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Interim effects of salt substitution on urinary electrolytes and blood pressure in the China Salt Substitute and Stroke Study (SSaSS).
Huang, L, Tian, M, Yu, J, Li, Q, Liu, Y, Yin, X, Wu, JH, Marklund, M, Wu, Y, Li, N, et al
American heart journal. 2020;:136-145
Abstract
The Salt Substitute and Stroke Study is an ongoing 5-year large-scale cluster randomized trial investigating the effects of potassium-enriched salt substitute compared to usual salt on the risk of stroke. The study involves 600 villages and 20,996 individuals in rural China. Intermediate risk markers were measured in a random subsample of villages every 12 months over 3 years to track progress against key assumptions underlying study design. Measures of 24-hour urinary sodium, 24-hour urinary potassium, blood pressure and participants' use of salt substitute were recorded, with differences between intervention and control groups estimated using generalized linear mixed models. The primary outcome of annual event rate in the two groups combined was determined by dividing confirmed fatal and non-fatal strokes by total follow-up time in the first 2 years. The mean differences (95% CI) were -0.32 g (-0.68 to 0.05) for 24-hour urinary sodium, +0.77 g (+0.60 to +0.93) for 24-hour urinary potassium, -2.65 mmHg (-4.32 to -0.97) for systolic blood pressure and +0.30 mmHg (-0.72 to +1.32) for diastolic blood pressure. Use of salt substitute was reported by 97.5% in the intervention group versus 4.2% in the control group (P<.0001). The overall estimated annual event rate for fatal and non-fatal stroke was 3.2%. The systolic blood pressure difference and the annual stroke rate were both in line with the statistical assumptions underlying study design. The trial should be well placed to address the primary hypothesis at completion of follow-up.
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Comparative risk of new-onset diabetes mellitus for antihypertensive drugs in elderly: A Bayesian network meta-analysis.
Zhang, J, Tong, A, Dai, Y, Niu, J, Yu, F, Xu, F
Journal of clinical hypertension (Greenwich, Conn.). 2019;(8):1082-1090
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Abstract
There is no study to compare different class of antihypertensive drugs on new-onset diabetes mellitus (NOD) in elderly. We aimed to investigate the risk of antihypertensive drugs on NOD in elderly patients. The databases were retrieved in an orderly manner from the dates of their establishment to October, 2018, including Medline, Embase, Clinical Trials, and the Cochrane Database, to collect randomized controlled trials (RCTs) of different antihypertensive drugs in elderly patients (age > 60 years). Then, a network meta-analysis was conducted using R and Stata 12.0 softwares. A total of 14 RCTs involving 74 042 patients were included. The relative risk of NOD mellitus associated with six classes of antihypertensive drugs was analyzed, including placebo, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, and β blockers. Patients with ACEIs or ARBs appeared to have significantly reduced risk of NOD compare with placebo: ACEIs (OR = 0.49, 95% CrI 0.28-0.85), ARBs (OR = 0.37, 95% CrI 0.26-0.52), while CCBs, diuretics, and β blockers appeared to have not significantly reduced risk of NOD mellitus compare with placebo: CCBs (OR = 1.10, 95% CrI 0.85-1.60), diuretics (OR = 1.40, 95% CrI 0.92-2.50), β blockers (OR = 1.40, 95% CrI 0.93-2.10). The SUCRA of placebo, ACEIs, ARBs, CCBs, diuretics, and β blockers was, respectively, 65.3%, 69.3%, 92.3%, 44.1%, 12.1%, and 16.5%. According to the evidence, ARBs have an advantage over the other treatments in reducing the risk of NOD in elderly patients.
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Telmisartan and hydrochlorothiazide antihypertensive treatment in high sodium intake population: a randomized double-blind trial.
