scholarly journals Non-inferiority trials using a surrogate marker as the primary endpoint: An increasing phenotype in cardiovascular trials

2020 ◽  
Vol 17 (6) ◽  
pp. 723-728
Author(s):  
Behnood Bikdeli ◽  
César Caraballo ◽  
John Welsh ◽  
Joseph S Ross ◽  
Sanjay Kaul ◽  
...  
Keyword(s):  
England Journal ◽  
Clinical Outcome ◽  
New England ◽  
Clinical Outcomes ◽  
Primary Endpoint ◽  
European Heart Journal ◽  
Surrogate Marker ◽  
Surrogate Markers ◽  
Primary Endpoints ◽  
Number Of Patients

Background/aims Non-inferiority trials are increasing in cardiovascular medicine, with approval of many drugs and devices on the basis of such studies. Surrogate markers as primary endpoints have been also more frequently used for efficient assessment of cardiovascular interventions. However, there is uncertainty about their concordance with clinical outcomes. Non-inferiority design using a surrogate marker as a primary endpoint may pose particular challenges in clinical interpretation. We sought to explore the publication trends, methodology, and reporting features of non-inferiority cardiovascular trials that used a primary surrogate marker as the primary endpoint. Methods We searched six high-impact journals ( The New England Journal of Medicine, The Journal of the American Medical Association, The Lancet, The Journal of the American College of Cardiology, Circulation, and European Heart Journal) from 1 January 1990 to 31 December 2018 and identified non-inferiority cardiovascular trials that used a surrogate marker as the primary endpoint. We assessed the non-inferiority margin reported in the manuscript and other publicly available platforms (e.g. protocol, clinicaltrials.gov). We also determined whether the included non-inferiority trials with surrogate markers as primary endpoints were followed by clinical outcome trials. Results We screened 15,553 publications and identified 247 cardiovascular trials that used a non-inferiority design. Of these, 37 had a surrogate marker as a primary endpoint (18 drug trials, 13 device trials, 6 others). All of these non-inferiority trials with surrogate outcomes were published after 2000, mostly in cardiology journals (13 in The Journal of the American College of Cardiology, 9 in European Heart Journal, 8 in Circulation, 6 in The Lancet, 1 in The New England Journal of Medicine), and their publication rate increased over time (p < 0.001 for linear trend). The median number of patients in the primary analysis was 300 (interquartile range: 202–465). The study protocol or a methods paper was publicly available for only 13 (35.1%) trials, of which the non-inferiority margin was not reported in 4 trials. In 16 studies (43.2%), the manuscript did not acknowledge the limitations of using a surrogate endpoint or the need for a definitive clinical outcome trial. Thirty-four trials (91.9%) concluded that the tested intervention met non-inferiority criteria. However, only five (13.5%) were followed by clinical outcomes trials the results of which did not always confirm non-inferiority. Conclusion Non-inferiority trials that use a surrogate marker as the primary endpoint are being increasingly performed. However, these trials pose particular challenges with design, reporting, and interpretation, which are not systematically and consistently addressed or reported.

Abstract 345: Non-inferiority Trials With a Primary Surrogate Endpoint: An Increasing Phenotype in Cardiovascular Trials

2020 ◽  
Vol 13 (Suppl_1) ◽  
Author(s):  
Cesar Caraballo ◽  
Behnood Bikdeli ◽  
John Welsh ◽  
Joseph S Ross ◽  
Sanjay Kaul ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Outcomes ◽  
European Heart Journal ◽  
Linear Trend ◽  
Surrogate Endpoint ◽  
Median Number ◽  
Publication Rate ◽  
Primary Analysis ◽  
Surrogate Outcome ◽  
Number Of Patients

