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In a trial involving patients with recurrent kidney stones who received once-daily 12.5-mg, 25-mg, or 50-mg doses of hydrochlorothiazide or placebo, the incidence of stone recurrence was similar in all groups.

The relative effectiveness of two-drug combinations for blood-pressure control in black African patients is unknown. In this three-group randomized trial, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide in lowering blood pressure.

Patients 65 or older with hypertension who switched from hydrochlorothiazide to chlorthalidone did not have fewer major cardiovascular events or non–cancer-related deaths than those who continued receiving hydrochlorothiazide.

Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill—a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14–23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

The optimal combination drug therapy for treatment of hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. This double-blind trial, in which high-risk patients with hypertension were randomly assigned to treatment with benazepril plus either amlodipine or hydrochlorothiazide, showed that benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular events in this population. This double-blind trial showed that benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular events in high-risk patients with hypertension. There is incomplete evidence that the cardiovascular benefits of specific classes of antihypertensive drugs extend beyond lowering blood pressure. 1 A review of clinical trials involving patients with hypertension who were at high risk for cardiovascular events showed that treatment with multiple antihypertensive medications was often necessary to attain blood-pressure goals recommended by guidelines. 2 , 3 In previous trials designed to test single agents, other drugs were often added for blood-pressure control, thus confounding the interpretation of the effects of the initial drug on the study end points. Initial therapy for hypertension with a combination of drugs is recommended by both the . . .

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease. ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12·5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1·73 m 2 or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950. The trial was terminated early (mean follow-up 2·9 years [SD 0·4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2·0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3·7%) in the benazepril plus hydrochlorothiazide group (HR 0·52, 0·41–0·65, p<0·0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33·7%; benazepril plus hydrochlorothiazide, 85 of 532, 16·0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group. Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent. Novartis.

In previous clinical trials in high-risk hypertensive patients, paradoxically higher cardiovascular event rates have been reported in patients of normal weight compared with obese individuals. As a prespecified analysis of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, we aimed to investigate whether the type of hypertension treatment affects patients' cardiovascular outcomes according to their body size. On the basis of body-mass index (BMI), we divided the full ACCOMPLISH cohort into obese (BMI ≥30, n=5709), overweight (≥25 to <30, n=4157), or normal weight (<25, n=1616) categories. The ACCOMPLISH cohort had already been randomised to treatment with single-pill combinations of either benazepril and hydrochlorothiazide or benazepril and amlodipine. We compared event rates (adjusted for age, sex, diabetes, previous cardiovascular events, stroke, or chronic kidney disease) for the primary endpoint of cardiovascular death or non-fatal myocardial infarction or stroke. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170950. In patients allocated benazepril and hydrochlorothiazide, the primary endpoint (per 1000 patient-years) was 30·7 in normal weight, 21·9 in overweight, and 18·2 in obese patients (overall p=0·0034). However, in those allocated benazepril and amlodipine, the primary endpoint did not differ between the three BMI groups (18·2, 16·9, and 16·5, respectively; overall p=0·9721). In obese individuals, primary event rates were similar with both benazepril and hydrochlorothiazide and benazepril and amlodipine, but rates were significantly lower with benazepril and amlodipine in overweight patients (hazard ratio 0·76, 95% CI 0·59–0·94; p=0·0369) and those of normal weight (0·57, 0·39–0·84; p=0·0037). Hypertension in normal weight and obese patients might be mediated by different mechanisms. Thiazide-based treatment gives less cardiovascular protection in normal weight than obese patients, but amlodipine-based therapy is equally effective across BMI subgroups and thus offers superior cardiovascular protection in non-obese hypertension. Novartis Pharmaceuticals.

