Incidence of Primary Aldosteronism in Patients with Hypokalemia (IPAHK+): Study Design and Baseline Characteristics.

Hypokalemia plays a central role for case finding, course, treatment decision, and prognosis of patients with primary aldosteronism. However, to date there is a lack of high-level evidence about the incidence of primary aldosteronism in hypokalemic patients. The IPAHK+study is an epidemiological, cross-sectional, monocentric study to provide evidence on the incidence of PA in a hypokalemic population. The aim of the current analysis was to describe the baseline characteristics of the first 100 patients eligible for study inclusion. The recruitment of patients with hypokalemia (≤3 mmol/l) is carried out continuously on a referral-basis by the central laboratory of the University Hospital Zurich through an automated suitability testing and data delivery system. The careful evaluation of the first 100 reported patients was based on the available reporting system. Out of 28 140 screened patients, 222 (0.79%) were identified with a serum potassium value of≤3 mmol/l (mean 2.89±0.02 mmol/l). Mean potassium levels were slightly lower in non-hypertensive subjects compared to hypertensive subjects (mean difference 0.07 mmol/l, p=0.033), while no significant difference was found between the sexes and patients with and without the diagnosis of primary aldosteronism, atrial fibrillation, or the use of diuretics. The incidence of PA was 4% in the total population studied and 7.5% in the subgroup of hypertensive patients. In conclusion, the continuous enrollment of patients from the IPHAK+hypokalemia registry into the IPAHK+trial will provide evidence about the actual incidence of primary aldosteronism in a hypokalemic outpatient population.

Long-term mortality and cardiovascular events in patients with unilateral primary aldosteronism after targeted treatments.

OBJECTIVE: Long-term outcomes (especially mortality and/or major cardiovascular events (MACE)) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery-targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported. DESIGN AND SETTINGS: Using the prospectively designed observational Taiwan Primary Aldosteronism Investigation cohort, we identified 858 uPA cases among 1220 primary aldosteronism patients and another 1210 EH controls. EXPOSURES: Operated uPA patients were grouped via their 1-year post-therapy statuses. RESULTS: Primary Aldosteronism Surgical Outcome clinical complete success (hypertension remission) was achieved in 272 (49.9%) of 545 surgically treated uPA patients. After follow-up for 6.3 ± 4.0 years, both hypertension-remissive (hazard ratio (HR): 0.54; P < 0.001) and not-cured (HR: 0.61; P < 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41; P = 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR: 1.38; P = 0.033), Af (sHR:1.62, P = 0.049), and CHF (sHR: 1.44; P = 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR: 0.57; P = 0.035), MACE (HR: 0.67; P = 0.037), and CHF (HR: 0.49; P = 0.005) compared to those of MRA therapy. CONCLUSIONS: Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.

Cardiovascular events and all-cause mortality in surgically or medically treated primary aldosteronism: A Meta-analysis.

OBJECTIVES: To compare the effect of surgical or medical treatment on the risk of cardiovascular diseases (CVD) and all-cause mortality in patients with established primary aldosteronism (PA). METHODS: We searched PUBMED, MEDLINE and Cochrane Library for the meta-analysis. We included patients who were diagnosed with PA following guideline-supported protocols and received surgery or mineralocorticoid receptor antagonist (MRA)-based medical treatment, and age-sex matched patients with treated essential hypertension (EH). Primary endpoints were CVD incidence and all-cause mortality. RESULTS: Compared with EH, patients with treated PA had a higher risk of CVD [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.39-2.31]. This elevated risk was only observed in patients with medically treated PA [OR 2.11; 95%CI 1.88-2.38] but not in those with surgically treated PA. The risk of all-cause mortality was significantly lower in patients with treated PA [OR 0.86; 95% CI 0.77-0.95] compared to EH. The reduced risk was only observed in patients with surgically treated PA [OR 0.47; 95% CI 0.34-0.66], but not in those with medically treated PA. CONCLUSIONS: Patients with medically treated PA have a higher risk of CVD compared to patients with EH. Surgical treatment of PA reduces the risk of CVD and all-cause mortality in patients with PA.

Long-Term Mortality for Patients of Primary Aldosteronism Compared With Essential Hypertension: A Systematic Review and Meta-Analysis.

