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One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.
Inati, A, Kahale, M, Sbeiti, N, Cappellini, MD, Taher, AT, Koussa, S, Nasr, TA, Musallam, KM, Abbas, HA, Porter, JB
Pediatric blood & cancer. 2017;(1):188-196
Abstract
BACKGROUND Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. RESULTS Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
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Multidisciplinary evaluation at baseline and during treatment improves the rate of compliance and efficacy of deferasirox in elderly myelodysplastic patients.
Del Corso, L, Biale, L, Parodi, EL, Russo, R, Filiberti, R, Arboscello, E
International journal of clinical oncology. 2017;(2):380-386
Abstract
BACKGROUND Deferasirox (DFX) is used to reduce iron levels in patients with myelodysplastic syndrome (MDS) who develop iron overload after chronic red blood cell infusions. However, DFX can be associated with renal and gastrointestinal toxicities, which may cause treatment interruption or discontinuation. This study aimed to determine the effectiveness and safety of DFX in patients with MDS. METHODS This multicenter, retrospective, observational study was conducted at two hospitals in Italy. Elderly patients with transfusion-dependent MDS received DFX for up to 12 months and were divided into two groups: group A comprised patients who were not under multidisciplinary assessment; group B comprised patients under multidisciplinary control. Treatment effectiveness was estimated by monitoring the serum ferritin (SF) levels throughout the study. Any treatment-related adverse events (AEs), clinically relevant analytical alterations, and reasons for treatment discontinuation were monitored. RESULTS The study included 44 patients (13 female, 31 male; median age 77.0 years). At 3 months, SF levels decreased by ≥20 % in 29 and 31 % of patients in groups A and B, respectively, in 17 and 36 % of patients at 6 months, and in 22 and 58 % at 12 months. The most common AEs were diarrhea and increased serum creatinine, which were more frequent in group A. The discontinuation rate after renal AE was 15 and 5 % in groups A and B, respectively. CONCLUSION Multidisciplinary evaluation can be an effective strategy for monitoring renal function in patients on DFX therapy, to improve treatment adherence and overall efficacy in elderly patients with MDS.
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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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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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Abstract
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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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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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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Effect of nifedipine versus telmisartan on prevention of atrial fibrillation recurrence in hypertensive patients.
Du, H, Fan, J, Ling, Z, Woo, K, Su, L, Chen, S, Liu, Z, Lan, X, Zhou, B, Xu, Y, et al
Hypertension (Dallas, Tex. : 1979). 2013;(4):786-92
Abstract
It is controversial whether angiotensin II receptor blockers provide better protection than calcium antagonists against atrial fibrillation (AF) recurrence in hypertensive patients. This study was designed to compare the effect of nifedipine- and telmisartan-based antihypertensive treatments for preventing AF recurrence in hypertensive patients with paroxysmal AF. A total of 149 hypertensive patients with paroxysmal AF were randomized to nifedipine- or telmisartan-based antihypertensive treatment groups. The target blood pressure (BP) was <130/80 mm Hg. Clinic BP, ECG, Holter monitoring, and echocardiography were followed up for 2 years. The primary end point was the incidence of overall and persistent AF recurrence. During follow-up, there was no statistical difference in the rate of patients lowering to target BP between both groups, whereas nifedipine group had slightly better BP control but similar heart rate control at 24 months. The incidence of AF recurrence was similar in both groups (nifedipine versus telmisartan: 58.7% versus 55.4%; P=0.742), and Kaplan-Meier analysis showed no significant difference in the freedom from AF recurrence (log-rank test; P=0.48). However, the rate of developing persistent AF in telmisartan group was lower than that in nifedipine group (5.4% versus 16.0%; P=0.035). Patients in telmisartan group had lower values of left atrial diameter, left atrial volume index, and left ventricular mass index at the end of follow-up. The effects of telmisartan in preventing AF recurrences in hypertensive patients with paroxysmal AF after intensive lowering BP is similar to that of nifedipine, but telmisartan has more potent effects on preventing progression to persistent AF.
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Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients.
Cassinerio, E, Roghi, A, Pedrotti, P, Brevi, F, Zanaboni, L, Graziadei, G, Pattoneri, P, Milazzo, A, Cappellini, MD
Annals of hematology. 2012;(9):1443-9
Abstract
Heart failure due to myocardial iron overload remains the leading cause of morbidity and mortality in adult thalassemia major (TM) patients. We evaluated the removal of cardiac iron and the changes of cardiac function by different iron chelation in TM patients by T2* cardiac magnetic resonance (CMR). Sixty-seven TM patients (27 males/40 females; mean age, 35 ± 6 years) on different chelation regimens underwent T2* CMR at baseline (t (0)), after 6-14 months (t (1)) and after 32 ± 7 months (t (2)). Patients were divided in four groups according to chelation treatment: group A (deferasirox), group B (deferoxamine), group C (combined treatment, deferoxamine plus deferiprone) and group D (deferiprone alone). Myocardial T2* at t (0) was <10 ms in 8 patients, between 10 and 20 ms in 22 patients and ≥ 20 ms in 37 patients. Progressive changes in T2* were observed at t (1) and t (2). Ten patients (10/36, 27.8 %) in group A, three patients (3/15, 20 %) in group B and three patients (3/12, 25 %) in group C moved from an abnormal T2* to normal values. We observed an improvement of left ventricular ejection fraction and a reduction of end-systolic and end-diastolic left ventricular volumes only in patients in group A with baseline cardiac T2* between 10 and 20 ms. Rigorous compliance to any chelation therapy at proper doses significantly improve myocardial T2*. Treatment with deferasirox significantly improves left ventricular function. Combination therapy seems to ameliorate cardiac T2* in a shorter period of time in severe siderosis.
