Comparative safety and effectiveness of angiotensin converting enzyme inhibitors and thiazides and thiazide-like diuretics under strict monotherapy.

Previous work comparing safety and effectiveness outcomes for new initiators of angiotensin converting-enzyme inhibitors (ACEi) and thiazides demonstrated more favorable outcomes for thiazides, although cohort definitions allowed for addition of a second antihypertensive medication after a week of monotherapy. Here, we modify the monotherapy definition, imposing exit from cohorts upon addition of another antihypertensive medication. We determine hazard ratios (HR) for 55 safety and effectiveness outcomes over six databases and compare results to earlier findings. We find, for all primary outcomes, statistically significant differences in effectiveness between ACEi and thiazides were not replicated (HRs: 1.11, 1.06, 1.12 for acute myocardial infarction, hospitalization with heart failure and stroke, respectively). While statistical significance is similarly lost for several safety outcomes, the safety profile of thiazides remains more favorable. Our results indicate a less striking difference in effectiveness of thiazides compared to ACEi and reflect some sensitivity to the monotherapy cohort definition modification.

Comparison of Class-Specific Side Effects Across Preventative Pharmacologic Therapies for Kidney Stone Disease.

INTRODUCTION: Clinical guidelines recommend monitoring for metabolic derangements while on preventive pharmacologic therapy for kidney stone disease. The study objective was to compare the frequency of side effects among patients receiving alkali citrate, thiazides, and allopurinol. METHODS: Using claims data from working-age adults with kidney stone disease (2008-2019), we identified those with a new prescription for alkali citrate, thiazide, or allopurinol within 12 months after their index stone-related diagnosis or procedure. We fit multivariable logistic regression models, adjusting for cohort characteristics like comorbid illness and medication adherence, to estimate 2-year measured frequencies of claims-based outcomes of acute kidney injury, falls/hip fracture, gastritis, abnormal liver function tests/hepatitis, hypercalcemia, hyperglycemia/diabetes, hyperkalemia, hypokalemia, hyponatremia, and hypotension. RESULTS: Our cohort consisted of 1776 (34%), 2767 (53%), and 677 (13%) patients prescribed alkali citrate, thiazides, or allopurinol, respectively. Comparing unadjusted rates of incident diagnoses, thiazides compared to alkali citrate and allopurinol were associated with the highest rates of hypercalcemia (2.3% vs 1.5% and 1.0%, respectively, P = .04), hypokalemia (6% vs 3% and 2%, respectively, P < .01), and hyperglycemia/diabetes (17% vs 11% and 16%, respectively, P < .01). No other differences with the other outcomes were significant. In adjusted analyses, compared to alkali citrate, thiazides were associated with a higher odds of hypokalemia (OR=2.01, 95% CI 1.44-2.81) and hyperglycemia/diabetes (OR=1.52, 95% CI 1.26-1.83), while allopurinol was associated with a higher odds of hyperglycemia/diabetes (OR=1.34, 95% CI 1.02-1.75). CONCLUSIONS: These data provide evidence to support clinical guidelines that recommend periodic serum testing to assess for adverse effects from preventive pharmacologic therapy.

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.

Association of Thiazide Diuretics With Diabetes Progression, Kidney Disease Progression, Cardiovascular Outcomes, and Death Among Patients With Diabetes Who Initiate Statins.

