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Impact of Moderate Sodium Restriction and Hydrochlorothiazide on Iodine Excretion in Diabetic Kidney Disease: Data from a Randomized Cross-Over Trial.
Binnenmars, SH, Corpeleijn, E, Kwakernaak, AJ, Touw, DJ, Kema, IP, Laverman, GD, Bakker, SJL, Navis, G
Nutrients. 2019;(9)
Abstract
Sodium restriction may potentially reduce iodine intake. This study aimed to determine the effect of sodium restriction (dietary counseling) on 24-h urinary iodine excretion. Diuretics provide an alternative to sodium restriction and are frequently added to sodium restriction, so the effects of hydrochlorothiazide (50 mg daily) and combined therapy were also studied. We performed a post-hoc analysis of a Dutch multi-center, randomized cross-over trial in 45 patients with diabetic kidney disease with a mean age of 65 ± 9 years, mean eGFR of 65 ± 27 mL/min/1.73 m2, median albuminuria of 648 [230-2008] mg/24 h and 84% were male. During regular sodium intake with placebo, mean 24 h urinary sodium and iodine excretion were 224 ± 76 mmol/24 h and 252 ± 94 ug/24 h, respectively (r = 0.52, p < 0.001). Mean iodine excretion did not change significantly if sodium restriction and hydrochlorothiazide were applied separately; mean difference -8 ug/day (95% CI -38, 22; p = 0.6) and 14 ug/day (95% CI -24, 52; p = 0.5), respectively. Combined therapy induced a significant decrease in mean iodine excretion (-37 ug/day; 95% CI -67, -7; p = 0.02), yet this was not seen to a clinically meaningful level. The number of patients with an estimated intake below recommended daily allowances did not differ significantly between the four treatment periods (p = 0.3). These findings show that sodium restriction is not a risk factor for iodine deficiency.
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Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial.
Dhayat, NA, Faller, N, Bonny, O, Mohebbi, N, Ritter, A, Pellegrini, L, Bedino, G, Schönholzer, C, Venzin, RM, Hüsler, C, et al
BMC nephrology. 2018;(1):349
Abstract
BACKGROUND Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known. METHODS The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response. DISCUSSION The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support. TRIAL REGISTRATION ClinicalTrials.gov, NCT03057431 . Registered on February 20 2017.
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Patient characteristics do not predict the individual response to antihypertensive medication: a cross-over trial.
van der Wel, MC, Biermans, M, Akkermans, R, Lenders, JWM, van Weel, C, Deinum, J
Family practice. 2018;(1):67-73
Abstract
BACKGROUND International guidelines on hypertension management do not agree on whether patient characteristics can be used for the first choice of treatment of uncomplicated essential hypertension. OBJECTIVE We wanted to identify predictive patient characteristics to the response of two different classes of antihypertensive drugs in patients with newly diagnosed hypertension in primary care. METHODS We conducted a prospective, open label, blinded endpoint cross-over trial in 120 patients with a new diagnosis of hypertension from 10 family practices. Patients received 4 weeks of 12.5 mgr hydrochlorothiazide once daily and 4 weeks of 80 mgr valsartan once daily, each followed by a 4-week washout. The sequence of drugs was randomized. Age, sex and menopausal state were recorded at run in and 24 h ambulatory blood pressure, office blood pressure, plasma renin concentration, NT-proBNP, potassium, estimated glomerular filtration rate, urinary albumin, body mass index and waist circumference at each regimen change. The difference in systolic blood pressure response between both study drugs, calculated from mean daytime ambulatory blood pressures, was the main outcome measure. RESULTS Ninety-eight patients (52% female; median age 53 years) were eligible for per-protocol-analysis. None of the studied variables were predictive for the difference in systolic blood pressure response. Individual systolic blood pressure responses ranged from an increase by 18 mmHg to a decrease of 39 mmHg. CONCLUSION In a relevant group of primary care patients with newly diagnosed hypertension, we were unable to detect predictors of treatment response. This study rather supports the United States and European guidelines than the United Kingdom and Dutch guidelines on hypertension.
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The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct.
Joseph, P, Pais, P, Dans, AL, Bosch, J, Xavier, D, Lopez-Jaramillo, P, Yusoff, K, Santoso, A, Talukder, S, Gamra, H, et al
American heart journal. 2018;:72-79
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Abstract
BACKGROUND It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood-pressure agents and a statin [with or without aspirin]) in a single "polypill". However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial. METHODS TIPS-3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events. RESULTS The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk. CONCLUSION Results of the TIP-3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD.