Background: Non-inferiority trials are increasing in cardiovascular medicine, with approval of many drugs and devices on the basis of such studies. Surrogate endpoints have been also increasingly used for efficient assessment of cardiovascular interventions, but there is uncertainty about their concordance with clinical outcomes. Non-inferiority designs using a primary surrogate endpoint in cardiovascular trials may pose particular challenges in clinical interpretation. Methods: We searched six high-impact journals (NEJM, JAMA, Lancet, JACC, Circulation, and EHJ) from 01/01/1990-12/31/2018 and identified non-inferiority cardiovascular trials that used a primary surrogate endpoint. We assessed the non-inferiority margin reported in the manuscript and other publicly available platforms (e.g. protocol, clinicaltrials.gov). We determined whether surrogate outcome non-inferiority trials were followed by clinical outcome trials. Results: We screened 15,553 publications and identified 247 cardiovascular trials that used a non-inferiority design. Of these, 37 had a primary surrogate endpoint (18 drug trials, 13 device trials, 6 others). All of these non-inferiority trials with surrogate outcomes were published after 2000, mostly in cardiology journals (13 in JACC, 9 in European Heart Journal, 8 in Circulation, 6 in Lancet, 1 in NEJM), and their publication rate increased over time (P<0.001 for linear trend). The median number of patients in the primary analysis was 263 (IQR: 191 - 460). The study protocol or a methods paper was publicly available for only 12 (32.4%) trials, of which the non-inferiority margin was not reported in 4. In 16 (43.2%) studies the manuscript did not acknowledge the limitations of using a surrogate endpoint, or the need for a definitive clinical outcome trial. Thirty-four trials (91.9%) concluded that the tested intervention met non-inferiority ocriteria. However, only 3 (9.1%) were followed by clinical outcomes trials the results of which did not always confirm non-inferiority (Figure). Conclusion: Non-inferiority trials with a primary surrogate endpoint are being increasingly performed. However, these trials pose particular challenges with design, reporting and interpretation, which are not systematically and consistently addressed or reported.

scholarly journals Farmakologi Kardiovaskuler, Mekanisme & Aplikasi Klinis

2019 ◽  
Author(s):  
Hadyanto Lim
Keyword(s):  
England Journal ◽  
New England ◽  
European Heart Journal ◽  
Life Sciences ◽  
Vascular Biology ◽  
Circulation Research

Untuk mencapai maksud tersebut, maka buku Farmakologi Kardiovaskuler edisi ke 3, tetap disusun sebanyak 8 bab, dengan pembahasan dilakukan secara berurutan : ● Pengantar terapeutik● Mekanisme kerja ● Farmakokinetik● Efek samping dan interaksi obat● Kedokteran berbasis bukti● Aplikasi klinisPenambahan informasi diperoleh dari berbagai sumber penerbitan terkini sesuai dengan kebutuhan penerapan dalam praktek klinis sehari-hari, termasuk hasil penelitian penulis. Untuk itu, revisi dilakukan dengan menambah informasi yang relevan mulai dari bab 1 sampai bab 8, terutama pemahaman terbaru patobiologi, yang mengantarkan pada perkembangan penemuan obat, mekanisme kerja obat, farmakokinetik, hasil penelitian eksperimental dan klinis, yang disari dari berbagai jurnal internasional terkemuka di dunia, seperti: Nature, Science, Lancet, New England Journal of Medicine, Circulation, Circulation Research, Cellular and Molecular Life Sciences, Journal of the American College of Cardiology, Hypertension, Stroke, European Heart Journal, Arteriosclerosis, Thrombosis and Vascular Biology, Current Cardiology Review dan berbagai buku Farmakologi. Karena itu, buku ini ditujukan kepada seluruh mahasiswa kedokteran dan kesehatan, para dokter umum dan spesialis, apoteker dan insan kesehatan, untuk memberikan tambahan informasi pengetahuan dalam pengobatan yang rasional, khususnya di bidang farmakologi kardiovaskuler, sekaligus memberikan motivasi dan inspirasi dalam penelitian.