Statins have been associated with diabetes mellitus (DM) progression but their cardiovascular benefit in patients with DM outweigh the harm. However, the effects of concurrent use of other medications that similarly increase blood glucose level, such as thiazide diuretics, are not well studied. This study aimed to evaluate the association of concurrent use of thiazide diuretics and statins on DM progression, cardiovascular and renal outcomes, and death in patients with DM. This is a retrospective cohort study of Veterans with DM who initiated statins between 2003 and 2015. The cohort comprised thiazide users (concomitantly used thiazides and statins for ≥6 months) and active comparators (concomitantly used calciun channel blockers [CCB] but not thiazides and statins for ≥6 months). We excluded patients who were <18 years old, with chronic kidney disease stage 4 or worse, or used loop diuretics. We propensity-score-matched comparison groups on 99 baseline characteristics including demographics, healthcare utilization, co-morbidities, cardiovascular and co-morbidity scores, vital signs, laboratory data, and medication class usage. Outcomes were: (1) DM progression (new insulin initiation, increase in the number of glucose-lowering medication classes, and hyperglycemic episodes); (2) kidney disease progression (doubling of serum creatinine, incidence of chronic kidney disease stage 5, initiation of renal replacement therapy, and incidence of diabetic nephropathy); (3) cardiovascular outcomes (acute myocardial infarction, stroke, cardiac arrest); and (4) total mortality. From 297,967 statin users (228,509 Thiazide-statin users and 69,458 active comparators), we successfully matched 67,614 pairs. In comparison to active comparators, thiazide-statin users had increased risk of DM progression (65.6% in CCB group vs 68.1% in thiazide group; odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.09 to 1.15), decreased risk of kidney progression (16.9% in CCB group vs 16.5 in thiazide group; OR: 0.97, 95% CI: 0.94 to 0.99), decreased risk of cardiovascular outcomes (15.7% in CCB group vs 14.6% in thiazide group; OR: 0.92, 95% CI: 0.89 to 0.95), and similar risk of total mortality (19.7% in each group; OR: 1.00, 95% CI: 0.98 to 1.03). This study attempted to answer an important clinical question whether thiazide diuretics should be discontinued or substituted upon statin initiation. Our results showed that concurrent use of statin and thiazides in patients with DM was associated with DM progression but with less kidney progression and cardiovascular outcomes and no difference in mortality. Clinicians should closely monitor DM control when thiazides and statins are used concurrently.

First-line diuretics versus other classes of antihypertensive drugs for hypertension.