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Long-term Effects of Statins, Blood Pressure-Lowering, and Both on Erectile Function in Persons at Intermediate Risk for Cardiovascular Disease: A Substudy of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) Randomized Controlled Trial.
Joseph, P, Lonn, E, Bosch, J, Lopez, P, Zhu, J, Keltai, M, Dans, A, Reid, C, Khunti, K, Toff, W, et al
The Canadian journal of cardiology. 2018;(1):38-44
Abstract
BACKGROUND It is unclear whether modifying cholesterol, blood pressure, or both affect erectile dysfunction. Also, there are concerns that erectile dysfunction is worsened by common medications used to treat these risk factors. In this study, we evaluated the effect of: (1) cholesterol-lowering with a statin; (2) pharmacologic blood pressure reduction; and (3) their combination, on erectile function. METHODS A priori, this was a secondary analysis of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) randomized controlled trial. Men were 55 years of age or older with at least 1 cardiovascular risk factor. Erectile function was measured using the erectile function domain of the International Index of Erectile Function (IIEF-EF) score. Men with incomplete scores, or who did not engage in sexual activity, were excluded. Using a 2 × 2 factorial design, participants were randomized to rosuvastatin (10 mg/d) or placebo, and to candesartan with hydrochlorothiazide (HCTZ; 16 mg/12.5 mg/d; Cand+HCTZ) or placebo. Primary outcome was change in IIEF-EF from baseline to end of study follow-up. RESULTS Two thousand one hundred fifty-three men were included; mean age was 61.5 years, and mean follow-up was 5.8 years. Mean IIEF-EF score at baseline was 23.0 (SD 5.6). Least square mean change in the IIEF-EF score did not differ with rosuvastatin compared with placebo (-1.4; standard error [SE], 0.3 vs -1.5; SE, 0.3; P = 0.74), Cand+HCTZ compared with placebo (-1.6; SE, 0.3 vs -1.3; SE, 0.3; P = 0.10), or combination therapy compared with double placebo (P = 0.35). CONCLUSIONS Cholesterol-lowering using a statin, and blood pressure-lowering using Cand+HCTZ, either alone or in combination, do not improve or adversely affect erectile function.
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Effects of Lipid-Lowering and Antihypertensive Treatments in Addition to Healthy Lifestyles in Primary Prevention: An Analysis of the HOPE-3 Trial.
Dagenais, GR, Jung, H, Lonn, E, Bogaty, PM, Dehghan, M, Held, C, Avezum, A, Jansky, P, Keltai, M, Leiter, LA, et al
Journal of the American Heart Association. 2018;(15)
Abstract
BACKGROUND It is not clear whether the effects of lipid-lowering or antihypertensive medications are influenced by adherence to healthy lifestyle factors. We assessed the effects of both drug interventions in subgroups by the number of healthy lifestyle factors in participants in the HOPE-3 (Heart Outcomes Prevention Evaluation) trial. METHODS AND RESULTS In this primary prevention trial, 4 healthy lifestyle factors (nonsmoking status, physical activity, optimal body weight, and healthy diet) were recorded in 12 521 participants who were at intermediate risk of cardiovascular disease (CVD) and were randomized to rosuvastatin, candesartan/hydrochlorothiazide, their combination, or matched placebos. Median follow-up was 5.6 years. The outcome was a composite of CVD events. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. Participants with ≥2 healthy lifestyle factors had a lower rate of CVD compared with those with fewer factors (HR: 0.85; 95% CI, 0.73-1.00). Rosuvastatin reduced CVD events in participants with ≥2 healthy lifestyle factors (HR: 0.74; 95% CI, 0.62-0.90) and in participants with <2 factors (HR: 0.79; 95% CI, 0.61-1.01). Consistent results were observed with combination therapy (≥2 factors: HR: 0.74; 95% CI, 0.57-0.97; <2 factors: HR: 0.61; 95% CI, 0.43-0.88). Candesartan/hydrochlorothiazide tends to reduce CVD only in participants with <2 healthy lifestyle factors (HR: 0.78; 95% CI, 0.61-1.00). CONCLUSIONS Healthy lifestyles are associated with lower CVD. Rosuvastatin alone and combined with candesartan/hydrochlorothiazide is beneficial regardless of healthy lifestyle status; however, the benefit of antihypertensive treatment appears to be limited to patients with less healthy lifestyles. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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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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Abstract
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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Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial.
