Intensification of pharmacological decongestion but not the actual daily loop diuretic dose predicts worse chronic heart failure outcome: insights from TIME-CHF.

BACKGROUND: Both loop diuretics (LDs) and congestion have been related to worse heart failure (HF) outcome. The relationship between the cause and effect is unknown. The aim of this study was to investigate the interaction between congestion, diuretic use and HF outcome. METHODS: Six hundred and twenty-two chronic HF patients from TIME-CHF were studied. Congestion was measured by means of a clinical congestion index (CCI). Loop diuretic dose was considered at baseline and month 6. Treatment intensification was defined as the increase in LD dose over 6 months or loop diuretic and thiazide or thiazide-like diuretic co-administration. The end-points were survival and HF hospitalisation-free survival. RESULTS: High-LD dose at baseline and month 6 (≥ 80 mg of furosemide per day) was not identified as an independent predictor of outcome. CCI at baseline remained independently associated with impaired survival [hazard ratio (HR) 1.34, (95% confidence interval) (95% CI) (1.20-1.50), p < 0.001] and HF hospitalisation-free survival [HR 1.09, 95% CI (1.02-1.17), p = 0.015]. CCI at month 6 was independently associated with HF hospitalisation-free survival [HR 1.24, 95% CI (1.11-1.38), p < 0.001]. Treatment intensification was independently associated with survival [HR 1.75, 95% CI (1.19-1.38), p = 0.004] and HF hospitalisation-free survival [HR 1.69, 95% CI (1.22-2.35), p = 0.002]. Patients undergoing treatment intensification resulting in decongestion had better outcome than patients with persistent (worsening) congestion despite LD dose up-titration (p < 0.001). CONCLUSION: Intensification of pharmacological decongestion but not the actual LD dose was related to poor outcome in chronic HF. If treatment intensification translated into clinical decongestion, outcome was better than in case of persistent or worsening congestion.

Safety implications of combining ACE inhibitors with thiazides for the treatment of hypertensive patients.

INTRODUCTION: ACE-inhibitors (ACEI) and diuretics are the typical first-line antihypertensive drugs with complementary mechanisms of action. The present paper is summarizing the evidence supporting the efficacy of their combination in a broad range of hypertensive patients. AREAS COVERED: This source of data is different trials investigating the use of ACEI and diuretics in different populations of patients. The available evidence supports some advantage for thiazide-type compounds (chlortalidone-CHT and indapamide-IND) in the prevention of major CV complications. In terms of safety, hydrochlorothiazide (HCTZ) and indapamide are associated with a lesser rate of hypokalemia and abnormalities of metabolic profile (glucose control, uric acid levels, serum potassium levels). As far as the results of clinical trials, the most relevant studies are involving the combination of benazepril or perindopril with HCTZ (benazepril) or IND (Perindopril) respectively. All these studies have resulted in a favorable clinical outcome. In terms of safety profile, the combination of ACEi and diuretic is safe and comparable with that of ACEi and calcium channel blockers with no differences in the rate of major adverse events (cough or angioedema) and a lower rate of ankle edema. EXPERT OPINION: The combination of ACEi and diuretic is safe and well-tolerated and should be considered among the first-line treatments in most of the patients with hypertension.

Development of a hyponatremia screening tool (ABCDF-S score) for patients with hypertension using thiazide diuretic agents.

WHAT IS KNOWN AND OBJECTIVE: Hyponatremia is a common side effect of thiazide diuretics that can lead to increased mortality and hospitalization. A rapid and accurate screening tool is needed for rapid and appropriate management. In this study, we report on the development of a simple clinical screening tool for hyponatremia using thiazide diuretics. METHODS: This nested case-control study was performed by collecting data from 1 January 2015 to 30 June 2017. Univariable and multivariable logistic regressions were used to identify potential risk factors. The regression coefficients were converted into item scores by dividing each regression coefficient with the minimum coefficient in the model and rounding to the nearest integer. This value was then summed to the total score. The prediction power of the model was determined by the area under the receiver operating characteristic curve (AuROC). RESULTS AND DISCUSSION: Six clinical risk factors, namely age ≥65 years, benzodiazepine use, history of a cerebrovascular accident, dose of hydrochlorothiazide ≥25 mg, female sex and statin use, were included in our ABCDF-S score. The model showed good power of prediction (AuROC 81.53%, 95% confidence interval [CI]: 78%-84%) and good calibration (Hosmer-Lemeshow X2  = 23.20; P = .39). The positive likelihood ratios of hyponatremia in patients with low risk (score ≤ 6) and high risk (score ≥ 8) were 0.26 (95% CI: 0.21-0.32) and 3.89 (95% CI: 3.11-4.86), respectively. WHAT IS NEW AND CONCLUSION: The screening tool with six risk predictors provided a useful prediction index for thiazide-associated hyponatremia. However, further validation of the tool is warranted prior to its utilization in routine clinical practice.

