Project description:The emerging role of colchicine in the treatment of cardiovascular diseases is a strong demand for a comprehensive understanding of its efficacy and safety. This meta-analysis and systematic review aimed to study the efficacy in the reduction of adverse cardiovascular outcomes (CO), and the risk of colchicine-related adverse events (CRAEs). Fourteen thousand and nine eighty three patients from 22 randomized controlled trials (RCTs) were included, 9 in patients with coronary artery disease-CAD, 9 in patients with pericarditis, 4 in patients with atrial fibrillation-AF or heart failure. Colchicine was efficacious in the reduction of adverse CO across different settings: pericardial diseases (reduced risk of recurrent pericarditis, 17.6% vs. 35%, RR 0.50, 95% CI 0.41-0.61), CAD (reduced risk of cardiac death, myocardial infarction, stroke,coronary revascularization or hospitalization, 6.1% vs. 8.5%, RR 0.73, 95% CI 0.64-0.83), AF (reduced risk of arrhythmia recurrence, 14.2% vs. 22.7%, RR 0.62, 95% CI 0.44-0.88). Colchicine was associated with increased risk of gastrointestinal CRAEs (11.2% vs. 8.8%, RR 1.87, 95% CI 1.41-2.47) and drug discontinuation (5.4% vs. 3.7%, RR 1.58, 95% CI 1.25-1.99). In both cases, the risk was proportional to the daily dose or duration of treatment, possibly due to early drug discontinuation or tolerance. Other CRAEs (muscle-related, liver,hematologic,cutaneous, infections) were not increased by colchicine, as long as all-cause death (2.2% vs. 1.9%, RR 1.11, 95% CI 0.79-1.54) or non-cardiovascular death (1.5% vs. 1%, RR 1.43, 95% CI 0.93-2.19). Colchicine is efficacious and safe for the treatment of cardiovascular diseases. The risk of gastrointestinal CRAEs and drug discontinuation is not significant if colchicine is used at lower doses (0.5 mg daily) or for longer periods of time (> 6 months).
Project description:Objectives(1) To conduct a network meta-analysis of clinical drugs used for cardiogenic shock and (2) provide evidence for the selection of medication for the treatment of this condition.MethodsPubMed, EMBASE, Cochrane library, China HowNet (CNKI), Wanfang database, and Weipu database were searched using keywords Dopamine, Dobutamine, Epinephrine, Adrenaline, Norepinephrine, Noradrenaline, Milrinone, Natriuretic peptide, Recombinant human brain natriuretic peptide, Levosimendan, Cardiac shock, and Cardiogenic shock. We select literature according to prespecified inclusion and exclusion criteria and record data such as drug type, mortality, and adverse reactions.ResultsTwenty-eight of 1387 articles met inclusion criteria, comprising 1806 patients who suffered from cardiogenic shock. Dopamine, dobutamine, epinephrine, norepinephrine, milrinone, recombinant human brain natriuretic peptide, and levosimendan were all commonly used in the treatment of cardiogenic shock. Milrinone was most effective at reducing mortality and had the lowest incidence of adverse reactions.ConclusionThis network meta-analysis demonstrated that milrinone was the most effective medication at reducing mortality and adverse events in patients suffering from cardiogenic shock.
