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BACKGROUND: According to drug labels, the frequency of thiazide-induced hyponatremia is unknown or uncommon to very rare (that is, <1 in 10 000 to <1 in 100), but the exact burden remains unclear. OBJECTIVE: To estimate the increase in the cumulative incidence of hyponatremia using thiazide diuretics compared with nonthiazide antihypertensive drugs in routine clinical practice. DESIGN: Population and register-based cohort study using target trial emulation. SETTING: Denmark, 1 January 2014 to 31 October 2018. PARTICIPANTS: Two target trials were emulated among persons aged 40 years or older who had no recent prescription for any antihypertensive drug, had no previous hyponatremia, and were eligible for the studied antihypertensive treatments. The first target trial emulation compared new use of bendroflumethiazide (BFZ) versus a calcium-channel blocker (CCB). The second target trial emulation compared new use of hydrochlorothiazide plus a renin-angiotensin system inhibitor (HCTZ-RASi; that is, combination pill) versus a RASi alone. MEASUREMENTS: Two-year cumulative incidences of sodium levels less than 130 mmol/L using stabilized inverse probability of treatment-weighted survival curves. RESULTS: The study compared 37 786 new users of BFZ with 44 963 of a CCB and 11 943 new users of HCTZ-RASi with 85 784 of a RASi. The 2-year cumulative incidences of hyponatremia were 3.83% for BFZ and 3.51% for HCTZ-RASi. The risk differences were 1.35% (95% CI, 1.04% to 1.66%) between BFZ and CCB and 1.38% (CI, 1.01% to 1.75%) between HCTZ-RASi and RASi; risk differences were higher with older age and higher comorbidity burden. The respective hazard ratios were 3.56 (CI, 2.76 to 4.60) and 4.25 (CI, 3.23 to 5.59) during the first 30 days since treatment initiation and 1.26 (CI, 1.09 to 1.46) and 1.29 (CI, 1.05 to 1.58) after 1 year. LIMITATION: The study assumed that filled prescriptions equaled drug use, and residual confounding is likely. CONCLUSION: Treatment initiation with thiazide diuretics suggests a more substantial excess risk for hyponatremia, particularly during the first months of treatment, than indicated by drug labeling. PRIMARY FUNDING SOURCE: Independent Research Fund Denmark.
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Hipertensión , Hiponatremia , Humanos , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Incidencia , Tiazidas/efectos adversos , Estudios de Cohortes , Hiponatremia/inducido químicamente , Hiponatremia/epidemiología , Antihipertensivos/efectos adversos , Hidroclorotiazida/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Bendroflumetiazida/efectos adversos , Hipertensión/tratamiento farmacológicoRESUMEN
OBJECTIVE: The renin-angiotensin system (RAS) has been shown to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD) because of the inflammatory properties of the system. Many patients with COPD use RAS-inhibiting (RASi) treatment. The aim was to determine the association between treatment with RASi and the risk of acute exacerbations and mortality in patients with severe COPD. METHODS: Active comparator analysis by propensity-score matching. Data were collected in Danish national registries, containing complete information on health data, prescriptions, hospital admissions and outpatient clinic visits. Patients with COPD (n=38 862) were matched by propensity score on known predictors of the outcome. One group was exposed to RASi treatment (cases) and the other was exposed to bendroflumethiazide as an active comparator in the primary analysis. RESULTS: The use of RASi was associated with a reduced risk of exacerbations or death in the active comparator analysis at 12 months follow-up (HR 0.86, 95% CI 0.78 to 0.95). Similar results were evident in a sensitivity analysis of the propensity-score-matched population (HR 0.89, 95% CI 0.83 to 0.94) and in an adjusted Cox proportional hazards model (HR 0.93, 95% CI 0.89 to 0.98). CONCLUSION: In the current study, we found that the use of RASi treatment was associated with a consistently lower risk of acute exacerbations and death in patients with COPD. Explanations to these findings include real effect, uncontrolled biases, and-less likely-chance findings.