Thiazide diuretics are widely used for the management of hypertension. In recent years, it has been actively debated that there is interchangeability of thiazide‐type diuretics hydrochlorothiazide and thiazide‐like diuretics including indapamide and chlorthalidone for the treatment of hypertension. With the purpose of seeking out the best thiazide diuretic for clinicians, we summarized the existing evidence on the two types of drugs and conducted a meta‐analysis on their efficacy in lowering blood pressure and effects on blood electrolyte, glucose and total cholesterol. Twelve trials were identified: five based on the comparison of indapamide versus hydrochlorothiazide and seven based on the chlorthalidone versus hydrochlorothiazide. In the meta‐analysis of blood pressure reduction, thiazide‐like diuretics seemed to further reduce systolic BP ([95% CI]; −5.59 [−5.69, −5.49]; P < 0.001) and diastolic BP ([95% CI]; −1.98 [−3.29, −0.66]; P = 0.003). Meanwhile, in the analysis of side effects, the incidence of hypokalemia ([95% CI]; 1.58 [0.80, 3.12]; P = 0.19), hyponatremia ([95% CI]; −0.14 [−0.57, 0.30], P = 0.54), change of blood glucose ([95% CI];0.13 [−0.16, 0.41], P = 0.39) and total cholesterol ([95% CI]; 0.13 [−0.16, 0.41], P = 0.39) showed that there is no statistical significant differences between the two groups of drugs. In conclusion, using thiazide‐like diuretics is superior to thiazide‐type diuretics in reducing blood pressure without increasing the incidence of hypokalemia, hyponatraemia and any change of blood glucose and serum total cholesterol.

Hyponatremia is a crucial complication of therapy with thiazide diuretics. This study compares the epidemiological and biochemical profiles and hospital course of patients using hydrochlorothiazide (HCTZ), indapamide (INDA), and chlorthalidone (CTD) admitted with thiazide‐associated hyponatremia (TAH). Data were obtained retrospectively from the hospital's digital registries. The epidemiological and biochemical parameters between the HCTZ, INDA, and CTD groups were compared. The correlation between dose and biochemical parameters in each group was performed. The thiazide groups without diuretic co‐medication were compared (HCTZ vs. INDA), and the correlation between dose and biochemical parameters in each group was examined. A comparison of the HCTZ (n = 135), INDA (n = 125), and CTD (n = 27) groups identified differences in serum potassium (s‐K; p = 0.03). The hyponatremia correction rate was slower in the CTD group at 96 h after admission (p < 0.001). After the exclusion of diuretic co‐medication, the HCTZ group (n = 64/135) showed a higher prevalence of ARBs, s‐K (both p < 0.001), and a lower median (IQR) equipotent dose (12.5 (o) mg vs. 2.5 (1.2) mg), prevalence of ACE‐I (p < 0.001), and eGFR (p = 0.03), when compared to the INDA group (n = 109/125). In conclusion, except for s‐K, we observed no significant difference in biochemical and epidemiological profiles between HCTZ, INDA, and CTD. After excluding the influence of other diuretics, we observed higher s‐K in the HCTZ group compared to the INDA group, potentially explained by the lower equipotent dose of HCTZ. The CTD group showed a statistically significant trend of slower hyponatremia correction.

Hypertension is a complex syndrome of multiple hemodynamic, neuroendocrine, and metabolic abnormalities. The goals of treatment in hypertension are to optimally control high blood pressure and to reduce associated cardiovascular morbidity and mortality using the most suitable therapy available. Hydrochlorothiazide (HCTZ) and chlorthalidone (CTLD) are with proven hypertensive effects. The topic of our meta-analysis is to compare the efficacy of HCTZ and CTLD therapy in patient with hypertension. A search of electronic databases PubMed, MEDLINE, Scopus, PsyInfo, eLIBRARY.ru was performed. We chose the random-effects method for the analysis and depicted the results as forest plots. Sensitivity analyses were performed in order to evaluate the degree of significance of each study. Of the 1289 identified sources, only nine trials directly compared HCTZ and CTLD and were included in the meta-analysis. Changes in SBP lead to WMD (95% CI) equal to −3.26 mmHg showing a slight but statistically significant prevalence of CTLD. Results from analyzed studies referring to DBP lead to WMD (95% CI) equal to −2.41 mmHg, which is also statistically significant. During our analysis, we found that there were not enough studies presenting enough data on the effect of CTLD and HCTZ on levels of serum potassium and serum sodium. Our meta-analysis has demonstrated a slight superiority for CTLD regarding blood pressure control. At the same time, the two medications do not show significant differences in their safety profile.