Institute for Pharmacology and Preventive Medicine

Germany

Institute for Pharmacology and Preventive Medicine

Germany
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Minguet J.,Institute for Research and Medicine Advancement IRMEDICA | Minguet J.,Institute for Pharmacology and Preventive Medicine | Sutton G.,Institute for Research and Medicine Advancement IRMEDICA | Ferrero C.,University of Seville | And 4 more authors.
Expert Opinion on Pharmacotherapy | Year: 2015

Introduction: Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. Currently, blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone of treatment; however, the combination of RAAS blockade with inhibition of neprilysin (NEP), an enzyme that degrades natriuretic peptides, has recently emerged as a potentially superior treatment strategy. Areas covered: Following the results of the recent Phase III Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure clinical trial in patients with chronic HF with reduced ejection fraction (HF-REF), this review focuses on LCZ696, a first-in-class angiotensin receptor NEP inhibitor. This drug consists of a supramolecular complex containing the angiotensin receptor inhibitor valsartan in combination with the NEP inhibitor prodrug, AHU377. Following oral administration, the LCZ696 complex dissociates and the NEP inhibitor component is metabolized to the active form (LBQ657). Aspects of the trial that might be relevant to clinical practice are also discussed. Expert opinion: Speculation that LCZ696 will pass the scrutiny of regulatory agencies for HF-REF appears to be justified, and it is likely to become a core therapeutic component in the near future. Replication of the eligibility criteria and titration protocol used in the PARADIGM-HF trial would be valuable in clinical practice and may minimize the risk of adverse events. Although long-term data remain to be generated, the promising results regarding hypertension are likely to expedite acceptance of the drug for HF-REF. © 2015 Informa UK, Ltd.


Bramlage P.,Institute for Pharmacology and Preventive Medicine | Bramlage P.,University of Seville | Swift S.L.,Institute for Pharmacology and Preventive Medicine | Thoenes M.,Leman Research Institute | And 3 more authors.
European Journal of Heart Failure | Year: 2016

Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease. © 2015 The Authors European Journal of Heart Failure.


PubMed | Friedrich - Alexander - University, Erlangen - Nuremberg, Institute for Pharmacology and Preventive Medicine, University of Seville and Leman Research Institute
Type: Journal Article | Journal: European journal of heart failure | Year: 2016

Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease.


PubMed | University of Barcelona, University of Cologne, Edwards Lifesciences, Bichat Hospital and 4 more.
Type: Journal Article | Journal: BMC cardiovascular disorders | Year: 2017

Severe aortic stenosis (AS) is a common, serious valve disease in which no effective medical therapy is available and, if not treated by intervention, has a 5-year survival of only 40-60%. Despite the availability of guidelines supporting the effective use of surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) to treat the majority of these patients, adherence to these guidelines in clinical practice is still unsatisfactory. Several recent studies have emphasised the necessity for improved communication between multidisciplinary teams, with the aim to ensure that severe AS patients receive appropriate treatment.IMPULSE is a prospective, multicentre, European registry designed to gather data over 12months on the treatment decisions made by referring physicians for patients newly diagnosed with severe AS. Each patient has a follow-up of 3months. The study will consist of two observational phases to assess the appropriateness and rate of referral based on current guidelines prior to and after an interventional phase aiming to determine whether a simple quality of care intervention improves patient management.Data will be analysed firstly, to determine the appropriateness of treatment decisions for the management of severe AS in current European clinical practice, and secondly, to evaluate the effectiveness of facilitated data relay from a designated echocardiography department nurse to the referring physician early after diagnosis in improving quality of care. Additionally, variables will be identified that are associated with inappropriate decision-making. Collectively, the aim will be to design a clinical pathway that will improve the timely management of patients with newly diagnosed severe AS.