Abstract 19637: Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990- 2011

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Behnood Bikdeli ◽  
Natdanai Punnanithinont ◽  
Yasir Akram ◽  
Ike Lee ◽  
Nihar R Desai ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Primary Endpoint ◽  
Surrogate Endpoint ◽  
Surrogate Endpoints ◽  
Surrogate Outcome ◽  
Surrogate Outcomes ◽  
Test Strategies ◽  
Outcome Trial ◽  
Primary Hypothesis

Background: Surrogate endpoint trials can test strategies more efficiently, but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We sought to determine recent trends in the publication of cardiovascular trials with surrogate outcomes. Methods: We identified cardiovascular trials with primary surrogate endpoints published in NEJM, Lancet, and JAMA from January 1990 to December 2011. Trends in publication of surrogate endpoint trials, and the success of the trials in meeting their primary endpoint were evaluated. We also tracked the above three journals for publication of clinical outcome trials on the interventions tested in surrogate trials. Results: We screened 3016 articles and identified 848 primary hypothesis cardiovascular trials, which included 220 surrogate endpoint trials. There was an increase over time in the number of surrogate endpoint trials (P=0.01). From the total of 220 surrogate trials, 157 (71.4 %) were positive for their primary endpoint. Sixty (27.5%) surrogate trials were followed by at least one clinical outcome trial. Among these 60 surrogate trials, in 24 cases the outcomes trial results validated the positive surrogates; whereas in 21 subsequent outcome trials were negative following positive results on a surrogate. However, we identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit (Figure). Conclusions: Cardiovascular surrogate outcomes trials are common, frequently show superiority of the tested intervention and are infrequently followed by a prominent outcomes trial. However, when there was a high profile clinical outcomes study, half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.

PS02.111: A 5-YEAR EXPERIENCE IN ANASTOMOTIC LEAK AFTER NEODJUVANT FOLLOWED ESOPHAGECTOMY IN A BRAZILIAN UNIVERSITY HOSPITAL

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 152-152
Author(s):  
Felipe Vieira ◽  
Ricardo Schramm ◽  
Marcio Chedid ◽  
André Ricardo Da Rosa ◽  
Cleber Dario Kruel
Keyword(s):  
England Journal ◽  
New England ◽  
Neoadjuvant Therapy ◽  
Anastomotic Leak ◽  
Combined Treatment ◽  
Neoadjuvant Treatment ◽  
Cervical Region ◽  
Anastomotic Leaks ◽  
Term Survival ◽  
Number Of Patients

Abstract Background Neoadjuvant treatment of esophageal cancer is world accepted since 2012 (1), showing benefits in long-term survival. However, there is still controversy relating to potential complications with the use of antineoplastic drugs and radiotherapy, notably because of the higher incidence of cervical esophageal leak. Our study describes a five-year experience in anastomotic leaks in esophagectomies after neoadjuvant therapy in a southern Brazilian referral center. Methods We have analyzed all patients submitted to the combined treatment of neoadjuvant therapy plus esophagectomy between 2012–2016, including patients with squamous cell carcinoma and adenocarcinoma. We describe the number of patients that experienced anastomotic leak after surgery. The diagnosis of an anastomotic leak is based in any quantity of digestive secretion in the neck wound, seen on the post-operative period. It did not secrete bacteriological analysis. McKeown and transhiatal esophagectomy were used, and esophagogastric anastomosis were conducted in the cervical region. Results Between the years of 2012–2016, thirty-six patients were submitted to a combined treatment of neoadjuvant therapy plus esophagectomy. Of these patients, 20 (55%) evolved with anastomotic leaks. All of these leaks occurred in the cervical region, and were treated in a conservative way. Conclusion The incidence of anastomotic leaks was exceptionally high, regardless of the usual care. Possible causes of this high number of leaks could be related to diagnostic criterion, the patient's own characteristics, local alterations associated to the neoadjuvant treatment, the surgical technique, or even microbiological factors. New studies are necessary with the goal to determine which of these factors contributes in the most significant way, with the means to improve the results of this unpleasant esofagectomy complication. 1) VAN HAGEN, P. et al. Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer. New England Journal Of Medicine,[s.l.], v. 366, n. 22, p.2074–2084, 31 maio 2012. New England Journal of Medicine (NEJM/MMS). http://dx.doi.org/10.1056/nejmoa1112088. Disclosure All authors have declared no conflicts of interest.

scholarly journals Nutrition Society Symposium on ‘End points in clinical nutrition trials’ Death, morbidity and economics are the only end points for trials

