title: Relationship between diclofenac dose and risk of gastrointestinal and cardiovascular events: meta-regression based on two systematic literature reviews.
abstract: BACKGROUND
  NSAIDs are associated with risks of gastrointestinal (GI) and cardiovascular (CV) toxicities. It has been reported that the risks of GI and CV events are dose related, resulting in guidance explicitly emphasizing the use of NSAIDs at the lowest effective dose for the shortest duration. To understand the potential benefits of using lower doses of diclofenac, a more detailed understanding of the relationship of diclofenac dose and the risks of GI and CV events is required.
  
  
  OBJECTIVE
  The objective of this study was to extend previous research quantifying the NSAID dose-toxicity relationship by modeling dose as a continuous measure, allowing for an assessment of the risks of major GI and CV events for patients taking specific diclofenac doses compared with NSAID nonusers.
  
  
  METHODS
  We used studies identified in 2 recently published systematic reviews of observational studies that examined the risks of major GI and CV events associated with the use of oral NSAIDs. We developed meta-regression models, considering dose as a continuous measure, to estimate the risks of major GI and CV events for different daily doses of conventional oral diclofenac relative to nonuse of NSAIDs.
  
  
  RESULTS
  Seven of the 59 GI publications, contributing 11 dose-specific risk ratio observations, and 12 of the 51 CV studies, contributing 21 dose-specific risk ratio observations, were eligible for inclusion in the meta-regression. The models indicated positive linear relationships between diclofenac dose and the relative risks of major GI and CV events for the range of doses examined.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study to quantify and aggregate the continuous relationship between the risk of GI or CV events and the dosage of an NSAID. With the recent availability of new low doses of diclofenac, the models may be used to estimate the potential reduction in risk of adverse events at these doses.
authors.affiliation: RTI Health Solutions, Research Triangle Park, North Carolina. Electronic address: dodom@rti.org.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Odom
authors.affiliation: RTI Health Solutions, Research Triangle Park, North Carolina.
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: Mladsi
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Saag
authors.affiliation: RTI Health Solutions, Research Triangle Park, North Carolina.
authors.forename: Bintu N
authors.initials: BN
authors.lastname: Sherif
authors.affiliation: RTI Health Solutions, Research Triangle Park, North Carolina.
authors.forename: LaStella
authors.initials: L
authors.lastname: Miles
authors.affiliation: RTI Health Solutions, Research Triangle Park, North Carolina.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ronquest
authors.affiliation: RTI Health Solutions, Research Triangle Park, North Carolina.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D004008:Diclofenac / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006801:Humans; D008875:Middle Aged; D018570:Risk Assessment
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac
keywords: cardiovascular safety; diclofenac; dose-related toxicity; gastrointestinal complications; meta-analysis