Meta-analysis and systematic review of the cardiotoxicity of TAS-102.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16053-e16053 ◽  
Author(s):  
Carlos Alberto Lopez ◽  
Elham Azimi-Nekoo ◽  
Su Yun Chung ◽  
James Newman ◽  
Janice Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Phase I ◽  
Phase Ii ◽  
Literature Search ◽  
Meta Analysis ◽  
Phase Iii ◽  
Cardiac Events ◽  
Phase Ii Studies ◽  
Increased Risk

e16053 Background: Fluoropyrimidines such as 5-FU and capecitabine are known to be cardiotoxic drugs. TAS-102 (trifluridine-tipiracil) is a novel oral fluoropyrimidine that was recently FDA approved to treat gastric and colon cancer. However, the incidence of cardiac related events of TAS-102 is not fully ascertained. We performed a meta-analysis and systematic review to determine the incidence of cardiotoxic events associated with TAS-102. Methods: We performed a literature search through PubMed, Embase, and Web of Science to identify any publications in any language up to December 31st, 2019 where TAS-102 (and equivalent terms such as “trifluridine-tipiracil” and “Lonsurf”) was used. These were then manually reviewed to identify any publications reporting cardiac events. Randomized controlled trials (RCTs) were included for meta-analysis to determine the incidence of cardiotoxic events, which were summarized as pooled odds ratios (OR) when compared to placebo. Non-randomized, non-controlled clinical trials (phase I and phase II studies) were included in the systematic review but excluded from the pooled OR calculation. Results: 869 publications were identified in the initial literature search, of which 17 trials (3 Phase III studies, 6 Phase II studies, and 8 phase I studies) met inclusion criteria. A total of 1,877 patients among 4 RCTs were included in the meta-analysis. Compared with placebo, TAS-102 did not increase the risk of myocardial infarction (OR 1.97 95% CI [0.22-17.89]), hypertension (OR 0.73 95% CI [0.37, 1.44]), palpitations (OR 1.51 95% CI [0.30, 7.56]), cardio-pulmonary arrest (OR 0.83 95% CI [0.11-6.32]), or syncope (OR 1.50 95% CI [0.06-37.14]). Among the 1,252 patients receiving TAS-102, the overall incidence of cardiovascular events was low, with hypertension being the most common side effect (21 events), followed by palpitations (6 events), cardiopulmonary arrest (2 events), and myocardial infarction (3 events), though there was no statistically significant increased risk compared to placebo. No deaths were reported. Conclusions: Unlike other fluoropyrimidines, TAS-102 appears to be a cardiogentle drug, with no increased risk of cardiac events compared to placebo. Since fluoropyrimidines remain the backbone of treatment for gastrointestinal malignancies, TAS-102 can offer an alternative to patients who developed cardiotoxicities from other agents. Prospective studies with consideration of cardiac risk factors are required.

Risk of fall and clinical fracture associated with androgen receptor inhibitors: A systematic review and meta-analysis.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 71-71
Author(s):  
Zin Myint ◽  
Harry D. Momo ◽  
Danielle E. Otto ◽  
Donglin Yan ◽  
Robert S. DiPaola ◽  
...  
Keyword(s):  
Systematic Review ◽  
Androgen Receptor ◽  
Phase Ii ◽  
Fixed Effects ◽  
Mixed Model ◽  
Meta Analysis ◽  
Pooled Analysis ◽  
Phase Iii ◽  
High Grade ◽  
Increased Risk