Hipoparatiroidismo postquirúrgico: un trastorno de interés creciente entre los endocrinólogos / Post-surgical hypoparathyroidism: a condition of growing interest among endocrinologists

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Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer's disease-nested case-control study.

We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer's disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer's disease. INTRODUCTION: To investigate the association between thiazide use and the risk of low-energy fractures (LEF), and hip fracture among community dwellers with Alzheimer's disease (AD). No prior study has evaluated the effect of thiazides on LEF risk of AD patients. METHODS: LEF cases were identified from the MEDALZ study, including all community-dwelling persons diagnosed with AD in Finland 2005-2011. During the follow-up from AD diagnoses until the end of 2015, cases with LEF (N = 10,416) and hip fracture (N = 5578) were identified. LEF cases were matched with up to three controls without LEF, according to time since AD diagnosis, age and gender. Thiazide use identified from the Prescription register data was modeled with PRE2DUP method. Current use was defined in 0-30 days' time window before the fracture/matching date, and duration of current use was assessed. The association between thiazide exposure and LEFs was assessed with conditional logistic regression. RESULTS: Current thiazide use was observed in 10.5% of LEF cases and 12.5% of controls. Current thiazide use was associated with a decreased risk of LEF (adjusted OR [aOR] 0.83, 95% CI 0.77-0.88). In terms of the duration of use, no association was observed with short-term use (< 1 year or 1-3 years), while longer use (> 3 years) was associated with a reduced risk of LEF (aOR 0.77, 95% CI 0.71-0.83) and hip fracture (aOR 0.68, 95% CI 0.60-0.78). CONCLUSIONS: Our study extends the previous knowledge of reduced fracture risk of thiazides to persons with AD, a population with significantly increased background risk of fractures.

Respuesta de los autores: Empleo de diuréticos y empagliflozina: ¿contraindicados? / Diuretics and empagliflozin use: authors' reply

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Association of urinary citrate excretion, pH, and net gastrointestinal alkali absorption with diet, diuretic use, and blood glucose concentration.

Urinary citrate (Ucit) protects against urinary stone formation. Acid base status and diet influence Ucit. However, the effect of demographics, diet, and glucose metabolism on Ucit excretion, urinary pH (U-pH) and net gastrointestinal alkali absorption (NAA) are not known. Twenty-four hour urine samples, blood glucose, creatinine, and cystatin C were obtained from non-Hispanic white sibships in Rochester, MN (n = 446; 64.5 ± 9 years; 58% female). Diet was assessed by a food frequency questionnaire. The impact of blood glucose, demographics and dietary elements on Ucit excretion, U-pH, and NAA were evaluated in bivariate and multivariable models and interaction models that included age, sex, and weight. NAA significantly associated with Ucit and U-pH In multivariate models Ucit increased with age, weight, eGFRCys, and blood glucose, but decreased with loop diuretic and thiazide use. U-pH decreased with serum creatinine, blood glucose, and dietary protein but increased with dietary potassium. NAA was higher in males and increased with age, weight, eGFRCys and dietary potassium. Significant interactions were observed for Ucit excretion with age and blood glucose, weight and eGFRCys, and sex and thiazide use. Blood glucose had a significant and independent effect on U-pH and also Ucit. This study provides the first evidence that blood glucose could influence urinary stone risk independent of urinary pH, potentially providing new insight into the association of obesity and urinary stone disease.

Melanoma and Non-Melanoma Skin Cancer Associated with Angiotensin-Converting-Enzyme Inhibitors, Angiotensin-Receptor Blockers and Thiazides: A Matched Cohort Study.