BACKGROUND: Different first-line drug classes for patients with hypertension are often assumed to have similar effectiveness with respect to reducing mortality and morbidity outcomes, and lowering blood pressure. First-line low-dose thiazide diuretics have been previously shown to have the best mortality and morbidity evidence when compared with placebo or no treatment. Head-to-head comparisons of thiazides with other blood pressure-lowering drug classes would demonstrate whether there are important differences. OBJECTIVES: To compare the effects of first-line diuretic drugs with other individual first-line classes of antihypertensive drugs on mortality, morbidity, and withdrawals due to adverse effects in patients with hypertension. Secondary objectives included assessments of the need for added drugs, drug switching, and blood pressure-lowering. SEARCH METHODS: Cochrane Hypertension's Information Specialist searched the Cochrane Hypertension Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers to March 2021. We also checked references and contacted study authors to identify additional studies. A top-up search of the Specialized Register was carried out in June 2022. SELECTION CRITERIA: Randomized active comparator trials of at least one year's duration were included. Trials had a clearly defined intervention arm of a first-line diuretic (thiazide, thiazide-like, or loop diuretic) compared to another first-line drug class: beta-blockers, calcium channel blockers, alpha adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, direct renin inhibitors, or other antihypertensive drug classes. Studies had to include clearly defined mortality and morbidity outcomes (serious adverse events, total cardiovascular events, stroke, coronary heart disease (CHD), congestive heart failure, and withdrawals due to adverse effects). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included 20 trials with 26 comparator arms randomizing over 90,000 participants. The findings are relevant to first-line use of drug classes in older male and female hypertensive patients (aged 50 to 75) with multiple co-morbidities, including type 2 diabetes. First-line thiazide and thiazide-like diuretics were compared with beta-blockers (six trials), calcium channel blockers (eight trials), ACE inhibitors (five trials), and alpha-adrenergic blockers (three trials); other comparators included angiotensin II receptor blockers, aliskiren (a direct renin inhibitor), and clonidine (a centrally acting drug). Only three studies reported data for total serious adverse events: two studies compared diuretics with calcium channel blockers and one with a direct renin inhibitor. Compared to first-line beta-blockers, first-line thiazides probably result in little to no difference in total mortality (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.84 to 1.10; 5 trials, 18,241 participants; moderate-certainty), probably reduce total cardiovascular events (5.4% versus 4.8%; RR 0.88, 95% CI 0.78 to 1.00; 4 trials, 18,135 participants; absolute risk reduction (ARR) 0.6%, moderate-certainty), may result in little to no difference in stroke (RR 0.85, 95% CI 0.66 to 1.09; 4 trials, 18,135 participants; low-certainty), CHD (RR 0.91, 95% CI 0.78 to 1.07; 4 trials, 18,135 participants; low-certainty), or heart failure (RR 0.69, 95% CI 0.40 to 1.19; 1 trial, 6569 participants; low-certainty), and probably reduce withdrawals due to adverse effects (10.1% versus 7.9%; RR 0.78, 95% CI 0.71 to 0.85; 5 trials, 18,501 participants; ARR 2.2%; moderate-certainty). Compared to first-line calcium channel blockers, first-line thiazides probably result in little to no difference in total mortality (RR 1.02, 95% CI 0.96 to 1.08; 7 trials, 35,417 participants; moderate-certainty), may result in little to no difference in serious adverse events (RR 1.09, 95% CI 0.97 to 1.24; 2 trials, 7204 participants; low-certainty), probably reduce total cardiovascular events (14.3% versus 13.3%; RR 0.93, 95% CI 0.89 to 0.98; 6 trials, 35,217 participants; ARR 1.0%; moderate-certainty), probably result in little to no difference in stroke (RR 1.06, 95% CI 0.95 to 1.18; 6 trials, 35,217 participants; moderate-certainty) or CHD (RR 1.00, 95% CI 0.93 to 1.08; 6 trials, 35,217 participants; moderate-certainty), probably reduce heart failure (4.4% versus 3.2%; RR 0.74, 95% CI 0.66 to 0.82; 6 trials, 35,217 participants; ARR 1.2%; moderate-certainty), and may reduce withdrawals due to adverse effects (7.6% versus 6.2%; RR 0.81, 95% CI 0.75 to 0.88; 7 trials, 33,908 participants; ARR 1.4%; low-certainty). Compared to first-line ACE inhibitors, first-line thiazides probably result in little to no difference in total mortality (RR 1.00, 95% CI 0.95 to 1.07; 3 trials, 30,961 participants; moderate-certainty), may result in little to no difference in total cardiovascular events (RR 0.97, 95% CI 0.92 to 1.02; 3 trials, 30,900 participants; low-certainty), probably reduce stroke slightly (4.7% versus 4.1%; RR 0.89, 95% CI 0.80 to 0.99; 3 trials, 30,900 participants; ARR 0.6%; moderate-certainty), probably result in little to no difference in CHD (RR 1.03, 95% CI 0.96 to 1.12; 3 trials, 30,900 participants; moderate-certainty) or heart failure (RR 0.94, 95% CI 0.84 to 1.04; 2 trials, 30,392 participants; moderate-certainty), and probably reduce withdrawals due to adverse effects (3.9% versus 2.9%; RR 0.73, 95% CI 0.64 to 0.84; 3 trials, 25,254 participants; ARR 1.0%; moderate-certainty). Compared to first-line alpha-blockers, first-line thiazides probably result in little to no difference in total mortality (RR 0.98, 95% CI 0.88 to 1.09; 1 trial, 24,316 participants; moderate-certainty), probably reduce total cardiovascular events (12.1% versus 9.0%; RR 0.74, 95% CI 0.69 to 0.80; 2 trials, 24,396 participants; ARR 3.1%; moderate-certainty) and stroke (2.7% versus 2.3%; RR 0.86, 95% CI 0.73 to 1.01; 2 trials, 24,396 participants; ARR 0.4%; moderate-certainty), may result in little to no difference in CHD (RR 0.98, 95% CI 0.86 to 1.11; 2 trials, 24,396 participants; low-certainty), probably reduce heart failure (5.4% versus 2.8%; RR 0.51, 95% CI 0.45 to 0.58; 1 trial, 24,316 participants; ARR 2.6%; moderate-certainty), and may reduce withdrawals due to adverse effects (1.3% versus 0.9%; RR 0.70, 95% CI 0.54 to 0.89; 3 trials, 24,772 participants; ARR 0.4%; low-certainty). For the other drug classes, data were insufficient. No antihypertensive drug class demonstrated any clinically important advantages over first-line thiazides. AUTHORS' CONCLUSIONS: When used as first-line agents for the treatment of hypertension, thiazides and thiazide-like drugs likely do not change total mortality and likely decrease some morbidity outcomes such as cardiovascular events and withdrawals due to adverse effects, when compared to beta-blockers, calcium channel blockers, ACE inhibitors, and alpha-blockers.

Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics.

Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.

Chloride and Potassium Assessment Is a Helpful Tool for Differential Diagnosis of Thiazide-Associated Hyponatremia.

CONTEXT: Differential diagnosis of thiazide-associated hyponatremia (TAH) is challenging. Patients can either have volume depletion or a syndrome of inappropriate antidiuresis (SIAD)-like presentation. OBJECTIVE: To evaluate the impact of the simplified apparent strong ion difference in serum (aSID; sodium + potassium - chloride) as well as the urine chloride and potassium score (ChU; chloride - potassium in urine) in the differential diagnosis of TAH, in addition to assessment of fractional uric acid excretion (FUA). METHODS: Post hoc analysis of prospectively collected data from June 2011 to August 2013 from 98 hospitalized patients with TAH < 125 mmol/L enrolled at University Hospital Basel and University Medical Clinic Aarau, Switzerland. Patients were categorized according to treatment response in volume-depleted TAH requiring volume substitution or SIAD-like TAH requiring fluid restriction. We computed sensitivity analyses with ROC curves for positive predictive value (PPV) and negative predictive value (NPV) of aSID, ChU, and FUA in differential diagnosis of TAH. RESULTS: An aSID > 42 mmol/L had a PPV of 79.1% in identifying patients with volume-depleted TAH, whereas a value < 39 mmol/L excluded it with a NPV of 76.5%. In patients for whom aSID was inconclusive, a ChU < 15 mmol/L had a PPV of 100% and a NPV of 83.3%, whereas FUA < 12% had a PPV of 85.7% and a NPV of 64.3% in identifying patients with volume-depleted TAH. CONCLUSION: In patients with TAH, assessment of aSID, potassium, and chloride in urine can help identifying patients with volume-depleted TAH requiring fluid substitution vs patients with SIAD-like TAH requiring fluid restriction.

What Dermatologists Should Know About Thiazides. / Tiazidas: lo que el dermatólogo debería saber.

Hydrochlorothiazide and other thiazide diuretics have been used for decades to treat high blood pressure, heart failure, and chronic kidney disease. Thiazides have been linked to photosensitivity with heterogeneous clinical manifestations and recovery times. Diagnosis can be aided by phototesting, photopatch testing, and skin biopsy. Long-term use of hydrochlorothiazide has been linked to an increased dose-dependent risk of certain types of skin cancer in recent years. In this review, we also look at other less common or lesser-known adverse effects of thiazide diuretics that have been described in isolated reports.

Thiazide-associated hyponatremia in internal medicine patients: analysis of epidemiological and biochemical profiles.

