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Randomized trial of an increased dose of calcium channel blocker or angiotensin II type 1 receptor blocker as an add-on intensive depressor therapy in type 2 diabetes mellitus patients with uncontrolled essential hypertension: the ACADEMIE Study.
Imaizumi, S, Shiga, Y, Ogawa, M, Sako, H, Nagata, Y, Matsunaga, A, Shirotani, T, Hoshino, F, Yahiro, E, Uehara, Y, et al
Heart and vessels. 2019;(4):698-710
Abstract
There is a lack of data on how to treat hypertensive patients with diabetes when treatment with medium doses of calcium channel blocker and angiotensin II type 1 receptor blocker (ARB) is insufficient to achieve the target blood pressure (BP). A total of 121 participants with type 2 diabetes and uncontrolled essential hypertension, who were receiving medium doses of amlodipine (5 mg/day) and ARB, were enrolled. Participants were randomized to receive either a high dose of amlodipine (10 mg/day) plus a medium dose of ARB (high-AML) or a medium dose of amlodipine (5 mg/day) plus a high dose of ARB (high-ARB). The depressor effects of these two regimens were monitored using a telemonitoring home BP-measuring system. Fifty-four patients were excluded after an observation period, and the remaining 67 eligible participants were randomized into the two groups; 42 which had a record of their home BP for analysis. The change in morning home systolic and diastolic BP was greater in the high-AML than in the high-ARB (systolic BP; - 7.9 mmHg vs. + 2.7 mmHg; p = 0.0002, diastolic BP; - 3.9 mmHg vs. + 0.6 mmHg; p = 0.0007). In addition, the home systolic and diastolic BP before going to bed and office systolic BP were significantly reduced from week 0 only in the high-AML. An increased dose of amlodipine, but not ARB, reduced home morning BP in hypertensive patients with type 2 diabetes who were already receiving combination therapy with medium doses of amlodipine and ARB.
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Abelmoschus manihot - a traditional Chinese medicine versus losartan potassium for treating IgA nephropathy: study protocol for a randomized controlled trial.
Li, P, Chen, YZ, Lin, HL, Ni, ZH, Zhan, YL, Wang, R, Yang, HT, Fang, JA, Wang, NS, Li, WG, et al
Trials. 2017;(1):170
Abstract
BACKGROUND IgA nephropathy (IgAN) is one of the most common primary glomerular diseases worldwide, but effective therapy remains limited and many patients progress to end-stage renal disease (ESRD). Only angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin-receptor blockers (ARB) show a high level of evidence (1B level) of being of value in the treatment for IgAN according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. However, traditional Chinese medicine has raised attention in kidney disease research. Abelmoschus manihot, a single medicament of traditional Chinese medicine has shown therapeutic effects in primary glomerular disease according to the randomized controlled clinical trial that we have completed. Here, we conduct a new study to assess the efficacy and safety of Abelmoschus manihot in IgAN. Also, this study is currently the largest double-blind, randomized controlled registered clinical research for the treatment of IgAN. METHODS We will conduct a multicenter, prospective, double-blind, double-dummy randomized controlled study. The study is designed as a noninferiority clinical trial. Approximately 1600 biopsy-proven IgAN patients will be enrolled at 100 centers in China and followed up for as long as 48 weeks. IgAN patients will be randomized assigned to the Abelmoschus manihot group (in the form of a huangkui capsule, 2.5 g, three times per day) and the losartan potassium group (losartan potassium, 100 mg/d). The primary outcome is the change in 24-h proteinuria from baseline after 48 weeks of treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after 48 weeks of treatment, the incidence of endpoint events (proteinuria ≥3.5 g/24 h, the doubling of serum creatinine, or receiving blood purification treatment) are the secondary outcomes. Twenty-four-hour proteinuria and eGFR are measured at 0, 4, 12, 24, 36 and 48 weeks. DISCUSSION This study will be of sufficient size and scope to evaluate the efficacy and safety of Abelmoschus manihot compared to losartan potassium in treating patients with IgAN. The results of this study may provide a new, effective and safe treatment strategy for IgAN. TRIAL REGISTRATION ClinicalTrials.gov, identifier: NCT02231125 . Registered on 30 August 2014.