INTRODUCTION: Controversy exists about an association between angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), and thiazides (TZs) and the risk of malignant melanoma (MM), and non-melanoma skin cancer-basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). OBJECTIVE: The aim of this study was to determine if an association exists for ACEI, ARB, or TZ exposure and skin cancers. METHODS: This was a matched cohort study using a large electronic medical records repository, the Northwestern Medicine Enterprise Data Warehouse (NMEDW). The exposed population consisted of patients with a documented order for an ACEI, ARB, or TZ with no prior history of skin cancer. The control population consisted of matched patients without documented exposure to ACEI, ARB, or TZ and no previous skin cancer. Incident MM, BCC, or SCC diagnosis by ICD-9 codes was recorded. Odds ratios (ORs) were obtained by using logistic regression analyses. RESULTS: Among the 27,134 patients exposed to an ACEI, 87 MM, 533 BCC, and 182 SCC were detected. Among the 13,818 patients exposed to an ARB, 96 MM, 283 BCC, and 106 SCC were detected. Among the 15,166 patients exposed to a TZ, 99 MM, 262 BCC, and 130 SCC were detected. Significant associations using ORs from logistic regression were found for MM and TZs (OR 1.82; 95% confidence interval [CI] 1.01-3.82); BCC and ARBs (OR 2.86; 95% CI 2.13-3.83), ACEIs (OR 2.23; 95% CI 1.78-2.81) and TZs (OR 2.11; 95% CI 1.60-2.79); SCC and ARBs (OR 2.22; 95% CI 1.37-3.61), ACEIs (OR 1.94; 95% CI 1.37-2.76), and TZs (OR 4.11; 95% CI 2.66-6.35). CONCLUSIONS: A safety signal for ACEIs, ARBs, and TZs and BCC and SCC, as well as for TZs and MM, was detected. An increased awareness and education, especially for those who are at high risk for skin cancer, are warranted for patients and healthcare providers. Further exploration of such associations for these commonly used drug classes is warranted.

The influence of thiazide intake on calcium and parathyroid hormone levels in patients with primary hyperparathyroidism.

OBJECTIVE: The effects of thiazide medication in patients with primary hyperparathyroidism (PHPT) have so far not been elucidated. The aim of this study was to analyse the extent to which the administration of thiazides may influence biochemical parameters and therefore the diagnosis of PHPT in a large cohort of patients. DESIGN AND PATIENTS: The biochemical parameters of 1066 patients with PHPT were analysed, and drug history was documented. Calcium (Ca)/creatinine clearance ratio (CCCR) was calculated. The results of patients given thiazides (n = 170) and those not given thiazides (n = 896) were analysed and compared. MEASUREMENTS: Twenty-four-hour urinary calcium excretion (24hU), albumin-corrected serum calcium, PTH, creatinine, 1,25OH- and 25OH-vitamin D were measured, and CCCR was calculated. RESULTS: 24hUC a and CCCR were significantly lower in patients on thiazides (P = 0·02 and P = 0·0068, resp.), and serum creatinine was significantly higher in those subjects (P < 0·0001). Serum Ca levels only proved different in an analysis of covariance among patients younger than 60 years (P = 0·003). Nevertheless, PTH was not different in both groups (P = 0·917). CONCLUSIONS: According to recently published guidelines, 24hUCa measurement is necessary to give indication for surgery in asymptomatic patients and to distinguish between PHPT and familial hypocalciuric hypercalcaemia [FHH]. Thiazides significantly decrease 24hUC a , yet neither increase serum Ca nor influence PTH levels in patients with PHPT. However, discontinuing thiazides is crucial for a correct CCCR calculation to pre-operatively rule out FHH. As a consequence, the withdrawal of thiazide medication must be recommended for the diagnosis of PHPT prior to surgery.

[Thiazide diuretics in the treatment of hypertensive patients]. / Anvendelse af thiaziddiuretika i hypertensions-behandlingen--en gennemgang af et Cochranereview.

This Cochrane review had the objectives to determine the dose-related decrease in blood pressure due to thiazide diuretics compared with placebo control in the treatment of hypertensive patients. Hydrochlorothiazide has a dose-related blood pressure-lowering effect over the dose range 6.25, 12.5, 25 and 50 mg/day of 4/2, 6/3, 8/3 and 11/5 mmHg, respectively. This exceeds the mean 3 mmHg reduction achieved by angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers as shown in other Cochrane reviews, which have compared these antihypertensive drugs with placebo having used similar inclusion/exclusion criteria.

Thiazide-like/calcium channel blocker agents: a major combination for hypertension management.