Project description:Background: Evidence from recent studies has shown the benefits of colchicine for patients with coronary artery disease. The aim was to assess the effect of colchicine treatment on cardiovascular events, with an estimation of the risk of discontinuation and net clinical benefit. Methods and Results: Fourteen trials with a total of 13,186 patients were selected through a systematic search. Colchicine therapy significantly reduced the relative risk of primary endpoint by about 30% [RR 0.70 (95%CI:0.56-0.88)]. Compared with placebo, colchicine significantly reduced the risk of ischemia-driven revascularization [RR 0.57 (95%CI 0.41-0.80)], ischemia-driven revascularization and resuscitation [RR 0.50 (95%CI 0.34-0.73)], myocardial infarction [RR 0.73 (95%CI 0.57-0.95)], and stroke [RR 0.49 (95%CI 0.30-0.7)]. Patients treated with colchicine in comparison with placebo have a significant increase in the risk of treatment cessation (RR 1.60 95%CI 1.06-2.42). However, in the analysis which excluded studies without placebo, the relative risk of discontinuation was smaller (RR 1.34 95%CI 0.97-1.84) and in the three largest studies, the risk of discontinuation was lower and insignificant [RR 1.26 (95%CI 0.87-1.83)]. The net clinical benefit was 17.8/1,000 patients (p < 0.001). Conclusion: In coronary artery disease, low-dose colchicine significantly reduces the risk of the primary composite endpoint by about 30%. The drug should be considered as part of the preventive treatment in patients with good tolerance.
Project description:Studies reporting an increased risk for cardiac toxicities with macrolide antibiotics have raised concern regarding their cardiovascular safety. We sought to assess the cardiac safety of macrolide antibiotics as a class and of the individual agents by conducting a systematic review and network meta-analysis. Medline, Embase, and the Cochrane Library were searched up to February 2018 for studies reporting on cardiovascular outcomes with macrolides. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random-effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for arrhythmia, cardiovascular death, and myocardial infarction (MI). A total of 33 studies and data on 22,601,032 subjects were retrieved and included in the current meta-analyses. Macrolide use was not associated with the risk of arrhythmia or cardiovascular mortality. In the primary analysis, macrolide use was associated with a small but statistically significant 15% increase in risk for MI (OR = 1.15 [95% CI, 1.01 to 1.30]). In indirect network meta-analysis, erythromycin and clarithromycin were ranked considerably more likely to be associated with a higher risk for MI and significantly associated with increased risk of MI compared to azithromycin (OR = 1.58 [95% CI, 1.18 to 2.11] and OR = 1.41 [95% CI, 1.11 to 1.81], respectively). Our findings indicate that macrolide antibiotics as a group are associated with a significant risk for MI but not for arrhythmia and cardiovascular mortality. Among the macrolides, erythromycin and clarithromycin were associated with a greater risk of MI. However, it is possible that the association between macrolide use and risk of MI is the result of residual confounding.
Project description:Aims/introductionRecently, the use of rosiglitazone has been limited or withdrawn from the market as a result of cardiovascular risk. However, theoretically adding rosiglitazone to insulin could help insulin to decrease the glucose level. The present meta-analysis was designed to investigate the effect and safety of adding rosiglitazone to insulin therapy in type 2 diabetes.Materials and methodsWe searched published and unpublished databases through to March 2012. Randomized controlled trials (RCTs) comparing rosiglitazone in combination with insulin (RSG + INS) vs insulin alone (INS) in type 2 diabetes with outcomes including glycated hemoglobin levels, insulin dose, lipid parameters, blood pressure, edema and cardiovascular adverse events were selected.ResultsNine RCTs with durations of 24-26 weeks involving 1,916 patients were included. The RSG + INS group showed significantly decreased glycated hemoglobin levels by 0.89% (P < 0.00001) with an 8.48-U reduction in daily insulin dose (P <0.00001). However, the risks of hypoglycemia and edema were more frequent in the RSG+INS group (P < 0.0001; P = 0.03, respectively). Total cholesterol level was significantly increased in the RSG+INS group (P < 0.00001), but none of the high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol or triglyceride levels were significantly different between groups. There were no significant differences between groups with regard to the risks of myocardial infarction, heart failure, cardiovascular death or all-cause death.ConclusionsRosiglitazone could help type 2 diabetes patients with poorly controlled glucose with insulin therapy to decrease glucose levels and reduce their daily insulin dose, but at the cost of increased total cholesterol level, hypoglycemia and edema risk. Compared with insulin therapy, adding rosiglitazone to insulin did not increase the risks of myocardial infarction, heart failure, cardiovascular death or all-cause death.