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Enfermedad Pulmonar Obstructiva Crónica , Renina , Humanos , Sistema de Registros , Bendroflumetiazida , Inhibidores Enzimáticos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , AngiotensinasRESUMEN
BACKGROUND: Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to some routine prescriptions and changed some patient health behaviours. AIM: This study, therefore, retrospectively investigated prescription reimbursement of cardiovascular (CVD) medicines as a proxy measure for patient adherence and access to medicines during the pandemic. METHODS: A cohort study of all primary care patients in England prescribed CVD medicines. The exposure was to the global pandemic. Prescriptions were compared before and after the pandemic's onset. Statistical variation was the outcome of interest. RESULTS: Descriptive statistics show changes to monthly prescriptions, with wide confidence intervals indicating varying underlying practice. Analysis of variance reveals statistically significant differences for bendroflumethiazide, potassium-sparing diuretics, nicorandil, ezetimibe, ivabradine, ranolazine, colesevelam and midodrine. After the pandemic began (March-October 2020), negative parameters are observed for ACE inhibitors, beta-blockers, calcium channel blockers, statins, antiplatelet, antithrombotics, ARBs, loop diuretics, doxazosin, bendroflumethiazide, nitrates and indapamide, indicating decelerating monthly prescription items (statistically significant declines of calcium channel blockers, antithrombotic, adrenoreceptor blockers and diuretics) of CVD medicines within the general population. Many data points are not statistically significant, but fluctuations remain clinically important for the large population of patients taking these medications. CONCLUSION: A concerning decline in uptake of CVD therapies for chronic heart disease was observed. Accessible screening and treatment alongside financial relief on prescription levies are needed. A video abstract is (4 min 51 s) available: https://bit.ly/39gvEHi.
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COVID-19 , Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Cardiopatías , Humanos , Pandemias , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bendroflumetiazida , Estudios Retrospectivos , Estudios de Cohortes , Antagonistas de Receptores de Angiotensina , Fármacos Cardiovasculares/efectos adversos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Cardiopatías/tratamiento farmacológico , Diuréticos/uso terapéutico , Prescripciones de MedicamentosRESUMEN
BACKGROUND: Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides. METHODS: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use. RESULTS: We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08-1.24; HR 1.26, 95% CI 1.04-1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06-1.65; HR 1.61, 95% CI 0.97-2.67), and melanoma (OR 1.11, 95% CI 1.02-1.20; HR 1.03, 95% CI 0.93-1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43-4.57; HR 1.20, 95% CI 1.00-1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05-1.33), nodular (OR 1.23, 95% CI 1.08-1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08-1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide. CONCLUSIONS: Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions. TRIAL REGISTRATION: PROSPERO CRD42021234317 .
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Carcinoma de Células Escamosas , Indapamida , Melanoma , Neoplasias Cutáneas , Bendroflumetiazida , Humanos , Hidroclorotiazida , Melanoma/inducido químicamente , Melanoma/epidemiología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/epidemiología , TiazidasRESUMEN
Thiazide diuretics have been the cornerstone of hypertension treatment for >5 decades. Most recent European and American guidelines recommend both thiazide-type and thiazide-like diuretics as first-line drugs for all patients with hypertension. In contrast, diuretics are not regarded as first-line treatment in the UK and in patients who are to be initiated on a diuretic treatment, thiazide-like molecules, such as chlortalidone and indapamide are the preferred option. This review examines the prescribing trend of the 4 most commonly prescribed thiazide diuretics for the treatment of hypertension in the UK. Prescription cost analysis data were obtained for both 2010 and 2016/2017 for each region of the UK to analyse the impact of the 2011 National Institute for Health and Care Excellence hypertension guidelines on the trend in thiazide diuretic prescribing. Overall, the prescriptions of thiazide diuretics declined over the years. Bendroflumethiazide is the most commonly prescribed diuretic in the UK and despite some geographical differences, thiazide-type diuretics are more widely used than thiazide-like. The use of indapamide increased significantly between 2010 and 2016/2017 while chlortalidone was rarely employed. Of the many factors affecting trends in prescriptions, clinical inertia, treatment adherence, availability of the products and the lack of fixed dose combinations may play a role.