In recent years, treatment strategies for hypertension have often focused on combination therapies that include diuretics and renin angiotensin aldosterone system blockers such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. However, in clinical practice, a significant number of patients do not respond completely to these combination treatments, and long-term reduction of cardiovascular risk remains insufficient. The particularly high residual cardiovascular risk of hypertensive patients, even when adequately treated with strategies based on renin angiotensin aldosterone system blockers, speaks in favor of new, innovative strategies. Thus, it has become relevant to consider whether it is always necessary to block plasma renin activation and whether other guideline-approved combinations should be considered routinely. Diuretic/calcium channel blocker combinations, which are supported by significant long-term evidence, are put forth as a preferred combination in the main guidelines, but are still underused by physicians who do not yet have easy access to such treatments. Fixed-dose indapamide sustained release/amlodipine is the first such single-pill combination to become available. Complementary mechanisms of action of these two molecules are expected to lead to greater and longer-term reductions in systolic blood pressure and pulse pressure and potentially to the reduction of cardiovascular risk.

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria.

The most common metabolic abnormality found in calcium (Ca) kidney stone formers is idiopathic hypercalciuria (IH). Using endogenous lithium (Li) clearance, we previously showed that in IH, there is decreased proximal tubule sodium absorption, and increased delivery of Ca into the distal nephron. Distal Ca reabsorption may facilitate the formation of Randall's plaque (RP) by washdown of excess Ca through the vasa recta toward the papillary tip. Elevated Ca excretion leads to increased urinary supersaturation (SS) with respect to calcium oxalate (CaOx) and calcium phosphate (CaP), providing the driving force for stone growth on RP. Thiazide (TZ) diuretics reduce Ca excretion and prevent stone recurrence, but the mechanism in humans is unknown. We studied the effect of chronic TZ administration on renal mineral handling in four male IH patients using a fixed three meal day in the General Clinical Research Center. Each subject was studied twice: once before treatment and once after 4-7 mo of daily chlorthalidone treatment. As expected, urine Ca fell with TZ, along with fraction of filtered Ca excreted. Fraction of filtered Li excreted also fell sharply with TZ, as did distal delivery of Ca. Unexpectedly, TZ lowered urine pH. Together with reduced urine Ca, this led to a marked fall in CaP SS, but not CaOx SS. Since CaOx stone formation begins with an initial CaP overlay on RP, by lowering urine pH and decreasing distal nephron Ca delivery, TZ might diminish stone risk both by reducing CaP SS, as well as slowing progression of RP.

Molecular insights from dysregulation of the thiazide-sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide-induced hyponatraemia.

Human blood pressure is dependent on balancing dietary salt intake with its excretion by the kidney. Mendelian syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the thiazide-sensitive pathway in particular. Gordon syndrome (GS), the phenotypic inverse of the salt-wasting Gitelman syndrome, is a condition of hyperkalaemic hypertension that is reversed by low-dose thiazide diuretics or a low-salt diet. Variants within at least four genes [i.e. with-no-lysine(K) kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and cullin 3 (CUL3)] can cause the phenotype of GS. Details are still emerging for some of these genes, but it is likely that they all cause a gain-of-function in the thiazide-sensitive Na(+) -Cl(-) cotransporter (NCC) and hence salt retention. Herein, we discuss the key role of STE20/sporulation-specific protein 1 (SPS1)-related proline/alanine-rich kinase (SPAK), which functions as an intermediary between the WNKs and NCC and for which a loss-of-function mutation produces a Gitelman-type phenotype in a mouse model. In addition to Mendelian blood pressure syndromes, the study of patients who develop thiazide-induced-hyponatraemia (TIH) may give further molecular insights into the role of the thiazide-sensitive pathway for salt reabsorption. In the present paper we discuss the key features of TIH, including its high degree of reproducibility on rechallenge, possible genetic predisposition and mechanisms involving excessive saliuresis and water retention. Together, studies of Gordon syndrome and TIH may increase our understanding of the molecular regulation of sodium trafficking via the thiazide-sensitive pathway and have important implications for hypertensive patients, both in the identification of new antihypertensive drug targets and avoidance of hyponatraemic side-effects.

Effects on insulin action of adding low-dose thiazide to angiotensin-converting enzyme inhibitor in essential hypertension.

