The Data: Observational Studies and Sequentially Randomized Trials

Author(s):  
Bibhas Chakraborty ◽  
Erica E. M. Moodie
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
David L Paterson ◽  
Burcu Isler ◽  
Patrick N A Harris

Abstract Ceftriaxone resistance in the Enterobacterales is typically the result of production of ESBLs or AmpC β-lactamases. The genes encoding these enzymes are often co-located with other antibiotic resistance genes leading to resistance to aminoglycosides, quinolones and trimethoprim/sulfamethoxazole. Carbapenems are stable to ESBLs and AmpC giving them reliable in vitro activity against producers of these β-lactamases. In contrast, piperacillin/tazobactam and amoxicillin/clavulanate are compromised by co-production of OXA-1, which is not inhibited by tazobactam or clavulanate. These in vitro findings provide an explanation for the MERINO trial outcomes, where 3.7% (7/191) randomized to meropenem died compared with 12.3% (23/187) randomized to piperacillin/tazobactam as definitive treatment of bloodstream infection due to ceftriaxone-resistant organisms. No randomized trials have yet put cefepime and carbapenems head to head, but some observational studies have shown worse outcomes with cefepime. We argue that carbapenems are the antibiotics of choice for ceftriaxone-resistant Enterobacterales.


2018 ◽  
Vol 10 (10) ◽  
pp. 195-199 ◽  
Author(s):  
Graeme Jones ◽  
Elena Panova

Rheumatoid arthritis is a leading musculoskeletal cause of disability in Western society. Therapeutic options have expanded rapidly with the advent of biological agents as treatment options. One of these, tocilizumab, targets the interleukin-6 receptor and has been approved since the late 2000s in many jurisdictions. This approval was based on 6–12 month trials. It is now appropriate to look at longer-term studies and what new insights they have provided into this agent. Data are based largely on observational studies with their well-known limitations as well as some further randomized trials and provide a number of important observations regarding both efficacy and safety. In conclusion, the longer-term data suggest tocilizumab efficacy increases over time for both signs and symptoms and radiographic change. It is also corticosteroid sparing. The safety data are consistent with the shorter-term trials and are largely reassuring but some questions still remain over cardiovascular safety and cancer risk.


2022 ◽  
Author(s):  
John P.A. Ioannidis

Importance. COVID-19 has resulted in massive production, publication and wide dissemination of clinical studies trying to identify effective treatments. However, several widely touted treatments failed to show effectiveness in large well-done randomized controlled trials (RCTs). Objective. To evaluate for COVID-19 treatments that showed no benefits in subsequent large RCTs how many of their most-cited clinical studies had declared favorable results for these interventions. Methods. Scopus (last update December 23, 2021) identified articles on lopinavir-ritonavir, hydroxycholoroquine/azithromycin, remdesivir, convalescent plasma, colchicine or interferon (index interventions) that represented clinical trials and that had received >150 citations. Their conclusions were assessed and correlated with study design features. The ten most recent citations for the most-cited article on each index intervention were examined on whether they were critical to the highly-cited study. Altmetric scores were also obtained. Findings. 40 articles of clinical studies on these index interventions had received >150 citations (7 exceeded 1,000 citations). 20/40 (50%) had favorable conclusions and 4 were equivocal. Highly-cited articles with favorable conclusions were rarely RCTs while those without favorable conclusions were mostly RCTs (3/20 vs 15/20, p=0.0003). Only 1 RCT with favorable conclusions had sample size >160. Citation counts correlated strongly with Altmetric scores, in particular news items. Only 9 (15%) of 60 recent citations to the most highly-cited studies with favorable or equivocal conclusions were critical to the highly-cited study. Conclusion. Many clinical studies with favorable conclusions for largely ineffective COVID-19 treatments are uncritically heavily cited and disseminated. Early observational studies and small randomized trials may cause spurious claims of effectiveness that get perpetuated.


2021 ◽  
Author(s):  
Michael Colacci ◽  
John Fralick ◽  
Ayodele Odutayo ◽  
Michael Fralick

Importance: The risk of diabetic ketoacidosis (DKA) with sodium-glucose cotransporter-2 (SGLT2) inhibitors is unclear. Objective: To examine the risk of DKA with SGLT2 inhibitors in both observational studies and large clinical trials. Data Sources: Searches of PubMed, EMBASE and CENTRAL (inception to 15 April 2019) without language restrictions; conference proceedings; and reference lists. Study Selection: Randomized controlled trials and observational studies that quantified the rate of diabetic ketoacidosis with an SGLT2 inhibitor in comparison to another diabetes medication or placebo. Data Extraction and Synthesis: Two independent investigators abstracted study data and assessed the quality of evidence. Data were pooled using random effects models with the Hartung-Knapp-Sidik-Jonkman method. Main Outcome and Measures: Absolute event rates and hazard ratios for diabetic ketoacidosis were extracted from each study. Results: Seven randomized trials encompassing 42,375 participants and five cohort studies encompassing 318,636 participants were selected. Among the 7 randomized controlled trials, the absolute rate of DKA among patients randomized to an SGLT2 inhibitor ranged from 0.6 to 2.2 events per 1000 person years. Four randomized trials were included in the meta-analysis, and compared to placebo or comparator medication, SGLT2 inhibitors had a 2.4-fold higher risk of DKA (Relative Risk [RR] = 2.46 [95% CI, 1.16-5.21]; I2 = 0%; P = 0.54). Among the 5 observational studies, the absolute rate of DKA associated with SGLT2 inhibitor use ranged from 0.6 to 4.9 per 1000 person years and a 1.7-fold higher rate of DKA compared to another diabetes medication (RR = 1.74 [95% CI, 1.01-2.93]; I2 = 45%; P = 0.12). Conclusions and Relevance: In adults with type 2 diabetes, SGLT2 inhibitors increase the risk of DKA in both observational studies and large randomized clinical trials. Registration: CRD42019146855 Funding Source: None


