The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
Thomas F Luscher - One of the best experts on this subject based on the ideXlab platform.
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Darusentan a selective endothelin a receptor antagonist for the oral treatment of resistant hypertension
Therapeutic Advances in Cardiovascular Disease, 2010Co-Authors: Frank Enseleit, Thomas F Luscher, Frank RuschitzkaAbstract:Resistant hypertension is defined as failure to lower blood pressure to target when a patient adheres to the maximum tolerated doses of three antihypertensive drugs including a diuretic. Notwithstanding the wide availability of several antihypertensive agents and the continued recommendation of dietary and lifestyle modifications, the prevalence of resistant hypertension remains high and is expected to increase thus underscoring the need for potential new treatment modalities in resistant hypertension. Endothelin-1 is a long-lasting potent vasoconstrictor and plays a key role in cardiovascular haemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The clinical experience and the evidence for therapy with Darusentan in resistant systemic hypertension are reviewed. The leading journals that publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. While results from early clinical studies suggested that Darusentan might emerge as new treatment option in patients with resistant hypertension, results from recent studies suggests that Darusentan appears unlikely to find its way in the armamentarium for treatment of resistant hypertension.
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Darusentan a new perspective for treatment of resistant hypertension
Expert Opinion on Investigational Drugs, 2008Co-Authors: Frank Enseleit, Thomas F Luscher, Frank RuschitzkaAbstract:Despite multi-drug therapy, hypertension remains uncontrolled in a significant amount of patients, especially those with multiple cardiovascular risk factors. Endothelin-1 is a long lasting and very potent vasoconstrictor and plays a key role in cardiovascular hemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The selective endothelin – A receptor antagonist Darusentan may be a new treatment option in patients with resistant hypertension. The objectives were that the clinical experience and the evidence for therapy with Darusentan in resistant systemic hypertension were reviewed. The methods by the authors were that the leading journals which publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. In conclusion, early clinical results from Phase II studies suggest that Darusentan may find a place in the treatment of resistant hypertension.
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long term effects of Darusentan on left ventricular remodelling and clinical outcomes in the endothelina receptor antagonist trial in heart failure earth randomised double blind placebo controlled trial
The Lancet, 2004Co-Authors: Inder S Anand, Frank Ruschitzka, John J V Mcmurray, Jay N Cohn, Marvin A Konstam, Thomas Notter, Kurt Quitzau, Thomas F LuscherAbstract:Summary Background Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. Methods 642 patients with chronic heart failure were assigned the oral endothelin A -antagonist Darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50–300 mg groups, Darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. Findings Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1·27 mL [95% CI −9·9 to 12·4] with 10 mg dose, −1·84 mL [−13·0 to 9·3] with 25 mg, −5·68 mL [−16·9 to 5·6] with 50 mg, −4·05 mL [−15·5 to 7·4] with 100 mg, and −4·34 mL [−15·7 to 7·0] with 300 mg). Heart failure worsened in 71 (11·1%) patients, and 30 (4·7%) died during the study with no difference between groups. Interpretation Endothelin A blockade with Darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, β blocker, or aldosterone antagonist. Thus, endothelin A blockade is unlikely to be useful as an add-on treatment in such patients.
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hemodynamic and neurohumoral effects of selective endothelin a et a receptor blockade in chronic heart failure the heart failure et a receptor blockade trial heat
Circulation, 2002Co-Authors: Thomas F Luscher, Frank Enseleit, Richard Pacher, Veselin Mitrovic, Matthias R Schulze, Roland Willenbrock, Rainer Dietz, Valentin Rousson, David Hurlimann, Sebastian PhilippAbstract:Background— The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ETA antagonist Darusentan in addition to modern standard therapy in patients with CHF. Methods and Results— A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure ≥12 mm Hg, and a cardiac index ≤2.6 L · min−1 · m−2 were randomly assigned to double-blind treatment with placebo or Darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of Darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pres...