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Antihipertensivos/uso terapéutico , Prescripciones de Medicamentos/estadística & datos numéricos , Utilización de Medicamentos/tendencias , Hipertensión/tratamiento farmacológico , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Bendroflumetiazida/administración & dosificación , Bendroflumetiazida/efectos adversos , Bendroflumetiazida/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Humanos , Indapamida/administración & dosificación , Indapamida/efectos adversos , Indapamida/uso terapéutico , Guías de Práctica Clínica como Asunto , Inhibidores de los Simportadores del Cloruro de Sodio/administración & dosificación , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversosRESUMEN
The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure, need for intensification of treatment and treatment withdrawal. Two authors independently screened the results of a literature search, assessed the risk of bias and extracted relevant data. Randomized clinical trials of hypertensive patients of at least a 1-year duration were included. When there was disagreement, a third reviewer was consulted. Risk ratio (RR) and mean differences were used as measures of effect. Two trials comparing bendroflumethiazide against placebo, one comparing indapamide with placebo and three of short duration directly comparing indapamide and Bendroflumethiazide, were included. No statistically significant difference was found between indapamide and bendroflumethiazide for all deaths [RR 0.82; 95% confidence interval (CI) 0.57, 1.18], cardiovascular deaths (RR 0.82; 95% CI 0.55, 1.20), noncardiovascular deaths (0.81; 95% CI 0.54, 1.22), coronary events (RR 0.73; 95% CI 0.30, 1.79) or all cardiovascular events (RR 0.89; 95% CI 0.67, 1.18). Indapamide performed worse for stroke (RR 2.21; 95% CI 1.19, 4.11), even though a reduction in RR compared with placebo was observed in both groups. There was no statistically or clinically significant difference between indapamide and bendroflumethiazide in blood pressure reduction (mean absolute difference <1 mmHg). The present review highlights a lack of studies to answer the review question but also a lack of evidence of superiority of one drug over the other. Therefore, there is a clear need for new studies directly comparing the effect of these drugs on the outcomes of interest.
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Bendroflumetiazida/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Diuréticos/administración & dosificación , Hipertensión/tratamiento farmacológico , Indapamida/administración & dosificación , Bendroflumetiazida/efectos adversos , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/prevención & control , Diuréticos/efectos adversos , Humanos , Hipertensión/complicaciones , Hipertensión/mortalidad , Indapamida/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: We applied a novel combined connectivity mapping and pharmacoepidemiological approach to identify medications that alter breast cancer risk. METHODS: The connectivity mapping process identified 6 potentially cancer-causing (meloxicam, azithromycin, rizatriptan, citalopram, rosiglitazone, and verapamil) and 4 potentially cancer-preventing (bendroflumethiazide, sertraline, fluvastatin, and budesonide) medications that were suitable for pharmacoepidemiological investigation. Within the UK Clinical Practice Research Datalink, we matched 45,147 breast cancer cases to 45,147 controls based on age, year, and general practice. Medication use was determined from electronic prescribing records. We used conditional logistic regression to calculate odds ratios (ORs) for the association between medication use and cancer risk after adjustment for comorbidities, lifestyle factors, deprivation, and other medication use. RESULTS: Bendroflumethiazide was associated with increased breast cancer risk (OR: 1.11; 95% CI: 1.06, 1.15); however the connectivity mapping exercise predicted that this medication would reduce risk. There were no statistically significant associations for any of the other candidate medications, with ever use ORs ranging from 0.93 (95% CI: 0.78, 1.11) for azithromycin to 1.16 (95% CI: 0.99, 1.37) for verapamil. CONCLUSIONS: In this instance, our combined connectivity mapping and pharmacoepidemiological approach did not identify any additional medications that were substantially associated with breast cancer risk. This could be due to limitations in the connectivity mapping, such as implausible dosage requirements, or the pharmacoepidemiology, such as residual confounding.