Luik A.,Medizinische Klinik IV | Radzewitz A.,Medizinische Klinik IV | Kieser M.,University of Heidelberg | Walter M.,Medizinische Klinik IV | And 10 more authors.
Circulation | Year: 2015

Background - There is a lack of data on the comparative efficacy and procedural safety of open irrigated radiofrequency (RF) and cryoballoon catheter (CB) ablation for pulmonary vein isolation in patients with paroxysmal atrial fibrillation. Methods and Results - In a prospective, noninferiority study, 315 patients were randomly assigned to RF (n=159) or CB (n=156) ablation. The primary end point was freedom from atrial arrhythmia with absence of persistent complications. Patients were largely comparable between groups with more vascular disease in the RF group (8.2% versus 2.6% for CB; P=0.028). The primary end point at 12 months was achieved by 70.7% with RF and 73.6% with CB (multiple procedure success), including 31 redo procedures in each group (19.5% of RF versus 19.9% of CB; P=0.933). For the intention-to-treat population, noninferiority of CB was revealed for the predefined inferiority margin (risk difference, 0.029; 95% confidence interval, -0.074 to 0.132; P<0.001). Rates at 6 months were 63.1% and 64.1% for the RF and CB groups (single procedure success), and noninferiority was confirmed (risk difference, 0.010; 95% confidence interval, -0.097 to 0.116; P=0.002). Periprocedural complications for the index procedure were more frequent in the CB group (5.0% RF, 12.2% CB; P=0.022) with a significant difference in phrenic nerve palsies (0% RF, 5.8% CB; P=0.002). Conclusion - This large, prospective, randomized, controlled study demonstrates noninferiority of CB ablation versus RF ablation for treating patients with paroxysmal atrial fibrillation. © 2015 The Authors. © 2015 The Authors.


Hanefeld M.,TU Dresden | Fleischmann H.,Sanofi S.A. | Schiffhorst G.,IGES Institute GmbH | Bramlage P.,Institute for Pharmacology and Preventive Medicine
Diabetes Technology and Therapeutics | Year: 2014

Background: It was the aim of this study to assess baseline predictors for glycosylated hemoglobin (HbA1c) reduction, treatment-to-target, and insulin glargine dose in patients with an HbA1c level of ≥7.5% (58 mmol/mol) at baseline despite 3 months of maximum tolerated dose of metformin under daily conditions. Subjects and Methods: This was an open, multicenter, prospective observational study with a 6-month follow-up including 1,438 patients with type 2 diabetes. Baseline variables independently associated with HbA1c (overall reduction and achievement of target values) and insulin glargine dose used were determined using a stepwise multivariate linear regression analysis. Results: In a multivariate linear regression analysis (R2=0.545) baseline HbA1c (β=-0.722; P<0.001) and retinopathy (β=-0.064; P=0.007) were associated with a greater HbA1c reduction at 6 months, whereas duration of diabetes was associated with a lesser HbA1c reduction (β=0.084; P<0.001). In another multivariate linear regression analysis, weight (odds ratio [OR] 0.99; 95% confidence interval [CI] 0.98 to <1.00), duration of diabetes (OR 0.96; 95% CI 0.93-0.99), and baseline HbA1c (OR 0.65; 95% CI 0.56-0.76) were associated with a reduced likelihood of achieving an HbA1c level of <7% (53 mmol/mol); baseline HbA1c (OR 0.66; 95% CI 0.51-0.85) was the only variable associated with a reduced likelihood of achieving an HbA1c level of <6.5% (48 mmol/mol). In a further analysis (R2=0.135) the insulin dose needed was increased in those with a higher body weight (β=0.230; P<0.001), a longer duration of diabetes (β=0.134; P<0.001), a higher baseline HbA1c level (β=0.205; P<0.001), and the presence of microalbuminuria (β=0.096; P=0.003). Conclusions: Identified predictors of greater HbA1c reduction, target goal achievement, and insulin dose needed may help to optimize the balance of benefits and risks with the use of insulin glargine. © 2014, Mary Ann Liebert, Inc.


Beime B.,Institute for Pharmacology and Preventive Medicine | Deutsch C.,Institute for Pharmacology and Preventive Medicine | Gomez T.,Institute for Research and Medicine Advancement IRMEDICA | Zwingers T.,Estimate GmbH | And 3 more authors.
Blood Pressure Monitoring | Year: 2016

Hypertension is a major risk factor for cardiovascular morbidity and mortality. Therefore, blood pressure selfmeasuring devices have emerged as valuable tools in patient care and the accuracy of these instruments is of fundamental importance. For this reason, several validation procedures for assessing the efficacy of blood pressure monitoring devices have been developed, including protocols by the Association for the Advancement of Medical Instrumentation, the British Hypertension Society, the German Hypertension League (Prüfsiegelprotokoll), and the International Protocol of the Working Group on Blood Pressure Monitoring of the European Society of Hypertension. In the past, most of the protocols have been reviewed and modified because of experiences gained during the validation studies carried out. However, each shows distinct differences, that is number and characteristics of patients required, blood pressure ranges, and the length of the validation procedure, which may result in unique advantages and/or limitations associated with their use. The continued standardization and evolution of these guidelines is essential to ensure the efficacy of blood pressure-measuring devices marketed for clinical and home use. Here, we aimed to compare four currently used validation protocols and to initiate a discussion on potential future improvements. © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Schmieder R.E.,Friedrich - Alexander - University, Erlangen - Nuremberg | Ott C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bramlage P.,Institute for Pharmacology and Preventive Medicine
Current Hypertension Reports | Year: 2016