71 Background: Patients treated with androgen receptor inhibitors (ARIs) report a higher incidence of falls; although a potential mechanism of action is unknown. This systematic review evaluates the relative risk (RR) of fall and fracture in prostate cancer (PCa) patients that receive ARIs. Methods: We conducted a comprehensive literature search using Cochrane, Scopus and MedlinePlus databases from inception through August 2019, and evaluated all published prospective phase II, III and IV randomized controlled trials that treated PCa patients with ARIs. Reported fall and fractures as adverse events (AEs) were extracted for analysis. Retrospective, phase I, non-randomized phase II, and studies with control arms that used one of the ARIs were excluded. A mixed effects model was used to estimate effects of ARI on the RR, with the included studies treated as random effects and study arms treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Results: Eleven studies met our inclusion criteria. The total population was 11,382; 6536 were in the ARI arm and 4846 in the control (CTL) arm. Study types were: 8 phase III; 2 phase II; 1 phase IV. Subjects in the ARI arm received enzalutamide, apalutamide or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations while in the CTL arm received placebo, bicalutamide or abiraterone. Treatment duration ranged from 5.4 to 20.5 mo for ARI vs. 5.4 to 18.3 mo for CTL. The reported incidence of fall was 481 (7.4%) in ARI and 201 (4.1%) for CTL. The incidence of fracture was 204 (3.1%) in ARI and 93 (1.9%) in control. The use of ARI was associated with an increased risk: all fall grades (RR 1.83; 95% CI 1.56-2.15; p <0.01); high grade fall (RR 1.69; 95% CI 1.09 – 2.62; p=0.019); all grade fracture (RR 1.56; 95% CI 1.23-1.97; p <0.01) and likely high grade fracture (RR 1.62; 95% CI 0.97 – 2.69; p=0.063). Conclusions: The use of ARI significantly increases falls and fractures in PCa patients as assessed by this meta-analysis study. Further studies would be warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.

scholarly journals AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1464.1-1465
Author(s):  
J. Blaess ◽  
J. Walther ◽  
J. E. Gottenberg ◽  
J. Sibilia ◽  
L. Arnaud ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systematic Review ◽  
B Cells ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Development ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Exclusion Criteria ◽  
Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

scholarly journals Association of myocardial fibrosis detected by late gadolinium-enhanced MRI with clinical outcomes in patients with diabetes: a systematic review and meta-analysis

BMJ Open ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. e055374
Author(s):  
Zhi Yang ◽  
Rong Xu ◽  
Jia-rong Wang ◽  
Hua-yan Xu ◽  
Hang Fu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Risk Stratification ◽  
Myocardial Fibrosis ◽  
Meta Analysis ◽  
Imaging Biomarker ◽  
Cardiac Events ◽  
Prognostic Information ◽  
Increased Risk ◽  
Patients With Diabetes

ObjectiveThis meta-analysis assessed the associations of myocardial fibrosis detected by late gadolinium-enhanced (LGE)-MRI with the risk of major adverse cardiac and cerebrovascular events (MACCEs) and major adverse cardiac events (MACEs) in patients with diabetes.DesignSystematic review and meta-analysis reported in accordance with the guidelines of the Meta-analysis of Observational Studies in Epidemiology statement.Data sourcesWe searched the Medline, Embase and Cochrane by Ovid databases for studies published up to 27 August 2021.Eligibility criteriaProspective or respective cohort studies were included if they reported the HR and 95% CIs for MACCEs/MACEs in patients with either type 1 or 2 diabetes and LGE-MRI-detected myocardial fibrosis compared with patients without LGE-MRI-detected myocardial fibrosis and if the articles were published in the English language.Data extraction and synthesisTwo review authors independently extracted data and assessed the quality of the included studies. Pooled HRs and 95% CIs were analysed using a random effects model. Heterogeneity was assessed using forest plots and I2 statistics.ResultsEight studies with 1121 patients with type 1 or type 2 diabetes were included in this meta-analysis, and the follow-up ranged from 17 to 70 months. The presence of myocardial fibrosis detected by LGE-MRI was associated with an increased risk for MACCEs (HR: 2.58; 95% CI 1.42 to 4.71; p=0.002) and MACEs (HR: 5.28; 95% CI 3.20 to 8.70; p<0.001) in patients with diabetes. Subgroup analysis revealed that ischaemic fibrosis detected by LGE was associated with MACCEs (HR 3.80, 95% CI 2.38 to 6.07; p<0.001) in patients with diabetes.ConclusionsThis study demonstrated that ischaemic myocardial fibrosis detected by LGE-MRI was associated with an increased risk of MACCEs/MACEs in patients with diabetes and may be an imaging biomarker for risk stratification. Whether LGE-MRI provides incremental prognostic information with respect to MACCEs/MACEs over risk stratification by conventional cardiovascular risk factors requires further study.

