Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized, double-blind, active-controlled, multicenter phase 3 trial.

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are -19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and -11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.

Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Safety, tolerability, and efficacy of azilsartan medoxomil with or without chlorthalidone during and after 8 months of treatment for hypertension.

A phase 3, 26-week, open-label, titrate-to-target study (n=418) assessed the safety of azilsartan medoxomil (AZL-M) alone and with chlorthalidone (CLD), followed by a 6-week, double-blind, placebo-controlled reversal phase with change in clinic diastolic blood pressure (DBP) as the primary endpoint. Target blood pressure (BP) was <140/90 mm Hg (<130/80 mm Hg with diabetes/chronic kidney disease). AZL-M was initiated at 40 mg once a day (QD), force-titrated to 80 mg at week 4. CLD 25 mg QD could be added (weeks 8-22), if required, to reach target, followed by additional antihypertensives from week 12. At the end of the open-label phase, mean change in systolic BP (SBP)/DBP from baseline was -23/-16 mm Hg. The most common adverse events, irrespective of treatment, were dizziness (8.9%) and headache (7.2%). Serious AEs were reported in eight patients (1.9%). Consecutive creatinine elevations ≥50% with values exceeding the upper limit of normal (ULN) were reported in nine (2.2%) patients. All returned to below the 50% threshold; most also returned to below the ULN after drug discontinuation. Mean DBP was maintained through the reversal phase in patients receiving AZL-M, but increased with placebo (difference: -7.8 mm Hg, 95% confidence interval, -9.8 to -5.8; P<.001). AZL-M alone or with CLD showed good long-term safety and stable BP improvements in a titrate-to-target approach. BP improvements caused by AZL-M therapy were safely reversible upon AZL-M withdrawal.

Risk of hyponatremia with diuretics: chlorthalidone versus hydrochlorothiazide.

BACKGROUND: Chlorthalidone and hydrochlorothiazide are often considered as interchangeable. However, greater (nighttime) blood pressure reduction, and alleged pleiotropic effects have renewed the interest in chlorthalidone. A recent study showed an increased risk of adverse events with chlorthalidone, including hyponatremia. METHODS: To investigate differences in risk of hyponatremia between chlorthalidone and hydrochlorothiazide, adjusted for daily dose, we conducted a population-based case-control study within the Dutch IPCI (Integrated Primary Care Information) database. The study population included all subjects ≥18 years without diabetes mellitus, heart failure, liver failure, and malignancy, who were registered in the IPCI database from 1996 to 2011. Cases were subjects with a serum sodium <130 millimoles per liter or hospitalization due to hyponatremia. Controls were matched on practice, age within 5 years, sex, and date of onset. RESULTS: A total of 1033 cases of hyponatremia were identified. Hyponatremia was more common with chlorthalidone than with hydrochlorothiazide at equal dose per day: adjusted odds ratio was 2.09 (95% confidence interval [CI], 1.13-3.88) for 12.5 milligrams per day and 1.72 (95% CI, 1.15-2.57) for 25 milligrams per day. Risks were not significantly increased with chlorthalidone compared with twice the dose per day of hydrochlorothiazide. CONCLUSIONS: This is the first study that shows an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. The need for a lower dose of chlorthalidone than hydrochlorothiazide to achieve similar blood pressure reduction likely compensates for the increased risk of hyponatremia at equal dose.

A comparison between diuretics and angiotensin-receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): study protocol for a randomized double-blind controlled trial.

BACKGROUND: Cardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted. METHODS/DESIGN: This is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution. DISCUSSION: The putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov: NCT00971165.

[Severe perioperative hypotension after nephrectomy with adrenalectomy]. / Hipotensión perioperatoria grave tras nefrectomía con suprarrenalectomía.