Zhang, P, Wang, H, Sun, L, Zhang, J, Xi, Y, Wu, Y, Yan, LL, Li, X, Sun, N
Journal of hypertension. 2017;(10):2077-2085
Abstract
OBJECTIVES To compare the blood pressure (BP)-lowering effects of telmisartan 40 mg/day and hydrochlorothiazide (HCTZ) 25 mg/day in high sodium intake patients with mild-to-moderate hypertension in China. METHODS In this randomized, double-blind trial, eligible patients were randomly divided into telmisartan and HCTZ groups with three follow-ups scheduled on days 15, 30, and 60 after enrollment to compare BP decrease, hypokalemia, and other adverse events after intervention. RESULTS A total of 1333 mild-to-moderate hypertensive patients with average sodium intake of 5909 mg/day were enrolled from 14 county hospitals in China. Baseline characteristics were well balanced. At 15, 30, and 60 days of follow-up, average SBP/DBP reduction in telmisartan and HCTZ group was 12.5/8.0, 14.3/9.1, 12.8/7.2, 11.0/5.8, 13.6/7.1, and 11.5/5.3 mmHg, respectively. Telmisartan showed greater BP response than HCTZ at three visits, with statistical significance for DBP (P < 0.001) regardless of the adjustment for baseline BP, sodium excretion, and pulse pressure (PP). SBP reduction was positively related to increasing urinary sodium and PP levels for patients in both groups but increased faster with increasing PP in HCTZ than in telmisartan (P = 0.0238 for group × PP). Compared with telmisartan, HCTZ showed more hypokalemia (0.4 vs. 4.5%, P < 0.001). CONCLUSION Both telmisartan and HCTZ were effective for the treatment of hypertensive patients with high sodium intake. Telmisartan showed better DBP-lowering effect and less hypokalemia than HCTZ among high sodium intake patients. Further studies are needed to evaluate the plausible superiority effect of hydrochlorothiazide among patients with large PP.
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Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy.
Wang, JG, Yukisada, K, Sibulo, A, Hafeez, K, Jia, Y, Zhang, J
Journal of hypertension. 2017;(4):877-885
Abstract
OBJECTIVE The objective of this study is to evaluate the efficacy and safety of sacubitril/valsartan (LCZ696, an angiotensin receptor and neprilysin inhibitor) add-on to amlodipine compared with amlodipine monotherapy in Asian patients with systolic hypertension uncontrolled with amlodipine. METHODS Patients with mean clinic SBP at least 145 mmHg and less than 180 mmHg after a 4-week treatment with amlodipine 5 mg/day were randomized to receive LCZ696/amlodipine (200/5 mg/day) or amlodipine 5 mg/day for 8 weeks. The primary assessment was the superiority of LCZ696/amlodipine versus amlodipine in lowering 24-h ambulatory SBP from baseline to week 8. Secondary assessments included 24-h ambulatory DBP and pulse pressure (PP), daytime and night-time BP, clinic BP and PP, BP control/responder rate (<140/90 mmHg or a reduction ≥20/10 mmHg from baseline), and safety. RESULTS Of the 371 patients screened, 266 (71.7%) patients (mean age 55.4 years; 24-h SBP/DBP 139.0/86.1 mmHg at baseline) who did not respond to 4-week treatment with amlodipine 5 mg/day were randomized. At week 8, LCZ696/amlodipine provided greater reductions in 24-h SBP compared with amlodipine monotherapy from baseline (-13.9 versus -0.8 mmHg, P < 0.001). All the secondary efficacy assessments were significantly (P < 0.001) in favour of LCZ696/amlodipine, for instance, 24-h PP (-5.8 versus -0.6 mmHg). Overall, the incidence of adverse events was 20.0% with LCZ696/amlodipine and 21.3% with amlodipine. CONCLUSION LCZ696/amlodipine showed significantly greater 24-h ambulatory BP and PP reductions compared with amlodipine monotherapy. Both treatments were generally well tolerated. Therefore, LCZ696/amlodipine combination could be an effective treatment for patients with systolic hypertension uncontrolled with amlodipine.
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Long-term (52-week) safety and efficacy of Sacubitril/valsartan in Asian patients with hypertension.
Supasyndh, O, Sun, N, Kario, K, Hafeez, K, Zhang, J
Hypertension research : official journal of the Japanese Society of Hypertension. 2017;(5):472-476
Abstract
Sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor-neprilysin inhibitor, demonstrated significant reductions in office and 24 h ambulatory blood pressure (BP) over 8 weeks in Asian patients with hypertension. This 52-week extension to the 8-week core study was aimed at evaluating the long-term safety, tolerability and efficacy of sacubitril/valsartan. Patients who completed an 8-week randomized study (the core study) were enrolled in this 52-week open-label study and received sacubitril/valsartan 200 mg QD. The sacubitril/valsartan dose was uptitrated to 400 mg QD if BP was uncontrolled (>140/90 mm Hg) after 4 weeks. Subsequently, in patients with uncontrolled BP, treatment was intensified every 4 weeks with amlodipine 5-10 mg followed by hydrochlorothiazide 6.25-25 mg. Of the 341 patients enrolled, 7 (2.1%) discontinued the study drug due to adverse events (AEs). The incidence of AEs and serious AEs were 63.9 and 3.8%, respectively, and no deaths were reported in this study. The most frequent AEs were nasopharyngitis (18.2%) and dizziness (8.8%). Events that were potentially indicative of low BP were infrequent. One patient reported mild transient angioedema (lasting 2.5 h) that resolved without treatment but led to study drug discontinuation. The sacubitril/valsartan-based regimen provided clinically significant mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-24.7/-16.2 mm Hg). The overall BP control, msSBP and msDBP response rates were 75.3, 90.6 and 87.6%, respectively. Long-term use of sacubitril/valsartan was generally safe and well-tolerated in patients with hypertension and provided significant BP reductions from baseline.