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Effects of a low-dose antihypertensive diuretic in combination with losartan, telmisartan, or candesartan on serum urate levels in hypertensive patients.
Hamada, T, Mizuta, E, Kondo, T, Hirai, M, Yamada, K, Kato, M, Shigemasa, C, Yamamoto, Y, Ninomiya, H, Igawa, O, et al
Arzneimittel-Forschung. 2010;(2):71-5
Abstract
BACKGROUND A combination therapy of a low-dose antihypertensive diuretic with an angiotensin II receptor blocker (ARB) may have unfavorable effects on serum urate levels. METHODS Forty-two hypertensive patients without hyperuricemia (18 men and 24 women, mean age 65 years) were randomly divided into three groups. Each of the group was allocated to a combination therapy with losartan (LOS; CAS 124750-99-8; 50 mg/day)/hydrochlorothiazide (HCTZ; CAS 58-93-5; 12.5 mg/day) (LOS/HCTZ group), telmisartan (TEL; CAS 144701-48-4; 40 mg/day)/HCTZ (12.5 mg/day) (TEL/HCTZ group), or candesartan (CND; CAS 145040-37-5; 8 mg/day)/HCTZ (12.5 mg/day) (CND/HCTZ group), respectively. Before and after the treatment, blood pressure and biochemical parameters of blood and urine were evaluated. RESULTS Both systolic and diastolic blood pressures significantly decreased in all groups (p < 0.01) without any statistical differences. The LOS/HCTZ group showed no changes in serum urate levels (5.8 +/- 1.0 mg/dl to 5.8 +/- 1.4 mg/dl) and in % fractional excretion of urate (FEUA). In the TEL/HCTZ group, the serum urate level was significantly increased, from 5.5 +/- 0.9 mg/dl to 6.5 +/- 1.2 mg/dl (p < 0.01), whereas FEUA significantly decreased (p < 0.01). Similarly, the CND/HCTZ group showed a significant increase in the serum urate level from 5.4 +/- 0.9 mg/dl to 6.0 +/- 1.2 mg/dl (p < 0.01) and a significant decrease in FEUA (p < 0.01). No significant differences were found in fasting plasma glucose and electrolytes levels in any of the groups. CONCLUSIONS A combination therapy with a low-dose HCTZ and ARBs resulted in reduced urate excretion and elevated serum urate levels. A combination therapy with the ARB losartan was not accompanied with these effects, likely because of its inhibitory action on urate transporter 1. The study limitations deserve mention in consideration of ethic restrictions, small size, short term examination and uncontrolled design.
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Comparison of the effects of three angiotensin II receptor type 1 blockers on metabolic parameters in hypertensive patients with type 2 diabetes mellitus.
Ozaki, N, Nomura, Y, Sobajima, H, Kondo, K, Oiso, Y
European journal of internal medicine. 2010;(3):236-9
Abstract
OBJECTIVE In a previous study involving 18 hypertensive patients with type 2 diabetes mellitus, we found that replacement of valsartan and candesartan by telmisartan significantly improved insulin sensitivity and significantly increased serum adiponectin levels in the patients. We investigated the effects of 3 angiotensin II type 1 receptor blockers (ARBs)-telmisartan, candesartan, and valsartan-on metabolic parameters in hypertensive patients with type 2 diabetes. METHODS A total of 308 hypertensive patients with diabetes were enrolled in our multicentre, randomized, open-label study. The patients received 40 mg telmisartan, 8 mg candesartan, or 80 mg valsartan for 3 months, and the data of 227 patients (telmisartan: n=74, candesartan: n=79, and valsartan: n=74) were analysed. RESULTS The systolic and diastolic blood pressures significantly decreased in all the groups at the end of the study; the decrease was comparable among the 3 groups. The changes in fasting plasma glucose, fasting insulin, glycated haemoglobin (HbA1c), total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, adiponectin, free fatty acids, high-sensitivity C-reactive protein (hs-CRP), and plasminogen activator inhibitor-1 (PAI-1) were comparable between the 3 groups. Telmisartan and candesartan administration tended to lower urinary albumin excretion. CONCLUSIONS Low dose telmisartan had a neutral effect on metabolic dysfunction in hypertensive patients with type 2 diabetes; the effect produced by 40 mg telmisartan was comparable with that of 8 mg candesartan and 80 mg valsartan. Failure to detect metabolic differences among the various ARB treatments could have been due to the low statistical power of the study design.