2013 ◽  
Vol 06 (02) ◽  
pp. 144 ◽  
Author(s):  
William G Christen ◽  
Emily Y Chew ◽  
◽  

Recent findings from observational epidemiologic studies have raised concern about a possible adverse effect of regular aspirin use in age-related macular degeneration (AMD), and in particular neovascular AMD, which is the leading cause of severe irreversible blindness in the US. In this report, we consider these findings in light of the relative strengths and limitations of observational studies and randomized trials. While the findings are important and warrant further investigation, the inherent limitations of observation studies, most notably uncontrolled confounding, preclude an interpretation of causality. Alternatively, the most reliable evidence with which to evaluate the effects of regular aspirin use in AMD will derive from well-designed randomized trials of sufficient size and duration.


2010 ◽  
Vol 4 (1) ◽  
pp. 135-145 ◽  
Author(s):  
Osmar Antonio Centurión

Strategies for preventing ischemic complications during percutaneous coronary interventions (PCI) in the setting of acute myocardial infarction (AMI) have focused on the platelet surface-membrane glycoprotein (GP) IIb/IIIa receptor. The platelet GP IIb/IIIa receptor inhibitors, by blocking the final common pathway of platelet aggregation, have become a breakthrough in the management of acute coronary syndromes. Current adjuvant pharmacological therapy of AMI with aspirin, clopidogrel, unfractionated heparin (UH), and platelet GP IIb/IIIa inhibitors provides useful therapeutic benefits. Although the use of more potent antithrombin and antiplatelet agents during PCI in AMI has reduced the rate of ischemic complications, in parallel, the rate of bleeding has increased. Several studies have reported an association between bleeding after PCI and an increase in morbidity and mortality. Therefore, investigational studies have focused in pharmacological agents that would reduce bleeding complications without compromising the rate of major adverse cardiovascular events. Based on the results of several randomized trials, abciximab with UH, aspirin and clopidogrel have become a standard adjunctive therapy with primary PCI for AMI. However, some of the trials were done before the use of stents and the widespread use of thienopyridines. In addition, GP IIb/IIIa inhibitors use have been associated with thrombocytopenia, high rates of bleeding, and the need for transfusions, which increase costs, length of hospital stay, and mortality. On the other hand, in the stent era, bivalirudin, a semi-synthetic direct thrombin inhibitor, has recently been shown to provide similar efficacy with less bleeding compared with unfractionated heparin plus platelet GP IIb/IIIa inhibitors in AMI patients treated with primary PCI. The impressive results of this recent randomized trial and other observational studies make a strong argument for the use of bivalirudin rather than heparin plus GP IIb/IIIa inhibitors for the great majority of patients with AMI treated with primary PCI. However, some controversial results and limitations in the studies with bivalirudin exert some doubts in the future widespread use of this drug.


2019 ◽  
Vol 46 (2) ◽  
pp. E14 ◽  
Author(s):  
Bradley Kolb ◽  
Hassan Fadel ◽  
Gary Rajah ◽  
Hamidreza Saber ◽  
Ali Luqman ◽  
...  

OBJECTIVESteno-occlusive diseases of the cerebral vasculature have been associated with cognitive decline. The authors performed a systematic review of the existing literature on intracranial steno-occlusive disease, including intracranial atherosclerosis and moyamoya disease (MMD), to determine the extent and quality of evidence for the effect of revascularization on cognitive performance.METHODSA systematic search of PubMed/MEDLINE, the Thomson Reuters Web of Science Core Collection, and the KCI Korean Journal Database was performed to identify randomized controlled trials (RCTs) in the English-language literature and observational studies that compared cognitive outcomes before and after revascularization in patients with steno-occlusive disease of the intracranial vasculature, from which data were extracted and analyzed.RESULTSNine papers were included, consisting of 2 RCTs and 7 observational cohort studies. Results from 2 randomized trials including 142 patients with symptomatic intracranial atherosclerotic steno-occlusion found no additional benefit to revascularization when added to maximal medical therapy. The certainty in the results of these trials was limited by concerns for bias and indirectness. Results from 7 observational trials including 282 patients found some cognitive benefit for revascularization for symptomatic atherosclerotic steno-occlusion and for steno-occlusion related to MMD in children. The certainty of these conclusions was low to very low, due to both inherent limitations in observational studies for inferring causality and concerns for added risk of bias and indirectness in some studies.CONCLUSIONSThe effects of revascularization on cognitive performance in intracranial steno-occlusive disease remain uncertain due to limitations in existing studies. More well-designed randomized trials and observational studies are needed to determine if revascularization can arrest or reverse cognitive decline in these patients.


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