Xue, C, Zhou, C, Yang, B, Lv, J, Dai, B, Yu, S, Wang, Y, Zhao, G, Mei, C
BMJ open. 2017;(2):e013672
Abstract
INTRODUCTION Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS AND ANALYSIS This study will be a multicentred, prospective, double-blind, randomised parallel controlled trial for hypertensive CKD patients in China. Patients will be randomised to one of two treatment groups: a combination of benidipine 4-8 mg/day and fosinopril 20 mg/day; or a combination of HCTZ 12.5-25 mg/day and fosinopril 20 mg/day. Patients will be followed up for 24 months after a month's fosinopril run-in. There will be dose-titration after 1 and 2 months. The primary endpoint is changes in estimated glomerular filtration rate (eGFR) from baseline to month 24. Secondary endpoints include changes in home blood pressure (BP), ambulatory BP, proteinuria, urinary albumin/creatinine ratio, and composite renal events in 24 months. Inclusion criteria are: age 18-80 years, non-dialysis CKD patients with eGFR >30 mL/min/1.73 m2, home BP >130 mm Hg systolic or BP >80 mm Hg diastolic at the screening and randomisation, and 24 hour proteinuria <3.5 g. Principal exclusions are hypertensive crisis, transplantation, cancer, severe diabetes complications, hyperkalaemia and severe allergy. The required sample size was 511 patients for detecting a difference in the change of eGFR (one sided α=0.025, power 1-β=0.90). ETHICS AND DISSEMINATION BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT02646397.
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Effect of Diuretic or Calcium-Channel Blocker Plus Angiotensin-Receptor Blocker on Diastolic Function in Hypertensive Patients.
Toh, N, Ishii, K, Kihara, H, Iwakura, K, Watanabe, H, Yoshikawa, J, Ito, H, ,
Circulation journal : official journal of the Japanese Circulation Society. 2016;(2):426-34
Abstract
BACKGROUND Hypertension increases the risk of left ventricular (LV) diastolic dysfunction, and anti-hypertensive therapy may improve LV relaxation. The aim of this study was to investigate whether combining an angiotensin-receptor blocker (ARB) with either hydrochlorothiazide (HCTZ) or a calcium-channel blocker (CCB) improves LV relaxation in patients with hypertension and diastolic dysfunction. METHODS AND RESULTS Hypertensive patients who had not achieved their target blood pressure with at least 4 weeks of ARB therapy were randomly assigned to receive either a fixed-dose combination of losartan and HCTZ (losartan/HCTZ; n=110) or a combination of amlodipine and a typical ARB dosage (CCB/ARB; n=121) and followed for 24 weeks. The primary endpoint was change in early diastolic mitral annular velocity (e', cm/s). Systolic blood pressure decreased in both groups after switch to the combination therapies. E' velocity increased both in the losartan/HCTZ (0.52 cm/s) and in the CCB/ARB (0.59 cm/s) groups. The mean (95% CI) treatment difference was -0.02 (-0.37 to 0.34) cm/s, indicating that improvement in LV relaxation was similar between the groups. The ratio of early mitral inflow velocity to e' velocity and left atrial volume index were significantly decreased in the losartan/HCTZ group. CONCLUSIONS The combination of losartan and HCTZ is as effective as amlodipine plus ARB in improving LV relaxation in hypertensive patients.
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Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design, and Participants' Baseline Characteristics.
Lonn, E, Bosch, J, Pogue, J, Avezum, A, Chazova, I, Dans, A, Diaz, R, Fodor, GJ, Held, C, Jansky, P, et al
The Canadian journal of cardiology. 2016;(3):311-8
Abstract
BACKGROUND Cholesterol and blood pressure (BP) can be effectively and safely lowered with statin drugs and BP-lowering drugs, reducing major cardiovascular (CV) events by 20%-30% within 5 years in high-risk individuals. However, there are limited data in lower-risk populations. The Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial is evaluating whether cholesterol lowering with a statin drug, BP lowering with low doses of 2 antihypertensive agents, and their combination safely reduce major CV events in individuals at intermediate risk who have had no previous vascular events and have average cholesterol and BP levels. METHODS A total of 12,705 women 65 years or older and men 55 years or older with at least 1 CV risk factor, no known CV disease, and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/d or placebo and to candesartan/hydrochlorothiazide 16/12.5 mg/d or placebo (2 × 2 factorial design) and will be followed for a mean of 5.8 years. The coprimary study outcomes are the composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke and the composite of CV death, nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, heart failure, and arterial revascularization. RESULTS Participants were recruited from 21 countries in North America, South America, Europe, Asia, and Australia. Mean age at randomization was 66 years and 46% were women. CONCLUSIONS The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate-risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.gov NCT00468923).