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Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study.
Zile, MR, Jhund, PS, Baicu, CF, Claggett, BL, Pieske, B, Voors, AA, Prescott, MF, Shi, V, Lefkowitz, M, McMurray, JJ, et al
Circulation. Heart failure. 2016;(1)
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Abstract
BACKGROUND Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction. METHODS AND RESULTS Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6-48.1] ng/mL) and galectin 3 (17.8 [14.1-22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5-230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3-6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B-type natriuretic peptide, E/E', and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N-terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time. CONCLUSIONS In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588.
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Does Antihypertensive Drug Class Affect Day-to-Day Variability of Self-Measured Home Blood Pressure? The HOMED-BP Study.
Asayama, K, Ohkubo, T, Hanazawa, T, Watabe, D, Hosaka, M, Satoh, M, Yasui, D, Staessen, JA, Imai, Y, ,
Journal of the American Heart Association. 2016;(3):e002995
Abstract
BACKGROUND Recent literature suggests that blood pressure variability (BPV) predicts outcome beyond blood pressure level (BPL) and that antihypertensive drug classes differentially influence BPV. We compared calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockade for effects on changes in self-measured home BPL and BPV and for their prognostic significance in newly treated hypertensive patients. METHODS AND RESULTS We enrolled 2484 patients randomly allocated to first-line treatment with a calcium channel blocker (n=833), an angiotensin-converting enzyme inhibitor (n=821), or angiotensin receptor blockade (n=830). Home blood pressures in the morning and evening were measured for 5 days off treatment before randomization and for 5 days after 2 to 4 weeks of randomized drug treatment. We assessed BPL and BPV changes as estimated by variability independent of the mean and compared cardiovascular outcomes. Home BPL response in each group was significant (P≤0.0001) but small in the angiotensin-converting enzyme inhibitor group (systolic/diastolic: 4.6/2.8 mm Hg) compared with the groups treated with a calcium channel blocker (systolic/diastolic: 8.3/3.9 mm Hg) and angiotensin receptor blockade (systolic/diastolic: 8.2/4.5 mm Hg). In multivariable adjusted analyses, changes in home variability independent of the mean did not differ among the 3 drug classes (P≥0.054). Evening variability independent of the mean before treatment significantly predicted hard cardiovascular events independent of the corresponding home BPL (P≤0.022), whereas BPV did not predict any cardiovascular outcome based on the morning measurement (P≥0.056). Home BPV captured after monotherapy had no predictive power for cardiovascular outcome (P≥0.22). CONCLUSIONS Self-measured home evening BPV estimated by variability independent of the mean had prognostic significance, whereas antihypertensive drug classes had no significant impact on BPV changes. Home BPL should remain the primary focus for risk stratification and treatment. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000137.
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Influence of Left Ventricular Ejection Fraction on the Effects of Supplemental Use of Angiotensin Receptor Blocker Olmesartan in Hypertensive Patients With Heart Failure.
Miura, M, Sakata, Y, Miyata, S, Shiba, N, Takahashi, J, Nochioka, K, Takada, T, Saga, C, Shinozaki, T, Sugi, M, et al
Circulation journal : official journal of the Japanese Circulation Society. 2016;(10):2155-64
Abstract
BACKGROUND There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and β-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).
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Adding Hydrochlorothiazide to Olmesartan/Amlodipine Increases Efficacy in Patients With Inadequate Blood Pressure Control on Dual-Combination Therapy.