Project description:Recently, the US Food and Drug Administration and European Medicines Agency have issued new guidance for industry on drug interaction studies, which outline comprehensive recommendations on a broad range of in vitro and in vivo studies to evaluate drug-drug interaction (DDI) potential. This paper aims to provide an overview of these new recommendations and an in-depth scientifically based perspective on issues surrounding some of the recommended approaches in emerging areas, particularly, transporters and complex DDIs. We present a number of theoretical considerations and several case examples to demonstrate complexities in applying (1) the proposed transporter decision trees and associated criteria for studying a broad spectrum of transporters to derive actionable information and (2) the recommended model-based approaches at an early stage of drug development to prospectively predict DDIs involving time-dependent inhibition and mixed inhibition/induction of drug metabolizing enzymes. We hope to convey the need for conducting DDI studies on a case-by-case basis using a holistic scientifically based interrogative approach and to communicate the need for additional research to fill in knowledge gaps in these areas where the science is rapidly evolving to better ensure the safety and efficacy of new therapeutic agents.
Project description:IntroductionColchicine has the potential in reducing patient morbidity and mortality in COVID-19 infection owing to its anti-inflammatory properties. This study aims to determine the efficacy of colchicine in optimizing inflammatory hematological biomarker levels among COVID-19 patients.MethodsIn accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement guidelines, a systematic search was conducted using the following keywords: Colchicine, covid*, SARS-CoV-2, anti-inflammatory, trials, clinical, hematological, laboratory. Databases were searched from December 2019 until August 26, 2021: MEDLINE/PubMed, Web of Science, Cochrane, Scopus, and EMBASE. Other sources were located through ClinicalTrials.Gov, manually searching SAGE, Science Direct, Elsevier, and Google Scholar. The meta-analysis was conducted using Review Manager 5.4.ResultsIn total, six studies were included, of which four reported c-reactive protein (CRP) standardized mean reductions in the colchicine group (N = 165) as opposed to the control (N = 252; SMD = -0.49, p < 0.001). On noting lactate dehydrogenase (LDH) values post treatment, the colchicine group (N = 204) showed significant reductions at the end of treatment compared to control (N = 290; SMD = -0.85, p < 0.001). Finally, the D-dimer values in colchicine groups (N = 129) compared to control (N = 216) also documented a negative effect size (SMD = -0.9, p < 0.001).ConclusionColchicine has efficacy in reducing inflammatory biomarkers observed in moderate-to-severe COVID-19 patients. It may be worthwhile to consider monitoring the clinical and laboratory parameters of patients in further trials to consider colchicine as a strong candidate for an adjunct to COVID-19 treatment.
Project description:ObjectivesOur objective was to compare the cardiovascular safety of tocilizumab and other biological disease-modifying antirheumatic drugs (bDMARD) in rheumatoid arthritis using a network meta-analysis (NMA).MethodsA systematic literature search through May 2018 identified randomized controlled trials (RCT) or observational studies (cohort only) reporting cardiovascular outcomes of tocilizumab (TCZ) and/or abatacept (ABA) and/or rituximab (RTX) and/or tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis patients. The composite primary outcome was the rate of major adverse cardiovascular outcomes (MACE, myocardial infarction (MI), peripheral artery disease (PAD) and cardiac heart failure (CHF)).Results19 studies were included in the NMA, including 11 RCTs and 8 cohort studies. We found less events with RTX (5.41 [1.70;17.26]. We found no difference between TCZ and other treatments. Concerning MI, we found no difference between TCZ and csDMARD (4.23 [0.22;80.64]), no difference between TCZ and TNFi (2.00 [0.18;21.84]). There was no difference between TCZ and csDMARD (1.51[0.02;103.50] and between TCZ and TNFi (1.00 [0.06;15.85]) for stroke event. With cohorts and RCT NMA, we found no difference between TCZ and other treatments for MACE (0.66 [0.42;1.03] with ABA, 1.04 [0.60;1.81] with RTX, 0.78[0.53;1.16] and 0.91 [0.54;1.51] with csDMARD), but the risk of myocardial infarction was lower with TCZ compared to ABA (0.67 [0.47;0.97]). We lacked data to compare TCZ and other bDMARD for stoke and MI. Not enough data was available to perform a NMA for CHF and PAD.ConclusionsDespite an increase in cholesterol levels, TCZ has safe cardiovascular outcomes compared to other bDMARD.