Background: Consistent evidence have demonstrated that patients with primary aldosteronism (PA) have higher risk of cardiovascular events to patients with essential hypertension (EH). Whether the long-term risk of mortality for PA patients is higher than EH patients is unclear. We aim to compare the long-term mortality of patients with PA to patients with EH. Methods: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for eligible studies from inception to 14 Nov 2018. We combined the relative risks (RR) of each included study by random-effect model. The amount of between study heterogeneity was measured by the I2 statistic. Results: We totally included six studies with cohort design, including 3,039 PA and 45,495 EH patients. The pooled RRs for patients with PA were 1.97 (95%CI: 1.33, 2.91; P = 0.0007) for a follow-up of 3 years, 0.96 (95%CI: 0.75, 1.23; P = 0.76) for 5 years, 0.86 (95%CI: 0.51, 1.46) for 7.5 years, and 0.95 (95%CI: 0.61, 1.48; P = 0.58) for 10 years. For patients with aldosterone-producing adenomas (APA), evidence of lower risk of long-term mortality was observed. Our sensitivity analysis suggested our results were stable. Conclusions: Current evidence supported a higher risk of mortality for patients with primary aldosteronism at 3 years compared to patients with essential hypertension, however this risk no longer sustains as the follow-up time increased to 5 or more years. Patients with aldosterone-producing adenomas may have lower long-term mortality rate than patients with essential hypertension due to the better recovery of adrenalectomy.

Influence of Different Treatment Strategies on New-Onset Atrial Fibrillation Among Patients With Primary Aldosteronism: A Nationwide Longitudinal Cohort-Based Study.

Background Primary aldosteronism (PA) is associated with higher atrial fibrillation prevalence and other cardiovascular complications. However, the effect of target treatment to prevent new-onset atrial fibrillation (NOAF) remains unclear. This study investigated incidence of NOAF under different treatment strategies in patients with PA. Methods and Results We analyzed longitudinal data for patients with PA without atrial fibrillation history from 1997 to 2009 within the National Health Insurance Research Database in Taiwan. Patients with essential hypertension matched by propensity score were enrolled as controls. The primary outcome measurement was NOAF, and secondary outcome measurements were mortality, major cardiac and cardiac/cerebrovascular events, and a combined end point of NOAF and mortality. We identified 2202 patients with PA (534 adrenalectomy, 1668 mineralocorticoid receptor antagonist [MRA] therapy) and 8808 essential hypertension controls with mean follow-up of 4.4 years. In primary outcome measurement, patients with PA who underwent adrenalectomy had a lower incidence of NOAF (adjusted hazard ratio; 0.28, P=0.011) than controls. In contrast, the patients with PA who received MRA therapy had comparable risk of NOAF (adjusted hazard ratio, 1.20; P=0.224). In secondary outcome measurement, patients with PA who underwent adrenalectomy had a lower rate of mortality and combined end point of NOAF and mortality than controls. Patients with PA who received MRA therapy had a higher risk of mortality, major cardiac and cardiac/cerebrovascular events, and combined NOAF with mortality than the essential hypertension controls. Conclusions Compared with patients with essential hypertension, patients with PA who underwent adrenalectomy had a lower incidence of NOAF. However, this finding was not observed in patients with PA who received MRA therapy with a lower dose. Differences between the 2 strategies may reduce with a higher dose of MRA therapy.

Surgery decreases the long-term incident stroke risk in patients with primary aldosteronism.

BACKGROUND: Hypertension with hyperaldosteronism could be associated with stroke attributable to endothelial injury. Whether the detrimental effect of aldosterone on stroke among primary aldosteronism patients could be mitigated by administration of mineralocorticoid receptor antagonist or by reduction of aldosterone level via adrenalectomy is still inconclusive. METHODS: Primary aldosteronism and essential hypertensive patients were enrolled in the Taiwan National Health Insurance from 1997 to 2009. We used a validated algorithm to enroll primary aldosteronism patients. We conducted a competing risk analysis, using a time-varying Cox proportional hazard model. RESULTS: We enrolled 3,167 primary aldosteronism patients with a subgroup of 1,047 aldosterone-producing adenoma patients, and matched these with essential hypertensive controls in a 1:4 ratio. The risk of incident stroke, both ischemic and hemorrhagic, was statistically higher in primary aldosteronism patients than in their essential hypertensive control. The differences in stroke incidences between primary aldosteronism and essential hypertensive patients significantly increased as the hypertensive period lengthened. Primary aldosteronism patients who received mineralocorticoid receptor antagonist treatment had higher risk of all stroke (competing hazard ratio = 1.83, P < .001) compared with their essential hypertensive controls. In light of this, aldosterone-producing adenoma patients had a lower risk of incident stroke after adrenalectomy (competing for hazard ratio = 0.75), but a higher cumulative risk of incident stroke after mineralocorticoid receptor antagonist only (competing for hazard ratio = 1.76) than their matched essential hypertensive patients. CONCLUSION: We observed an increased stroke risk among primary aldosteronism patients than among their matched essential hypertensive controls. A prolonged duration of hypertension was proportionate to the raised risk of stroke. Our findings emphasize the importance of aldosterone-producing adenoma benefitting from adrenalectomy in attenuating the cerebrovascular event.

