Non‐steroidal anti‐inflammatory drugs and cardiac failure: meta‐analyses of observational studies and randomised controlled trials

Abstract

Aims: To determine the risks of cardiac failure with non-steroidal anti-inflammatory drugs (NSAIDs) and the specific risks with Cox-2 specific NSAIDs (COXIBs). Methods: We performed meta-analyses examining the risks of developing cardiac failure in observational studies and in randomised controlled trials (RCTs) involving patients with arthritis and non-rheumatic disorders. Electronic databases and published bibliographies were systematically searched (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008). Results: Five case-control studies (4657 patients, 45,862 controls) showed a non-significant association between NSAIDs and cardiac failure in a random effect model (odds ratio (OR) 1.36; 95% CI 0.99-1.85). Two cohort studies (27,418 patient years, 55,367 control years) showed a significant risk of cardiac failure with NSAIDs (relative risk 1.97; 95% CI 1.73-2.25). Six placebo-controlled trials (naproxen, rofecoxib and celecoxib) in non-rheumatic diseases (15,750 patients) showed more cardiac failure with NSAIDs (Peto OR 2.31; 95% CI 1.34, 4.00). Six RCTs comparing conventional NSAIDs and COXIBs in arthritis (62,653 patients) showed no difference in cardiac failure risk (Peto OR 1.14; 95% CI 0.85-1.53). Conclusion: Observational studies and RCTs all show that NSAIDs increase the risk of cardiac failure. Overall risks are relatively small and are similar with conventional NSAIDs and COXIBs. Pre-existing cardiac failure increases risk.

Cardiorenal Syndrome Type 1

“…Combinations of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors, and especially aldosterone blockers when glomerular filtration rate is reduced below 45 ml/min, may lead to secondary hyperkalemia. Nonsteroidal inflammatory agents reversibly inhibit cyclooxygenases 1 and 2, impair prostaglandin synthesis, and result in sodium and fluid retention, as well as tissue edema, which consistently worsen HF outcomes (97). In the kidney, edema may result in impaired oxygenation and metabolite diffusion, distorted tissue architecture, obstruction of capillary blood flow and lymphatic drainage, and disturbed cell-cell interactions that may then contribute to progressive organ dysfunction (98).…”

Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study

“…Similarly, a meta-analysis of six trials did not show differences in heart failure risk between traditional NSAIDs and COX 2 inhibitors. 13 Estimates provided by the few published observational studies on the NSAID heart failure association are compatible with an increased risk of heart failure associated with naproxen, ibuprofen, ketoprofen, piroxicam, indomethacin, and rofecoxib, but not for celecoxib. 14 23-27 Our results also accord with the body of evidence supporting the relative cardiovascular safety of low to medium doses of celecoxib for treatment of arthritis compared with all other COX 2 inhibitors.…”

Macrophage-Assisted Inflammation and Pharmacological Regulation of the Cholinergic Anti-Inflammatory Pathway

“…2) include not only the reduction of the inflammation through COX-2 but also inhibition of COX-1. Although for many years selective inhibitors of COX-2 were searched for, it unfortunately turned out, that selective COX-2 inhibitors such as rofecoxib and colexcoxib exhibited serious side effects such as cardiac failure [15]. These effects were caused by setting the actions of COX-1 and COX-2 out of balance leading to an enhancement of blood clotting [16].…”