OBJECTIVES: Thiazide-associated hyponatremia (TAH) is a clinically important side effect of the therapy with thiazide and thiazide-like diuretics. This study aims to analyze epidemiological, biochemical, and symptomatological profiles (including volume status) of patients admitted with TAH. METHODS: A retrospective hospital record study was performed. Epidemiological and biochemical parameters and symptoms were compared between the thiazide (n = 143) and non-thiazide (n = 282) groups. Patients in the thiazide group were classified as hypo-, normo-, or hypervolemic. Furthermore, the comparison of epidemiological, biochemical, partially pharmacotherapeutical, and symptomatological parameters between the hypovolemic and normovolemic TAH groups was performed. RESULTS: The thiazide group showed lower s-Na (p = 0.008), s-K (p < 0.001), s-Cl (p < 0.001), measured s-osmolality (p = 0.021), and eGFR (p < 0.001); higher s-urea (p < 0.001), s-creatinine (p = 0.023), s-glucose (p < 0.001), u-osmolality (p = 0.012), u-Na (p < 0.001), u-K (p = 0.023), and u-Cl (p < 0.001). Patients using thiazide were older (p < 0.001), more likely to be female (p = 0.011), and with symptoms corresponding more to chronic hyponatremia. Compared to the normovolemic group (n = 93; 65%), the hypovolemic patients (n = 47; 32.9%) showed higher s-urea (p = 0.005), s-creatinine (p = 0.045), and s-UA (p = 0.010); lower eGFR (p = 0.032), u-Na (p = 0.015), u-Cl (p = 0.016), anorexia (p < 0.001), and a higher frequency of furosemide use (p < 0.001). CONCLUSIONS: Thiazide use is a crucial etiological cause of hypotonic hyponatremia among internal medicine inpatients, associated with more severe hyponatremia, but with no difference in the in-hospital mortality. Even in hypo-osmolar conditions of TAH, 32.9% of patients exhibited signs of volume depletion. FE-UA did not differ between the hypovolemic and the normovolemic patients in TAH conditions. Anorexia and the combination of thiazide together with furosemide, rather than thiazide use alone, were risk factors for hypovolemic hyponatremia without affecting FE-UA.

Impact of Antihypertensive Drug Class on Outcomes in SPRINT.

BACKGROUND: The primary objective of this analysis is to assess if greater exposure to any major antihypertensive drug class was associated with reduced primary composite outcome events in SPRINT (Systolic Blood Pressure Intervention Trial). METHODS: This is a secondary analysis of the SPRINT trial evaluating whether longitudinal, time varying exposure to any major antihypertensive drug class had any impact on primary outcome events, after adjusting for effects of randomization arm, time varying achieved systolic blood pressure, other drug class exposure, and baseline characteristics. RESULTS: Nine thousand two hundred fifty-two participants were included. After adjustments, exposure of one year or greater to thiazide-type diuretics or renin-angiotensin system blockers was associated with significantly fewer primary events than exposure of less than one year (hazard ratio, 0.78 [95% CI, 0.64-0.94]). There was no significant difference with longer versus shorter exposure to calcium channel blockers. Greater exposure to beta-blockers was associated with an increase in primary events compared with exposure of <1 year (hazard ratio, 1.35 [95% CI, 1.13-1.62]). Furthermore, thiazide-type diuretics were associated with a reduction in heart failure events and renin-angiotensin system blockers with reduced myocardial infarction. Both were associated with less cardiovascular deaths. CONCLUSIONS: The SPRINT trial demonstrated a lower target blood pressure led to reductions in adverse cardiovascular events. This analysis suggests greater exposure to thiazide-type diuretics and renin-angiotensin system blockers also contributed to reduced adverse cardiovascular events. Greater exposure to beta-blockers was associated with increased cardiovascular events.

Diuretic-induced hypokalaemia: an updated review.

Diuretic-induced hypokalaemia is a common and potentially life-threatening adverse drug reaction in clinical practice. Previous studies revealed a prevalence of 7%-56% of hypokalaemia in patients taking thiazide diuretics. The clinical manifestations of hypokalaemia due to diuretics are non-specific, varying from asymptomatic to fatal arrhythmia. Diagnosis of hypokalaemia is based on the level of serum potassium. ECG is useful in identifying the more severe consequences. A high dosage of diuretics and concomitant use of other drugs that increase the risk of potassium depletion or cardiac arrhythmias can increase the risk of cardiovascular events and mortality. Thiazide-induced potassium depletion may cause dysglycaemia. The risk of thiazide-induced hypokalaemia is higher in women and in black people. Reducing diuretic dose and potassium supplementation are the most direct and effective therapies for hypokalaemia. Combining with a potassium-sparing diuretic or blocker of the renin-angiotensin system also reduces the risk of hypokalaemia. Lowering salt intake and increasing intake of vegetables and fruits help to reduce blood pressure as well as prevent hypokalaemia.

[Hyponatremia and thiazides]. / Hyponatrémie et diurétiques thiazidiques.