Risk of Fracture in Primary Aldosteronism: A Population-Based Cohort Study.

Primary aldosteronism (PA) is associated with increased urinary calcium excretion and osteoporosis prevalence. We studied the long-term effect of hyperaldosterone on fracture risk and possible risk mitigation via treatments, by comparing PA patients and their essential hypertension (EH) counterparts extracted by propensity score match. We used a longitudinal population database from the Taiwan National Health Insurance, and used a validated algorithm to identify PA patients diagnosed in 1997-2010. Our sample included 2533 PA patients, including 921 patients with aldosterone-producing adenoma (APA). Our methods for assessing excessive fracture risk included multivariable Cox regression and the competing risk regression. The incidence rate of fracture at any site was 14.4 per 1000 person-years for PA, and 11.2 per 1000 person-years for APA. In contrast, the incidence rate of fracture at any site was 8.3 per 1000 person-years in EH controls for PA, and 6.5 per 1000 person-years in EH controls for APA. Mineralocorticoid receptor antagonist (MRA) treatment might be associated with higher risk of osteoporotic fracture in the whole female PA cohort (subdistribution hazard ratio [SHR] = 2.12, p = 0.008) as well as female APA patients (SHR = 1.15, p = 0.049). As to fracture at any site, MRA treatment was also associated with higher risk; the SHR was 1.88 (p < 0.001) in the whole female PA cohort, and 2.17 (p = 0.019) in female APA patients. PA is tightly associated with higher risk of bone fracture, even in the case where the competing risk of death was controlled. Particularly, female PA patients treated with MRA were confronted with significantly higher risk in bone fracture than their EH controls. © 2017 American Society for Bone and Mineral Research.

Long term outcome of Aldosteronism after target treatments.

There exists a great knowledge gap in terms of long-term effects of various surgical and pharmacological treatments on outcomes among primary aldosteronism (PA) patients. Using a validated algorithm, we extracted longitudinal data for all PA patients diagnosed in 1997-2010 and treated in the Taiwan National Health Insurance. We identified 3362 PA patients for whom the mean length of follow-up was 5.75 years. PA has higher major cardiovascular events (MACE) than essential hypertension (23.3% vs 19.3%, p = 0.015). Results from the Cox model suggest a strong effect of adrenalectomy on lowering mortality (HR = 0.23 with residual hypertension and 0.21 with resolved hypertension). While the need for mineralocorticoid receptor antagonist (MRA) after diagnosis suggests that a defined daily dose (DDD) of MRA between 12.5 and 50 mg may alleviate risk of death in a U-shape pattern. A specificity test identified patients who has aldosterone producing adenoma (HR = 0.50, p = 0.005) also confirmed adrenalectomy attenuated all-cause mortality. Adrenalectomy decreases long-term all-cause mortality independently from PA cure from hypertension. Prescription corresponding to a DDD between 12.5 and 50 mg may decrease mortality for patients needing MRA. It calls for more attention on early diagnosis, early treatment and prescription of appropriate dosage of MRA for PA patients.

SFE/SFHTA/AFCE consensus on primary aldosteronism, part 1: Epidemiology of PA, who should be screened for sporadic PA?

Depending on the study, the prevalence of primary aldosteronism (PA) in patients with hypertension varies from 6 to 18%. Prevalence is higher in each of the following conditions, any one of which requires screening for PA: severe hypertension (systolic blood pressure [BP]≥180mmHg and/or diastolic BP≥110mmHg); resistant hypertension (systolic BP≥140mmHg and/or diastolic BP≥90mmHg despite adherence to a tritherapy including a thiazide diuretic); hypertension associated with hypokalemia (either spontaneous or associated with a diuretic); Hypertension or hypokalemia associated with adrenal incidentaloma. It should be borne in mind that PA can induce hypertension without hypokalemia or, less frequently, hypokalemia without hypertension. Finally, as cardiovascular and renal morbidity in PA is greater than in essential hypertension of equivalent level, screening for PA is indicated when cardiovascular or renal morbidity is more severe than predicted from BP level.

