Cumulative Incidence of Thiazide-Induced Hyponatremia : A Population-Based Cohort Study.

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.

A review of the prescribing trend of thiazide-type and thiazide-like diuretics in hypertension: A UK perspective.

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.

The effect of indapamide vs. bendroflumethiazide for primary hypertension: a systematic review.

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.

A combined connectivity mapping and pharmacoepidemiology approach to identify existing medications with breast cancer causing or preventing properties.

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.

[Rhabdomyolysis caused by thiazid-induced hypokalaemia].

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.

Life-threatening hyponatraemia.

A 31-year-old hypertensive woman was admitted to hospital with palpitations. Her hypertension was treated with bendroflumethiazide, which had been increased from 2.5 to 5 mg daily by her general practitioner about 18 months prior to her admission. She was also on ramipril 10 mg once daily. There were no abnormal findings on examination, and a 12-lead ECG showed sinus rhythm, rate 75, with Q waves in leads V1-V2. Telemetry (over 24 h) showed ventricular bigeminy when she had her typical palpitations. Her admission serum sodium and potassium concentrations were 132 and 3.4 mmol/l, respectively. Immediately prior to planned discharge the following day, she experienced paraesthesiae, weakness, confusion and seizures accompanied by 10 s asystole on the ECG monitor. Her serum sodium had fallen to 120 mmol/l and potassium to 2.3 mmol/l. Bendroflumethiazide and ramipril were discontinued and the patient was restricted to fluids of 1.5 l/24 h. She also received potassium supplements. Her serum sodium concentration rose to normal over 6 days, and she was discharged on feeling well.

Comparison of effects of combined ACE inhibitor and low-dose thiazide diuretic with ACE inhibitor alone on insulin action in patients with hypertension and Type 2 diabetes: a double-blind crossover study.

AIMS: To establish the safety in terms of insulin sensitivity of a low dose thiazide/ACE inhibitor combination. METHODS: We examined the effects on insulin sensitivity of captopril either alone or in combination with low-dose bendroflumethiazide (1.25 mg) in 15 hypertensive Type 2 diabetic patients. Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomised, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendroflumethiazide (CB) (1.25 mg). RESULTS: Blood pressure was lower following CB compare to C (138/83 vs. 144/85 mmHg; P < 0.05) and both were lower than baseline (153/92 mmHg; P < 0.01). CB resulted in a significant increase in fasting plasma glucose compared to C (9.6 +/- 2.6 vs. 8.5 +/- 1.6 mmol/l; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (25.1 +/- 13.3 vs. 34.2 +/- 16.8 micromol/kg/min; P < 0.01) as were isotopically determined glucose utilisation rates (29.0 +/- 12.4 vs. 36.6 +/- 17.3 micromol/kg/min; P < 0.05). There was no significant difference in fasting endogenous glucose production between treatments (CB 9.3 +/- 3.3 vs. C 8.6 +/- 1.6 micromol/kg/min), nor between suppression following insulin (CB 4.0 +/- 2.1 vs. C 4.3 +/- 3.1 micromol/kg/min). CONCLUSIONS: Combination of low-dose bendroflumethiazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.

Flecainide cardiotoxicity precipitated by electrolyte imbalance. Caution with thiazide diuretics.

A man presented with recurrent syncope, weakness and fatigue. His ECG showed marked QRS widening and he had gross hyponatraemia and hypokalaemia. His medications included bendroflumethiazide (long term) and flecainide (started 2 months previously). This presentation was consistent with flacainide cardiotoxicity exacerbated by electrolyte disturbance. The syncopal episodes probably represented life-threatening arrhythmias. The ECG and symptoms resolved completely once the electrolytes were corrected. Increased cardiotoxicity with hypokalaemia is documented, but not widely recognised. Hyponatraemia-induced flecainide cardiotoxicity has not been documented. The clinical effects of flecainide are due to use-dependent block of sodium channels. There are reports that support the use of hypertonic sodium salts to reverse flecainide toxicity via antagonism at the receptor. By this rationale, hyponatraemia would lead to Flecainide toxicity. Flecainide has been shown to reduce salt absorption in animal bowel. It is possible that in combination with bendroflumethiazide it acted synergistically to produce profound electrolyte disturbance. Flecainide cardiotoxicity has a significant mortality and can present non-specifically. Thus, early recognition is essential. This case demonstrates the importance of strict electrolyte control in patients who are on flecainide. We would discourage concomitant use of flecainide and bendroflumethiazide.