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Bendroflumetiazida/efectos adversos , Neoplasias de la Mama/epidemiología , Farmacoepidemiología/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/prevención & control , Estudios de Casos y Controles , Factores de Confusión Epidemiológicos , Prescripciones de Medicamentos/estadística & datos numéricos , Femenino , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Farmacoepidemiología/métodos , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of treatment is to reduce these events. Systematic reviews have shown proven benefit of antihypertensive drug therapy in reducing cardiovascular morbidity and mortality but most of the evidence is in people 60 years of age and older. We wanted to know what the effects of therapy are in people 18 to 59 years of age. OBJECTIVES: To quantify antihypertensive drug effects on all-cause mortality in adults aged 18 to 59 years with mild to moderate primary hypertension. To quantify effects on cardiovascular mortality plus morbidity (including cerebrovascular and coronary heart disease mortality plus morbidity), withdrawal due adverse events and estimate magnitude of systolic blood pressure (SBP) and diastolic blood pressure (DBP) lowering at one year. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to January 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomized trials of at least one year' duration comparing antihypertensive pharmacotherapy with a placebo or no treatment in adults aged 18 to 59 years with mild to moderate primary hypertension defined as SBP 140 mmHg or greater or DBP 90 mmHg or greater at baseline, or both. DATA COLLECTION AND ANALYSIS: The outcomes assessed were all-cause mortality, total cardiovascular (CVS) mortality plus morbidity, withdrawals due to adverse events, and decrease in SBP and DBP. For dichotomous outcomes, we used risk ratio (RR) with 95% confidence interval (CI) and a fixed-effect model to combine outcomes across trials. For continuous outcomes, we used mean difference (MD) with 95% CI and a random-effects model as there was significant heterogeneity. MAIN RESULTS: The population in the seven included studies (17,327 participants) were predominantly healthy adults with mild to moderate primary hypertension. The Medical Research Council Trial of Mild Hypertension contributed 14,541 (84%) of total randomized participants, with mean age of 50 years and mean baseline blood pressure of 160/98 mmHg and a mean duration of follow-up of five years. Treatments used in this study were bendrofluazide 10 mg daily or propranolol 80 mg to 240 mg daily with addition of methyldopa if required. The risk of bias in the studies was high or unclear for a number of domains and led us to downgrade the quality of evidence for all outcomes.Based on five studies, antihypertensive drug therapy as compared to placebo or untreated control may have little or no effect on all-cause mortality (2.4% with control vs 2.3% with treatment; low quality evidence; RR 0.94, 95% CI 0.77 to 1.13). Based on 4 studies, the effects on coronary heart disease were uncertain due to low quality evidence (RR 0.99, 95% CI 0.82 to 1.19). Low quality evidence from six studies showed that drug therapy may reduce total cardiovascular mortality and morbidity from 4.1% to 3.2% over five years (RR 0.78, 95% CI 0.67 to 0.91) due to reduction in cerebrovascular mortality and morbidity (1.3% with control vs 0.6% with treatment; RR 0.46, 95% CI 0.34 to 0.64). Very low quality evidence from three studies showed that withdrawals due to adverse events were higher with drug therapy from 0.7% to 3.0% (RR 4.82, 95% CI 1.67 to 13.92). The effects on blood pressure varied between the studies and we are uncertain as to how much of a difference treatment makes on average. AUTHORS' CONCLUSIONS: Antihypertensive drugs used to treat predominantly healthy adults aged 18 to 59 years with mild to moderate primary hypertension have a small absolute effect to reduce cardiovascular mortality and morbidity primarily due to reduction in cerebrovascular mortality and morbidity. All-cause mortality and coronary heart disease were not reduced. There is lack of good evidence on withdrawal due to adverse events. Future trials in this age group should be at least 10 years in duration and should compare different first-line drug classes and strategies.