Thiazide diuretics (hydrochlorothiazide) and « thiazide-like ¼ (chlorthalidone, indapamide) are widely prescribed due to their effectiveness in the treatment of arterial hypertension. The use of thiazides may be complicated by hyponatremia that is associated with increased morbidity and mortality. The pathophysiology of thiazide-induced hyponatremia is not yet clear. It is currently difficult to predict who will develop thiazide-induced hyponatremia. Genetic predisposition is considered, and several studies are attempting to clarify it in order to identify patients at risk of developing hyponatremia after taking a thiazide. Their reintroduction to a patient who already presented hyponatremia upon thiazide should be avoided.

Les diurétiques thiazidiques (hydrochlorothiazide) et thiazidiques apparentés (chlortalidone, indapamide) sont largement prescrits du fait de leur efficacité dans le traitement de l'hypertension artérielle. La prise de thiazidiques peut se compliquer d'une hyponatrémie associée à une morbidité et une mortalité augmentées. La physiopathologie de cette hyponatrémie n'est pas encore totalement élucidée. Il est à l'heure actuelle difficile de prédire qui va présenter une hyponatrémie induite par les thiazidiques. Une susceptibilité génétique a été envisagée et plusieurs études tentent de la préciser dans le but d'identifier les patients à risque de développer une hyponatrémie après la mise sous thiazidiques. Chez un patient qui a présenté une hyponatrémie sur thiazidiques, leur réintroduction devrait être évitée.

Correlations Among Visit-to-Visit Blood Pressure Variability and Treatment With Antihypertensive Medication With Long-Term Adverse Outcomes in a Large Veteran Cohort.

BACKGROUND: Blood pressure variability (BPV) is associated with adverse events (AEs) independently of hypertension. It has been suggested that calcium channel blockers (CCBs) may reduce BPV, and thus be particularly valuable in hypertensives with high BPV. We sought to investigate how CCB affect BPV progression and whether long-term adverse effects of BPV differ after CCB treatment than after treatment with other antihypertensives. METHODS: We retrospectively analyzed 25,268 US veterans who had been followed for 3 years without hypertensive therapy, started on a single class of antihypertensive agents (thiazides, CCBs, ACE inhibitors, or beta blockers [BBs]), treated for 6 years, and then followed for 3 additional years. BPV was calculated as SD of systolic or diastolic blood pressures from at least 10 measurements over each 3-year period. A combined AE endpoint included hospitalization, coronary artery bypass grafting, carotid endarterectomy, angioplasty, amputation, arteriovenous fistula creation, and mortality was assessed in years 9-12. RESULTS: Post-medication high BPV and BB or thiazide use were associated with increased AE risk. Medication type also affected mean post-medication BPV. The effects of medications except for BBs on AE and mortality was independent of the patient BPV. CONCLUSIONS: The possible deleterious effects of thiazides should be considered within the context of the study population, who were mostly male and received only a single class of hypertensives. While CCB may ameliorate BPV over time, this study does not support choosing CCB over other agents specifically to lessen BPV-associated risk.

Risk of skin cancer in new users of thiazides and thiazide-like diuretics: a cohort study using an active comparator group.

BACKGROUND: Case-control studies report a dose-dependent increased risk of skin cancer in users of hydrochlorothiazide (HCTZ) vs. nonusers. The degree to which other thiazides and thiazide-like diuretics (TZs) are associated with skin cancer is less certain. OBJECTIVES: To assess the risk of skin cancer in new users of different TZs compared with new users of calcium channel blockers (CCBs). METHODS: We conducted a cohort study using a UK primary-care database (1998-2017), including 271 154 new TZ users [87·6% bendroflumethiazide (BFT), 5·8% indapamide and 3·6% HCTZ] and 275 263 CCB users. The outcomes were basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). We estimated incidence rates (IRs) and IR ratios (IRRs) in short-term (< 20 prescriptions) and long-term (≥ 20 prescriptions) users of TZs and CCBs using negative binomial regression, and calculated rate differences (RDs) for selected results. We used fine stratification on the propensity score (PS) to control for 23 baseline covariates. RESULTS: Long-term use of HCTZ increased absolute and relative risks of SCC [PS-weighted IRR 1·95; 95% confidence interval (CI) 1·87-2·02; RD per 100 000 person-years 87.4], but not of BCC or CMM. Long-term use of indapamide was associated with an increased incidence of CMM (IRR 1·43; 95% CI 1·35-1·50). BFT was not meaningfully associated with the risk of any type of skin cancer. CONCLUSIONS: Our results corroborate the previously reported increased risk of SCC (but not of BCC or CMM) for long-term use of HCTZ. BFT may be a safer alternative for patients at increased risk of skin cancer.