Efficacy and safety of 24 weeks of therapy with bendroflumethiazide 1.25 mg/day or 2.5 mg/day and potassium chloride compared with enalapril 10 mg/day and amlodipine 5 mg/day in patients with mild to moderate primary hypertension : a multicentre, randomised, open study.

BACKGROUND: The efficacy and safety of therapy with low-dose bendroflumethiazide 1.25 mg/day or 2.5 mg/day and potassium chloride was compared with that of enalapril 10 mg/day and amlodipine 5 mg/day in patients with mild to moderate primary hypertension. STUDY DESIGN: This was a multicentre study in general practice with patients randomised in a double-blind fashion and on open-label treatment. After a washout phase that lasted 4-6 weeks, 312 patients with a diastolic blood pressure of between 100 and 115 mm Hg were randomised in a double-blind fashion to treatment with either bendroflumethiazide 1.25 mg/day and potassium chloride (n = 117), bendroflumethiazide 2.5 mg/day and potassium chloride (n = 60), amlodipine 5 mg/day (n = 61) or enalapril 10 mg/day (n = 60), all given once daily (numbers in parentheses indicate the intention-to-treat population, with a total of 298 patients). The primary efficacy parameter was the reduction in diastolic blood pressure. Effects on systolic blood pressure, heart rate, biochemical variables, adverse events and quality of life were studied as secondary efficacy parameters. RESULTS: All treatments reduced diastolic blood pressure significantly; reductions were as follows: 6.8 mm Hg with bendroflumethiazide 1.25 mg/day, 9.1 mm Hg with bendroflumethiazide 2.5 mg/day, 10.8 mm Hg with amlodipine 5 mg/day and 6.8 mm Hg with enalapril 10 mg/day. The reduction in diastolic blood pressure on amlodipine was significantly greater than on bendroflumethiazide 1.25 mg/day and enalapril 10 mg/day (p = 0.013). The percentage of patients achieving a diastolic blood pressure of < 95 mm Hg was 34% (SD 4.4) with bendroflumethiazide 1.25 mg/day, 48% (SD 6.5) with bendroflumethiazide 2.5 mg/day (p = 0.075 vs bendroflumethiazide 1.25 mg/day), 57% (SD 6.3) with amlodipine 5 mg/day (p = 0.004 vs bendroflumethiazide 1.25 mg/day) and 41% (SD 6.4) with enalapril 10 mg/day (p = 0.41 vs bendroflumethiazide 1.25 mg/day) [mean reductions]. The effect on systolic blood pressure was similar with all treatments. No clinically significant changes occurred in heart rate, serum potassium, blood glucose, serum urate or serum cholesterol levels. The incidences of adverse events were similar in the low-dose bendroflumethiazide groups, with significantly higher incidences in the enalapril and amlodipine groups. Quality of life was similar in the different treatment groups, but the study had limited power to detect any difference in this parameter. CONCLUSION: The present study has confirmed, in a general practice population, that low-dose bendroflumethiazide (bendroflumethiazide 1.25-2.5 mg/day) in combination with potassium chloride is a well tolerated and efficacious first-line treatment for patients with mild to moderate essential hypertension.

Thiazide diuretic prescription and electrolyte abnormalities in primary care.

AIMS: Thiazide diuretics have a number of well-documented metabolic adverse effects. The aim of this study was to estimate the frequency of hyponatraemia and hypokalaemia amongst patients taking a thiazide diuretic in primary care. METHODS: A computerized search of the electronic prescribing and laboratory records of six UK general practices was performed. Of the 32 218 adult patients identified, 3773 had received at least one prescription for a thiazide between the years 1990 and 2002. RESULTS: Detailed prescribing data were available for 2942 patients of whom 951 (32.3%) had a recorded check of their electrolytes. One hundred and ninety-six (20.6%) had a sodium and/or potassium concentration below the normal range. The sodium distribution had a negative skew (-1.8) and in 130 (13.7%) patients was within the hyponatraemic range. Hypokalaemia was less common, occurring in 79 (8.5%) patients. Hyponatraemia was significantly associated with increased age; the odds ratio for developing hyponatraemia in patients over 70 years was 3.87 compared with those of < or = 70 years. Hypokalaemia was significantly associated with increased thiazide dose. CONCLUSIONS: Prescription of a thiazide diuretic in primary care is associated with a high frequency of hyponatraemia and hypokalaemia. Thiazides should be prescribed at low dose and the risk of hyponatraemia, especially in the elderly, should be considered and monitored for when prescribing these agents.