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Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Adulto , Antihipertensivos/efectos adversos , Bendroflumetiazida/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Causas de Muerte , Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/prevención & control , Humanos , Hipertensión/mortalidad , Metildopa/uso terapéutico , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/prevención & control , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Propranolol/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/prevención & control , Adulto JovenRESUMEN
INTRODUCTION Thiazide diuretics are commonly prescribed in the treatment of hypertension. However, thiazide diuretics may not all be equal in their ability to reduce cardiovascular disease outcomes. AIM To determine if bendroflumethiazide/bendrofluazide, the most commonly used diuretic for hypertension in New Zealand, is as effective as other diuretics in terms of cardiovascular disease outcomes. METHODS Using recent reviews of thiazide-like (chlorthalidone or indapamide) and thiazide-type diuretics (hydrochlorothiazide and bendrofluazide) and a separate search of bendrofluazide, data on cardiovascular disease outcomes was extracted. RESULTS Nineteen relevant papers with 21 comparisons were found. All thiazide-based diuretics have been reported in at least one trial showing them to be more effective than placebo for cardiovascular disease outcomes, with the exception of chlorothiazide. There were no comparisons of bendrofluazide alone with other medications, but there were two studies with either bendrofluazide or hydrochlorothiazide compared with ß-blockers; however, the pooled relative risk (RR) was not significant (RR = 1.10 (95% CI, 0.84-1.43)). For chlorthalidone, there were four comparisons with other medications, and the summary RR was statistically significant for cardiovascular disease outcomes (RR = 0.91 (95% CI, 0.85-0.98)). Chlorthalidone was significantly more effective for some cardiovascular disease outcomes when compared with doxazosin, amlodipine and lisinopril. CONCLUSIONS All thiazide-based medicines available in New Zealand are effective in terms of cardiovascular disease outcomes compared with placebo when used for treating hypertension, with the exception of chlorothiazide. Of the diuretics available in New Zealand for hypertension, only chlorthalidone has been shown to be more effective than other blood pressure-lowering medicines. It may be time to change from using bendrofluazide and start using chlorthalidone as a treatment for hypertension.
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Antihipertensivos/administración & dosificación , Bendroflumetiazida/administración & dosificación , Clortalidona/administración & dosificación , Sustitución de Medicamentos , Hipertensión/tratamiento farmacológico , HumanosRESUMEN
We report the association between excessive consumption of green tea and hypokalaemia in an Oriental couple. Both patients were asymptomatic and the abnormal electrolyte level was only detected on routine blood tests. When they were advised to reduce the consumption of green tea, the abnormally low potassium level was reversed. We have not found such an association reported in the medical literature. The health benefits of green tea consumption are well publicised but the potential side-effects of overconsumption are less well known. We would like to report this association to alert clinicians about this potentially serious complication. This is especially relevant for those who are also taking prescribed medications that can lower potassium levels and/or sensitise patients to potential harm from hypokalaemia.
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Conducta de Ingestión de Líquido , Hipopotasemia/etiología , Té/efectos adversos , Anciano , Amlodipino/uso terapéutico , Antihipertensivos/uso terapéutico , Bendroflumetiazida/uso terapéutico , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Lisinopril/uso terapéutico , MasculinoRESUMEN
Percutaneous drainage proved to be successful in managing a renal subcapsular haematoma that was causing acute renal failure and hypertension in a 74-year-old woman. The patient presented with oliguria, nausea and malaise 2 days after a ureteronephroscopic procedure with biopsies of a suspected urothelial neoplasm in the right renal pelvis. The left kidney had recently been removed due to renal cell carcinoma. At admission, the patient's blood pressure and plasma creatinine levels were massively elevated. Ultrasonography revealed a moderate right-sided renal subcapsular haematoma. When the patient did not respond to antihypertensive treatment, Page kidney was suspected. A pigtail catheter was placed in the haematoma and, shortly after drainage, the diuresis resumed and plasma creatinine together with blood pressure decreased. This condition had previously been managed by open surgery, but recent case reports have described successful management by laparoscopy-assisted and radiology-assisted drainage, as described in this case report.