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

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

Risk of Developing Hypokalemia in Patients With Hypertension Treated With Combination Antihypertensive Therapy.

Little is known about the occurrence of hypokalemia due to combination therapy for hypertension. Using data from Danish administrative registries, we investigated the association between different combinations of antihypertensive therapy and risk of developing hypokalemia. Using incidence density matching, 2 patients without hypokalemia were matched to a patient with hypokalemia (K, <3.5 mmol/L) on age, sex, renal function, and time between index date and date of potassium measurement. Combination therapies were subdivided into 10 groups including ß-blockers (BB)+thiazides (BB+thiazides), calcium channel blockers (CCB)+renin angiotensin system inhibitors (RASi)+thiazides (CCB+RASi+Thiazides), calcium channel blockers+thiazides (CCB+thiazides), and ß-blockers+renin angiotensin system inhibitors+thiazides (BB+RASi+thiazides). We used conditional logistic regression to estimate the odds of developing hypokalemia for different combinations of antihypertensive drugs within 90 days of combination therapy initiation. We matched 463 patients with hypokalemia to 926 patients with normal potassium concentrations. The multivariable analysis showed 5.82× increased odds of developing hypokalemia if administered CCB+thiazides (95% CI, 3.06-11.08) compared with CCB+RASi. Other combinations significantly associated with increased hypokalemia odds were BB+thiazides (odds ratio, 3.34 [95% CI, 1.67-6.66]), CCB+RASi+thiazides (odds ratio, 3.07 [95% CI, 1.72-5.46]), and BB+RASi+thiazides (odds ratio, 2.78 [95% CI, 1.41-5.47]). Combinations of thiazides with CCB, RASi, or BB were strongly associated with increased hypokalemia risk within 90 days of treatment initiation.

Thiazide Exposure and Cardiovascular Risk in Type 2 Diabetes Mellitus: A Point of Clarification.

A recently published analysis in Hypertension suggests that thiazide use, versus nonuse, is associated with excess risk of adverse cardiovascular outcomes in patients with diabetes mellitus enrolled in the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes). Here, we replicate these findings using the same publicly available datasets and following their reported methods. We further show that possible misclassification of thiazide exposure exists in the original analysis. We perform alternative analyses that correct for this misclassification to highlight the impact that misclassification can have on observed associations between an exposure (eg, thiazides) and outcomes (eg, stroke and major adverse cardiovascular events).

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

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

Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology.

Hyponatremia can complicate thiazide use in a minority of susceptible individuals and can result in significant morbidity and even mortality. Risk factors for thiazide-associated hyponatremia include age, female sex, and possibly low body mass. A genetic susceptibility has recently been uncovered. Although frequently developing early after thiazide treatment initiation, many cases of hyponatremia present after months or years of use. Many cases are asymptomatic or have mild symptoms, but seizures and/or coma may develop, especially in those with acute onset. The pathophysiology is incompletely understood and includes some combination of excessive fluid intake, cation (sodium and potassium) depletion, osmotic inactivation of sodium, and reduced ability to excrete free water. Reduced distal delivery of filtrate, reduced solute load (urea), direct inhibition of the sodium-chloride cotransporter, and increased collecting duct permeability to water mediated by some combination of antidiuretic hormone, prostaglandins, and thiazides themselves may contribute to this diluting defect. The predominant pathophysiologic mechanism(s) varies from patient to patient. The cornerstone of therapy is cessation of thiazide use, cation repletion, and oral fluid restriction. If severely symptomatic, 3% saline solution may be indicated. Overly rapid correction of chronic hyponatremia must be avoided in all cases.