P960Association of peri-procedural intravenous morphine use on clinical outcomes in ST-elevation myocardial infarction treated by percutaneous coronary intervention: systematic review and meta-analysis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Batchelor ◽  
D Liu ◽  
J Bloom ◽  
S Noaman ◽  
W Chan
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Percutaneous Coronary Intervention ◽  
Clinical Outcomes ◽  
Odds Ratio ◽  
Meta Analysis ◽  
Coronary Intervention ◽  
Increased Risk ◽  
Percutaneous Coronary ◽  
St Elevation

Abstract Background Morphine analgesia may affect absorption of co-prescribed P2Y12 antagonists attenuating platelet inhibition. The impact of peri-procedural intravenous (IV) morphine administration on clinical outcomes in patients undergoing primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is not well defined. Purpose To conduct a systematic review and meta-analysis exploring clinical outcomes with peri-procedural IV morphine in patients undergoing PPCI for STEMI. Methods Analysis of the electronic databases MEDLINE, EMBASE, CENTRAL, Scopus, Web of Science and ClinicalTrials.gov for association of peri-PCI IV morphine use with myocardial infarction (MI) and mortality. Primary and secondary outcomes were in-hospital or 30-day MI and all-cause mortality respectively. Results Eleven studies (1 randomised controlled trial; 10 cohort studies) were included for systematic review. Five studies, including 3,748 patients were included in meta-analysis of the primary outcome. Of 3,748 patients, 2,239 were treated concurrently with ticagrelor, 1,256 treated with clopidogrel and 253 with prasugrel. As shown in the Figure, there was a trend towards increased risk of myocardial infarction with IV morphine (odds ratio 1.88; 95% CI 0.87–4.09, I2 0%). Across seven studies and 6585 patients, no increased risk of mortality at the same composite time endpoint was evident (odds ratio 0.70, 95% CI 0.40–1.23, I2 19%). Figure 1. MI in hospital or at 30 days Conclusion Based on current literature, evidence of an association between IV morphine and myocardial infarction in patients undergoing PPCI for STEMI is limited by observational methodology and conflicting results. There is no evidence of an association between intravenous peri-procedural morphine and mortality. Clinical trial evidence with strong documentation of adverse events data is required to demonstrate association or causality. Acknowledgement/Funding None

scholarly journals Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses

BMJ ◽  
2020 ◽  
pp. l7078 ◽  
Author(s):  
Joshua D Wallach ◽  
Kun Wang ◽  
Audrey D Zhang ◽  
Deanna Cheng ◽  
Holly K Grossetta Nardini ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Systematic Review ◽  
Cardiovascular Risk ◽  
Meta Analysis ◽  
Odds Ratios ◽  
Level Data ◽  
Increased Risk ◽  
Meta Analyses ◽  
Analytical Approaches

AbstractObjectivesTo conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing.DesignSystematic review and meta-analysis of randomized controlled trials.Data sourcesGlaxoSmithKline’s (GSK’s) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK’s Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data.Eligibility criteria for selecting studiesRandomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults.Data extraction and synthesisFor analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals.Results33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK’s summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used.ConclusionsThe results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety.Systematic review registrationOSF Home https://osf.io/4yvp2/.

Reno-vascular toxicities associated with carfilzomib: Systematic review and meta-analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21622-e21622
Author(s):  
Chintan Shah ◽  
Harini Bejjanki ◽  
Rohit Bishnoi ◽  
Ankur Jain ◽  
Subhankar Samal ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Phase I ◽  
Meta Analysis ◽  
Random Effect ◽  
Random Effect Model ◽  
Dose Effect ◽  
Phase Iii ◽  
Control Group ◽  
Phase Iii Clinical Trials

