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End points, hard and surrogate

Giuseppe M C Rosano, Juan Tamargo, Keld P Kjeldsen, Mitja Lainscak, Stefan Agewall, Stefan D Anker, Claudio Ceconi, Andrew J S Coats, Heinz Drexel, Gerasimos Filippatos, Juan Carlos Kaski, Lars Lund, Alexander Niessner, Gianluigi Savarese, Thomas A Schmidt, Petar Seferovic, Sven Wassmann, Thomas Walther, Basil S Lewis
Renin angiotensin aldosterone system inhibitors/antagonists/blockers (RAASi) are a cornerstone in treatment of patients with cardiovascular diseases especially in those with heart failure (HF) due to their proven effect on surrogate and hard end-points. RAASi are also the basis in treatment of arterial hypertension and they are furthermore indicated to reduce events and target organ damage in patients with diabetes and chronic kidney disease, where they have specific indication because of the evidence of benefit...
May 3, 2018: European Heart Journal. Cardiovascular Pharmacotherapy
Jonathan R Weir-McCall, Liam Brown, Jennifer Summersgill, Piotr Talarczyk, Michael Bonnici-Mallia, Sook C Chin, Faisel Khan, Allan D Struthers, Frank Sullivan, Helen M Colhoun, Angela C Shore, Kunihiko Aizawa, Leif Groop, Jan Nilsson, John R Cockcroft, Carmel M McEniery, Ian B Wilkinson, Yoav Ben-Shlomo, J Graeme Houston
Current distance measurement techniques for pulse wave velocity (PWV) calculation are susceptible to intercenter variability. The aim of this study was to derive and validate a formula for this distance measurement. Based on carotid femoral distance in 1183 whole-body magnetic resonance angiograms, a formula was derived for calculating distance. This was compared with distance measurements in 128 whole-body magnetic resonance angiograms from a second study. The effects of recalculation of PWV using the new formula on association with risk factors, disease discrimination, and prediction of major adverse cardiovascular events were examined within 1242 participants from the multicenter SUMMIT study (Surrogate Markers of Micro- and Macrovascular Hard End-Points for Innovative Diabetes Tools) and 825 participants from the Caerphilly Prospective Study...
May 2018: Hypertension
F Koinis, S Agelaki, V Karavassilis, N Kentepozidis, E Samantas, S Peroukidis, P Katsaounis, E Hartabilas, I I Varthalitis, I Messaritakis, G Fountzilas, V Georgoulias, A Kotsakis
BACKGROUND: Pazopanib is a tyrosine kinase inhibitor with antiangiogenic activity. Vascular endothelial growth factor expression is increased in SCLC and is correlated with poor prognosis. The efficacy and tolerance of second-line pazopanib in SCLC was evaluated. PATIENTS AND METHODS: Patients with platinum-sensitive (cohort A; n=39) and -resistant/refractory (cohort B; n=19) SCLC were enrolled in a multicentre phase II study. The primary end point was the progression-free survival rate (PFS-R) at week 8 in each cohort...
June 27, 2017: British Journal of Cancer
Christopher S Almond, Helena Hoen, Joseph W Rossano, Chesney Castleberry, Scott R Auerbach, Lingyao Yang, Ashwin K Lal, Melanie D Everitt, Matthew Fenton, Seth A Hollander, Elfriede Pahl, Elizabeth Pruitt, David N Rosenthal, Doff B McElhinney, Kevin P Daly, Manisha Desai
BACKGROUND: There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT. METHODS: Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT...
April 2018: Journal of Heart and Lung Transplantation
Panagiota Veloudi, Graeme Jones, James E Sharman
There is a plausible physiological theory, supported by many observational studies, that vitamin D supplementation should be effective for improving cardiovascular end points, such as blood pressure (BP), large artery stiffness, atherosclerosis, endothelial function and clinical events. However, results from randomised controlled trials (RCTs) have been inconsistent. In this review, we evaluated the evidence regarding the effectiveness of vitamin D supplementation for cardiovascular surrogate and hard clinical end points...
January 2017: Pulse (Basel, Switzerland)
Giuseppe Coppolino, Anna Pisano, Laura Rivoli, Davide Bolignano
BACKGROUND: Resistant hypertension is highly prevalent among the general hypertensive population and the clinical management of this condition remains problematic. Different approaches, including a more intensified antihypertensive therapy, lifestyle modifications, or both, have largely failed to improve patients' outcomes and to reduce cardiovascular and renal risk. As renal sympathetic hyperactivity is a major driver of resistant hypertension, renal sympathetic ablation (renal denervation) has been recently proposed as a possible therapeutic alternative to treat this condition...