Cyclooxygenase inhibition causes marked impairment of renal function in elderly subjects treated with diuretics and ACE-inhibitors.

BACKGROUND: Treatment with angiotensin-converting enzyme (ACE)-inhibitors is known to cause an initial reduction in glomerular filtration rate (GFR) in patients with congestive heart failure. The long-term beneficial effects of ACE-inhibitors in these patients can be counteracted by cyclooxygenase-inhibitors. AIMS: To quantify the negative renal effects of the cyclooxygenase-inhibitor diclofenac in elderly healthy subjects and to assess how treatment with an ACE-inhibitor, after activation of the renin-angiotensin system, influences these renal effects. METHODS: Fourteen elderly, healthy subjects received oral diclofenac and placebo in a double-blind cross-over fashion. The study was divided in two parts; in part one, subjects received no pre-treatment and in part two, the subjects were given pre-treatment with bendroflumethiazide and enalapril in order to activate the renin-angiotensin system. RESULTS: Diclofenac induced significant (p<0.05) decreases in GFR, urine flow, excretion rates of sodium and potassium, electrolyte clearance, osmolality clearance and free water clearance both with and without renin-angiotensin system activation. Least square means (95% CI) of all observations during the first 6 h after dosing showed that diclofenac caused a reduction in GFR from 71 (64-78) to 59 (52-66) ml/min. After pre-treatment, diclofenac further reduced GFR from 60 (52-67) to 48 (40-55) ml/min. After diclofenac administration, urine flow fell from 7.4 (6.4-8.3) to 5.1 (4.2-6.1) ml/min, after pre-treatment, diclofenac gave a further reduction from 4.1 (3.1-5.1) to 2.2 (1.3-3.2) ml/min. More than half of the reductions were caused by the pre-treatment. CONCLUSION: Renal function in elderly, healthy subjects is impaired after acute intake of diclofenac. This impairment is observed both with and without activation of the renin-angiotensin system and ACE-inhibitor treatment but is more pronounced after pre-treatment.

Effects of furosemide and bendroflumethiazide on saliva flow rate and composition.

Aim of this study was to evaluate the effect on saliva flow rate and composition and on perceived xerostomia. The study used a Latin square design, all subjects being once daily (at 7.00 a.m.) taking the bendroflumethiazide (2.5 mg), furosemide (40 mg), or placebo, in a randomised order. Each treatment period of 7 days was separated by wash-out periods of 14 days. Unstimulated and paraffin chewing stimulated whole saliva, and 3% citric acid stimulated parotid and submandibular-sublingual secretion were collected twice daily, at 7.30 a.m., with the patients in a fasting condition (morning values), and at 10.30 a.m., about 2 h after intake of a standard breakfast (lunchtime values), on day 0 (baseline), day 1 (acute treatment), and day 7 (chronic treatment). Saliva flow rates were measured and all four secretions were analysed for the concentration of sodium, potassium, chloride, and total protein. Xerostomia was assessed by means of a Visual Analogue Scale. Statistical analysis used the Wilcoxon signed rank test. For flow rate, only that of submandibular-sublingual secretion was affected, significantly so in the morning during chronic treatment with both drugs. In resting whole saliva the output of both sodium and chloride tended to decrease especially during treatment with bendroflumethiazide, while in submandibular-sublingual secretion the output of all the electrolytes was decreased, especially for potassium and chloride and during treatment with furosemide. Further, xerostomia tended to increase during treatment with furosemide, statistically significant at lunchtime during chronic treatment. In conclusion, this study has demonstrated a modest effect on salivary flow rate and a more pronounced effect on saliva composition, especially in submandibular-sublingual secretion during treatment of healthy volunteers with therapeutic doses of two different diuretics, encouraging clinical studies in hypertensive patients and basic research as to the presence of a thiazide sensitive Na-Cl cotransporter in human salivary glands.