Cardiovascular safety of non-steroidal anti-inflammatory drugs: Network meta-analysis

British Medical Journal January 11, 2011; Vol. 342:c7086 Sven Trelle, Stephan Reichenbach, Simon Wandel, Pius Hildebrand, BeatriceTschannen, Peter M Villiger, Matthias Egger FROM ABSTRACT Objective : To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Design: Network meta-analysis. Network meta-analysis allows a unified, coherentanalysis of all randomised controlled trials that compare non-steroidal anti-inflammatory drugs head to head or with placebo while fully respectingrandomisation. We analysed the cardiovascular safety of non-steroidal anti-inflammatory drugs by integrating all available direct and indirect evidence innetwork meta-analyses. Data sources: Bibliographic databases, conference proceedings, study registers,the Food and Drug Administration website, reference lists of relevant articles, andreports citing relevant articles through the Science Citation Index. Study selection: All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugsor placebo. Data extraction:The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and deathfrom any cause. Data synthesis: 31 trials in 116,429 patients with more than 115,000 patientyears of follow-up were included.Patients were allocated to naproxen [Aleve], ibuprofen [Motrin, Advil], diclofenac [Voltaren], celecoxib [Celebrex], etoricoxib [Arcoxia], rofecoxib [Vioxx], lumiracoxib[Prexige], or placebo. Compared with placebo, rofecoxib [Vioxx] was associated with the highest risk ofmyocardial infarction (increased risk by 112%), followed by lumiracoxib [Prexige](increased risk by 100%). Ibuprofen was associated with the highest risk of stroke (increase risk by 236%),followed by diclofenac [Voltaren] (increased risk by 186%).Etoricoxib [Arcoxia] (increased risk by 307%) and diclofenac [Voltaren] (increasedrisk by 298%) were associated with the highest risk of cardiovascular death. Conclusions Little evidence exists to suggest that any of the investigated drugs are safe incardiovascular terms.Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug. KEY POINTS FROM THIS STUDY: 1) This study is unique. It is the largest network meta-analysis looking at allrandomized controlled trials that assess the risk of myocardial infarction, stroke,death from cardiovascular disease, and death from any cause, as a consequence oftaking non-steroidal anti-inflammatory drugs (NSAIDs). 2) Non-steroidal anti-inflammatory drugs (NSAIDs) have been the cornerstoneof pain management in patients with osteoarthritis and other painful conditions. 3) In the United States an estimated 5% of all visits to a doctor are related toprescriptions of non-steroidal anti-inflammatory drugs and they are among themost commonly used drugs. 4) Cardiovascular death A)) The analysis showed that cardiovascular death accounted for 46% of alldeaths in those evaluated in this study.3 B)) All drugs except naproxen showed some evidence for an increased risk ofcardiovascular death compared with placebo. 5) Death from any cause A)) All the drugs seemed to be associated with increased risks of death from anycause compared with placebo. B)) All drugs seemed to be associated with increased risks of the composite ofnon-fatal myocardial infarction, non-fatal stroke, or cardiovascular death comparedwith placebo. 6) Discussion A)) Non-steroidal anti-inflammatory drugs are mainly used for symptomatictreatment of musculoskeletal conditions. Clearly, as for any symptomatic treatment,doing more harm than good with this class of drugs should be avoided. B)) Our study confirms previous notions of regulatory bodies, mainly based onobservational evidence, that all non-steroidal anti-inflammatory drugs areassociated with an increased risk of cardiovascular adverse effects. C)) Our results are based on randomised evidence and we therefore believe thatour study provides the best available evidence on the safety of this class of drugs. D)) Naproxen seems to be the safest analgesic for patients with osteoarthritis incardiovascular terms but this advantage has to be weighed against gastrointestinaltoxicity and the need for concomitant prescription of a proton pump inhibitor inmany patients. E)) Paracetamol [acetaminophen] results in only a small reduction in pain and isassociated with clinically relevant hepatotoxicity, even in dosages recommended formusculoskeletal pain. F)) The analgesic effects of opioids are better than acetaminophen, butoutweighed by large increases in the risk of adverse events. G)) In conclusion, the options for the treatment of chronic musculoskeletal painare limited and patients and clinicians need to be aware that cardiovascular riskneeds to be taken into account when prescribing. H)) In 2004, Vioxx, a COX 2 selective inhibitor, was withdrawn from the marketbecause it increased the risk of cardiovascular events. Cardiovascular safety of NSAIDs Editorial British Medical Journal January 11, 2011; Vol. 342:c6618 Wayne A Ray: Professor and Director, Division of Pharmacoepidemiology, Department of Preventive Medicine, Nashville, TN SOME POINTS FROM THIS EDITORIAL: 1) The cardiovascular risks from NSAIDs should prompt evaluation of a broaderrange of alternatives. 2) Millions of patients with chronic musculoskeletal symptoms are long-termusers of non-steroidal anti-inflammatory drugs (NSAIDs). Unfortunately, thesedrugs have common and potentially severe adverse effects, including renalimpairment, gastrointestinal complications, and cardiotoxicity. 3) The cardiotoxicity from NSAIDs is particularly worrying because manypatients with musculoskeletal disease also have cardiovascular disease. 4) All cyclo-oxygenase-2 [COX-2] inhibitors studied in large placebo controlledtrials have been found to confer an increased risk of serious cardiovasculardisease. 5) What does this all mean when prescribing NSAIDs for patients at high risk ofcardiovascular disease? Current data suggest that selective cyclo-oxygenase-2inhibitors, particularly in higher doses, should be avoided. COMMENTS FROM DAN MURPHY: Apparently all pain drugs have serious side effects. The drugs include NSAIDs,acetaminophen, and opiates. The side effects I have reviewed in studies includegastrointestinal bleeding, kidney disease, liver disease, heart attack, stroke,increase in all cause mortality, dementia, Alzheimers dementia, hearing loss, anderectile dysfunction. As noted above, this wake-up information should prompt evaluation of a broaderrange of alternatives. A list of such non-toxic alternatives for pain managementwas presented by Dr. Joseph Maroon, the neurosurgeon for the Pittsburgh Steelers,in the journal Surgical Neurology International, December 2010. I reviewed Dr.Maroons article, its Article Review #8-12. As chiropractors, we should recall that in 2003, Spine published a study comparingchiropractic adjustments to the NSAIDs Celebrex and Vioxx in patients with chronicneck and back pain. Chiropractic was better then 5 times more effective than thesedrugs, caused no side effects, and had a stable therapeutic benefit a year later(Article Reviews 12-03 and 34-04).