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Medicina Clinica Apr 2014We evaluated the risk of hepatotoxicity associated to endothelin receptor antagonists. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
We evaluated the risk of hepatotoxicity associated to endothelin receptor antagonists.
PATIENTS AND METHOD
Systematic searches in PubMed/MEDLINE, the Cochrane Library as well as regulatory agencies websites were performed. Randomized controlled trials in patients receiving endothelin receptor antagonists (bosentan, sitaxentan or ambrisentan) in at least one treatment group were included. Prior to data extraction, definitions of hepatotoxicity were established. Effect sizes with 95% confidence intervals were calculated using random effects models. Heterogeneity was analysed using Cochran's Q and I(2) tests. Publication bias was assessed using Egger's method and funnel plots were generated.
RESULTS
Twenty-one trials met the inclusion criteria (3,644 patients). Bosentan was the evaluated drug in 1,689 (74%) patients who received endothelin receptor antagonists. Compared with controls, relative risk for any hepatic adverse reaction was 2.92 (1.85-4.62; I(2)=30.6%). When hepatotoxicity was defined as elevations of liver alanine or aspartate aminotransferases equal or greater than 3 times the upper limit of normal, relative risk was 2.98 (1.69-5.25; I(2) = 40.9%). No evidence of publication bias was found (Egger's method: p = 0.68).
CONCLUSIONS
Our results suggest an increased risk of hepatotoxicity in patients receiving endothelin receptor antagonists. Given the limited data available for endothelin receptor antagonists other than bosentan, it is not possible to draw firm conclusions about the individual risk associated for the remaining endothelin receptor antagonists.
Topics: Antihypertensive Agents; Biomarkers; Bosentan; Chemical and Drug Induced Liver Injury; Endothelin Receptor Antagonists; Humans; Hypertension; Isoxazoles; Phenylpropionates; Pyridazines; Randomized Controlled Trials as Topic; Safety-Based Drug Withdrawals; Sulfonamides; Thiophenes; Transaminases
PubMed: 23540381
DOI: 10.1016/j.medcli.2013.01.042 -
The Cochrane Database of Systematic... Oct 2014Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammatory pain and swelling in inflammatory bowel disease (IBD) patients with rheumatological... (Review)
Review
BACKGROUND
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammatory pain and swelling in inflammatory bowel disease (IBD) patients with rheumatological manifestations. While these drugs effectively reduce musculoskeletal pain and stiffness, long-term use is limited by gastrointestinal (GI) adverse effects (AEs) and disease exacerbation. As an alternative to NSAIDs, selective cyclooxygenase 2 (COX-2) inhibitors were developed to improve GI safety and tolerability. COX-2 inhibitors include drugs such as celecoxib, rofecoxib, valdecoxib, etoricoxib, and lumiracoxib. Rofecoxib and valdecoxib have been withdrawn from the market worldwide due to safety concerns (most importantly for cardiovascular adverse events) and lumiracoxib has been withdrawn in many countries due to liver toxicity. However, celecoxib and etoricoxib continue to be available for use in many countries. Several studies have examined whether COX-2 inhibitors can be safely used for the treatment of rheumatological manifestations of IBD with inconsistent results. Some investigators report acceptable safety profiles associated with these drugs while others found that COX-2 inhibitors are associated with high rates of disease exacerbation.
OBJECTIVES
The objective of this systematic review was to evaluate the tolerability and safety of COX-2 inhibitors used for the treatment of rheumatological manifestations of IBD.
SEARCH METHODS
We searched the following databases from inception to 19 September 2013: PubMed, EMBASE, MEDLINE and CENTRAL. The search was not limited by language. Additional trials were identified by manually searching the reference lists of relevant papers and conference proceedings and through correspondence with experts and pharmaceutical companies.
SELECTION CRITERIA
Randomized controlled trials (RCTs) that compared COX-2 inhibitors to placebo were considered for inclusion. Participants were adult patients with IBD presenting with rheumatological manifestations of at least two weeks duration.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial eligibility and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients with disease exacerbation as defined by the included studies. Secondary outcomes included GI adverse effects, renal toxicity, cardiovascular and thrombotic events. Data were analysed on an intention-to-treat basis where patients with missing final outcomes were assumed to have had an exacerbation of IBD. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. The overall quality of the evidence was assessed using the GRADE criteria.