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Efficacy and Safety of Sacubitril/Valsartan (LCZ696) Compared With Olmesartan in Elderly Asian Patients (≥65 Years) With Systolic Hypertension.
Supasyndh, O, Wang, J, Hafeez, K, Zhang, Y, Zhang, J, Rakugi, H
American journal of hypertension. 2017;(12):1163-1169
Abstract
OBJECTIVE Systolic hypertension is common in elderly patients and remains a challenge to treat effectively. The efficacy and safety of sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, vs. olmesartan was evaluated in elderly Asian patients (≥65 years) with systolic hypertension. METHODS In this randomized, double-blind, 14-week study, patients initially received once-daily sacubitril/valsartan 100 mg or olmesartan 10 mg, increased to sacubitril/valsartan 200 mg or olmesartan 20 mg at week 4. At week 10, for patients with blood pressure (BP) >140/90 mm Hg, the doses were up-titrated to sacubitril/valsartan 400 mg or olmesartan 40 mg. The primary assessment was superiority of sacubitril/valsartan vs. olmesartan in reducing office mean sitting (ms) systolic BP (msSBP) from baseline at week 10. Secondary efficacy assessments included changes from baseline in ms diastolic BP (msDBP), ms pulse pressure (msPP), 24-hour mean ambulatory (ma) BP (maBP), and maPP at week 10; msBP and msPP at weeks 4 and 14. RESULTS Overall, 588 patients were randomized (mean age, 70.7 years; baseline msBP, 160.3/84.9 mm Hg; msPP, 75.4 mm Hg). At week 10, sacubitril/valsartan provided superior msSBP reductions vs. olmesartan (22.71 vs. 16.11 mm Hg, respectively; P < 0.001); similarly, reductions from baseline in other BP and PP assessments were significantly greater with sacubitril/valsartan. At week 14, despite more patients requiring up-titration in the olmesartan group, msBP and msPP reductions from baseline were significantly greater with sacubitril/valsartan. Both treatments were generally well-tolerated. CONCLUSION Sacubitril/valsartan is more effective than olmesartan in reducing BP in elderly Asian patients with systolic hypertension.
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Early intervention of long-acting nifedipine GITS reduces brachial-ankle pulse wave velocity and improves arterial stiffness in Chinese patients with mild hypertension: a 24-week, single-arm, open-label, prospective study.
Zhang, J, Wang, Y, Hu, H, Yang, X, Tian, Z, Liu, D, Gu, G, Zheng, H, Xie, R, Cui, W
Drug design, development and therapy. 2016;:3399-3406
Abstract
BACKGROUND Nifedipine gastrointestinal therapeutic system (GITS) is used to treat angina and hypertension. The authors aimed to study the early intervention impact on arterial stiffness and pulse wave velocity (PWV) independent of its blood-pressure-(BP) lowering effect in mild hypertensive patients. METHODS This single-center, single-arm, open-label, prospective, Phase IV study recruited patients with mild hypertension and increased PWV from December 2013 to December 2014 (N=138; age, 18-75 years; systolic blood pressure, 140-160 mmHg; diastolic BP, 90-100 mmHg; increased brachial-ankle pulse wave velocity [baPWV, ≥12 m/s]). Nifedipine GITS (30 mg/d) was administered for 24 weeks to achieve target BP of <140/90 mmHg. The dose was uptitrated at 60 mg/d in case of unsatisfactory BP reduction after 4 weeks. Primary study end point was the change in baPWV after nifedipine GITS treatment. Hemodynamic parameters (office BP, 24-hour ambulatory BP monitoring, and heart rate and adverse events) were evaluated at baseline and followed-up at 2, 4, 8, 12, 18, and 24 weeks. RESULTS Majority of patients (n=117; 84.8%) completed the study. baPWV decreased significantly at 4 weeks compared with baseline (1,598.87±239.82 vs 1,500.89±241.15 cm/s, P<0.001), was stable at 12 weeks (1,482.24±215.14 cm/s, P<0.001), and remained steady through 24 weeks (1,472.58±205.01 cm/s, P<0.001). Office BP reduced from baseline to week 4 (154/95 vs 136/85 mmHg) and remained steady until 24 weeks. Nifedipine GITS significantly decreased 24-hour ambulatory BP monitoring (P<0.001) after 24 weeks from baseline. Mean arterial pressure and pulse pressure were lowered significantly after 4, 12, and 24 weeks of treatment (P<0.001). These changes in baPWV were significantly correlated with changes in systolic blood pressure, diastolic BP, and mean arterial pressure (P<0.05), but not with changes in pulse pressure (P>0.05). There were no other drug-related serious adverse events. CONCLUSION Nifedipine GITS was considerably effective in reducing baPWV and BP, indicating improvement in arterial stiffness as early as 4 weeks.