Rump, LC, Ammentorp, B, Laeis, P, Scholze, J
Journal of clinical hypertension (Greenwich, Conn.). 2016;(1):60-9
Abstract
This randomized, parallel-group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg, using seated blood pressure (SeBP) measurements and ambulatory blood pressure (BP) monitoring. Enrolled patients were screened and tapered off of therapy if required. All patients received OLM/AML 40/10 mg and those with mean seated BP (SeBP) ≥140/90 mm Hg after 8 weeks (n=808) were randomized (1:1:1) to continue with OLM/AML 40/10 mg or receive OLM/AML/HCTZ 40/10/12.5 or 40/10/25 mg for a further 8 weeks. The primary endpoint was the change in seated diastolic BP (SeDBP) from the start to the end of the randomized treatment period. The addition of HCTZ 25 mg significantly reduced SeDBP (-2.8 mm Hg; P<.0001), lowered seated systolic BP (SeSBP) and ambulatory DBP and SBP, and improved BP goal rates. In patients uncontrolled on OLM/AML 40/10 mg, adding HCTZ led to further BP reductions, particularly in ambulatory BP.
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Dose Timing of an Angiotensin II Receptor Blocker/Calcium Channel Blocker Combination in Hypertensive Patients With Paroxysmal Atrial Fibrillation.
Kario, K, Hoshide, S, Uchiyama, K, Yoshida, T, Okazaki, O, Noshiro, T, Aoki, H, Mizuno, H, Matsumoto, Y
Journal of clinical hypertension (Greenwich, Conn.). 2016;(10):1036-1044
Abstract
It has long been thought that there is a close association between hypertension and atrial fibrillation (AF). However, the efficacy of an angiotensin II receptor blocker for the prevention of organ damage in hypertensive individuals with AF is still controversial. The present study was a multicentered, prospective, randomized, open-label clinical trial investigating the differences in the effect of treatment with telmisartan/amlodipine combination tablets on blood pressure (BP) levels and BP variability between morning and bedtime administration in hypertensive patients with paroxysmal AF, using ambulatory BP monitoring (ABPM) and home BP. With this treatment, the patients' 24-hour BP, nighttime BP, preawake BP, and morning BP shown by ABPM were significantly reduced, and the antihypertensive effects were similar regardless of the timing of the drug administration. The standard deviation of day-by-day home systolic BP and the maximum home systolic BP were also significantly reduced, and these effects were similar regardless of the treatment timing. The N-terminal pro-brain natriuretic peptide level was significantly decreased only in the bedtime administration group. A larger study will demonstrate whether the bedtime administration of telmisartan/amlodipine combination tablets maximizes the risk-lowering effect against AF recurrence in paroxysmal AF hypertensive patients.
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Age-related difference in the sleep pressure-lowering effect between an angiotensin II receptor blocker and a calcium channel blocker in Asian hypertensives: the ACS1 Study.
Kario, K, Hoshide, S
Hypertension (Dallas, Tex. : 1979). 2015;(4):729-35
Abstract
Sleep blood pressure (BP), which is partly determined by salt sensitivity and intake, is an important cardiovascular risk in hypertensives. However, there have been no studies on age-related differences in the sleep BP-lowering effect between angiotensin II receptor blockers and calcium channel blockers in Asians. Azilsartan Circadian and Sleep Pressure-the 1st Study was a multicenter, randomized, open-label, 2-parallel-group study conducted to compare the efficacy of 8-week oral treatment with an angiotensin II receptor blocker (azilsartan 20 mg) or a calcium channel blocker (amlodipine 5 mg) on sleep BP as evaluated by ambulatory BP monitoring. Among the overall population, amlodipine treatment achieved significantly greater reduction in sleep BP, awake BP, and 24-hour BP than azilsartan treatment. BP reduction by amlodipine was particularly pronounced in elderly hypertensive patients aged ≥60 years old. Among patients ≥60 years old, the amlodipine group had numerically, but not significantly, higher control rate of sleep BP compared with the azilsartan group. Similar results were found for awake BP and 24-hour BP. These results suggest a greater BP reduction/control by amlodipine compared with azilsartan and that reduction/control of BP by amlodipine was also more effective in the elderly population. As recommended in the American Society of Hypertension/The international Society of Hypertension and the National Institute for Health and Clinical Excellence guidelines for differentiating treatment according to age, amlodipine should be one of the options for starting treatment in the elderly population. CLINICAL TRIAL URL http://clinicaltrials.gov/show/NCT01762501 CLINICAL TRIAL ID NCT01762501.