MAIN RESULTS
There were no RCTs that assessed the tolerability or safety of the withdrawn COX-2 inhibitors rofecoxib, valdecoxib, or lumiracoxib. Two RCTs (n = 381 IBD patients with rheumatological manifestations) were included in the review. One study (n = 159) compared etoricoxib (60 to 120 mg/day) to placebo in IBD patients with quiescent or active ulcerative colitis or Crohn's disease. The other study (n = 222) compared celecoxib (200 mg twice daily) to placebo in patients with quiescent ulcerative colitis. Both studies were judged to be at low risk of bias. The two included studies were not pooled for meta-analysis due to differences in patient populations and treatment duration. There was no statistically significant difference in exacerbation of IBD between etoricoxib and placebo. After 12 weeks of treatment the IBD exacerbation rate was 17% (14/82) in the etoricoxib group compared to 19% (15/77) in the placebo group (RR 0.88, 95% CI 0.45 to 1.69). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (29 events). There was no statistically significant difference in exacerbation of ulcerative colitis between celecoxib and placebo. After two weeks of treatment 4% (5/112) of celecoxib patients experienced an exacerbation of ulcerative colitis compared to 6% (7/110) of patients in the placebo group (RR 0.70, 95% CI 0.23 to 2.14). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (12 events). The study comparing etoricoxib to placebo documented but did not report on AEs. The proportion of patients who experienced AEs was similar in the celecoxib and placebo groups (21% and 17%, respectively, P > 0.20). No patients in either group died or experienced serious adverse events. Eleven percent of patients in the celecoxib and placebo groups experienced GI AEs (RR 0.97, 95% CI 0.46 to 2.07). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (24 events). GI AEs led to premature withdrawal from the study in 3% of patients in celecoxib and placebo groups respectively. GI AEs included increased stool frequency, rectal bleeding, and inflamed mucosa. No patients experienced any cardiovascular adverse events. Renal toxicity or thrombotic AEs were not reported.
AUTHORS' CONCLUSIONS
The results for disease exacerbation and AEs between the COX-2 inhibitors celecoxib and etoricoxib and placebo were uncertain. Thus no definitive conclusions regarding the tolerability and safety of the short term use of celecoxib and etoricoxib in patients with IBD can be drawn. The two included studies suggest that celecoxib and etoricoxib do not exacerbate IBD symptoms. However, it should be noted that both studies had relatively small sample sizes and short follow-up durations. Clinicians need to continue to weigh the risks and benefits of these drugs when treating patients IBD patients with rheumatological manifestations in order to avoid disease exacerbation and other adverse effects. Further RCTs are needed to determine the tolerability and safety of celecoxib and etoricoxib in these patients.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Colitis, Ulcerative; Crohn Disease; Cyclooxygenase 2 Inhibitors; Diclofenac; Etoricoxib; Humans; Isoxazoles; Lactones; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Safety-Based Drug Withdrawals; Sulfonamides; Sulfones
PubMed: 25340915
DOI: 10.1002/14651858.CD007744.pub2 -
The Journal of Surgical Research Mar 2020Medical devices introduced to market through the 510K process often have limited research of low quality and substantial conflict of interest (COI). By the time...
BACKGROUND
Medical devices introduced to market through the 510K process often have limited research of low quality and substantial conflict of interest (COI). By the time high-quality safety and effectiveness research is performed, thousands of patients may have already been treated by the device. Our aim was to systematically review the trends of outcomes, research quality, and financial relationships of published studies related to de-adopted meshes for ventral hernia repair.
MATERIALS AND METHODS
Literature was systematically reviewed using PubMed to obtain all published studies related to three de-adopted meshes: C-QUR, Physiomesh, and meshes with polytetrafluoroethylene. Primary outcome was change in cumulative percentage of subjects with positive published outcomes. Secondary outcome was percentage of published manuscript with COI.
RESULTS
A total of 723 articles were screened, of which, 129 were analyzed and included a total of 8081 subjects. Percentage of subjects with positive outcomes decreased over time for all groups: (1) C-QUR from 100% in 2009 to 22% in 2018, (2) Physiomesh from 100% in 2011 to 20% in 2018, and (3) polytetrafluoroethylene from 100% in 1979 to 49% in 2018. Authors of only 20% of articles self-reported no COI, most representing later publications and were more likely to show neutral or negative results.
CONCLUSIONS
Among three de-adopted meshes, early publications demonstrated overly optimistic results followed by disappointing outcomes. Skepticism over newly introduced, poorly proven therapies is essential to prevent adoption of misleading practices and products. Devices currently approved under the 510K processes should undergo blinded, randomized controlled trials before introduction to the market.
Topics: Clinical Trials as Topic; Conflict of Interest; Device Approval; Herniorrhaphy; Humans; Medical Device Recalls; Safety-Based Medical Device Withdrawals; Surgical Mesh
PubMed: 31668430
DOI: 10.1016/j.jss.2019.09.061