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The effect of trichlormethiazide in autosomal dominant polycystic kidney disease patients receiving tolvaptan: a randomized crossover controlled trial.
Uchiyama, K, Kitayama, C, Yanai, A, Ishibashi, Y
Scientific reports. 2021;(1):17666
Abstract
The vasopressin V2 receptor antagonist tolvaptan delays the progression of autosomal dominant polycystic kidney disease (ADPKD). However, some patients discontinue tolvaptan because of severe adverse aquaretic events. This open-label, randomized, controlled, counterbalanced, crossover trial investigated the effects of trichlormethiazide, a thiazide diuretic, in patients with ADPKD receiving tolvaptan (n = 10) who randomly received antihypertensive therapy with or without trichlormethiazide for 12 weeks. The primary and secondary outcomes included amount and osmolarity of 24-h urine and health-related quality-of-life (HRQOL) parameters assessed by the Kidney Disease Quality of Life-Short Form questionnaire, renal function slope, and plasma/urinary biomarkers associated with disease progression. There was a significant reduction in urine volume (3348 ± 584 vs. 4255 ± 739 mL; P < 0.001) and a significant increase in urinary osmolarity (182.5 ± 38.1 vs. 141.5 ± 38.1 mOsm; P = 0.001) in patients treated with trichlormethiazide. Moreover, trichlormethiazide improved the following HRQOL subscales: effects of kidney disease, sleep, emotional role functioning, social functioning, and role/social component summary. No significant differences were noted in renal function slope or plasma/urinary biomarkers between patients treated with and without trichlormethiazide. In patients with ADPKD treated with tolvaptan, trichlormethiazide may improve tolvaptan tolerability and HRQOL parameters.
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Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response.
Shahin, MH, Sá, AC, Webb, A, Gong, Y, Langaee, T, McDonough, CW, Riva, A, Beitleshees, AL, Chapman, AB, Gums, JG, et al
Circulation. Cardiovascular genetics. 2017;(1)
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BACKGROUND Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to identify novel biomarkers of thiazide diuretics BP response. METHODS AND RESULTS Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P <5×10-5 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (Δ systolic BP/Δ diastolic BP: -12.3/-8.2 versus -6.8/-3.5 mm Hg, respectively, Δ systolic BP P=3×10-4, Δ diastolic BP P=5×10-5). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P=0.01). This finding was replicated in independent participants treated with chlorthalidone (P=0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r2=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression. CONCLUSIONS This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.
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[Not Available].
Muheim, L
Praxis. 2017;(5):271-272
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Patterns and Correlates of Baseline Thiazide-Type Diuretic Prescription in the Systolic Blood Pressure Intervention Trial.
Chang, TI, Evans, G, Cheung, AK, Cushman, WC, Diamond, MJ, Dwyer, JP, Huan, Y, Kitzman, D, Kostis, JB, Oparil, S, et al
Hypertension (Dallas, Tex. : 1979). 2016;(3):550-5
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Thiazides and thiazide-type diuretics are recommended as first-line agents for the treatment of hypertension, but contemporary information on their use in clinical practice is lacking. We examined patterns and correlates of thiazide prescription in a cross-sectional analysis of baseline data from participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). We examined baseline prescription of thiazides in 7582 participants receiving at least 1 antihypertensive medication by subgroup, and used log-binomial regression to calculate adjusted prevalence ratios for thiazide prescription (versus no thiazide). Forty-three percent of all participants were prescribed a thiazide at baseline, but among participants prescribed a single agent, the proportion was only 16%. The prevalence of thiazide prescription differed significantly by demographic factors, with younger participants, women, and blacks all having higher adjusted prevalence of thiazide prescription than other corresponding subgroups. Participants in the lowest category of kidney function (estimated glomerular filtration rate <30 mL/min per 1.73 m2) were half as likely to be prescribed a thiazide as participants with preserved kidney function. In conclusion, among persons with hypertension and heightened cardiovascular risk, we found that thiazide prescription varied significantly by demographics and kidney disease status, despite limited evidence about relative differences in effectiveness.
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Relationship Between Changes in Serum Urate and Bone Mineral Density During Treatment with Thiazide Diuretics: Secondary Analysis from a Randomized Controlled Trial.