2005 ◽  
Vol 64 (3) ◽  
pp. 277-284 ◽  
Author(s):  
Ronald L. Koretz
Keyword(s):  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Skin Testing ◽  
Surrogate Marker ◽  
Nutrition Support ◽  
Anthropometric Measures ◽  
End Points ◽  
Nutritional Outcome ◽  
Duration Of Hospitalization ◽  
Better Than

In order to determine whether surrogate markers predict clinical outcome, randomized controlled trials (RCT) of nutrition supportv. no nutrition support that have reported at least one clinical outcome (mortality, infections, total complications, or duration of hospitalization) and at least one nutritional outcome (energy or protein intake, weight gain, N balance, albumin, prealbumin, transferrin, three anthropometric measures, skin testing, lymphocyte count) were assessed for concordance. If changes in nutritional markers predict clinical outcome, changes in both outcomes should go in the same direction. Concordance is defined as both outcomes changing in the same direction or both outcomes showing no difference. Discordance is defined as one outcome changing and the other not (partial) or both outcomes changing in opposite directions (complete). Ninety-nine RCT were identified, of which most were underpowered to see statistically significant changes, especially in clinical outcomes. Thus, the results were analysed only in relation to the direction of the respective changes in outcomes. Forty-eight comparisons (4×12) were made. The rates of concordance were ≤50% in forty-one of forty-eight comparisons; the rate was never >75%. A complete discordance rate of ≥25% was present in forty-three (≥50% in thirteen) of the forty-eight comparisons. The discordance was usually a result of the nutritional outcome being better than the clinical outcome. Changes in nutritional markers do not predict clinical outcomes. Before adopting any surrogate marker as an end point for a clinical trial, it has to be known that improving it will result in patient benefit.

Molekularbiologie

2018 ◽  
Vol 09 (05) ◽  
pp. 242-243
Author(s):  
Dr. Susanne Krome
Keyword(s):  
England Journal ◽  
Medical School ◽  
New England ◽  
Harvard Medical School

Zehntausende nichtproteinkodierende RNAs haben die Kenntnisse über die normale Physiologie sowie die Entstehung und Behandlung von Krankheiten auf den Kopf gestellt, schreibt Prof. Frank Slack, Harvard Medical School, Boston/USA, im New England Journal of Medicine über den überwiegenden Teil unseres Genoms. Diese RNA-Sub typen regulieren Wachstum, Entwicklung und Organfunktion. Ihre Gewebespezifität eröffnet neue, unerwartete Möglichkeiten in der Onkologie. Der größte Teil ihrer Funktionen ist allerdings noch nicht erforscht.

Effect of Manipulation under Anesthesia of the First Knee in Staged Bilateral Total Knee Arthroplasty on Clinical Outcome and Satisfaction

2020 ◽  
Author(s):  
Jung-Won Lim ◽  
Yong-Beom Park ◽  
Dong-Hoon Lee ◽  
Han-Jun Lee
Keyword(s):  
Total Knee Arthroplasty ◽  
Patient Satisfaction ◽  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Knee Arthroplasty ◽  
Knee Flexion ◽  
Functional Score ◽  
Manipulation Under Anesthesia ◽  
Total Knee

AbstractThis study aimed to evaluate whether manipulation under anesthesia (MUA) affect clinical outcome including range of motion (ROM) and patient satisfaction after total knee arthroplasty (TKA). It is hypothesized that MUA improves clinical outcomes and patient satisfaction after primary TKA. This retrospective study analyzed 97 patients who underwent staged bilateral primary TKA. MUA of knee flexion more than 120 degrees was performed a week after index surgery just before operation of the opposite site. The first knees with MUA were classified as the MUA group and the second knees without MUA as the control group. ROM, Knee Society Knee Score, Knee Society Functional Score, Western Ontario and McMaster Universities (WOMAC) score, and patient satisfaction were assessed. Postoperative flexion was significantly greater in the MUA group during 6 months follow-up (6 weeks: 111.6 vs. 99.8 degrees, p < 0.001; 3 months: 115.9 vs. 110.2 degrees, p = 0.001; 6 months: 120.2 vs. 117.0 degrees, p = 0.019). Clinical outcomes also showed similar results with knee flexion during 2 years follow-up. Patient satisfaction was significantly high in the MUA group during 12 months (3 months: 80.2 vs. 71.5, p < 0.001; 6 months: 85.8 vs. 79.8, p < 0.001; 12 months: 86.1 vs. 83.9, p < 0.001; 24 months: 86.6 vs. 85.5, p = 0.013). MUA yielded improvement of clinical outcomes including ROM, and patient satisfaction, especially in the early period after TKA. MUA in the first knee could be taken into account to obtain early recovery and to improve patient satisfaction in staged bilateral TKA.