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Lesión Renal Aguda/etiología , Antihipertensivos/uso terapéutico , Bendroflumetiazida/uso terapéutico , Drenaje/métodos , Hematoma/complicaciones , Hipertensión/etiología , Metoprolol/uso terapéutico , Lesión Renal Aguda/terapia , Anciano , Presión Sanguínea/fisiología , Femenino , Hematoma/terapia , Humanos , Riñón/patologíaRESUMEN
In this paper, a Bayesian approach is developed for simultaneously comparing multiple experimental treatments with a common control treatment in an exploratory clinical trial. The sample size is set to ensure that, at the end of the study, there will be at least one treatment for which the investigators have a strong belief that it is better than control, or else they have a strong belief that none of the experimental treatments are substantially better than control. This criterion bears a direct relationship with conventional frequentist power requirements, while allowing prior opinion to feature in the analysis with a consequent reduction in sample size. If it is concluded that at least one of the experimental treatments shows promise, then it is envisaged that one or more of these promising treatments will be developed further in a definitive phase III trial. The approach is developed in the context of normally distributed responses sharing a common standard deviation regardless of treatment. To begin with, the standard deviation will be assumed known when the sample size is calculated. The final analysis will not rely upon this assumption, although the intended properties of the design may not be achieved if the anticipated standard deviation turns out to be inappropriate. Methods that formally allow for uncertainty about the standard deviation, expressed in the form of a Bayesian prior, are then explored. Illustrations of the sample sizes computed from the new method are presented, and comparisons are made with frequentist methods devised for the same situation.
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Drogas en Investigación , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Tamaño de la Muestra , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Teorema de Bayes , Bendroflumetiazida/administración & dosificación , Bendroflumetiazida/farmacología , Sesgo , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Determinación de Punto Final , Humanos , Hipertensión/tratamiento farmacológico , Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , IncertidumbreAsunto(s)
Parálisis de Bell/diagnóstico , Nervio Facial/fisiopatología , Parálisis Facial/fisiopatología , Hipertensión Maligna/complicaciones , Hipertensión Maligna/diagnóstico , Adulto , Antihipertensivos/uso terapéutico , Bendroflumetiazida/uso terapéutico , Bisoprolol/uso terapéutico , Humanos , Hipertensión Maligna/tratamiento farmacológico , Imagen por Resonancia Magnética , Masculino , Nifedipino/uso terapéuticoRESUMEN
BACKGROUND: Increased arterial stiffness independently predicts adverse prognosis. While different antihypertensive strategies produce different magnitudes of left ventricular hypertrophy (LVH) regression, there are no comparative data on how these strategies affect arterial stiffness. The aim was to determine the longitudinal change in aortic stiffness following the treatment of essential hypertension with two mechanistically different antihypertensive treatment strategies. METHODS AND RESULTS: Forty-two patients with essential hypertension and CMR confirmed with LVH were randomly assigned to antihypertensive regimes for 6 months. Treatment strategies were designed either to inhibit the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) (valsartan and moxonidine, group VM) or to have neutral effect on these systems (bendroflumethiazide and amlodipine, group BA). Both treatment groups underwent identical baseline and a 6-month follow-up CMR and were compared with a healthy age-matched control group. Baseline aortic distensibility (AD) was lower in both hypertensive groups compared with controls (2.8 × 10(-3 )mmHg(-1) in group VM (p = 0.001) and 3.3 × 10(-3 )mmHg(-1) group BA (p = 0.039) compared with 4.5 × 10(-3 )mmHg(-1) in the control group). AD increased after antihypertensive therapy (VM: 2.8 × 10(-3 )mmHg(-1)-4.2 × 10(-3 )mmHg(-1) (p = 0.001); BA 3.3 × 10(-3 )mmHg(-1)-4.6 × 10(-3 )mmHg(-1) (p < 0.01)). In both treatment groups AD returned to a level comparable with the normal control group (p = 0.81) after 6 months. CONCLUSIONS: In patients with essential hypertension and LVH, AD was lower than in matched normal controls. Despite the opposing pharmacological mechanisms utilised across the treatment groups, the improvement in AD was similar, suggesting that blood pressure reduction per se may be more important than RAAS and SNS inhibition for the improvement of aortic remodelling.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Antihipertensivos/administración & dosificación , Aorta Torácica/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/fisiopatología , Imagen por Resonancia Cinemagnética/métodos , Remodelación Vascular/fisiología , Adulto , Anciano , Amlodipino/administración & dosificación , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Bendroflumetiazida/administración & dosificación , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Hipertensión Esencial , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/etiología , Imidazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Simpaticolíticos , Resultado del Tratamiento , Valsartán/administración & dosificación , Remodelación Vascular/efectos de los fármacos , Rigidez Vascular/efectos de los fármacosRESUMEN
This case report presents a 38-year-old woman who developed rhabdomyolysis following severe hypokalaemia due to a thiazid diuretic. Rhabdomyolysis is a severe condition with an incidence of 28% in hypokalaemic patients. It should be considered to measure concentrations of S-myoglobin and S-creatine kinase in severe cases of hypokalaemia. Thiazid diuretics can cause severe hypokalaemia with life-threatening complications and monitoring of S-potassium is advised during therapy.