A 70-year-old obese, hypertensive woman taking angiotensin converting enzyme (ACE) inhibitors and chlorthalidone but with no history of corticosteroid treatment or hypothalamus-hypophyseal-adrenal disease, underwent nephrectomy and adrenalectomy under combined general and epidural anesthesia. Severe hypotension with oliguria developed during surgery and persisted during postoperative recovery, with anuria, metabolic acidosis, hyponatremia and hyperpotassemia. Although the symptoms were initially attributed to prior treatment with ACE inhibitors and diuretics together with combined anesthesia, the patient's lack of response to crystalloid, colloid and inotropic catecholamine therapy in the context of anuria, metabolic acidosis, hyponatremia and hyperpotassemia led us to consider a diagnosis of Addisonian crisis. Blood samples were taken to determine adrenocorticotropic hormone levels, and hydrocortisone treatment was started. The patient responded to treatment and cortisol levels fell, confirming the diagnosis of adrenal insufficiency. Compensatory endrocrine secretion of cortisol by the contralateral adrenal gland has been observed in patients undergoing nephrectomy and adrenalectomy for excision of a hypernephroma, and replacement therapy is therefore not recommended. Perioperative Addisonian crises have also been described in patients suffering great surgical stress, and severe hypotension has been observed in patients on long-term treatment with ACE inhibitors after induction of general anesthesia and after epidural anesthesia with local anesthetics. The combination of these factors made rapid diagnosis and start of appropriate therapy difficult.

[Intermittent fever of unknown origin]. / Unklarer Status febrilis.

HISTORY AND CLINICAL FINDINGS: A 58-year-old woman was admitted because of intermittent fever for 4 weeks accompanied by slowly developing anaemia and increase in inflammatory parameters. She was being treated for hypertension with atenolol and chlorthalidone, but until 6 weeks before the onset of the described symptoms she had only taken the beta blocker, at which time the diuretic was added because the hypertension was inadequately controlled. Other than slightly impaired general condition and nocturnal fever up to 39.5 degrees C physical examination was unremarkable. INVESTIGATIONS: She had a normochromic normocytic anaemia and the erythrocyte sedimentation rate and C-reactive protein were clearly elevated. Other biochemical tests and blood cultures as well as serological and immunological tests were negative. Bone marrow biopsy showed nonspecific reactive changes. The chest radiograph, lung scintigraphy and abdominal ultrasound were unremarkable. TREATMENT AND COURSE: There was no further fever after the antihypertensive medication had been discontinued. The patient's general condition rapidly improved and all biochemical tests became normal. The lymphocyte transformation test demonstrated stimulation by chlorthalidone. CONCLUSION: Drug fever, in this case due to a sulphonamide derivative, should always be considered in the differential diagnosis of fever of unknown aetiology. No previous case of hypersensitivity reaction to chlorthalidone has been found on a search of the literature.

Estudo aberto comparativo captopril + hidroclorotiazida versus clortalidona para tratamento da hipertensäo primária leve e moderada / An open comparative study of captopril + hydrochlorothiazide versus chlorthalidone for the treatment of mild and moderate primary hypertension

Objetivo - Comparar o efeito anti-hipertensivo e alterações metabólicas da associação captopril + hidroclorotiazida (C+HCTZ) contra clortalidona (CT) para tratamento de hipertensão arterial primária leve e moderada. Métodos - cinqüenta e cinco pacientes que tiveram a sua medicação anti-hipertensiva suspensa por 15 dias ou sem tratamento prévio, foram randomizados para tratamentos com a associação captopril 50mg + hidroclorotiazida 25mg (n=29) ou clortalidona 50mg (n=26). A avaliação clínica foi realizada previamente à medicação e mensalmente durante 3 meses e os exames laboratoriais foram feitos no início e ao final do estudo. Resultados - A pressão arterial (PA) no período placebo não foi diferente entre os grupos (C+CHTZ: 161 ± 25/102 ± 6 - CT: 155 ± 18/101 ± 6 mmHg), porém a diminuição da pressão diastólica já no 1° mês foi estatisticamente significante no grupo C+HCTZ (89±8 mmHg) comparado ao grupo CT (94±8 mmHg, p<0,05). O perceptual de queda da PA diastólica em média, de 12% no grupo C+HCTZ e no grupo CT variou de 7 (1° e 2° mês) a 11% (3° mês). Embora sem diferença estatística, obteve-se normalização pressórica em 69% dos pacientes com captopril associado ao diurético e, em 50%, com clortalidona. Observou-se uma redução significativa da potassemia com clortalidona (4,2±0,7 para 3,7±0,4 mEq/L, p<0,01) e manutenção dos níveis de potássio com associação captopril e tiazídico. Este último tratamento também reduziu significativamente os níveis de colesterol (219±39 mg/dl para 202±39 mg/dl, p<0,04). Conclusão - Os resultados mostraram que a associação de captopril com dose baixa de tiazídico normaliza a PA em 69% de pacientes portadores de hipertensão arterial primária leve e moderada e age mais rapidamente que a clortalidona no controle pressórico, apresentando efeito metabólico benéfico de reduzir os níveis de colesterol sem alterar a potassemia