e21622 Background: Carfilzomib (Carf) is a novel proteasome inhibitor that is approved for patients with relapsed multiple myeloma (RMM) who have failed ≥ 1 prior lines of therapy. The incidence and seriousness of Carf associated reno-vascular toxicities (RVT) is not well known. We performed systematic review of Carf literature with meta-analysis to determine its incidence and overall risk. Methods: Initial search of literature led to a total of 175 Carf related articles. However, we used a total of 29 publications; phase I/II, phase II and phase III clinical trials (n = 3) which used Carf as monotherapy or in combination. We excluded phase I studies. Incidence rates and odds ratios (OR) were calculated with either fixed effect or random effect model based on the heterogeneity of included studies. Toxicity such as hypertension (HTN), renal failure (RF) and venous thromboembolism (VTE) were reported according to CTCAE v4.0. Results: A total of 4560 patients with various hematological and solid malignancies were included. Incidences of toxicities were: 15.9% and 4.7 % for HTN, 11.2% and 3.44% for RF, 6.47% and 2.22% for VTE, respectively for all grades and high grades in each category. When compared to control group taken from phase III clinical trials, the risk of HTN and RF due to Carf was significantly higher [OR = 2.91 and 3.32 in HTN (P < 0.001)], [OR = 1.71 and 1.79 (P < 0.05) for RF], respectively for all grade and high grade in each category. Moreover, incidence of HTN with higher than standard dose of carf (27 mg/m2 twice weekly) was significantly higher (P < 0.001). RF and VTE did not have the dose effect. Concomitant use of immunomodulator (IMiD) significantly increased, as expected, the incidence of VTE (P < 0.001). There was no variation in the incidence of RVT among newly diagnosed versus RMM (P = 0.4). Conclusions: Overall incidence and risk of hypertension and renal toxicities seems to be high when using Carf. Higher doses of Carf seem to lead to higher incidence of HTN, while the risk of VTE is higher with concomitant IMiD use. The pathophysiology for these complications is poorly understood, however it could be secondary to endothelial effect of carf. Physician should be vigilant about these effects as it can lead to poor overall outcomes.

Serum potassium levels and mortality of patients with acute myocardial infarction: A systematic review and meta-analysis of cohort studies

2019 ◽  
Vol 26 (2) ◽  
pp. 145-156 ◽  
Author(s):  
Hui Xi ◽  
Rong-Hui Yu ◽  
Ning Wang ◽  
Xue-Zhi Chen ◽  
Wen-Chao Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Acute Myocardial Infarction ◽  
Cohort Studies ◽  
Serum Potassium ◽  
Reference Group ◽  
Meta Analysis ◽  
Geographic Location ◽  
Relative Risks ◽  
Increased Risk

Background The evidence of current epidemiological studies investigating the association between serum potassium levels and mortality of acute myocardial infarction (AMI) patients is controversial and inadequate. Design Systematic review and meta-analysis. Methods Two researchers independently searched the PubMed, EMBASE and Web of Science databases to identify observational studies published prior to 31 October 2017. Similarly, two researchers separately extracted data and any differences were resolved by discussion. Pooled relative risks and 95% confidence intervals (CIs) were computed with an inverse variance-weighted random-effects model. Heterogeneity among studies was assessed with the I2 statistic. Results Seven cohort studies were included for analysis. Compared with the reference group (3.5 to <4.0 mEq/L), the pooled relative risks of mortality were 1.15 (95% CI = 1.00–1.32), 1.09 (95% CI = 0.97–1.24), 1.42 (95% CI = 1.19–1.70) and 1.85 (95% CI = 1.39–2.47) for AMI patients with a potassium level of<3.5, 4.0 to <4.5, 4.5 to <5.0, and ≥5.0 mEq/L, respectively. For admission and post-admission potassium, although J-shaped associations were also indicated, non-significant results were observed for AMI patients with potassium levels of <3.5 mEq/L when compared with the reference group. Notably, in subgroup analyses of study characteristics, stratified by study quality, geographic location, type of outcome, number of cases, type of AMI, and adjustment for potential confounders, the findings were broadly consistent across strata. Conclusions These findings indicate that both lower (<3.5 mEq/L) and higher (≥4.5 mEq/L) serum potassium levels are associated with an increased risk of mortality of patients with AMI.

Rash to mTOR inhibitor everolimus: Systematic review and meta-analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19624-e19624 ◽  
Author(s):  
Marigdalia K. Ramirez-Fort ◽  
Emily Christine Case ◽  
Alyx C. Rosen ◽  
Shenhong Wu ◽  
Mario E. Lacouture
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Fixed Effects ◽  
Mtor Inhibitor ◽  
Meta Analysis ◽  
Significant Risk ◽  
Phase Iii ◽  
Subependymal Giant Cell Astrocytoma ◽  
High Grade ◽  
Increased Risk