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Comparison of the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus.
Derosa, G, Querci, F, Franzetti, I, Dario Ragonesi, P, D'Angelo, A, Maffioli, P
Hypertension research : official journal of the Japanese Society of Hypertension. 2015;(10):690-4
Abstract
The aim of this study was to evaluate the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus. We enrolled 148 normocholesterolemic patients with mild-to-moderate hypertension and type 2 diabetes mellitus. Patients were treated with barnidipine, 20 mg day(-1), in combination with losartan, 100 mg day(-1), or with telmisartan+hydrochlorothiazide, 80/12.5 mg day(-1), for 6 months. We assessed blood pressure (BP) on a monthly basis; additionally, blood samples were collected to assess, at baseline and after 6 months, the following parameters: fasting plasma glucose; glycated hemoglobin; fasting plasma insulin; HOMA index; and some adipocytokines, such as adiponectin (ADN), resistin, leptin, visfatin and vaspin. Patients were also subjected to an euglycemic hyperinsulinemic clamp to assess the M value and glucose infusion rate to ascertain their insulin sensitivity. One hundred and forty-one patients completed the study. The BP was reduced in both groups, although the reduction was greater with barnidipine+losartan (P<0.001 vs. baseline and P<0.01 vs. telmisartan+hydrochlorothiazide). Barnidipine+losartan increased the M value and glucose infusion rate during the euglycemic hyperinsulinemic clamp (P<0.05 vs. baseline and vs. telmisartan+hydrochlorothiazide). With respect to the levels of adipocytokines, ADN was increased (P<0.05), and resistin and leptin were reduced from baseline with barnidipine+losartan (P<0.05 vs. baseline), but they were not reduced with telmisartan+hydrochlorothiazide. Visfatin and vaspin were reduced by barnidipine+losartan compared with baseline (P<0.05). The adipocytokine levels obtained with barnidipine+losartan were significantly better than those obtained with telmisartan+hydrochlorothiazide (P<0.05 for all parameters). In addition to providing a greater BP reduction, barnidipine+losartan improved the insulin sensitivity, as assessed by an euglycemic hyperinsulinemic clamp, and improved some of the adipocytokines related to insulin resistance.
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Probucol combined with valsartan in immunoglobulin A nephropathy: a multi-centre, open labelled, randomized controlled study.
Ye, Z, Zhang, L, Xu, L, Shi, W, Hu, H, Shi, X, Zhong, W, Hou, S, Yan, H, Zhang, B, et al
Nephrology (Carlton, Vic.). 2014;(1):40-6
Abstract
AIM: Angiotensin receptor antagonists (ARBs) and anti-oxidants reduce urinary protein excretion and delay progression of immunoglobulin A (IgA) nephropathy. We investigated the efficacy and safety of probucol (an anti-oxidant) combined with valsartan (an ARB) on the progression of IgA nephropathy. METHODS Patients with IgA nephropathy (n = 69) were recruited from five centres and randomly assigned to a treatment group (750 mg/day probucol plus 160 mg/day valsartan) or a control group (160 mg/day valsartan) and were followed for 3 years. RESULTS At baseline, the two groups in any measured clinical information were comparable. The primary endpoint (doubling serum creatinine) showed no significant difference between the two groups during 3-year follow-up. The secondary endpoint (50% reduction in 24-h urinary protein) occurred in 23 patients in the treatment group and 20 patients in the control group. The time to the secondary end-point was shorter in the treatment group than the control group (8.13 months vs 19.63 months, P = 0.019). However, at the 3-year follow-up, the 24-h urinary protein levels were not significantly different from the baseline levels (P = 0.99 and P = 0.66, respectively). At the 1-year follow-up, plasma cholesterol in the treatment group was markedly lower than in the control group (4.12 ± 1.28 vs 5.03 ± 1.01, P = 0.02). CONCLUSION Kidney function remained stable and there was no significant difference in two group patients. Probucol combined with valsartan led to a more rapid decrease of 24-h urinary protein excretion than valsartan alone. However, the long-term effect needs further investigation.