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treatment with Darusentan over 21 days improved cgmp generation in patients with chronic heart failure
Clinical Science, 2002Co-Authors: Sebastian Philipp, Thomas F Luscher, Rainer Dietz, Frank Ruschitzka, Thomas Notter, Jan Monti, Ines Pagel, Thomas Langenickel, Roland WillenbrockAbstract:In heart failure, the cGMP to natriuretic peptide ratio is decreased and infusion of atrial natriuretic peptide (ANP) induces less cGMP generation. The ratio of the second messenger cGMP to plasma concentrations of ANP or brain natriuretic peptide (BNP) correlates with the effectiveness of natriuretic peptides. It was investigated whether blockade of the ET(A) receptor might improve the cGMP:NP ratio in heart failure. Patients with chronic heart failure (n = 142; mean age = 57 years) received oral treatment with the ET(A) antagonist Darusentan (either 30, 100, 300mg/day or placebo) on top of standard therapy over a period of 21 days in a randomized, double-blind, placebo-controlled, multicentre study. Plasma concentrations of ANP, BNP and cGMP were determined before randomization and after 21 days of treatment. In parallel with decreased pulmonary and systemic vascular resistance, 3 weeks of oral treatment with the ET(A) receptor antagonist Darusentan reduced BNP plasma levels and increased the cGMP:BNP ratio significantly. The improved cGMP:BNP ratio might reflect the ability of chronic ET(A) receptor blockade to facilitate the generation of the second messenger cGMP, which points towards a favourable modulation of the natriuretic peptide effector system, in addition to haemodynamic improvement in heart failure patients.
Jennifer V. Linseman - One of the best experts on this subject based on the ideXlab platform.
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Clinical Trials Divergent Results Using Clinic and Ambulatory Blood Pressures
2016Co-Authors: Hypertension Trial, George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Stuart Linas, Jennifer V. Linseman, Sarah Arterburn, Philip Sager, Michael WeberAbstract:Abstract—Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving 3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist Darusentan, placebo, or the central -2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for Darusentan (1514 mm Hg) were greater than for guanfacine (1213 mm Hg; P0.05) but not greater than placebo (1414 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (912 mm Hg) more than placebo (212 mm Hg) or guanfacine (412 mm Hg) after 14 weeks of treatment (P0.001 for each comparison). The most frequent adverse event associated with Darusentan was fluid retention/edema at 28 % versus 12 % in each of the other groups. More patients withdrew because of adverse events on Darusentan as compared with placebo or guanfacine. We conclude that Darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies. (Hypertension. 2010;56: 824-830.
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divergent results using clinic and ambulatory blood pressures report of a Darusentan resistant hypertension trial
Hypertension, 2010Co-Authors: George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Jennifer V. Linseman, Sarah Arterburn, Stuart L Linas, Philip T Sager, Michael A WeberAbstract:Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist Darusentan, placebo, or the central α-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for Darusentan (-15±14 mm Hg) were greater than for guanfacine (-12±13 mm Hg; P<0.05) but not greater than placebo (-14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (-9±12 mm Hg) more than placebo (-2±12 mm Hg) or guanfacine (-4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with Darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on Darusentan as compared with placebo or guanfacine. We conclude that Darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.
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divergent results using clinic and ambulatory blood pressures report of a Darusentan resistant hypertension trial
Hypertension, 2010Co-Authors: George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Jennifer V. Linseman, Sarah Arterburn, Philip Sager, Stuart L Linas, Michael A WeberAbstract:Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resist ...
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a selective endothelin receptor antagonist to reduce blood pressure in patients with treatment resistant hypertension a randomised double blind placebo controlled trial
The Lancet, 2009Co-Authors: Michael A Weber, George L. Bakris, Henry R. Black, Henry Krum, Jennifer V. Linseman, Stuart L Linas, Robert G Weiss, Brian L Wiens, Marshelle Warren, Lars H. LindholmAbstract:Summary Background Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, Darusentan, in patients with treatment-resistant hypertension. Methods This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or Darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. Findings All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with Darusentan 50 mg, 18/10 mm Hg (16/9) with Darusentan 100 mg, and 18/11 mm Hg (18/10) with Darusentan 300 mg (p Interpretation Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Funding Gilead Sciences.
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a selective endothelin receptor antagonist to reduce blood pressure in patients with treatment resistant hypertension a randomised double blind placebo controlled trial
The Lancet, 2009Co-Authors: Michael A Weber, George L. Bakris, Henry R. Black, Henry Krum, Jennifer V. Linseman, Stuart L Linas, Robert G Weiss, Brian L Wiens, Marshelle Warren, Lars H. LindholmAbstract:Summary Background Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, Darusentan, in patients with treatment-resistant hypertension. Methods This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or Darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. Findings All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with Darusentan 50 mg, 18/10 mm Hg (16/9) with Darusentan 100 mg, and 18/11 mm Hg (18/10) with Darusentan 300 mg (p Interpretation Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Funding Gilead Sciences.
Frank Ruschitzka - One of the best experts on this subject based on the ideXlab platform.
