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Comparative effect of fixed-dose combination tablets of candesartan cilexetil/amlodipine versus olmesartan medoxomil/azelnidipine on laboratory parameters in patients with hypertension: a retrospective cohort study.
Susa, N, Nishida, Y, Yada, Y, Nakayama, T, Asai, S, Takahashi, Y
Clinical and experimental hypertension (New York, N.Y. : 1993). 2016;(2):173-9
Abstract
We conducted a retrospective cohort study to evaluate and compare the long-term effects of two single-pill fixed-dose combinations (FDCs), candesartan/amlodipine and olmesartan/azelnidipine, on laboratory parameters in patients in routine clinical practice. We identified an equal number of new users (n = 182) of a candesartan/amlodipine (8/5 mg/day) FDC tablet (CAN/AML users) and a propensity-score matched cohort (n = 182) receiving an olmesartan/azelnidipine (20/16 mg/day) FDC tablet (OLM/AZ users). Generalized estimating equations were used to estimate and compare the effects of the drugs on serum levels of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid, sodium, potassium, aspartate aminotransferase, and alanine aminotransferase levels up to 12 months after the start of study drug administration. There was a significant increase of serum creatinine level and a significant decrease of eGFR from the baseline period to during the exposure period in both CAN/AML and OLM/AZ users, and a significant increase of BUN level in CAN/AML users. However, there were no significant differences in the mean changes of laboratory parameters between CAN/AML and OLM/AZ users. Our findings suggested that the effects of CAN/AML and OLM/AZ on laboratory parameters, including an unfavorable effect on renal function, were similar at least during 1 year of administration.
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Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease.
Yusuf, S, Lonn, E, Pais, P, Bosch, J, López-Jaramillo, P, Zhu, J, Xavier, D, Avezum, A, Leiter, LA, Piegas, LS, et al
The New England journal of medicine. 2016;(21):2032-43
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BACKGROUND Elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially. METHODS In a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg per day) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years. RESULTS The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups. CONCLUSIONS The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).
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Anaerobic biosynthesis of the lower ligand of vitamin B12.
Hazra, AB, Han, AW, Mehta, AP, Mok, KC, Osadchiy, V, Begley, TP, Taga, ME
Proceedings of the National Academy of Sciences of the United States of America. 2015;(34):10792-7
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Abstract
Vitamin B12 (cobalamin) is required by humans and other organisms for diverse metabolic processes, although only a subset of prokaryotes is capable of synthesizing B12 and other cobamide cofactors. The complete aerobic and anaerobic pathways for the de novo biosynthesis of B12 are known, with the exception of the steps leading to the anaerobic biosynthesis of the lower ligand, 5,6-dimethylbenzimidazole (DMB). Here, we report the identification and characterization of the complete pathway for anaerobic DMB biosynthesis. This pathway, identified in the obligate anaerobic bacterium Eubacterium limosum, is composed of five previously uncharacterized genes, bzaABCDE, that together direct DMB production when expressed in anaerobically cultured Escherichia coli. Expression of different combinations of the bza genes revealed that 5-hydroxybenzimidazole, 5-methoxybenzimidazole, and 5-methoxy-6-methylbenzimidazole, all of which are lower ligands of cobamides produced by other organisms, are intermediates in the pathway. The bza gene content of several bacterial and archaeal genomes is consistent with experimentally determined structures of the benzimidazoles produced by these organisms, indicating that these genes can be used to predict cobamide structure. The identification of the bza genes thus represents the last remaining unknown component of the biosynthetic pathway for not only B12 itself, but also for three other cobamide lower ligands whose biosynthesis was previously unknown. Given the importance of cobamides in environmental, industrial, and human-associated microbial metabolism, the ability to predict cobamide structure may lead to an improved ability to understand and manipulate microbial metabolism.
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Dietary flavonoids added to pharmacological antihypertensive therapy are effective in improving blood pressure.
de Jesús Romero-Prado, MM, Curiel-Beltrán, JA, Miramontes-Espino, MV, Cardona-Muñoz, EG, Rios-Arellano, A, Balam-Salazar, LB
Basic & clinical pharmacology & toxicology. 2015;(1):57-64
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Epidemiological studies have suggested that the daily intake of flavonoids is associated with a decreased risk of developing cardiovascular disease. Our purpose was to evaluate the effect of the addition of dietary flavonoids (DF) to antihypertensive treatment (AHT), based on telmisartan (Tms) or captopril (Cpr), on blood pressure (BP), body mass index (BMI), waist/hip ratio, leptin, lipid profile and inflammation in hypertensive young patients. An open-label, randomized, controlled trial was performed among 79 patients aged 20-55 years with grade I or grade II systemic arterial hypertension. The subjects were assigned to one of four groups for AHT plus DF during 6 months: Cpr (n = 14), Cpr + DF (n = 19), Tms (n = 25) and Tms + DF (n = 21). DF consisted of dark chocolate, dehydrated red apple and green tea in an infusion to obtain a daily dose of 425.8 ± 13.9 mg epicatechin equivalents. The BP and anthropometric parameters were measured every 2 weeks. Lipid profile, leptin and hsCRP were determined by standard methods. The combination AHT-DF produced an additional and significant reduction in (i) SBP/DBP of -5/-4 mmHg, being -7/-5 for Cpr + DF and -4/-3 for Tms + DF; (ii) triglyceride levels (-30.6%) versus AHT alone (-9.6%); and (iii) leptin: Cpr + DF versus Tms + DF (p < 0.005). Finally, C-reactive protein plasma levels were reduced significantly in all groups independently of the applied treatment. We conclude that the addition of flavonoids to pharmacological antihypertensive therapy shows additional benefits on BP, lipid profile, leptin, obesity and inflammation.
