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Annals of Internal Medicine Jan 2024According 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...
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.
Topics: Humans; Sodium Chloride Symporter Inhibitors; Incidence; Thiazides; Cohort Studies; Hyponatremia; Antihypertensive Agents; Hydrochlorothiazide; Calcium Channel Blockers; Bendroflumethiazide; Hypertension
PubMed: 38109740
DOI: 10.7326/M23-1989 -
Current Opinion in Cardiology Jul 2015To determine usefulness and versatility of hydrochlorothiazide (HCTZ) relative to other thiazide diuretics in the treatment of hypertension. (Review)
Review
PURPOSE OF REVIEW
To determine usefulness and versatility of hydrochlorothiazide (HCTZ) relative to other thiazide diuretics in the treatment of hypertension.
RECENT FINDINGS
HCTZ was found to be less potent in lowering blood pressure (BP) than other thiazide diuretics, including chlorthalidone (CTD) and bendroflumethiazide. A recent meta-analysis also suggested HCTZ (12.5-25 mg daily) to be less potent than antihypertensive agents from several other classes, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and calcium antagonists. The risk of hyponatremia, hypokalemia, and hyperuricemia associated with HCTZ was lower than with CTD, while the risk of gouty arthritis was similar. Despite lower risks of metabolic side-effects, meta-analysis of clinical trials showed that, for any given difference in achieved clinic SBP, HCTZ therapy was associated with 18% higher adverse cardiovascular events when compared with CTD.
SUMMARY
Increasing evidence suggests inferiority of HCTZ in lowering BP and cardiovascular outcomes in hypertensive patients when compared with other drugs in the same class, particularly CTD and indapamide. Thus, HCTZ is neither more useful nor more versatile than other thiazide diuretics. CTD and indapamide should be preferred over HCTZ in most hypertensive patients when diuretics are required for treatment of hypertension.
Topics: Blood Pressure; Diuretics; Humans; Hydrochlorothiazide; Hypertension
PubMed: 26049382
DOI: 10.1097/HCO.0000000000000178 -
BMC Medicine Jul 2022Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with... (Meta-Analysis)
Meta-Analysis
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 .
Topics: Bendroflumethiazide; Carcinoma, Squamous Cell; Humans; Hydrochlorothiazide; Indapamide; Melanoma; Skin Neoplasms; Thiazides
PubMed: 35794547
DOI: 10.1186/s12916-022-02419-9 -
Danish Medical Journal Jun 2020Polypharmacy is associated with an increased risk of adverse health outcomes. This study aims to describe the prevalence of polypharmacy and medication use among older...
INTRODUCTION
Polypharmacy is associated with an increased risk of adverse health outcomes. This study aims to describe the prevalence of polypharmacy and medication use among older Danish citizens.
METHODS
From national registers, we extracted medicine use in relation to age group and residential region for the entire Danish population for the first half of 2016. The most frequently redeemed medicines among older citizens (≥ 75 years) in 2016 were grouped into clinically meaningful medication classes.
RESULTS
The prevalence of polypharmacy (> 5 different medicines) was 51% among citizens ≥ 75 years compared with 12% for the entire Danish population. The prevalence of polypharmacy increased with age and was 7% among citizens aged 40-49 years compared with 66% among citizens aged ≥ 90 years. There were only minor regional differences in the prevalence of polypharmacy. The most commonly redeemed medicine classes and individual medicines for older citizens were: 1) pain medication: paracetamol (50%) and tramadol (14%); 2) cardiovascular medicines: acetylsalicylic acid (26%), simvastatin (25%), metoprolol (22%), amlodipine (21%), furosemide (20%), bendroflumethiazide (17%), and losartan (14%); and 3) gastrointestinal medicines: pantoprazole (15%).
CONCLUSIONS
Polypharmacy is prevalent in Denmark with no relevant regional differences. The prevalence of polypharmacy increased with age, and more than half of the population aged ≥ 75 years redeemed prescriptions for > 5 different medicines. The most redeemed medicines among older citizens were against pain and cardiovascular disease.
FUNDING
none.
TRIAL REGISTRATION
not relevant.
Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Child; Child, Preschool; Cross-Sectional Studies; Denmark; Drug Prescriptions; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Polypharmacy; Prevalence; Young Adult
PubMed: 32741431
DOI: No ID Found -
Journal of Hypertension Oct 2019Thiazide diuretics and particularly hydrochlorothiazide were recently linked to an increased risk of skin cancer, which was attributed to the photosensitizing properties... (Review)
Review
BACKGROUND
Thiazide diuretics and particularly hydrochlorothiazide were recently linked to an increased risk of skin cancer, which was attributed to the photosensitizing properties of these drugs. Given the widespread use of thiazide diuretics, a potential skin cancer promoting effect would impose an important public health concern.
OBJECTIVE
To critically appraise in a narrative review, the association between use of thiazide and thiazide-like diuretics and risk of skin cancer.
METHODS
We evaluated chemical structures and photosensitizing potential of selected thiazide and thiazide-like diuretics. Moreover, we searched PubMed up to December 2018 for observational studies assessing the association between use of thiazide or thiazide-like diuretics and risk of skin cancer. Study quality was assessed for major methodological biases.
RESULTS
Commonly used thiazide and thiazide-like diuretics carry resonating structural components, such as sulfonamide groups that contribute to their photosensitizing activity. Overall, 13 observational (9 case-control, 4 cohort) studies assessed the association between use of different thiazide or thiazide-like diuretics and risk of several skin cancer types. Of those, nine studies showed positive associations ranging from 3% increased risk for bendroflumethiazide and basal cell carcinoma to 311% increased risk for thiazide diuretics and squamous cell carcinoma. All studies had important design-related methodological limitations including potential confounding by indication, detection bias, and time-window bias.
CONCLUSION
Commonly used thiazide and thiazide-like diuretics have photosensitizing potential, and some observational studies with important methodological limitations have linked their use to an increased risk of skin cancer. Well designed observational studies are needed to provide more solid evidence on this possible association.
Topics: Humans; Hydrochlorothiazide; Hypertension; Skin Neoplasms; Sodium Chloride Symporter Inhibitors
PubMed: 31145177
DOI: 10.1097/HJH.0000000000002136 -
Wilderness & Environmental Medicine Mar 2019The British Antarctic Survey Medical Unit works in a very remote area of the world, with several Antarctic bases receiving only a single annual resupply of consumable...
INTRODUCTION
The British Antarctic Survey Medical Unit works in a very remote area of the world, with several Antarctic bases receiving only a single annual resupply of consumable goods. Pharmaceuticals supplied in this manner will often be approaching or past the end of their nominal shelf life before the following year's resupply. Drugs are transported from the UK via ship; the hold is not temperature controlled, and the ship crosses through the tropics (air temperature 25-30°C for approximately 3 wk). The drugs then must be transported from the ship to the base, often in temperatures substantially below freezing. This study assessed the stability of 5 expired drugs (atropine, nifedipine, flucloxacillin, naproxen, and bendroflumethiazide) returned from Antarctic bases.
METHODS
Drugs were opportunistically obtained and tested using stability-indicating assays.
RESULTS
All tested drugs were stable.
CONCLUSIONS
The results suggest that the studied drugs may be stable beyond expiry, even when not maintained in strictly temperature-controlled conditions.
Topics: Antarctic Regions; Drug Stability; Drug Storage; Humans; Prescription Drugs; Time Factors; Wilderness Medicine
PubMed: 30718138
DOI: 10.1016/j.wem.2018.11.003 -
British Journal of Clinical Pharmacology Feb 2019The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure,... (Comparative Study)
Comparative Study
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.
Topics: Bendroflumethiazide; Blood Pressure; Coronary Artery Disease; Diuretics; Humans; Hypertension; Indapamide; Randomized Controlled Trials as Topic; Stroke; Survival Analysis; Treatment Outcome
PubMed: 30312512
DOI: 10.1111/bcp.13787 -
The Cochrane Database of Systematic... Aug 2017Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Adult; Antihypertensive Agents; Bendroflumethiazide; Blood Pressure; Cause of Death; Coronary Disease; Humans; Hypertension; Methyldopa; Middle Aged; Myocardial Infarction; Patient Dropouts; Propranolol; Randomized Controlled Trials as Topic; Stroke; Young Adult
PubMed: 28813123
DOI: 10.1002/14651858.CD008276.pub2