e19624 Background: Everolimus is an mTOR inhibitor approved for treatment of renal cell carcinoma, subependymal giant cell astrocytoma, and progressive neuroendocrine tumors of pancreatic origin. Its use may be hindered due to adverse events, including rash. The reported incidence and risk of rash to everolimus varies widely and has not been closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing rash. Methods: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology from 1998 to July 2011 using the keyword “everolimus” to identify relevant clinical trials. Eligible studies included prospective phase II and phase III clinical trials of cancer patients on 10 mg of everolimus daily with available data on incidence of rash. The summary incidence and relative risk (RR) of rash were calculated using either the random-effects or fixed-effects model, depending on the heterogeneity of the constituent studies. Results: A total of 2,242 patients with various malignancies from 13 clinical trials were included in the analysis. The summary incidences of all-grade and high-grade rash in patients on everolimus were28.6% (95% CI: 20.8 – 38.0) and 1.0% (95% CI: 0.6 – 1.7), respectively. Everolimus was associated with a statistically significant increased risk of all-grade rash (RR=3.853, 95% CI: 2.470 – 6.013, p=0.000), but the RR for high-grade rash (RR= 2.997, 95% CI: 0.633 – 14.185) was not statistically significant, with a p value of 0.166. Conclusions: Everolimus is associated with a significant risk of developing rash. Management of rash to everolimus is critical to prevent dose modifications and decreased quality of life, both of which can negatively affect clinical outcomes.

Abstract 15722: Proton Pump Inhibitors and Risk of Myocardial Infarction: A Systematic Review and Meta-analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ahmed Ullah Mishuk ◽  
Shahariar Mohammed Fahim ◽  
Richard Hansen ◽  
Li Chen ◽  
Philippe Gaillard ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Clinical Trials ◽  
Quality Assessment ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Observational Studies ◽  
Meta Analysis ◽  
Pharmacovigilance System ◽  
Increased Risk

Introduction: Proton Pump Inhibitors (PPIs) are generally considered safe, but recent evidence suggests otherwise. Objective: This systematic review and meta-analysis assessed the association between PPIs and the risk of myocardial infarction (MI), using both clinical trials and observational studies. Methods: A systematic search was performed in December 2019 to retrieve all potential studies using PubMed, PsycInfo, International Pharmaceutical Abstracts, Web of Science, and Clinicaltrials.gov. This search initially identified any published studies describing any adverse event (AE) or outcomes related to PPI. Records were included in this study if 1) studies were published in English, 2) study design was clinical trials or observational studies, 3) PPI use was the exposure or treatment, and 4) study outcome was the incidence of MI. Two researchers independently reviewed all identified records, performed full article review, extracted data into structured evidence table, and conducted quality assessment using Newcastle-Ottawa Scale and Quality Assessment Tool for Quantitative Studies. Meta-analysis was performed using the RStudio software to assess the risk of MI with PPI use. Results: A total of 4,507 abstracts meeting the inclusion criteria were identified, and 20 full articles were included in this study, among which 10 were cohort, 3 were case-control, 3 were RCT post-hoc analysis, and 4 were RCT studies. The pooled Odds Ratio (OR)=1.40 with 95% CI=1.20-1.63 for all studies indicated the presence of an association between PPI use and increased risk of MI compared to PPI non-users. Meta-analysis found a similar association between PPI use and increased risk of MI in observational studies (OR=1.40; 95% CI=1.20, 1.64) but no association (OR=0.90; 95% CI=0.47, 1.73) in RCT-studies. Heterogeneity was high (I 2 > 75%) for all analyses except for RCTs (I 2 =0%). Conclusion: Although our meta-analysis identified the association between PPI use and increased risk of MI, results from RCTs did not agree with observational studies. Due to the mixed findings by study designs and high variation of heterogeneity among studies, the pharmacovigilance system should evaluate different levels of evidence to support decision making in safety of drug products.

Evolution of Clinical Trial Design in Early Drug Development: Systematic Review of Expansion Cohort Use in Single-Agent Phase I Cancer Trials

2013 ◽  
Vol 31 (33) ◽  
pp. 4260-4267 ◽  
Author(s):  
Arif Manji ◽  
Irene Brana ◽  
Eitan Amir ◽  
George Tomlinson ◽  
Ian F. Tannock ◽  
...  
Keyword(s):  
Systematic Review ◽  
Phase I ◽  
Phase Ii ◽  
Data Extraction ◽  
Single Agent ◽  
Clinical Trial Design ◽  
Phase I Trials ◽  
Phase Ii Studies ◽  
Cancer Trials ◽  
Expansion Cohort

Purpose To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use. Methods We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression. Results We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation. Conclusion The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.

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