Project description:ObjectiveTo analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs.DesignNetwork meta-analysis.Data sourcesBibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data.Study selectionAll large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility.Data extractionThe primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data.Data synthesis31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death.ConclusionsAlthough uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.
Project description:BACKGROUND:Colchicine is an anti-inflammatory drug that is used for a wide range of inflammatory diseases. Cardiovascular disease also has an inflammatory component but the effects of colchicine on cardiovascular outcomes remain unclear. Previous safety analyses were restricted to specific patient populations. OBJECTIVES:To evaluate potential cardiovascular benefits and harms of a continuous long-term treatment with colchicine in any population, and specifically in people with high cardiovascular risk. SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry, citations of key papers, and study references in January 2015. We also contacted investigators to gain unpublished data. SELECTION CRITERIA:Randomised controlled trials (parallel-group or cluster design or first phases of cross-over studies) comparing colchicine over at least six months versus any control in any adult population. DATA COLLECTION AND ANALYSIS:Primary outcomes were all-cause mortality, myocardial infarction, and adverse events. Secondary outcomes were cardiovascular mortality, stroke, heart failure, non-scheduled hospitalisations, and non-scheduled cardiovascular interventions. We conducted predefined subgroup analyses, in particular for participants with high cardiovascular risk. . MAIN RESULTS:We included 39 randomised parallel-group trials with 4992 participants. Colchicine had no effect on all-cause mortality (RR 0.94, 95% CI 0.82 to 1.09; participants = 4174; studies = 30; I² = 27%; moderate quality of evidence). There is uncertainty surrounding the effect of colchicine in reducing cardiovascular mortality (RR 0.34, 95% CI 0.09 to 1.21, I² = 9%; participants = 1132; studies = 7; moderate quality of evidence). Colchicine reduced the risk for total myocardial infarction (RR 0.20, 95% CI 0.07 to 0.57; participants = 652; studies = 2; moderate quality of evidence). There was no effect on total adverse events (RR 1.52, 95% CI 0.93 to 2.46; participants = 1313; studies = 11; I² = 45%; very low quality of evidence) but gastrointestinal intolerance was increased (RR 1.83, 95% CI 1.03 to 3.26; participants = 1258; studies = 11; I² = 74%; low quality of evidence). Colchicine showed no effect on heart failure (RR 0.62, 95% CI 0.10 to 3.88; participants = 462; studies = 3; I² = 45%; low quality of evidence) and no effect on stroke (RR 0.38, 95% CI 0.09 to 1.70; participants = 874; studies = 3; I² = 45%; low quality of evidence). Reporting of serious adverse events was inconsistent; no event occurred over 824 patient-years (4 trials). Effects on other outcomes were very uncertain. Summary effects of RCTs specifically focusing on participants with high cardiovascular risk were similar (4 trials; 1230 participants). AUTHORS' CONCLUSIONS:There is much uncertainty surrounding the benefits and harms of colchicine treatment. Colchicine may have substantial benefits in reducing myocardial infarction in selected high-risk populations but uncertainty about the size of the effect on survival and other cardiovascular outcomes is high, especially in the general population from which most of the studies in our review were drawn. Colchicine is associated with gastrointestinal side effects based on low-quality evidence. More evidence from large-scale randomised trials is needed.