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Bendroflumetiazida/efectos adversos , Hipopotasemia/inducido químicamente , Rabdomiólisis/inducido químicamente , Tiazidas/efectos adversos , Adulto , Femenino , Humanos , Rabdomiólisis/patología , Rabdomiólisis/terapiaRESUMEN
Previous studies of central diabetes insipidus suggested that thiazides acutely exerted a paradoxical antidiuresis by either indirectly activating volume-homeostatic reflexes to decrease distal fluid-delivery, or directly stimulating distal water-reabsorption. This study investigated whether the direct and indirect actions of bendroflumethiazide (BFTZ) simultaneously cooperated and also whether the renal nerves were involved in inducing long-term antidiuresis in nephrogenic diabetes insipidus (NDI). BFTZ or vehicle was gavaged into bilateral renal denervated and innervated rats with lithium-induced NDI for 10 days, constituting four groups. At one day before (D0) and one, five and ten days after starting administration of BFTZ or vehicle, rats were placed in metabolic cages to collect urine for 6 hours. BFTZ-treatment in both renal innervated and denervated rats caused equivalent reductions in urine-flow, creatinine clearance, lithium clearance and free-water clearance, but rises in urine-osmolality, fractional proximal reabsorption and fractional distal reabsorption at all days compared to D0, as well as to those of their relevant vehicle-received group. Therefore, the chronic antidiuretic response to BFTZ in conscious NDI rats was exerted through a concomitant cooperation of its direct distal effect of stimulating water-reabsorption and its indirect effect of reducing distal fluid-delivery by activating volume-homeostatic mechanisms, which appeared independent of the renal nerves.
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Fármacos Antidiuréticos/farmacología , Bendroflumetiazida/farmacología , Diabetes Insípida Nefrogénica/tratamiento farmacológico , Diuresis/efectos de los fármacos , Riñón/efectos de los fármacos , Cloruro de Litio , Animales , Desnervación Autonómica , Biomarcadores/sangre , Biomarcadores/orina , Presión Sanguínea/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Peso Corporal/efectos de los fármacos , Creatinina/sangre , Diabetes Insípida Nefrogénica/sangre , Diabetes Insípida Nefrogénica/inducido químicamente , Diabetes Insípida Nefrogénica/fisiopatología , Diabetes Insípida Nefrogénica/orina , Modelos Animales de Enfermedad , Ingestión de Líquidos/efectos de los fármacos , Riñón/inervación , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Natriuresis/efectos de los fármacos , Concentración Osmolar , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Urodinámica/efectos de los fármacos , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
Antihypertensive treatment can improve tissue Doppler indices of left ventricular diastolic function in the short term, but little is known about the longer-term effect of different antihypertensive treatments on progression of left ventricular diastolic function and left ventricular hypertrophy. We hypothesized that long-term treatment of hypertension will lead to improvements in left ventricular hypertrophy and diastolic function. We collected detailed cardiovascular phenotypic data on 1006 participants from a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. Patients randomized to either an amlodipine±perindopril-based or an atenolol±bendroflumethiazide-based regimen underwent conventional and tissue Doppler echocardiography at time of control of blood pressure after randomization (≈1.5 years; phase 1) and after a further 2 years of antihypertensive treatment (phase 2). There were no