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Association of obstructive sleep apnea plus hypertension and prevalent cardiovascular diseases: A cross-sectional study.
Wang, L, Cai, A, Zhang, J, Zhong, Q, Wang, R, Chen, J, Zhou, Y
Medicine. 2016;(39):e4691
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Current study sought to evaluate the associations of obstructive sleep apnea (OSA) plus hypertension (HTN) and prevalent cardiovascular diseases (CVD).This was a cross-sectional study and a total of 1889 subjects were enrolled. The apnea-hypopnea index (AHI) was measured by polysomnography and OSA degree was classified as mild (AHI 5-14.9) and moderate-severe (AHI ≥ 15), and AHI < 5 was considered no-OSA. Mean and lowest oxyhemoglobin saturation (SaO2) was detected by pulse oximetry. Between-group differences were assessed and logistic regression analysis was used to analyze the association of OSA plus HTN and prevalent CVD.Compared to normotensive subjects, hypertensive subjects were older and had higher body mass index (BMI), neck girth, waist-hip ratio, AHI, and low-density lipoprotein cholesterol (LDL-C) level. Conversely, mean and lowest SaO2 levels were significantly lower. Logistic regression analysis showed that in an unadjusted model, compared to subjects with no-OSA and no-HTN (reference group), the association of HTN plus moderate-severe-OSA and prevalent CVD was the most prominent (odds ratio [OR]: 2.638 and 95% confidence interval [CI]: 1.942-3.583). In normotensive subjects, after adjusted for potential covariates, the associations of OSA (regardless of severity) and prevalent CVD were attenuated to nonsignificant. In hypertensive subjects, however, the associations remained significant but were reduced. Further adjusted for mean and lowest SaO2, the associations remained significant in HTN plus no-OSA (OR: 1.808, 95% CI: 1.207-2.707), HTN plus mild-OSA (OR: 2.003, 95% CI: 1.346-2.980), and HTN plus moderate-severe OSA (OR: 1.834, 95% CI: 1.214-2.770) groups.OSA plus HTN is associated with prevalent CVD, and OSA may potentiate the adverse cardiovascular effects on hypertensives patients but not normotensives.
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Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study.
Williams, B, Cockcroft, JR, Kario, K, Zappe, DH, Cardenas, P, Hester, A, Brunel, P, Zhang, J
BMJ open. 2014;(2):e004254
Abstract
INTRODUCTION Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics. METHODS AND ANALYSIS In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12-24 weeks, if the BP target has not been attained (msSBP <140 and ms diastolic BP <90 mm Hg), amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance. ETHICS AND DISSEMINATION The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection. CLINICAL TRIALS IDENTIFIER EUDract number 2012-002899-14 and ClinicalTrials.gov NCT01692301.
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Efficacy and safety of aliskiren and amlodipine combination therapy in patients with hypertension: a randomized, double-blind, multifactorial study.
Littlejohn, TW, Jones, SW, Zhang, J, Hsu, H, Keefe, DL
Journal of human hypertension. 2013;(5):321-7
Abstract
Most patients with hypertension need more than one drug to achieve blood pressure (BP) control. This randomized, double-blind, multifactorial study evaluated whether combinations of aliskiren and amlodipine provided superior BP reductions to component monotherapies in patients with hypertension (mean sitting diastolic BP (msDBP) 95-<110 mm Hg). Overall, 1688 patients were randomized to once-daily monotherapy with aliskiren 150 or 300 mg or amlodipine 5 or 10 mg, combination therapy with one of four corresponding aliskiren/amlodipine doses, or placebo for 8 weeks. At week 8 end point, aliskiren/amlodipine combinations provided significant msDBP reductions from baseline of 14.0-16.5 mm Hg, compared with reductions of 8.0 and 10.2 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 11.0 and 13.8 mm Hg for amlodipine 5 and 10 mg, respectively (P<0.05). Aliskiren/amlodipine combinations provided reductions in mean sitting systolic BP 20.6-23.9 mm Hg, compared with decreases of 10.7 and 15.4 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 15.8 and 21.0 mm Hg for amlodipine 5 (P< or =0.001) and 10 mg (P=NS), respectively. Aliskiren/amlodipine combination therapy provides greater BP lowering than either agent alone, hence offering an effective treatment option for patients with hypertension.