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Darusentan a selective endothelin a receptor antagonist for the oral treatment of resistant hypertension
Therapeutic Advances in Cardiovascular Disease, 2010Co-Authors: Frank Enseleit, Thomas F Luscher, Frank RuschitzkaAbstract:Resistant hypertension is defined as failure to lower blood pressure to target when a patient adheres to the maximum tolerated doses of three antihypertensive drugs including a diuretic. Notwithstanding the wide availability of several antihypertensive agents and the continued recommendation of dietary and lifestyle modifications, the prevalence of resistant hypertension remains high and is expected to increase thus underscoring the need for potential new treatment modalities in resistant hypertension. Endothelin-1 is a long-lasting potent vasoconstrictor and plays a key role in cardiovascular haemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The clinical experience and the evidence for therapy with Darusentan in resistant systemic hypertension are reviewed. The leading journals that publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. While results from early clinical studies suggested that Darusentan might emerge as new treatment option in patients with resistant hypertension, results from recent studies suggests that Darusentan appears unlikely to find its way in the armamentarium for treatment of resistant hypertension.
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Darusentan a new perspective for treatment of resistant hypertension
Expert Opinion on Investigational Drugs, 2008Co-Authors: Frank Enseleit, Thomas F Luscher, Frank RuschitzkaAbstract:Despite multi-drug therapy, hypertension remains uncontrolled in a significant amount of patients, especially those with multiple cardiovascular risk factors. Endothelin-1 is a long lasting and very potent vasoconstrictor and plays a key role in cardiovascular hemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The selective endothelin – A receptor antagonist Darusentan may be a new treatment option in patients with resistant hypertension. The objectives were that the clinical experience and the evidence for therapy with Darusentan in resistant systemic hypertension were reviewed. The methods by the authors were that the leading journals which publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. In conclusion, early clinical results from Phase II studies suggest that Darusentan may find a place in the treatment of resistant hypertension.
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long term effects of Darusentan on left ventricular remodelling and clinical outcomes in the endothelina receptor antagonist trial in heart failure earth randomised double blind placebo controlled trial
The Lancet, 2004Co-Authors: Inder S Anand, Frank Ruschitzka, John J V Mcmurray, Jay N Cohn, Marvin A Konstam, Thomas Notter, Kurt Quitzau, Thomas F LuscherAbstract:Summary Background Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. Methods 642 patients with chronic heart failure were assigned the oral endothelin A -antagonist Darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50–300 mg groups, Darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. Findings Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1·27 mL [95% CI −9·9 to 12·4] with 10 mg dose, −1·84 mL [−13·0 to 9·3] with 25 mg, −5·68 mL [−16·9 to 5·6] with 50 mg, −4·05 mL [−15·5 to 7·4] with 100 mg, and −4·34 mL [−15·7 to 7·0] with 300 mg). Heart failure worsened in 71 (11·1%) patients, and 30 (4·7%) died during the study with no difference between groups. Interpretation Endothelin A blockade with Darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, β blocker, or aldosterone antagonist. Thus, endothelin A blockade is unlikely to be useful as an add-on treatment in such patients.
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erythropoietin induced excessive erythrocytosis activates the tissue endothelin system in mice
The FASEB Journal, 2003Co-Authors: Thomas Quaschning, Frank Ruschitzka, Thomas Stallmach, Sidney Shaw, Henning Morawietz, Winfried Goettsch, Matthias Hermann, Torsten Slowinski, Franz Theuring, Berthold HocherAbstract:The endothelium controls blood flow and pressure by releasing several vasoactive factors, among them the vasodilator nitric oxide (NO) and the potent vasoconstrictor endothelin-1 (ET-1). Although increased NO levels have been found in excessive erythrocytosis, little is known concerning ET-1 expression in this condition. Thus, we examined the endothelin system in transgenic mice that due to constitutive overexpression of erythropoietin (Epo) reached hematocrit levels of approximately 80%. Surprisingly, despite generalized vasodilatation, polycythemic mice exhibited a two- to fivefold elevation in ET-1 mRNA levels in aorta, liver, heart, and kidney. In line with this, increased expression of ET-1 protein was detected in the pulmonary artery by immunohistochemical analysis. Compared with their wild-type littermates, aortic rings of Epo transgenic animals exhibited a marked reduction in vascular reactivity to ET-1 and big ET-1, but this effect was abrogated upon preincubation with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME). Pretreatment of polycythemic mice with the ET(A) receptor antagonist Darusentan for 3 wk significantly prolonged their survival upon acute exposure to L-NAME. Taken together, these results demonstrate for the first time that excessive erythrocytosis induces a marked activation of the tissue endothelin system that results in increased mortality upon blockade of NO-mediated vasodilatation. Because ETA antagonism prolonged survival after acute blockade of NO synthesis, endothelin may be regarded as a contributor to the adverse cardiovascular effects of erythrocytosis and may thus represent a new target in the treatment of cardiovascular disease associated with erythrocytosis.
