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End points, hard and surrogate

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
John E Femino, Tanawat Vaseenon, Phinit Phisitkul, Phinit Phistkul, Yuki Tochigi, Donald D Anderson, Annunziato Amendola
BACKGROUND: External rotation stress is used intraoperatively for diagnosing medial ankle and syndesmotic instability in rotational ankle fractures after reduction and fixation of the fibula. However, external rotation includes hindfoot, midfoot, and ankle motion. The purpose of this study was to determine the effect of hindfoot positioning when using the external rotation stress test. Isolated deep deltoid ligament (DDL) instability and combined DDL and syndesmotic instability were modeled...
February 2013: Foot & Ankle International
Benoit J Arsenault, Ekaterini A Kritikou, Jean-Claude Tardif
Atherosclerotic cardiovascular disease (CVD) is a complex disorder that leads to premature death and hospitalization. Several drugs have been, or are currently being tested for their ability to reduce cardiovascular mortality and/or promote regression of atherosclerotic lesions. In addition to "hard end point" clinical trials in which total and cardiovascular mortality as well as risk of incident myocardial infarction are considered as outcomes, trials with surrogate end points using imaging biomarkers can rapidly assess the efficacy of new cardiovascular drugs...
August 2012: Current Cardiology Reports
Zh D Kobalava, Iu V Kotovskaia
Most important value of lowering of substantially elevated arterial pressure (AP) for improvement of outcomes in patients with arterial hypertension (AH) was convincingly confirmed by large truly placebo controlled randomized clinical trials (RCT) with the use of mainly diuretics, and/or beta-adrenoblockers in the 60-80ths. Later comparative RCT confirmed equal antihypertensive efficacy of 5 main drug classes relative to AP level in brachial artery. In this review we discuss merit of auxiliary class-specific properties of antihypertensive agents potentially affecting prognosis besides AP lowering...
2011: Kardiologiia
M Rizzo, K Berneis, S Koulouris, S Pastromas, G B Rini, D Sakellariou, A S Manolis
Beyond low-density lipoprotein (LDL)-cholesterol concentrations, in recent years, several clinical studies have shown that both oxidised and small, dense LDL have a strong predictive role for the presence of vascular atherosclerosis. These two lipid parameters seem to have a synergistic impact on cardiovascular risk, with a greater importance in patients at higher-risk, such as those with type-2 diabetes. Increased levels of oxidised and small, dense LDL levels are a feature of diabetic dyslipidaemia, and small, dense LDL have been shown to be a good predictor of future cardiovascular events, at both univariate and multivariate analyses...
November 2010: International Journal of Clinical Practice
Massimo Colombo
The retrospective scrutiny of studies that were originally designed to assess the antiviral activity of interferon (IFN) and nucleos(t)ide analogues (NUC) suggested reduced incidence of hepatocellular carcinoma (HCC) in responders. The interpretation of these studies, however, is questioned by the heterogeneity of patient referral, adoption of surrogate end-points, lack of control arms and, overall, by the lack of power to capture enough hard end-points of the natural history of hepatitis B, including HCC. Another point of criticism is that above all, IFN studies could have been affected by study enrolment skewed towards patients with less advanced liver disease, who had a better predicted compliance to therapy but a lower risk of developing HCC in the short-term...
July 2010: Digestive and Liver Disease
Monisankar Roy, Noman Mahmood, Clive Rosendorff
Lowering blood pressure (BP) reduces the risk of major cardiovascular mortality and morbidity. Current consensus targets for BP reduction are less than 140/90 mm Hg in uncomplicated hypertension and less than 130/80 mm Hg in those patients with diabetes, chronic kidney disease, and coronary artery disease or in those who are at high risk for developing coronary artery disease (defined as a Framingham risk score of > or = 10%). There is solid epidemiologic evidence for lower BP targets, supported by some clinical studies with surrogate end points...
March 2010: Current Atherosclerosis Reports
Giorgina Barbara Piccoli, Rossella Attini, Elena Vasario, Anne Conijn, Marilisa Biolcati, Federica D'Amico, Valentina Consiglio, Salvatore Bontempo, Tullia Todros
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is a challenge for pregnancy. Its recent classification underlines the importance of its early phases. This study's aim was to evaluate outcomes of pregnancy according to CKD stage versus low-risk pregnancies followed in the same center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The prospective analysis was conducted from January 2000 to May 2009 with the start of observation at referral and end of observation 1 month after delivery...
May 2010: Clinical Journal of the American Society of Nephrology: CJASN
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