February 21, 2017: Cochrane Database of Systematic Reviews
Holly Gooding, Heather M Johnson
It is well established that atherosclerosis, the pathological basis of cardiovascular disease (CVD), begins in childhood and progresses steadily between the ages of 15 to 35 years. These adolescent and young adult years are also marked by significant physiological, psychological, and sociodemographic changes that impact both CVD risk factor development and CVD prevention and treatment strategies. In this review, we highlight the importance of the primordial prevention of CVD risk factors before they ever occur and the primary prevention of CVD by treating CVD risk factors in this age group...
September 2016: Current Cardiovascular Risk Reports
Osmar Antonio Centurión
Assessment of carotid intima-media thickness (IMT) has emerged as a simple and noninvasive technique for measuring atherosclerotic burden. Although serum biomarkers have been linked to the risk of developing atherosclerosis, carotid IMT has the theoretical advantage of directly visualizing a final consequence of the disease itself, namely atherosclerosis in the vessel wall. The current widespread application of carotid IMT measurements has been based on the validity, standardization, and reproducibility of the measurement and the evidence that an increased carotid IMT can be regarded as an attractive biomarker of atherosclerosis and of increased cardiovascular risk, potentially useful as a therapeutic target in those at increased cardiovascular risk...
December 2016: Critical Pathways in Cardiology
Vinay Prasad
Translation failure occurs when the results of preclinical, observational and/or early phase studies fail to predict the results of well done (i.e. appropriately controlled, adequately powered, and properly conducted) phase III or randomised clinical trials. Some failures occur when promising basic science findings fail to replicate in human studies, while others happen when promising uncontrolled trial data show an exaggerated effect that vanishes in the setting of a randomised trial. Medical reversals occur when the results of preclinical, observational and/or early phase studies fail to predict the results of subsequent randomized clinical trials, but the practice has already gained widespread acceptance...
January 2016: European Journal of Cancer
Rupali S Avasare, Jai Radhakrishnan
Observational studies in glomerular diseases suggest that proteinuria reduction translates to improved outcomes. Because of a dearth of high-quality studies supporting this association, proteinuria is not universally recognized as a surrogate end point. Barbour et al. report on the longitudinal measure of proteinuria that best predicts hard renal outcomes. Their finding that time-varying proteinuria is the most reliable proteinuria metric is a necessary step in establishing proteinuria as a surrogate end point...
December 2015: Kidney International
Goce Spasovski
INTRODUCTION: Hyperphosphatemia in chronic kidney disease (CKD) is considered as an independent risk factor for surrogate clinical end points like vascular calcification (VC) and bone disease, or hard clinical outcomes like cardiovascular events. Various treatment options are available for phosphate removal or reduction. Calcium-based phosphate binders (CBB) with their possible positive calcium balance became culprits for progressive VC and increased mortality risk. Non-calcium-based binders (NCBB) treatment allowed a comparable control of hyperphosphatemia with a lower risk of hypercalcemia and a slower progression of VC...
2015: Expert Opinion on Pharmacotherapy
Isabel Goncalves, Eva Bengtsson, Helen M Colhoun, Angela C Shore, Carlo Palombo, Andrea Natali, Andreas Edsfeldt, Pontus Dunér, Gunilla Nordin Fredrikson, Harry Björkbacka, Gerd Östling, Kunihiko Aizawa, Francesco Casanova, Margaretha Persson, Kim Gooding, David Strain, Faisel Khan, Helen C Looker, Fiona Adams, Jill Belch, Silvia Pinnoli, Elena Venturi, Michaela Kozakova, Li-Ming Gan, Volker Schnecke, Jan Nilsson
OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus...
July 2015: Arteriosclerosis, Thrombosis, and Vascular Biology
María José Pérez-Sáez, Mónica Marín-Casino, Julio Pascual
INTRODUCTION: Transplant physicians have tried to avoid graft rejection and early graft loss for many years. However, physicians are now aware about improving long-term kidney and patient survival, a challenge that needs to focus on cardiovascular risk management. One major contributor of this risk is the development of posttransplant diabetes mellitus (PTDM). AREAS COVERED: We performed a literature search based on PubMed, covering prevalence, risk factors, prevention and treatment of PTDM...