Concern exists regarding adverse metabolic effects of antihypertensive agents. In the United States, diuretics are recommended first-line but additional agents, usually angiotensin-converting enzyme (ACE) inhibitors, are often required to meet blood pressure targets. We have previously shown that the combination of low-dose diuretic with an ACE inhibitor has detrimental effects on insulin action compared with ACE inhibitor alone in hypertensive type 2 diabetic patients. Our aim was to establish whether similar effects occur in nondiabetic hypertensive patients using this combination. A randomized double-blind placebo-controlled crossover design was used. After a 6-week run-in, when regular antihypertensive medications were withdrawn and placebo substituted, patients received captopril 50 mg twice daily with either bendroflumethiazide 1.25 mg (CB) or placebo (CP) for 12 weeks with a 6-week wash-out between treatments. Insulin action was assessed by hyperinsulinemic euglycemic clamp after the 6-week run-in and at the end of each treatment period. There were no differences between treatments in fasting glucose or insulin concentrations. Glucose infusion rates required to maintain euglycemia were the same with each treatment (CP 22.1±2.2 vs CB 22.2±2.2 µmol/kg per minute). There was no difference in endogenous glucose production in the basal state (CP 8.9±0.5 vs CB 9.5±0.7 µmol/kg per minute; P=0.23) or during hyperinsulinemia (CP 2.2±0.6 vs CB 1.5±0.3 µmol/kg per minute; P=0.30). In contrast to the situation in type 2 diabetes mellitus, ACE inhibitor combined with low-dose thiazide diuretic does not adversely affect insulin action when compared with ACE inhibitor alone in nondiabetic hypertensive patients.

[Patterns in the prescription of antihypertensive drugs in Norway, 1975-2010]. / Forskrivning av antihypertensive legemidler 1975-2010.

BACKGROUND: A complete overview of drugs used for hypertension is not available from official data sources. The aim of this study was to investigate the use of blood pressure medication over the years to identify trends in consumption patterns. MATERIAL AND METHOD: Data were collected from the Norwegian drug wholesaler statistics for the years 1975-2010 and from the Norwegian prescription database 2004-2010. Defined daily doses (DDD) per 1000 inhabitants per day, number of users and prevalence by gender and age were analysed. RESULTS: In the period 1975 to 2010 the use of antihypertensives increased from 55 to 248 DDD/1000 inhabitants/day (Norwegian drug wholesaler statistics). Data from the Norwegian prescription database show that in 2010 there were a total of 754 909 users of antihypertensives, of whom 638 830 had received the diagnosis hypertension. Thiazides and angiotensin II antagonists had the greatest increase in number of users from 2004 to 2010. In all ages up to 73 years, a higher proportion of men were prescribed drugs for hypertension in 2010, whereas in the over-73 s these drugs were most widely used by women. INTERPRETATION: The use of antihypertensives is steadily increasing. Angiotensin II antagonists and thiazides are the most commonly used drugs. The authorities'' decision in 2004 that thiazides should be regarded as first-line therapy for hypertension probably contributed to increased use of thiazides.

Use of amiloride and multiple sclerosis: registry-based cohort studies.

PURPOSE: Amiloride reduces functional neurological deficits and neuronal damage in animal models of multiple sclerosis (MS). We investigated whether amiloride use was associated with reduced risk of incident MS and of MS hospitalization and death in humans. METHODS: We conducted two propensity score-matched cohort studies, linking nationwide registry data on filled drug prescriptions, diagnostic information, and covariates. First, we compared rates of incident MS in new users of amiloride and new users of an active control treatment, thiazide diuretics. Second, rates of hospitalizations for MS and of death were compared between users of amiloride and thiazides in a cohort of MS patients. Treatment groups were matched 1 : 4 on propensity scores that included a wide range of covariates, and Cox regression was used to estimate hazard ratios (HRs). RESULTS: Comparing 36 659 users of amiloride and 177 031 users of thiazides, there were 19 cases of incident MS during 92 548 person-years of follow-up among amiloride users and 81 cases during 567 599 person-years of follow-up among thiazide users. There was no significantly decreased risk of MS associated with amiloride use (HR 1.34, 95%CI 0.81-2.20). In the cohort of MS patients, amiloride use was not associated with significantly decreased risk of MS hospitalization (HR 1.11, 95%CI 0.79-1.59) or death (HR 1.38, 95%CI 0.83-2.28). CONCLUSION: Amiloride use was not associated with significantly decreased risk of incident MS or hospitalizations and death among patients with MS. Because amiloride users were represented by older patients, risks could not be evaluated in younger individuals.