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The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

ABSTRACT: Increased use of azithromycin (AZ) in treating infections associated with coronavirus disease 2019 (COVID-19) and reports of increased incidence of prolonged corrected QT (QTc) interval associated with AZ used with hydroxychloroquine prompted us to review the latest evidence in the literature, present additional analyses of human cardiovascular (CV) electrophysiology studies, and to describe sequential steps in research and development that were undertaken to characterize the benefit-risk profile of AZ. Combined QTc findings from electrocardiograms taken during oral and i.v. pharmacokinetic-pharmacodynamic studies of AZ suggest that clinically meaningful QTc prolongation is unlikely. Findings from several observational studies were heterogeneous and not as consistent as results from at least two large randomized controlled trials (RCTs). The QTc findings presented and observational data from studies with large numbers of events are not consistent with either a proarrhythmic action of AZ or an increase in frequency of CV deaths. Well-powered RCTs do not suggest a presence of increased risk of CV or sudden cardiac death after short-term or protracted periods of AZ usage, even in patients at higher risk from pre-existing coronary disease.

SUBMITTER: Cook J

PROVIDER: S-EPMC7537091 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

Cook Jack J Pressler Milton L ML Damle Bharat B Alemayehu Demissie D Knirsch Charles A CA

Clinical and translational science 20200921 1

Increased use of azithromycin (AZ) in treating infections associated with coronavirus disease 2019 (COVID-19) and reports of increased incidence of prolonged corrected QT (QTc) interval associated with AZ used with hydroxychloroquine prompted us to review the latest evidence in the literature, present additional analyses of human cardiovascular (CV) electrophysiology studies, and to describe sequential steps in research and development that were undertaken to characterize the benefit-risk profil ...[more]

PMID: 32956575

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Project description:BackgroundAlthough several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death.MethodsWe studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score-matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).ResultsDuring 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.ConclusionsDuring 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.).

Project description:ImportanceAzithromycin is one of the most commonly prescribed antibiotics in the US. It has been associated with an increased risk of cardiovascular death in some observational studies.ObjectiveTo estimate the relative and absolute risks of cardiovascular and sudden cardiac death after an outpatient azithromycin prescription compared with amoxicillin, an antibiotic not known to increase cardiovascular events.Design, setting, and participantsThis retrospective cohort study included 2 large, diverse, community-based integrated care delivery systems with comprehensive capture of encounters and prescriptions from January 1, 1998, to December 31, 2014. The cohort included patients aged 30 to 74 years who had at least 12 months of health-plan enrollment prior to antibiotic exposure. The exclusion criteria were absence of prescription benefits, prescription for more than 1 type of study antibiotic within 10 days, hospitalization or nursing home residence, and serious medical conditions. Risk of cardiovascular death associated with azithromycin vs amoxicillin exposure was calculated after controlling for confounding factors using a propensity score. Data were analyzed from December 1, 2016, to March 30, 2020.ExposuresOutpatient prescription of azithromycin or amoxicillin.Main outcomes and measuresThe primary outcomes were cardiovascular death and sudden cardiac death. An a priori subgroup analysis quantified the effects of azithromycin exposure among patients with increased baseline cardiovascular risk. The secondary outcomes were noncardiovascular death and all-cause mortality.ResultsThe study included 7 824 681 antibiotic exposures, including 1 736 976 azithromycin exposures (22.2%) and 6 087 705 amoxicillin exposures (77.8%), among 2 929 008 unique individuals (mean [SD] age, 50.7 [12.3] years; 1 810 127 [61.8%] women). Azithromycin was associated with a significantly increased hazard of cardiovascular death (hazard ratio [HR], 1.82; 95% CI, 1.23-2.67) but not sudden cardiac death (HR, 1.59; 95% CI, 0.90-2.81) within 5 days of exposure. No increases in risk were found 6 to 10 days after exposure. Similar results were observed in patients within the top decile of cardiovascular risk (HR, 1.71; 95% CI, 1.06-2.76). Azithromycin was also associated with an increased risk of noncardiovascular death (HR, 2.17; 95% CI, 1.44-3.26) and all-cause mortality (HR, 2.00; 95% CI, 1.51-2.63) within 5 days of exposure.Conclusions and relevanceThese findings suggest that outpatient azithromycin use was associated with an increased risk of cardiovascular death and noncardiovascular death. Causality cannot be established, particularly for noncardiovascular death, owing to the likelihood of residual confounding.

