Use of nonsteroidal anti-inflammatory drugs in patients with cardiovascular disease: a cautionary tale.
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit production of prostaglandins by acting on cyclooxygenase (COX) isoenzymes 1 and 2. Nonselective NSAIDs inhibit both COX 1 and 2 isoenzymes (eg, ibuprofen and naproxen). Selective NSAIDs act on COX-1 (eg, aspirin) or COX-2 (eg, celecoxib) isoenzymes, respectively. Prostaglandins are produced in platelets and gastric mucosal cells through constitutively expressed COX-1 isoenzyme. They are involved in the regulation of hemostasis, functional integrity of the gastrointestinal and renal tracts, platelet function, and macrophage differentiation. Inhibition of COX-1 isoenzymes impedes platelet aggregation, impairs maintenance of protective gastric mucosal barrier, and affects renal function. Prostaglandin production in inflamed tissue results from de novo induction of COX-2 expression by inflammatory cytokines and other noxious stimuli. Thus, COX-2 isoenzyme inhibition either selectively or nonselectively helps in reducing inflammation in the setting of musculoskeletal disorders. Safety and efficacy of NSAIDs are related to their relative actions on COX-1 or COX-2 inhibition. Given the multisystem (gastrointestinal, hematopoietic, and renal) adverse effect profile of COX-1 inhibition, formulation of NSAIDs with relative COX-2 selectivity became a highly desirable target during the 90's. However, studies in the first half of this decade revealed adverse effects of COX-2 inhibition on the cardiovascular system, including increased risks of myocardial infarction, exacerbation of stable congestive heart failure, and worsening high blood pressure. Randomized trials and meta-analyses confirmed these findings, which led to withdrawal of some of the COX-2 inhibitors from the market by the federal Food and Drug Administration a few years ago. Here, we review the effects of COX-2 isoenzyme inhibitors on the cardiovascular system to provide a safe strategy for prescribing these agents in patients with existing cardiovascular disease. We did not find adequate long-term randomized controlled trials appropriately powered to evaluate cardiovascular outcomes. Potentially, all NSAIDs possess a fair risk of adverse effects on gastrointestinal, cardiovascular, and renal systems. Until more evidence for safety via randomized trials is available, we recommend caution in prescribing COX-1 and 2 inhibitors for musculoskeletal disorders in patients with existing gastrointestinal or cardiovascular conditions.
Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA. mamer1@jhmi.edu
Muhammad
M
Amer
Valeriani R
VR
Bead
Joan
J
Bathon
Roger S
RS
Blumenthal
David N
DN
Edwards
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000009:adverse effects; D050197:Atherosclerosis / Q000139:chemically induced; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006333:Heart Failure / Q000139:chemically induced; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D010974:Platelet Aggregation / Q000187:drug effects; D018570:Risk Assessment / Q000379:methods; D013927:Thrombosis / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D001241:Aspirin