Purpose - To compara the antihypertensive and metabolic effects of captopril combined with hydrochlorothiazide (C+HCTZ) versus chlorthalidone (CT) in mild and moderate primary hypertensive patients. Methods - Fifty five patients, whithout treatment or treated with 15 days placebo were randomized for treatment with the combination of captopril 50mg and hydrochlorothiazide 25mg (n=29) against chlorthalidone (n=26). The clinical evaluation was done during placebo and monthly throughout three months, and the laboratory tests were done before and at the end of the study. Results - The blood pressure were similar between groups during placebo period (C+HCTZ: 161±25/102±6 - CT: 155±18/101±6 mmHg); the diastolic blood pressure decreases significantly at first month already in the group C+HCTZ (89±8 mmHg) comparad to group CT (94±8 mmHg, p<0,05). The percentile diastolic and mean blood pressure dropped, in average, 12% in C+HCTZ group and in CT varied between 7 (1st and 2nd month) to 11% (3rd month). Without statistical difference, the blood pressure normalization was obtained in 69% of the patients with the association captopril and diuretic and in 50% of the patients in the chlorthalidone group. It was observed a significant reduction of potassium in patients treated with chlorthalidone (4,2±0,7 to 3,7±0,4 mEq/L, p<0,01) that was not observed with the captopril and the thyazide associated. The last treatment also significantly reduced the cholesterol levels (219±39mg/dl to 202±39mg/dl, p<0,04). Conclusion - Our results indicate that captopril combined with low diuretic dose normalize the blood pressure in 69% mild to moderate primary hypertensive patients, and acts faster than chlorthalidone in this control. In addition has metabolic benefits reducing cholesterol levels with no alteration in potassium levels

Diureticos tiazidicos e hiperglicemia / Thiazide diuretics and hyperglycemia

Diureticos tiazidicos sao agentes diabetogenicos que atuam atraves de mecanismo nao perfeitamente esclarecido, que pode envolver disturbios na secrecao de insulina. A hipopotassemia pode ter papel na genese deste efeito. O tempo de uso da droga, necessario para que a acao hiperglicemiante se manifeste, depende da existencia ou nao de alteracao previa na tolerancia a glicose, e guarda relacao direta com a dose utilizada. Este efeito e, na maior parte dos casos, reversivel, e nao contra-indica o uso dos tiazidicos no tratamento da hipertensao, desde que sejam monitorizados os possiveis efeitos hiperglicemiantes.

Clortalidona em baixas doses no tratamento da hipertensäo arterial leve e moderada: análise de eficácia, freqüência de hipocalemia e distúrbios do ritmo cardíaco / Chlortalidone in low dosis in treatment of moderate arterial hypertension: analysis of efficacy, frequency of hypokalemia and disorders of cardiac rhythm

Clortalidona, 50 mg, foi administrada a cada 48 horas a 24 pacientes com hipertensäo arterial leve ou moderada, durante oito semanas consecutivas, após um período de duas semanas de placebo. Os níveis de pressäo arterial (PA) foram determinados nas posiçöes supina e ortostática, a cada duas semanas. Ao final da 2ª e 10ª semanas foram determinadas as seguintes variáveis laboratoriais: hemoglobina, hematócrito, creatinina, ácido úrico, potássio e glicose no sangue, além de eletrocardiograma em repouso. Eletrocardiografia dinâmica (sistema Holter) foi realizada no período placebo e após quatro e oito semanas de tratamento ativo. Houve reduçäo significativa da PA em ambas as posiçöes, com o tratamento anti-hipertensivo. Controle da PA (PAM < ou = 107 mmHg) foi observado em 62,5% dos pacientes. Das variáveis bioquímicas, apenas o potássio plasmático sofreu reduçäo significativa. Hipocalemia leve a moderada (3,0 K < 3,5 mEq/1) foi detectada em 25% dos pacientes. Hipocalemia severa (K*+ < 3,0 mEq/1) esteve ausente. Apenas um dos pacientes com hipocalemia desenvolveu extra-sistolia ventricular; este distúrbio do ritmo cardíaco também foi detectado em um paciente sem reduçäo significativa dos níveis séricos de potássio. Concluiu-se que a clortalidona, administrada em baixas doses (50 mg/48 horas) é eficaz no tratamento da hipertensäo arterial leve e moderada, com efeitos colaterais menos intensos e menos severos do que quando administrada em doses maiores, e que näo há associaçäo entre hipocalemia e disritmias cardíacas

[Photoallergy to Neotri and cross reaction to tenoretic--detection by systemic photoprovocation]. / Photoallergie auf Neotri mit Kreuzreaktion auf Teneretic--Nachweis durch systemische Photoprovokation.