Dalbeth, N, Gamble, GD, Horne, A, Reid, IR
Calcified tissue international. 2016;(5):474-8
Abstract
In observational studies, serum urate concentrations associate with bone mineral density (BMD) and reduced risk of fractures. Thiazide diuretics slow the bone loss in healthy older adults, are associated with reduced incidence of fracture and also increase serum urate. We hypothesized that changes in serum urate are associated with changes in BMD during treatment with thiazide diuretics. We analysed data from a double-blind randomized controlled trial of hydrochlorothiazide (50 mg per day) and placebo in normal post-menopausal women. The relationship between change in serum urate and change in BMD after 2 years of treatment was examined using Spearman correlation and multiple linear regression models. Total body BMD increased in the hydrochlorothiazide group by 0.52 % and reduced in the placebo group by 0.29 % over 2 years (between group difference P = 0.0034). Serum urate increased in the hydrochlorothiazide group by 0.038 mmol/L and reduced in the placebo group by 0.004 mmol/L (between group difference P < 0.0001). At Year 2, there was a positive relationship between the change in serum urate and change in total body BMD for entire study population (r = 0.32, P = 0.0002) and for the hydrochlorothiazide group (r = 0.29, P = 0.023). The association between change in serum urate and change in total body BMD persisted after adjusting for treatment allocation, and change in weight, serum calcium, urinary calcium and serum creatinine (P change in serum urate = 0.043). These data raise the possibility that the effects of hydrochlorothiazide on BMD may be mediated, in part, by changes in serum urate concentrations.
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A theory-based process evaluation alongside a randomised controlled trial of printed educational messages to increase primary care physicians' prescription of thiazide diuretics for hypertension [ISRCTN72772651].
Presseau, J, Grimshaw, JM, Tetroe, JM, Eccles, MP, Francis, JJ, Godin, G, Graham, ID, Hux, JE, Johnston, M, Légaré, F, et al
Implementation science : IS. 2016;(1):121
Abstract
BACKGROUND Pragmatic trials of implementation interventions focus on evaluating whether an intervention changes professional behaviour under real-world conditions rather than investigating the mechanism through which change occurs. Theory-based process evaluations conducted alongside pragmatic randomised trials address this by assessing whether the intervention changes theoretical constructs proposed to mediate change. The Ontario Printed Educational Materials (PEM) cluster trial was designed to increase family physicians' guideline-recommended prescription of thiazide diuretics. The trial found no intervention effect. Using the theory of planned behaviour (TPB), we hypothesised that changes in thiazide prescribing would be reflected in changes in intention, consistent with changes in attitude and subjective norm, with no change to their perceived behavioural control (PBC), and tested this alongside the RCT. METHODS We developed and sent TPB postal questionnaires to a random sub-sample of family physicians in each trial arm 2 months before and 6 months after dissemination of the PEMs. We used analysis of covariance to test for group differences using a 2 × 3 factorial design. We content-analysed an open-ended question about perceived barriers to thiazide prescription. Using control group data, we tested whether baseline measures of TPB constructs predicted self-reported thiazide prescribing at follow-up. RESULTS Four hundred twenty-six physicians completed pre- and post-intervention questionnaires. Baseline scores on measures of TPB constructs were high: intention mean = 5.9 out of 7 (SD = 1.4), attitude mean = 5.8 (SD = 1.1), subjective norm mean = 5.8 (SD = 1.1) and PBC mean = 6.2 (SD = 1.0). The arms did not significantly differ post-intervention on any of the theory-based constructs, suggesting a possible ceiling effect. Content analysis of perceived barriers suggested post-intentional barriers to prescribing thiazides most often focused on specific patient clinical characteristics and potential side effects. Baseline intention (β = 0.63, p < 0.01) but not PBC (β = 0.04, p = 0.78) predicted 42.6 % of the variance in self-reported behaviour at follow-up in the control group. CONCLUSIONS Congruent with the Ontario Printed Educational Messages trial results and aligned with the TPB, we saw no impact of the intervention on any TPB constructs. The theoretical basis of this evaluation suggests possible explanations for the failure of the PEM intervention to change professional behaviour, which can directly inform the design and content of future theory-based PEM interventions to change professional behaviour. TRIAL REGISTRATION ISRCTN, Canada ISRCTN72772651.
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Printed educational messages fail to increase use of thiazides as first-line medication for hypertension in primary care: a cluster randomized controlled trial [ISRCTN72772651].