In the last decade, intravenous renal denervation (RDN) has emerged as an alternative to pharmacological treatment in patients with resistant hypertension, but currently involves an invasive and technically challenging procedure. The Surround Sound™ system utilises externally delivered ultrasound to achieve RDN using a completely non-invasive, automated real-time tracking system coupled with a therapeutic delivery module thereby addressing these limitations. A brief history, technical overview and summary of preclinical and clinical studies of the KonaMedical Surround Sound™ system are presented. A literature search using the terms “renal denervation”, “resistant hypertension” and “external ultrasound” was performed using PubMed, and references retrieved were selected based on relevancy and year of publication (date range 1991–2015). The Surround Sound™ system appears to be a promising approach to RDN which eliminates several of the factors currently limiting the intravenous approach. So far, it has demonstrated efficacy for reducing blood pressure in resistant hypertension patients with minimal adverse effects. Several double-blind, sham-controlled clinical trials are currently underway to confirm the validity of these findings. © 2016, Springer Science+Business Media New York.


Hanefeld M.,Study Center Professor Hanefeld | Bramlage P.,Institute for Pharmacology and Preventive Medicine
Current Diabetes Reports | Year: 2013

There has been a recent shift from a uniform treatment targeting HbA1c to a patient centered approach due to disappointing results of intensified glucose control in mega-trials such as VADT, ADVANCE, and ACCORD. In addition, morbidity and mortality has been substantially reduced since the UKPDS leading to an overestimation of the absolute risk for cardiovascular complications in randomized controlled trials. With substantial progress in prevention of cardiovascular complications, patients with type 2 diabetes now survive long enough to face diabetes-related complications and cancer risk. This requires rethinking of antidiabetic treatment strategies as exemplified by a recent consensus statement of the EASD and ADA, calling for a more patient centered treatment. Within this context the value of early insulin initiation was reinforced, the clinical utility of which has been demonstrated in the recent ORIGIN trial. ORIGIN demonstrated neutral results for the primary endpoint, but reduced microangiopathy in patients with an HbA1c value of ≥6.4 % with basal insulin glargine. After 5 years of follow-up 77 % of the patients in the glargine arm and 66 % with standard care remained at an HbA1c <7 %. An ongoing long-term follow-up (ORIGINALE) will clarify whether this also translates into a reduction of macrovascular events and mortality. © 2013 The Author(s).


Bramlage P.,Institute for Pharmacology and Preventive Medicine | Strauch J.,Institute for Pharmacology and Preventive Medicine | Schrofel H.,Institute for Pharmacology and Preventive Medicine
BMC cardiovascular disorders | Year: 2014

BACKGROUND: In patients with severe calcific aortic stenosis, balloon aortic valvuloplasty (BAV) is routinely performed in order to pre-dilate the stenosed aortic valve prior to transcatheter aortic valve implantation (TAVI). Although pre-dilation is considered to be essential for the preparation of the valve landing zone, there is no clear evidence to support its clinical value. In contrast, BAV has been suggested to be linked to several complications. Notably, while preliminary evidence has supported the feasibility and safety of TAVI without pre-dilation, larger studies directly comparing the benefit/risk profile of TAVI in the presence and absence of pre-dilation are required.METHODS/DESIGN: Therefore, a prospective, two-armed, multicenter registry (EASE-IT) was designed to obtain essential data concerning procedural success rates, adverse events, and mortality in a large cohort of patients undergoing transapical (TA)-TAVI using the Edwards SAPIEN 3 balloon expandable heart valves with and without pre-ballooning.DISCUSSION: Data provided by EASE-IT will be used to assess the relevance of BAV during the TAVI procedure and to investigate associations between patient characteristics and outcomes. Therefore, results obtained from the EASE-IT registry could contribute to reduced rates of TAVI-associated morbidity and mortality in patients with severe, calcific aortic stenosis.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02127580.

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