Preferred diuretic therapy for primary hypertension: Chlorthalidone or hydrochlorothiazide?

ABSTRACT: Because of its greater reduction of major adverse cardiovascular events (MACE), chlorthalidone is recommended over hydrochlorothiazide as the preferred diuretic for patients with primary hypertension. However, hydrochlorothiazide is more commonly prescribed than chlorthalidone for this condition. This article reviews recent studies investigating the effectiveness of chlorthalidone and hydrochlorothiazide in reducing MACE, to help clinicians make an evidence-based informed decision on which diuretic to prescribe.

Diuretics use in the management of hypertension.

Diuretics have been used for decades in the treatment of hypertension. Its efficacy has been demonstrated in numerous clinical trials. It is well known that the reduction in cardiovascular risk is a consequence of the reduction in blood pressure levels regardless of the drug used, but thiazide diuretics continue to be first-line drugs, especially in low doses and combined with other drugs. The debate on the advantages of using chlorthalidone or hydrochlorothiazide continues, however hydrochlorothiazide is drug most used and for which there is greater availability. The association with potassium-sparing diuretics increases the effectiveness and reduces the adverse reactions of thiazides. A new group of drugs, close to potassium-sparing diuretics, that antagonise aldosterone synthase are showing promising results as antihypertensives. There are no significant differences between men and women regarding the antihypertensive effect of thiazide diuretics.

Effect of antihypertensive agents on sleep apnea and ambulatory blood pressure in patients with hypertension: A randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) and hypertension are common conditions that may be linked through sympathetic activation and water retention. We hypothesized that diuretics, which reduce the body water content, may be more effective than amlodipine, a blood pressure (BP)-lowering agent implicated with edema, in controlling OSA in patients with hypertension. We also aimed to compare the effects of these treatments on ambulatory blood pressure monitoring (ABPM). METHODS: In a randomized, double-blind clinical trial, we compared the effects of chlorthalidone/amiloride 25/5 mg with amlodipine 10 mg on OSA measured by portable sleep monitor and BP measured by ABPM. The study included participants older than 40 who had moderate OSA (10-40 apneas/hour of sleep) and BP within the systolic range of 140-159 mmHg or diastolic range of 90-99 mmHg. RESULTS: The individuals in the experimental groups were comparable in age, gender, and other relevant characteristics. Neither the combination of diuretics nor amlodipine alone reduced the AHI after 8 weeks of treatment (AHI 26.3 with diuretics and 25.0 with amlodipine. P = 0.713). Both treatments significantly lowered office, 24-h, and nighttime ABP, but the two groups had no significant difference. CONCLUSION: Chlorthalidone associated with amiloride and amlodipine are ineffective in decreasing the frequency of sleep apnea episodes in patients with moderate OSA and hypertension. Both treatments have comparable effects in lowering both office and ambulatory blood pressure. The notion that treatments could offer benefits for both OSA and hypertension remains to be demonstrated. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT01896661.

Chlorthalidone vs Hydrochlorothiazide for Hypertension Treatment After Myocardial Infarction or Stroke: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures: Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures: Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results: The DCP randomized 13 523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12 068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance: Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ. Trial Registration: ClinicalTrials.gov Identifier: NCT02185417.

Use trends of chlorthalidone and hydrochlorothiazide among United States adults with hypertension: National Health and Nutrition Examination Survey 2009-2018.

OBJECTIVES: To estimate the national prevalence of chlorthalidone and hydrochlorothiazide use among adults diagnosed with hypertension by sociodemographic subgroup, healthcare access status, and clinical factors. METHODS: Data was extracted from the National Health and Nutrition Examination Survey for 2009-2010 through 2017-2018 survey waves. Patients at least 20 years old, diagnosed with hypertension, and on hydrochlorothiazide or chlorthalidone were included. Uni-variable logistic regression models estimated the odds of being on chlorthalidone compared with hydrochlorothiazide use by sociodemographic and clinical factors. Analyses were adjusted for multi-stage complex survey design and are nationally representative. RESULTS: Two thousand five hundred and eighty-five participants were included with 95.2% participants using hydrochlorothiazide and 4.8% using chlorthalidone. Participants over 65 years were more likely to be on chlorthalidone compared with younger counterparts [odds ratio (OR) 1.8; 95% confidence interval (CI) 1.12-2.88]. Participants with hypokalemia (OR 2.62; 95% CI 1.56-4.42) or hyponatremia [OR 2.298; 95% CI 1.23-4.30) were more likely to be using chlorthalidone compared with patients with normal levels. CONCLUSION: Chlorthalidone, a potent and effective first-line antihypertensive agent and thoroughly studied thiazide diuretic with substantial cardiovascular benefits, continues to be underutilized in patients with hypertension. Findings demonstrated that individuals receiving chlorthalidone were more likely to be 65 years or older and to experience hyponatremia or hypokalemia. Sociodemographic factors, healthcare access and use, clinical factors, and medical conditions did not appear to sway the choice in thiazide diuretic use.