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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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A comparison of results of the US food and drug administration's mini-sentinel program with randomized clinical trials: the case of gastrointestinal tract bleeding with dabigatran.
Sipahi, I, Celik, S, Tozun, N
JAMA internal medicine. 2014;(1):150-1
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The effect of ramipril and telmisartan on serum potassium and its association with cardiovascular and renal events: results from the ONTARGET trial.
Heerspink, HJ, Gao, P, de Zeeuw, D, Clase, C, Dagenais, GR, Sleight, P, Lonn, E, Teo, KT, Yusuf, S, Mann, JF
European journal of preventive cardiology. 2014;(3):299-309
Abstract
AIMS: In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET), dual agent renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent. Dual therapy however increased the incidence of hyperkalemia. We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes. METHODS A post-hoc analysis of the ONTARGET trial comparing dual therapy (ramipril and telmisartan) vs monotherapy (ramipril or telmisartan) was performed. The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis. RESULTS Six weeks after randomization, hyperkalemia developed in 210 (2.7%) patients on dual therapy vs. 264 (1.6%) patients on monotherapy (p < 0.001 vs. dual therapy). Hypokalemia developed in 87 (1.1%) patients on dual therapy vs. 200 (1.2%)patients on monotherapy. Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0-5.0 mmol/l for cardiovascular and 4.0-4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks. This association was independent of age, gender, diabetes, estimated glomerular filtration rate, systolic blood pressure and diuretic use. CONCLUSIONS With the precautions stipulated by the protocol of the ONTARGET trial, hypokalemia and hyperkalemia were infrequent events. Nevertheless, both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease.
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Comparative coronary risks of apixaban, rivaroxaban and dabigatran: a meta-analysis and adjusted indirect comparison.
Loke, YK, Pradhan, S, Yeong, JK, Kwok, CS
British journal of clinical pharmacology. 2014;(4):707-17
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AIMS: There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran. METHODS We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I(2) . We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran. RESULTS Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran. Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran. CONCLUSIONS There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events.
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TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension (TRIUMPH): Study protocol.
Salam, A, Webster, R, Singh, K, Kallakuri, S, Rodgers, A, Prabhakaran, D, Maulik, PK, Jan, S, Thom, S, Naik, N, et al
American heart journal. 2014;(2):127-32
Abstract
BACKGROUND Hypertension management strategies have traditionally focused on "tailored therapy" and "stepped-care" approaches. These tend to be costly and time consuming and often fail to achieve adequate blood pressure (BP) control. The TRIUMPH study aims to investigate the effectiveness, cost-effectiveness, and acceptability of early use of a 3-in-1 BP-lowering pill ("Triple Pill") compared with usual care for the management of hypertension. METHODS The prospective, open, randomized controlled clinical trial (n = 700) will compare Triple Pill-based strategy to usual care among individuals with persistent mild-to-moderate hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg, or systolic BP >130 mm Hg and/or diastolic BP >80 mm Hg in patients with diabetes or chronic kidney disease) on no or minimal drug therapy. The study will be conducted within approximately 20 hospital-based clinics in India. Participants will be randomized to the Triple Pill (initially strength 1-telmisartan 20 mg, amlodipine 2.5 mg, hydrochlorothiazide 6.25 mg, with the option of subsequent titration to strength 2-telmisartan 40 mg, amlodipine 5 mg, hydrochlorothiazide 12.5 mg) or continued usual care. Participants will be followed up for 6 months. The primary outcome is the proportion of participants achieving target BP at the end follow-up. CONCLUSION This study will determine whether early use of a low-dose triple combination therapy has the potential to address some of the challenges in hypertension control through earlier achievement of BP control, better adherence, and fewer adverse effects, in the context of less intensive clinical follow-up.
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Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation.
Larsen, TB, Gorst-Rasmussen, A, Rasmussen, LH, Skjøth, F, Rosenzweig, M, Lip, GY
The American journal of medicine. 2014;(7):650-656.e5
Abstract
BACKGROUND The bleeding risk among patients with atrial fibrillation is higher early after initiating therapy with vitamin K antagonists (VKAs). Evidence is limited on how prior VKA experience affects bleeding risk when initiating novel oral anticoagulant therapy. We investigated this among patients with atrial fibrillation initiating dabigatran therapy. METHODS By using nationwide Danish prescription and patient registries, we identified 11,315 first-time dabigatran users with atrial fibrillation. Warfarin controls were matched in a 2:1 ratio according to VKA experience status. The average follow-up time was 13 months. Across the 6 combinations of treatment (dabigatran 110 mg, dabigatran 150 mg, and warfarin) and VKA experience status (naive or experienced), VKA-naïve warfarin initiators had the highest rate of any bleeding event. Cox regressions adjusted for baseline characteristics showed reductions relative to this group ranging from 19% for VKA-experienced dabigatran 110 mg users (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66-1.00) to 41% for VKA-experienced dabigatran 150 mg users (HR, 0.59; 95% CI, 0.46-0.75). Among switchers to dabigatran from warfarin, when comparing with warfarin-persisting users, the rate of any bleeding was nonsignificantly decreased for switchers to dabigatran 150 mg (HR, 0.80; 95% CI, 0.62-1.03) but not for switchers to dabigatran 110 mg (HR, 1.12; 95% CI, 0.90-1.41). Results for major bleeding were similar. Crude rates of fatal, intracranial, and gastrointestinal bleeding were low. CONCLUSIONS VKA-naïve warfarin initiators had the highest overall bleeding rate. We found no evidence of marked excess of overall bleeding events when comparing dabigatran with warfarin users, irrespective of prior VKA experience.