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treatment with Darusentan over 21 days improved cgmp generation in patients with chronic heart failure
Clinical Science, 2002Co-Authors: Sebastian Philipp, Thomas F Luscher, Rainer Dietz, Frank Ruschitzka, Thomas Notter, Jan Monti, Ines Pagel, Thomas Langenickel, Roland WillenbrockAbstract:In heart failure, the cGMP to natriuretic peptide ratio is decreased and infusion of atrial natriuretic peptide (ANP) induces less cGMP generation. The ratio of the second messenger cGMP to plasma concentrations of ANP or brain natriuretic peptide (BNP) correlates with the effectiveness of natriuretic peptides. It was investigated whether blockade of the ET(A) receptor might improve the cGMP:NP ratio in heart failure. Patients with chronic heart failure (n = 142; mean age = 57 years) received oral treatment with the ET(A) antagonist Darusentan (either 30, 100, 300mg/day or placebo) on top of standard therapy over a period of 21 days in a randomized, double-blind, placebo-controlled, multicentre study. Plasma concentrations of ANP, BNP and cGMP were determined before randomization and after 21 days of treatment. In parallel with decreased pulmonary and systemic vascular resistance, 3 weeks of oral treatment with the ET(A) receptor antagonist Darusentan reduced BNP plasma levels and increased the cGMP:BNP ratio significantly. The improved cGMP:BNP ratio might reflect the ability of chronic ET(A) receptor blockade to facilitate the generation of the second messenger cGMP, which points towards a favourable modulation of the natriuretic peptide effector system, in addition to haemodynamic improvement in heart failure patients.
Henry R. Black - One of the best experts on this subject based on the ideXlab platform.
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Clinical Trials Divergent Results Using Clinic and Ambulatory Blood Pressures
2016Co-Authors: Hypertension Trial, George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Stuart Linas, Jennifer V. Linseman, Sarah Arterburn, Philip Sager, Michael WeberAbstract:Abstract—Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving 3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist Darusentan, placebo, or the central -2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for Darusentan (1514 mm Hg) were greater than for guanfacine (1213 mm Hg; P0.05) but not greater than placebo (1414 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (912 mm Hg) more than placebo (212 mm Hg) or guanfacine (412 mm Hg) after 14 weeks of treatment (P0.001 for each comparison). The most frequent adverse event associated with Darusentan was fluid retention/edema at 28 % versus 12 % in each of the other groups. More patients withdrew because of adverse events on Darusentan as compared with placebo or guanfacine. We conclude that Darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies. (Hypertension. 2010;56: 824-830.
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divergent results using clinic and ambulatory blood pressures report of a Darusentan resistant hypertension trial
Hypertension, 2010Co-Authors: George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Jennifer V. Linseman, Sarah Arterburn, Stuart L Linas, Philip T Sager, Michael A WeberAbstract:Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist Darusentan, placebo, or the central α-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for Darusentan (-15±14 mm Hg) were greater than for guanfacine (-12±13 mm Hg; P<0.05) but not greater than placebo (-14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (-9±12 mm Hg) more than placebo (-2±12 mm Hg) or guanfacine (-4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with Darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on Darusentan as compared with placebo or guanfacine. We conclude that Darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.
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divergent results using clinic and ambulatory blood pressures report of a Darusentan resistant hypertension trial
Hypertension, 2010Co-Authors: George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Jennifer V. Linseman, Sarah Arterburn, Philip Sager, Stuart L Linas, Michael A WeberAbstract:Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resist ...
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a selective endothelin receptor antagonist to reduce blood pressure in patients with treatment resistant hypertension a randomised double blind placebo controlled trial
The Lancet, 2009Co-Authors: Michael A Weber, George L. Bakris, Henry R. Black, Henry Krum, Jennifer V. Linseman, Stuart L Linas, Robert G Weiss, Brian L Wiens, Marshelle Warren, Lars H. LindholmAbstract:Summary Background Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, Darusentan, in patients with treatment-resistant hypertension. Methods This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or Darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. Findings All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with Darusentan 50 mg, 18/10 mm Hg (16/9) with Darusentan 100 mg, and 18/11 mm Hg (18/10) with Darusentan 300 mg (p Interpretation Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Funding Gilead Sciences.