Arterial Hypertension-clinical trials update 2023.

Arterial hypertension is associated with increased morbidity and mortality and research in the field is highly dynamic. This summary reviews the most important clinical trials published in 2022 and early 2023. Findings on new pharmacological approaches to treat resistant hypertension are presented and new knowledge about the optimal timing of the antihypertensive medication intake is discussed. It is focused on optimal blood pressure treatment targets and the problem of treatment and guideline inertia is acknowledged. Information about pregnancy-related hypertension is presented and blood pressure control following percutaneous thrombectomy after ischemic stroke is discussed. Finally, novel clinical data on device-based approaches to treat hypertension are summarized. The hypertension trials update summarizes the most important clincal trials on hypertension research in 2022 and early 2023. CTD - chlorthalidone, CV - cardiovascular, HCT - hydrochlorothiazide, SBP - systolic blood pressure, RDN - renal denervation *depicts systolic blood pressure only.

Chlorthalidone versus hydrochlorothiazide for preventing cardiovascular disease in hypertension: Is the case closed?

The optimal diuretic choice [hydrochlorothiazide (HCTZ) or chlorthalidone (CTD)] for the management of hypertension has been an ongoing debate for several years. HCTZ is widely used in the form of single-pill combinations, whereas CTD is a more potent drug vs. HCTZ, especially in reducing nighttime blood pressure (BP), with some indirect evidence suggesting a superiority in terms of cardiovascular (CV) risk reduction. In addition, recent data showed that CTD was safe and effective in terms of BP lowering in predialysis patients with stage 4 chronic kidney disease. The Diuretic Comparison Project was the first head-to-head pragmatic, open-label trial that randomly assigned elderly patients with hypertension under HCTZ therapy to continue with HCTZ or to switch to CTD (equivalent doses). Office BP was similar for both groups throughout the study. The trial showed no difference in major CV events or non-cancer-related deaths during a median follow-up of 2.4 years; yet, CTD was associated with a benefit in participants with a previous myocardial infarction or stroke, which might be a chance finding but could also indicate that a high-risk population is more suitable for revealing the impact of slight differences in the 24-hour BP profile in a relatively short-term follow-up. Interestingly CTD vs. HCTZ was associated with higher hypokalemia rates apart from the latter group of patients where there was no difference. Overall, the available data do not confirm the superiority of CTD over HCTZ in general, but this could be questionable in selected patients.

Usefulness of urinary potassium to creatinine ratio to predict diuretic response in patients with acute heart failure and preserved ejection fraction.

BACKGROUND: Patients with acute heart failure (AHF) require intensification in the diuretic strategy. However, the optimal diuretic strategy remains unclear. In this work, we aimed to evaluate the role of urinary potassium to creatinine ratio (K/Cr) to predict diuretic and natriuretic response to thiazide or mineralocorticoid receptor antagonists (MRAs) in a cohort of patients with AHF and preserved ejection fraction (AHF-pEF). HYPOTHESIS: Patients with a high urinary K/Cr ratio will have a better diuretic and natriuretic response with spironolactone versus chlorthalidone. METHODS: This is a study of 44 patients with AHF-pEF with suboptimal loop diuretic response. The primary endpoint was the baseline K/Cr associated with natriuretic and diuretic effect of chlorthalidone versus spironolactone at 24 and 72 h. Mixed linear regression models were used to analyze the endpoints. Estimates were reported as least squares mean with their respective 95% confidence interval (CIs). RESULTS: The median age of the study population was 85 years (82.5-88.5), and 30 (68.2%) were women. The inferential multivariate analysis suggested a greater natriuretic and diuretic effect of chlorthalidone across K/Cr levels. In the upper category, chlorthalidone translated into a statistically increase in natriuresis at 24 and 72 h. Chlorthalidone versus spironolactone showed ∆uNa of 25.7 mmol/L at 24 h (95% CI = -3.7 to 55.4, p = .098) and ∆uNa of 24.8 mmol/L at 72 h (95% CI = -4 to 53.6, p = .0106). The omnibus p value is .027. Multivariate analyses revealed a significant increase in 72 h cumulative diuresis irrespective of K/Cr status in those on chlorthalidone. CONCLUSIONS: In patients with AHF-pEF and suboptimal diuretic response, diuresis and natriuresis are higher with the administration of chlorthalidone over spironolactone. These data don't support the hypothesis that the K/Cr ratio can help guide the choice of thiazide diuretic versus MRA in AHF-pEF patients on loop diuretic.

Hypertension in chronic kidney disease-treatment standard 2023.

Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin-angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD.