A patient is presented who suffered for 3 years from increasing photosensitivity with chronic eczematous lesions in sun-exposed areas. He had taken one Neotri (triamterene, xipamide) tablet daily for 6 years. After discontinuation of the drug, phototesting and a photopatch test failed to reveal pathological reactions. Eczematous lesions, however, were induced in test areas upon systemic photochallenging with Neotri. One year later, after the antihypertensive medication had been changed from Adalat (nifedipine) to Teneretic (atenolol, chlortalidone) the eczematous photosensitive reaction recurred. Since both xipamide and chlortalidone have a chlorsulfamoyl-substituted aromatic ring in common, it seems that a photoallergic cross-reaction occurred.

Protean manifestations of neonatal hyperinsulinism.

Endogenous hyperinsulinism is the leading cause of persistent hypoglycemia in children under one year of age. Classically, the symptoms of neonatal hypoglycemia have been referable to central nervous system dysfunction, with seizures described in nearly all patients. Our experience with eight neonates emphasizes the protean manifestations of this disease. One patient presented with a maternal history of diuretic use, and developed asymptomatic hyperinsulinism documented by provocative testing. The hyperinsulinism cleared after two weeks of medical therapy. This transient hyperinsulinism may have been secondary to use of a thiazide-type diuretic. A second patient presented, as a neonate, with a large abdominal mass but no seizure activity. Exploratory laparotomy revealed an 11 x 5 x 3 cm pancreatic tumor, which required splenectomy, 60% gastrectomy and duodenectomy for removal. Histologic examination demonstrated an insulin-secreting hamartoma. A third patient died suddenly without prior symptoms, and was found to have striking nesidioblastosis on pathologic examination. One infant presented with absence of the abdominal musculature (prune belly syndrome) and features of the Beck-with-Wiedeman syndrome, as well as profound hypoglycemia. Only three patients had seizures, and an additional patient had jitteriness. Pathologic diagnoses were: nesidioblastosis (n = 2); islet cell hyperplasia (n = 1); adenoma (n = 1); hamartoma (n = 1); transient hyperinsulinism (n = 1). One patient's pancreas showed areas of nesidioblastosis, islet cell hyperplasia, and a discrete adenoma in the region of the common bile duct. Careful diagnostic testing is essential in these patients, inasmuch as hypoglycemia is poorly tolerated by neonates and infants. Using the diagnostic algorithm presented here, all patients' endogenous hyperinsulinism was documented quickly and efficiently. Recognition of the broad spectrum of symptoms with which these patients may present is essential if serious neurologic sequelae are to be avoided.

Drug-induced pancreatitis: a critical review.

We critically reviewed the English language literature pertaining to drug-induced pancreatitis and attempted to determine whether the reported association between each drug and pancreatitis was valid. The following drugs seem to cause pancreatitis: azathioprine, thiazides, sulfonamides, furosemide, estrogens, and tetracycline. Less convincing, but suggestive evidence exists for: 1-asparaginase, iatrogenic hypercalcemia, chlorthalidine, corticosteroids, ethacrynic acid, phenformin, and procainamide. Evidence implicating other drugs is either inadequate or contradictory. Little is known about the pathogenesis of drug-induced pancreatitis. Ethanol was not considered in this review.

Acute stomatitis medicamentosa. Two case reports.

Two cases of acute drug reaction with oral mucosal lesions and problems of diagnosis in the absence of specific clinical and histopathological findings are presented.

[Clinical and muscle istochemical observations in secondary hypokalaemia (author's transl)]. / Osservazioni cliniche ed istochimiche muscolari nell'ipopotassiemia secondaria: a proposito di un caso.

A case of hypokalaemia due to chronic administration of Clortalydone is reported. The histochemistry of muscle biopsy showed the morphologic changes which are usually found in the muscle fibers of periodic familial paralysis (necrotic fibers, accumulation of PAS positive substance, inflammatory cells, intermyofibrillar network degeneration, increase of lipids content). Such findings suggest some clues to the pathophysiology of the essential hypokalaemic paralysis and the possible practical importance of these histopathologic muscular findings in the diagnosis of secondary hypokalaemia.