2015: Expert Opinion on Pharmacotherapy
Suvi E Heinonen, Guillem Genové, Eva Bengtsson, Thomas Hübschle, Lina Åkesson, Katrin Hiss, Agnes Benardeau, Seppo Ylä-Herttuala, Ann-Cathrine Jönsson-Rylander, Maria F Gomez
Diabetes mellitus is a lifelong, incapacitating metabolic disease associated with chronic macrovascular complications (coronary heart disease, stroke, and peripheral vascular disease) and microvascular disorders leading to damage of the kidneys (nephropathy) and eyes (retinopathy). Based on the current trends, the rising prevalence of diabetes worldwide will lead to increased cardiovascular morbidity and mortality. Therefore, novel means to prevent and treat these complications are needed. Under the auspices of the IMI (Innovative Medicines Initiative), the SUMMIT (SUrrogate markers for Micro- and Macrovascular hard end points for Innovative diabetes Tools) consortium is working on the development of novel animal models that better replicate vascular complications of diabetes and on the characterization of the available models...
2015: Journal of Diabetes Research
D A Healy, W A Khan, C S Wong, M Clarke Moloney, P A Grace, J C Coffey, C Dunne, S R Walsh, U Sadat, M E Gaunt, S Chen, S Tehrani, D J Hausenloy, D M Yellon, R S Kramer, R F Zimmerman, V V Lomivorotov, V A Shmyrev, D N Ponomarev, I A Rahman, J G Mascaro, R S Bonser, Y Jeon, D M Hong, R Wagner, M Thielmann, G Heusch, K Zacharowski, P Meybohm, B Bein, T Y Tang
BACKGROUND: A number of 'proof-of-concept' trials suggest that remote ischaemic preconditioning (RIPC) reduces surrogate markers of end-organ injury in patients undergoing major cardiovascular surgery. To date, few studies have involved hard clinical outcomes as primary end-points. METHODS: Randomised clinical trials of RIPC in major adult cardiovascular surgery were identified by a systematic review of electronic abstract databases, conference proceedings and article reference lists...
September 2014: International Journal of Cardiology
Sara S Roscioni, Hiddo J Lambers Heerspink, Dick de Zeeuw
Drug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out...
July 2014: Kidney International
Mihai Onofriescu, Simona Hogas, Luminita Voroneanu, Mugurel Apetrii, Ionut Nistor, Mehmet Kanbay, Adrian C Covic
BACKGROUND: Chronic subclinical volume overload happens very frequently in hemodialysis patients and is associated directly with hypertension, increased arterial stiffness, left ventricular hypertrophy, and ultimately higher mortality. STUDY DESIGN: Randomized controlled parallel-group trial. SETTING & PARTICIPANTS: 131 patients from one hemodialysis center, randomly assigned into 2 groups. INTERVENTION: Dry weight prescription using results derived from repeated 3-month bioimpedance measurements to guide ultrafiltration for strict volume control (bioimpedance group; n=62) compared with clinical judgment without bioimpedance measures (clinical-methods group; n=69) for 2...
July 2014: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Paavo J Halonen, Jussi Nurro, Antti Kuivanen, Seppo Ylä-Herttuala
INTRODUCTION: In the previous gene therapy trials for vascular diseases, safety of the therapies has been demonstrated with some evidence for clinical benefits. In the future, it will be important to also test the potential clinical benefits of the treatments in randomized and controlled trials with sufficient numbers of patients. AREAS COVERED: This review covers 15 currently ongoing cardiovascular gene therapy trials that aim to treat coronary artery disease, heart failure and peripheral artery disease...
March 2014: Expert Opinion on Biological Therapy
Sharon M Moe, Ravi Thadhani
PURPOSE OF REVIEW: The treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) has traditionally focused on improvement in biochemical parameters of the disease. However, studies evaluating hard clinical end points or surrogate end points are limited. RECENT FINDINGS: Two randomized controlled trials have recently been published. In the EVOLVE study (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), cinacalcet was compared with placebo in 3883 haemodialysis patients with secondary hyperparathyroidism...
November 2013: Current Opinion in Nephrology and Hypertension
Gunnar Tomasson
The primary vasculitides are a life- and organ-threatening set of diseases with a course often marked by alternating periods of active vasculitis and remission. As opposed to clinical trials within the fields of cardiology and oncology, where treatment interventions have been tested in a controlled fashion using hard 'end' points, such as mortality and hospitalisation, surrogate 'end' points have to be used in randomised clinical trials (RCTs) in vasculitis. Given the multisystem nature of the vasculitides, their heterogeneous clinical presentations and rarity, outcome-measure development is a challenging task...
February 2013: Best Practice & Research. Clinical Rheumatology
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