Clortalidona para adultos com hipertensão arterial sistêmica com controle inadequado da pressão arterial / Chlorthalidone for adults with systemic arterial hypertension with inadequate blood pressure control

INTRODUÇÃO: A hipertensão arterial sistêmica (HAS), uma doença crônica, é um grave problema de saúde pública, caracterizada por níveis elevados e persistentes da pressão sanguínea, medidos em geral como uma razão da pressão arterial sistólica e diastólica (respectivamente maior ou igual a 140 mmHg; e/ou maior ou igual a 90 mmHg). Esta é uma doença altamente prevalente em todo o mundo. No Brasil, os números podem variar de acordo com a metodologia utilizada. Reportou-se na Pesquisa Nacional de Saúde de 2013, cujos dados são obtidos por autorrelato, a prevalência de hipertensão em 21% dos pacientes, mas ao considerar a aferição da pressão arterial e uso de medicamentos, o percentual de adultos com pressão arterial ≥140/90 mmHg foi de 32%. Sabe-se que a falta de controle da pressão arterial pode elevar o risco de ocorrência de eventos cardiovasculares, como infarto agudo do miocárdio, insuficiência cardíaca, acidente vascular cerebral, doenças renais, entre outros. Isso consequentemente pode causar problemas crônicos que reduzem a qualidade de vida do indivídu

In older adults with hypertension, chlorthalidone vs. hydrochlorothiazide did not reduce major CV events or deaths at 2.4 y.

SOURCE CITATION: Diuretic Comparison Project Writing Group; Ishani A, Cushman WC, Leatherman SM, et al. Chlorthalidone vs. hydrochlorothiazide for hypertension-cardiovascular events. N Engl J Med. 2022;387:2401-10. 36516076.

Reduced efficacy of blood pressure lowering drugs in the presence of diabetes mellitus-results from the TRIUMPH randomised controlled trial.

We investigated whether diabetes mellitus (DM) affects the efficacy of a low-dose triple combination pill and usual care among people with mild-moderate hypertension. TRIUMPH (TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension) was a randomised controlled open-label trial of patients requiring initiation or escalation of antihypertensive therapy. Patients were randomised to a once-daily low-dose triple combination polypill (telmisartan-20mg/amlodipine-2.5 mg/chlorthalidone-12.5 mg) or usual care. This analysis compared BP reduction in people with and without DM, both in the intervention and control groups over 24-week follow-up. Predicted efficacy of prescribed therapy was calculated (estimation methods of Law et al.). The trial randomised 700 patients (56 ± 11 yrs, 31% DM). There was no difference in the number of drugs prescribed or predicted efficacy of therapy between people with DM and without DM. However, the observed BP reduction from baseline to week 24 was lower in those with DM compared to non-diabetics in both the triple pill (25/11 vs 31/15 mmHg, p ≤ 0.01) and usual care (17/7 vs 22/11 mmHg, p ≤ 0.01) groups, and these differences remained after multivariable adjustment. DM was a negative predictor of change in BP (ß-coefficient -0.08, p = 0.02). In conclusion, patients with DM experienced reduced efficacy of BP lowering therapies as compared to patients without DM, irrespective of the type of BP lowering therapy received.

Financial implications of protocol-based hypertension treatment: an insight into medication costs in public and private health sectors in India.

Hypertension is a major public health challenge in low- and middle-income countries (LMICs) and calls for large-scale effective hypertension control programs. Adoption of drug and dose-specific treatment protocols recommended by the World Health Organization-HEARTS Initiative is key for hypertension control programs in LMICs. We estimated the annual medication cost per patient using three such protocols (protocol-1 and protocol-2 with Amlodipine, Telmisartan, using add-on doses and different drug orders, adding Chlorthalidone; protocol-3 with a single-pill combination (SPC) of Amlodipine/Telmisartan with dose up-titration, and addition of Chlorthalidone, if required) in India. The medication cost was simulated with different hypertension control assumptions for each protocol and calculated based on prices in the public and private sectors in India. The estimated annual medication cost per patient for protocol-1 and protocol-2 was $33.88-58.44 and $51.57-68.83 for protocol-3 in the private sector. The medication cost was lower in the generic stores ($5.78-9.57 for protocol-1 and protocol-2, and $7.35-9.89 for protocol-3). The medication cost for patients was the lowest ($2.05-3.89 for protocol-1 and protocol-2, and $2.94-3.98 for protocol-3) in the public sector. At less than $4 per patient per annum, scaling up a hypertension control program with specific treatment protocols is a potentially cost-effective public health intervention. Expanding low-cost generic retail networks would extend affordability in the private sector. The cost of treatment with SPC is comparable with non-SPC protocols and can be adopted in a public health program considering the advantage of simplified logistics, reduced pill burden, improved treatment adherence, and blood pressure control.