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a selective endothelin receptor antagonist to reduce blood pressure in patients with treatment resistant hypertension a randomised double blind placebo controlled trial
The Lancet, 2009Co-Authors: Michael A Weber, George L. Bakris, Henry R. Black, Henry Krum, Jennifer V. Linseman, Stuart L Linas, Robert G Weiss, Brian L Wiens, Marshelle Warren, Lars H. LindholmAbstract:Summary Background Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, Darusentan, in patients with treatment-resistant hypertension. Methods This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or Darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. Findings All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with Darusentan 50 mg, 18/10 mm Hg (16/9) with Darusentan 100 mg, and 18/11 mm Hg (18/10) with Darusentan 300 mg (p Interpretation Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Funding Gilead Sciences.
George L. Bakris - One of the best experts on this subject based on the ideXlab platform.
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Clinical Trials Divergent Results Using Clinic and Ambulatory Blood Pressures
2016Co-Authors: Hypertension Trial, George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Stuart Linas, Jennifer V. Linseman, Sarah Arterburn, Philip Sager, Michael WeberAbstract:Abstract—Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving 3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist Darusentan, placebo, or the central -2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for Darusentan (1514 mm Hg) were greater than for guanfacine (1213 mm Hg; P0.05) but not greater than placebo (1414 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (912 mm Hg) more than placebo (212 mm Hg) or guanfacine (412 mm Hg) after 14 weeks of treatment (P0.001 for each comparison). The most frequent adverse event associated with Darusentan was fluid retention/edema at 28 % versus 12 % in each of the other groups. More patients withdrew because of adverse events on Darusentan as compared with placebo or guanfacine. We conclude that Darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies. (Hypertension. 2010;56: 824-830.
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divergent results using clinic and ambulatory blood pressures report of a Darusentan resistant hypertension trial
Hypertension, 2010Co-Authors: George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Jennifer V. Linseman, Sarah Arterburn, Stuart L Linas, Philip T Sager, Michael A WeberAbstract:Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist Darusentan, placebo, or the central α-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for Darusentan (-15±14 mm Hg) were greater than for guanfacine (-12±13 mm Hg; P<0.05) but not greater than placebo (-14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (-9±12 mm Hg) more than placebo (-2±12 mm Hg) or guanfacine (-4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with Darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on Darusentan as compared with placebo or guanfacine. We conclude that Darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.
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divergent results using clinic and ambulatory blood pressures report of a Darusentan resistant hypertension trial
Hypertension, 2010Co-Authors: George L. Bakris, Lars H. Lindholm, Henry R. Black, Henry Krum, Jennifer V. Linseman, Sarah Arterburn, Philip Sager, Stuart L Linas, Michael A WeberAbstract:Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resist ...
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a selective endothelin receptor antagonist to reduce blood pressure in patients with treatment resistant hypertension a randomised double blind placebo controlled trial
The Lancet, 2009Co-Authors: Michael A Weber, George L. Bakris, Henry R. Black, Henry Krum, Jennifer V. Linseman, Stuart L Linas, Robert G Weiss, Brian L Wiens, Marshelle Warren, Lars H. LindholmAbstract:Summary Background Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, Darusentan, in patients with treatment-resistant hypertension. Methods This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or Darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. Findings All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with Darusentan 50 mg, 18/10 mm Hg (16/9) with Darusentan 100 mg, and 18/11 mm Hg (18/10) with Darusentan 300 mg (p Interpretation Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Funding Gilead Sciences.
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a selective endothelin receptor antagonist to reduce blood pressure in patients with treatment resistant hypertension a randomised double blind placebo controlled trial
The Lancet, 2009Co-Authors: Michael A Weber, George L. Bakris, Henry R. Black, Henry Krum, Jennifer V. Linseman, Stuart L Linas, Robert G Weiss, Brian L Wiens, Marshelle Warren, Lars H. LindholmAbstract:Summary Background Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, Darusentan, in patients with treatment-resistant hypertension. Methods This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or Darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. Findings All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with Darusentan 50 mg, 18/10 mm Hg (16/9) with Darusentan 100 mg, and 18/11 mm Hg (18/10) with Darusentan 300 mg (p Interpretation Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Funding Gilead Sciences.