prerandomization data. Five hundred thirty-six patients had complete data collection at both phases. Left ventricular mass index regressed from phase 1 to 2 with no significant difference between treatment groups (amlodipine: 119.5-116.8; atenolol: 122.9-117.5; P<0.001 for both). Conversely, tissue Doppler diastolic indices did not change in the amlodipine±perindopril-based regimen (E/e', 7.5-7.6 cm/s; P=not significant), but deteriorated in the atenolol±bendroflumethiazide-based regimen (E/e', 8.0-8.5 cm/s; P<0.01). Despite regression of left ventricular hypertrophy, there was no associated improvement in diastolic function. In fact, long-term treatment with atenolol±bendroflumethiazide resulted in a progressive deterioration in E/e'. This may be a factor contributing to the previously described worse clinical outcome in patients treated with atenolol±bendroflumethiazide compared with amlodipine±perindopril.
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Amlodipino/administración & dosificación , Antihipertensivos/administración & dosificación , Atenolol/administración & dosificación , Bendroflumetiazida/administración & dosificación , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Perindopril/administración & dosificación , Adulto , Anciano , Quimioterapia Combinada , Ecocardiografía Doppler , Femenino , Humanos , Hipertrofia Ventricular Izquierda/prevención & control , Masculino , Persona de Mediana Edad , Tiempo , Insuficiencia del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Población BlancaRESUMEN
Emerging evidences suggest that Ca(2+)activated-K(+)-(BK) channel is involved in the regulation of cell viability. The changes of the cell viability observed under hyperkalemia (15 mEq/L) or hypokalemia (0.55 mEq/L) conditions were investigated in HEK293 cells expressing the hslo subunit (hslo-HEK293) in the presence or absence of BK channel modulators. The BK channel openers(10(-11)-10(-3)M) were: acetazolamide(ACTZ), Dichlorphenamide(DCP), methazolamide(MTZ), bendroflumethiazide(BFT), ethoxzolamide(ETX), hydrochlorthiazide(HCT), quercetin(QUERC), resveratrol(RESV) and NS1619; and the BK channel blockers(2 x 10(-7)M-5 x 10(-3)M) were: tetraethylammonium(TEA), iberiotoxin(IbTx) and charybdotoxin(ChTX). Experiments on cell viability and channel currents were performed using cell counting kit-8 and patch-clamp techniques, respectively. Hslo whole-cell current was potentiated by BK channel openers with different potency and efficacy in hslo-HEK293. The efficacy ranking of the openers at -60 mV(Vm) was BFT> ACTZ >DCP ≥RESV≥ ETX> NS1619> MTZ≥ QUERC; HCT was not effective. Cell viability after 24 h of incubation under hyperkalemia was enhanced by 82+6% and 33+7% in hslo-HEK293 cells and HEK293 cells, respectively. IbTx, ChTX and TEA enhanced cell viability in hslo-HEK293. BK openers prevented the enhancement of the cell viability induced by hyperkalemia or IbTx in hslo-HEK293 showing an efficacy which was comparable with that observed as BK openers. BK channel modulators failed to affect cell currents and viability under hyperkalemia conditions in the absence of hslo subunit. In contrast, under hypokalemia cell viability was reduced by -22+4% and -23+6% in hslo-HEK293 and HEK293 cells, respectively; the BK channel modulators failed to affect this parameter in these cells. In conclusion, BK channel regulates cell viability under hyperkalemia but not hypokalemia conditions. BFT and ACTZ were the most potent drugs either in activating the BK current and in preventing the cell proliferation induced by hyperkalemia. These findings may have relevance in disorders associated with abnormal K(+) ion homeostasis including periodic paralysis and myotonia.