Project description:ImportanceObjective response rate (ORR) is an increasingly important end point for accelerated development of highly active anticancer therapies, yet its relationship to regulatory approval is not well characterized.ObjectiveTo identify circumstances in which a high ORR is associated with regulatory approval, and therefore might be an appropriate end point for definitive single-arm studies of anticancer therapies.Data sourceA database of all oncology clinical trials registered at clinicaltrials.gov between October 1, 2007, and September 30, 2010.Study selectionTrials of palliative systemic therapies for 4 measurable solid tumor types, limited to those with trial arms of at least 20 patients reporting ORR per Response Evaluation Criteria in Solid Tumors (RECIST).Data extraction and synthesisA systematic search was used to identify the reported ORR for each eligible treatment arm that had been presented publicly.Main outcomes and measuresFor each treatment regimen, defined as a single-agent or unique combination of agents for 1 cancer type, the mean ORR and the maximum ORR statistically exceeded were calculated, and their association with regulatory approval was studied. A regimen was considered approved for a specific cancer type if it had received regulatory approval in any country for treatment of advanced cancer of that type.ResultsFrom 1800 trials, 874 eligible trial arms in 578 eligible trials were identified; 542 arms had ORR data available for 294 regimens. Maximum ORR and mean ORR were significantly associated with regulatory approval (τ = 0.27, P < .001; τ = 0.12, P = .01); this relationship was stronger for single-agent therapies (τ = 0.49; τ = 0.41) than for combination regimens (τ = 0.28; τ = 0.17). Evaluation of ORR thresholds between 20% and 60% as potential trial end points demonstrated that ORR statistically exceeding 30% with a single agent had 98% specificity and 89% positive predictive value for identifying regimens achieving regulatory approval.Conclusions and relevanceFor single-agent regimens, high ORR was associated with regulatory approval; this relationship was less strong for combination regimens. Our data suggest that high ORR (eg, statistically exceeding an ORR of 30%) is an appropriate end point for single-arm trials aiming to demonstrate breakthrough activity of a single-agent anticancer therapy.

Project description:BackgroundNow that excessive weight gain during pregnancy is recognized as leading to complications during pregnancy that affect foetal growth, limiting weight gain during pregnancy has become a public health concern. Our aim was to perform a systematic review to assess whether observational studies reported associations between Physical Activity (PA) and Gestational Weight Gain (GWG). We were particularly interested in whether insufficient PA might be associated with high GWG.MethodsUsing Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we searched the MEDLINE ® databases for articles published up to February 2020 concerning case-control, cohort, and ecological studies assessing the association between PA during pregnancy and the risk of excessive and/or inadequate GWG.Results21 observational studies on the PA of pregnant women were screened. 11 of these focused on excessive GWG, and of these a majority tend to show a significant association between various aspects of PA and excessive GWG. However, the results were more mitigated when it came to rate of GWG: three studies found that neither meeting PA recommendations nor high levels of total PA nor time spent in moderate vigorous physical activity (MVPA) or engaged in sedentary behaviour were associated with weekly GWG, while two others suggested that pregnant women not meeting PA guidelines in late pregnancy did have a higher rate of GWG. Of the seven studies investigating total GWG, only one found no association with PA. All studies suggested an inverse association between PA and total GWG - yet not all studies are statistically significant.ConclusionDespite the small number of observational studies selected for our research, our findings support the main international findings, suggesting that active pregnant women gained less weight than inactive women; a lack of PA may therefore contribute to excessive GWG. The limitations of this body of evidence impede the formulation of firm conclusions. Further studies focusing clearly on the general PA assessment classification scheme are called for, to address limitations capable of affecting the strength of association.

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The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

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The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

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