Clinicopathological and Imaging Features Predictive of Clinical Outcome in Metaplastic Breast Cancer

2020 ◽  
Vol 16 (6) ◽  
pp. 729-738
Author(s):  
Ga Young Yoon ◽  
Joo Hee Cha ◽  
Hak Hee Kim ◽  
Hee Jung Shin ◽  
Eun Young Chae ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Tumor Size ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Imaging Features ◽  
Peritumoral Edema ◽  
Imaging Findings ◽  
Metaplastic Breast Cancer

Background: Metaplastic breast cancer (MC) is a rare disease, thus it is difficult to study its clinical outcomes. Objective: To investigate whether any clinicopathological or imaging features were associated with clinical outcome in MC. Methods: We retrospectively evaluated the clinicopathological and imaging findings, and the clinical outcomes of seventy-two pathologically confirmed MCs. We then compared these parameters between triple-negative (TNMC) and non-TNMCs (NTNMC). Results: Oval or round shape, and not-circumscribed margin were the most common findings on mammography, ultrasound (US), and magnetic resonance imaging (MRI). It was mostly a mass without calcification on mammography, and revealed complex or hypoechoic echotexture, and posterior acoustic enhancement on US, and rim enhancement, wash-out kinetics, peritumoral edema, and intratumoral necrosis on MRI. Of all 72, 64 were TNMCs, and eight were NTNMCs. Clinicopathological and imaging findings were similar between the two groups, except that MRI showed peritumoral edema more frequently in TNMCs than NTNMCs (p=0.045). There were 21 recurrences and 13 deaths. Multivariable analysis showed that larger tumor size and co-existing DCIS were significantly predictive of Disease free survival (DFS), and larger tumor size and neoadjuvant chemotherapy were significantly predictive of overall survival (OS). Conclusion: MC showed characteristic imaging findings, and some variables associated with survival outcome may help to predict prognosis.

The ENT emergency clinic: does senior input matter?

2012 ◽  
Vol 127 (1) ◽  
pp. 15-19 ◽  
Author(s):  
A Mirza ◽  
L McClelland ◽  
M Daniel ◽  
N Jones
Keyword(s):  
Quality Of Care ◽  
Discharge Rate ◽  
Surrogate Marker ◽  
Operating Theatre ◽  
Number Of Children ◽  
Discharge Rates ◽  
Time Period ◽  
Number Of Patients

AbstractBackground:Many ENT conditions can be treated in the emergency clinic on an ambulatory basis. Our clinic traditionally had been run by foundation year two and specialty trainee doctors (period one). However, with perceived increasing inexperience, a dedicated registrar was assigned to support the clinic (period two). This study compared admission and discharge rates for periods one and two to assess if greater registrar input affected discharge rate; an increase in discharge rate was used as a surrogate marker of efficiency.Method:Data was collected prospectively for patients seen in the ENT emergency clinic between 1 August 2009 and 31 July 2011. Time period one included data from patients seen between 1 August 2009 and 31 July 2010, and time period two included data collected between 1 August 2010 and 31 July 2011.Results:The introduction of greater registrar support increased the number of patients that were discharged, and led to a reduction in the number of children requiring the operating theatre.Conclusion:The findings, which were determined using clinic outcomes as markers of the quality of care, highlighted the benefits of increasing senior input within the ENT emergency clinic.

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