Observational study mortality in treated primary aldosteronism: the German Conn's registry.

In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04-12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P<0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls.

Outcomes of adrenalectomy in patients with unilateral primary aldosteronism: a review.

Aldosterone hypersecretion in primary aldosteronism is unilateral (aldosterone producing adenoma and primary unilateral hyperplasia) or bilateral (idiopathic adrenal hyperplasia). Laparoscopic adrenalectomy is nowadays the preferred approach to treat patients with unilateral primary aldosteronism. We review the outcomes of this intervention in recently published series. Laparoscopic adrenalectomy has a morbidity of 5-14%, mortality below 1%, and a mean hospital stay around 3 days. It generally results in the normalization of aldosterone secretion and in a large decrease of blood pressure and antihypertensive medication, but normotension without treatment is only achieved in 42% of all cases. Normotension following adrenalectomy is more likely in young and lean women with recent low grade hypertension than in obese men with long-standing high grade hypertension or a family history of hypertension. However, individual prediction of the blood pressure outcome is not accurate and predictors of hypertension cure should not be used to select patients for surgery. Age, associated health conditions and preferences of the patient are more relevant to this end.

Laparoscopic approach to adrenalectomy: review of perioperative outcomes in a single center.

Laparoscopic expertise increases the volume of adrenalectomies at referral centers. We report our 10-year experience with laparoscopic adrenalectomy. All laparoscopic adrenalectomies at a single institution were prospectively recorded in a surgical outcomes database. Patient demographics, operative/perioperative outcomes, and adrenal pathology were reviewed retrospectively. From March 1999 through July 2009, 154 laparoscopic adrenalectomies were performed in 150 patients. Average patient age was 49.9 years (range 15-82); mean body mass index was 31.1 kg/m(2) (range 17-56). Pathologic diagnoses included hyperaldosteronism (n = 69), nonfunctional adenoma (n = 28), pheochromocytoma (n = 23), hypercortisolism (n = 14), malignancy (primary n = 3, metastasis n = 9), and cyst (n = 4). Seventy-three per cent (n = 110) occurred on the left, 23 per cent (n = 35) on the right, 2.6 per cent (n = 4) bilateral, and 0.6 per cent (n = 1) as extra-adrenal. The average tumor measured 3.6 cm (range 0.4-12). The average operative time was 156 minutes (range 62-409), the mean estimated blood loss was 60 mL (range 10-400), and mean American Society of Anesthesiologists score was 2.6 (range 1-4). Three operations (0.2%) were converted to open. Three patients (0.2%) experienced perioperative complications (respiratory failure, urinary tract infection, line sepsis, and readmission within 30 days). The average length of stay was 3.4 days (range 1-44) and mean follow-up was 96.9 days (5-2567). No wound-related complications or deaths occurred. Pathologic diagnosis was not associated with a particular side or development of a complication (P > 0.5). Patients with pheochromocytomas had the longest operative times, highest estimated blood loss, and highest American Society of Anesthesiologists scores (218.2 minutes, 128 mL, 3.0; P < 0.004). Laparoscopic adrenalectomy is safe and effective. Removal of pheochromocytomas is more challenging and may be more appropriate for referral to a specialized center for optimal outcomes.

Glucocorticoid remediable aldosteronism: low morbidity and mortality in a four-generation italian pedigree.

Glucocorticoid remediable hyperaldosteronism (GRA) is a monogenic form of inherited hypertension caused by a chimeric gene originating from an unequal cross-over between the 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. GRA is characterized by high plasma levels of aldosterone (regulated by ACTH) with suppressed plasma renin activity and the production of two rare steroids, 18hydroxycortisol and 18oxocortisol. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Affected women have a high risk of developing preeclampsia during pregnancy. Here, we describe a 5-generation pedigree from Sardinia in which the presence of the chimeric gene is demonstrated in 4 generations. This family displays a mild phenotype with average blood pressure levels of 131/86 mm Hg for GRA+ patients. The occurrence of stroke is very low, and preeclampsia was not observed in 29 pregnancies from 8 GRA+ mothers. We investigated whether the cross-over site (between the CYP11B1 and CYP11B2 genes) or biochemical characteristics could explain this phenotype. The cross-over site was located at the end of intron 3, in the same region as described in other families. We found a significant correlation between blood pressure and 18hydroxycortisol, 18oxocortisol, and plasma aldosterone levels, but not with kallikrein. However, none of the biochemical or genetic parameters investigated could explain the mild phenotype of the family.