.02–1.04] for each 0.1 mmol/l change of sK+ above 4.5 mmol/L). Interaction tests revealed that the association between hyperkalemia and outcome was significantly affected by chronic medications. The association between hyperkalemia and mortality was absent for patients treated with beta blockers and in those with preserved renal function. In patients with AHF, sK+ > 4.5 mmol/L appears to be associated with 90-day mortality. B-blockers have potentially a protective effect in the setting of hyperkalemia.

Adrenal Vein Sampling Is the Preferred Method to Select Patients With Primary Aldosteronism for Adrenalectomy: Con Side of the Argument.

Abstract: Primary aldosteronism (PA) is a secondary form of hypertension caused by autonomous secretion of the sodium-retaining hormone aldosterone by one or both adrenal glands, leading to hypertension and in a subset of patients to hypokalemia.1 PA can be cured by adrenalectomy in patients who have a unilateral aldosterone-producing adrenocortical adenoma (APA), present in about half of patients. Cure has 2 aspects in this disease: most, but not all, patients are cured biochemically, that is, have normalization of aldosterone secretion, whereas only a minority will be cured from hypertension.2 The majority of patients who remain hypertensive after adrenalectomy will reach lower blood pressure levels with less medication. They will rarely need mineralocorticoid receptor antagonists like spironolactone. These mineralocorticoid receptor antagonists are indicated for the other half of patients with PA, who are thought to have bilateral adrenocortical hyperplasia. Although blood pressure and hypokalemia can be controlled in almost all patients by adrenalectomy or mineralocorticoid receptor antagonists, quality of life improves most after adrenalectomy.3 Hence, proper selection of patients for adrenalectomy is of critical importance to achieve an optimal outcome for patients. The Endocrine Society Clinical Practice guideline (guideline)1 recommends adrenal vein sampling (AVS) as the preferred method to select patients with PA for adrenalectomy. In AVS, adrenal veins are cannulated and from each a blood sample is drawn that is used to determine cortisol and aldosterone. Measurement of cortisol is critical to assess selectivity of cannulation of an adrenal vein and to correct for admixture of nonadrenal blood. The widely available and most frequently used alternative to AVS, the adrenal computed tomographic (CT) scan, is considered by the guideline to be inferior to identify APA. Indeed, the results of CT scanning and AVS differ in their conclusion on the presence of APA in almost 40% of cases …

Amiloride resolves resistant edema and hypertension in a patient with nephrotic syndrome; a case report.

Abstract: Sodium and fluid retention is a hallmark and a therapeutic challenge of the nephrotic syndrome (NS). Studies support the "overfill" theory of NS with pathophysiological proteolytic activation of the epithelial sodium channel (ENaC) which explains the common observation of suppressed renin -angiotensin system and poor therapeutic response to ACE inhibitors. Blockade of ENaC by the diuretic amiloride would be a rational intervention compared to the traditionally used loop diuretics. We describe a 38-year-old male patient with type1 diabetes who developed severe hypertension (200/140 mmHg), progressive edema (of at least 10 L), and overt proteinuria (18.5 g/24 h), despite combined administration of five antihypertensive drugs. Addition of amiloride (5 mg/day) to treatment resulted in resolution of edema, weight loss of 7 kg, reduction in blood pressure (150/100-125/81 mmHg), increased 24 h urinary sodium excretion (127-165 mmol/day), decreased eGFR (41-29 mL/min), and increased plasma potassium concentration (4.6-7.8 mmol/L). Blocking of ENaC mobilizes nephrotic edema and lowers blood pressure in NS. However, acute kidney injury and dangerous hyperkalemia is a potential risk if amiloride is added to multiple other antihypertensive medications as ACEi and spironolactone. The findings support that ENaC is active in NS and is a relevant target in adult NS patients.

Mineralocorticoid hypertension and hypokalaemia induced by posaconazole

Abstract: We describe severe hypokalaemia and hypertension due to a mineralocorticoid effect in a patient with myelodysplastic syndrome taking posaconazole as antifungal prophylaxis. Two distinct mechanisms due to posaconazole are identified: inhibition of 11β hydroxylase leading to the accumulation of the mineralocorticoid hormone 11-deoxycorticosterone (DOC) and secondly, inhibition of 11β hydroxysteroid dehydrogenase type 2 (11βHSD2), as demonstrated by an elevated serum cortisol-to-cortisone ratio. The effects were ameliorated by spironolactone. We also suggest that posaconazole may cause cortisol insufficiency. Patients taking posaconazole should therefore be monitored for hypokalaemia, hypertension and symptoms of hypocortisolaemia, at the onset of treatment and on a monthly basis. Treatment with mineralocorticoid antagonists (spironolactone or eplerenone), supplementation of glucocorticoids (e.g. hydrocortisone) or dose reduction or cessation of posaconazole should all be considered as management strategies. Learning points Combined hypertension and hypokalaemia are suggestive of mineralocorticoid excess; further investigation is appropriate.If serum aldosterone is suppressed, then further investigation to assess for an alternative mineralocorticoid is appropriate, potentially using urine steroid profiling and/or serum steroid panelling.Posaconazole can cause both hypokalaemia and hypertension, and we propose that this is due to two mechanisms - both 11β hydroxylase inhibition and 11β HSD2 inhibition.Posaconazole treatment may lead to cortisol insufficiency, which may require treatment; however, in this clinical case, the effect was mild.First-line treatment of this presentation would likely be use of a mineralocorticoid antagonist.Patients taking posaconazole should be monitored for hypertension and hypokalaemia on initiation and monthly thereafter.

Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study.

Abstract: Background While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies -evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. Methods Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of -135-160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker -(unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m2. Screening serum potassium must be 4.3-5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. Results Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m2. Conclusion AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.

Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study

Abstract: Background While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies -evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. Methods Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of -135-160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker -(unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m2. Screening serum potassium must be 4.3-5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. Results Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m2. Conclusion AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.

Clinical findings and survival time in dogs with advanced heart failure.

Abstract: Background Dogs with advanced heart failure are a clinical challenge for veterinarians but there are no studies reporting clinical features and outcome of this population. Hypothesis/objectives To describe clinical findings and outcome of dogs with advanced heart failure caused by degenerative mitral valve disease (DMVD). Animals Fifty-four dogs with advanced heart failure because of DMVD. Methods For study purposes, advanced heart failure was defined as recurrence of congestive heart failure signs despite receiving the initially prescribed dose of pimobendan, angiotensin-converting-enzyme inhibitor (ACEI), and furosemide >4 mg/kg/day. Data were collected for the time of diagnosis of Stage C heart failure and time of diagnosis of advanced heart failure. Date of death was recorded. Results At the diagnosis of advanced heart failure, doses of pimobendan (n = 30), furosemide (n = 28), ACEI (n = 13), and spironolactone (n = 4) were increased, with ≥1 new medications added in most dogs. After initial diagnosis of advanced heart failure, 38 (70%) dogs had additional medications adjustments (median = 2 [range, 0-27]), with the final total medication number ranging from 2-10 (median = 5). Median survival time after diagnosis of advanced heart failure was 281 days (range, 3-885 days). Dogs receiving a furosemide dose >6.70 mg/kg/day had significantly longer median survival times (402 days [range, 3-885 days] versus 129 days [range 9-853 days]; P = .017). Conclusions and clinical importance Dogs with advanced heart failure can have relatively long survival times. Higher furosemide dose and non-hospitalization were associated with longer survival.

Low Dose Spironolactone Monotherapy in the Management of Stage I Essential Hypertension: A Pilot Randomized, Double-Blind, Placebo-Controlled Trial.

Abstract: Background High blood pressure (BP) is a common chronic disease needs long life drug consumption to control. Spironolactone could be used as the fourth-line therapy in patients with resistant hypertension. However, there is no study to determine the effects of low dose spironolactone as a first line therapy in treatment of essential hypertension. The aim of this study is to investigate the effect of low dose spironolactone monotherapy in management of essential hypertension. Methods In this double blind randomized clinical trial, 40 patients who had stage I essential hypertension were randomly divided into two groups: intervention group received spironolactone 25 milligram once daily for one month and control group received placebo once daily. At the baseline and after one month, 24-hour BP holter-monitoring and serum potassium assay were done. Results Systolic BP was reduced from 143.5 ± 8.2 mmHg to 137.10 ± 7.57 mmHg in the intervention group, while it did not change significantly in control (between group treatment difference = -4.5 mmHg, p = 0.004). There was no significant reduction of diastolic BP in the intervention group in comparison to placebo group (between group treatment difference = -1.3 mmHg, p = 0.099). Conclusions Short course monotherapy with low dose spironolactone is effective in reducing systolic BP in patients with stage I essential hypertension.

Controlling resistant hypertension

Abstract: Resistant hypertension (failure to achieve target blood pressures with three or more antihypertensive drugs including a diuretic) is an important and preventable cause of stroke. Hypertension is highly prevalent in China (>60% of persons above age 65), and only ~6% of hypertensives in China are controlled to target levels. Most strokes occur among persons with resistant hypertension; approximately half of strokes could be prevented by blood pressure control. Reasons for uncontrolled hypertension include (1) non-compliance; (2) consumption of substances that aggravated hypertension, such as excess salt, alcohol, licorice, decongestants and oral contraceptives; (3) therapeutic inertia (failure to intensify therapy when target blood pressures are not achieved); and (4) diagnostic inertia (failure to investigate the cause of resistant hypertension). In China, an additional factor is lack of availability of appropriate antihypertensive therapy in many healthcare settings. Sodium restriction in combination with a diet similar to the Cretan Mediterranean or the DASH (Dietary Approaches to Stop Hypertension) diet can lower blood pressure in proportion to the severity of hypertension. Physiologically individualised therapy for hypertension based on phenotyping by plasma renin activity and aldosterone can markedly improve blood pressure control. Renal hypertension (high renin/high aldosterone) is best treated with angiotensin receptor antagonists; primary aldosteronism (low renin/high aldosterone) is best treated with aldosterone antagonists (spironolactone or eplerenone); and hypertension due to overactivity of the renal epithelial sodium channel (low renin/low aldosterone; Liddle phenotype) is best treated with amiloride. The latter is far more common than most physicians suppose.