Zwarenstein, M, Grimshaw, JM, Presseau, J, Francis, JJ, Godin, G, Johnston, M, Eccles, MP, Tetroe, J, Shiller, SK, Croxford, R, et al
Implementation science : IS. 2016;(1):124
Abstract
BACKGROUND Evidence on the effectiveness of printed educational messages in contributing to increasing evidence-based clinical practice is contradictory. Nonetheless, these messages flood physician offices, in an attempt to promote treatments that can reduce costs while improving patient outcomes. This study evaluated the ability of printed educational messages to promote the choice of thiazides as the first-line treatment for individuals newly diagnosed with hypertension, a practice supported by good evidence and included in guidelines, and one which could reduce costs to the health care system. METHODS The study uses a pragmatic, cluster randomized controlled trial (randomized by physician practice group). SETTING The setting involves all Ontario general/family practice physicians. Messages advising the use of thiazides as the first-line treatment of hypertension were mailed to each physician in conjunction with a widely read professional newsletter. Physicians were randomized to receive differing versions of printed educational messages: an "insert" (two-page evidence-based article) and/or one of two different versions of an "outsert" (short, directive message stapled to the outside of the newsletter). One outsert was developed without an explicit theory and one with messages developed targeting factors from the theory of planned behaviour or neither (newsletter only, with no mention of thiazides). The percentage of patients aged over 65 and newly diagnosed with hypertension who were prescribed a thiazide as the sole initial prescription medication. The effect of the intervention was estimated using a logistic regression model estimated using generalized estimating equation methods to account for the clustering of patients within physician practices. RESULTS Four thousand five hundred four physicians (with 23,508 patients) were randomized, providing 97 % power to detect a 5 % absolute increase in prescription of thiazides. No intervention effect was detected. Thiazides were prescribed to 27.6 % of the patients who saw control physicians, 27.4 % for the insert, 26.8 % for the outsert and 28.3 % of the patients who saw insert + outsert physicians, p = 0.54. CONCLUSIONS The study conclusively failed to demonstrate any impact of the printed educational messages on increasing prescribing of thiazide diuretics for first-line management of hypertension. TRIAL REGISTRATION ISRCTN72772651.
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TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives.
Chittani, M, Zaninello, R, Lanzani, C, Frau, F, Ortu, MF, Salvi, E, Fresu, G, Citterio, L, Braga, D, Piras, DA, et al
Journal of hypertension. 2015;(6):1301-9
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BACKGROUND Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. METHODS AND RESULTS We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. CONCLUSION This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.
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Should thiazide diuretics be given as first line antihypertensive therapy or in addition to other medications?
Trimarco, V, Izzo, R, Migliore, T, Rozza, F, Marino, M, Manzi, MV, De Marco, M, de Simone, G, De Luca, N
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension. 2015;(1):55-9
Abstract
INTRODUCTION The recommendation to start antihypertensive therapy with diuretics (D) might produce delay in blood pressure (BP) control and, possibly, increase cost/benefit ratio. AIM: We evaluate the effects of D in relation to the administration of other anti-hypertensive medications, in clinical practice. METHODS General practitioners recruited 2,409 hypertensive patients with indication to antihypertensive therapy, who were randomized to start treatment with chlorthalidone (12.5-25 mg daily, group D) or any other single medications (excluding thiazides, group A). The patients have been followed for at least 2 years. RESULT Among the 2,409 patients recruited (42.5 % women), 1,205 were randomized in group D and 1,204 in group A, of which 1,051 (or 87 %) and 1026 (or 85 %) respectively, completed the study. The number of patients in optimal BP control was similar in the two groups (65.0 vs 64.0 %; p = NS). During follow-up, the group D had prescribed a slightly greater number of medications compared to the group A who added D as second line (2.3 vs 2.1; p < 0.0001). In particular group D took more β-blockers (27.1 vs 14.9 %; p < 0.0001) with a similar number of patients in optimal BP control (64.35 vs 63.9 %; p = NS). CONCLUSION The beginning of antihypertensive therapy with diuretics is more often subject to the addition of one or more medications to obtain an effective blood pressure control, since the diuretic administered at the beginning of the antihypertensive regimen is only rarely associated with optimal blood pressure control.
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Renal function in patients treated with a combination of renin-angiotensin blockers and thiazide diuretics. Is this appropriate?
Manzano-Sánchez, D, Leal-Hernández, M, Guerrero-Pérez, E, Martínez-Monje, F
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2014;(3):419-20