Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials

Summary Background The vascular and gastrointestinal eff ects of non-steroidal anti-infl ammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-infl ammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 personyears) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial in farction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, ob struction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefl y due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also signifi cantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not signifi cantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased signifi cantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), nonsignifi cantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional eff ects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. Funding UK Medical Research Council and British Heart Foundation. Introduction Non-steroidal anti-infl ammatory drugs (NSAIDs) are among the most widely used drugs in the world. They are chiefl y used to treat pain, but their long-term use is limited by serious gastrointestinal side-eff ects. NSAIDs inhibit the two recognised forms of prostaglandin G/H synthase (also referred to as cyclo-oxygenase [COX]), namely COX-1 and COX-2. 1 Since the analgesic and antiinfl ammatory eff ects of NSAIDs are mediated by inhibition of COX-2, and their gastrointestinal side eff ects mostly by inhibition of COX-1, NSAIDs which selectively inhibit COX-2 might reduce the risk of gastrointestinal toxicity compared with other NSAIDs. Several such COX-2 selective drugs (collectively known as coxibs) were developed in the 1990s, and early trials comparing coxibs versus traditional NSAIDs (tNSAIDS) seemed to confi rm that coxibs at doses with similar analgesic effi cacy had less gastrointestinal toxicity. 2,3 Unfortunately, however, subsequent placebo-controlled trials also showed unequivocally that coxibs were associated with an increased risk of atherothrombotic vascular events. 4,5 Soon after these placebo-controlled trials were reported, a meta-analysis of randomised trials comparing a coxib versus placebo or a coxib versus tNSAID indicated that some tNSAIDs might also have adverse eff ects on atherothrombotic events, but that these hazards might depend on the degree and duration of suppression of platelet COX-1

Gout is more frequent in sickle cell disease than in haemoglobin AA among sub-Saharan Africans

Background: Sickle Cell Disease (SCD) is a common autosomal recessive disorder worldwide that mostly affects Africans. Hyperuricemia, a common biochemical finding, occurs in up to 41% of SCD patients. Although hyperuricaemia is the most important risk factor for gout, thelatter is uncommonly reported in SCD.Objective: To determine the frequency and factors associated with hyperuricaemia and gout among patients with Sickle Cell Disease  (SCD).Design: This was a cross sectional study.Methods: The study involved 104 SCD patients and 104 haemoglobin AA (HbAA) controls. The diagnosis of gout was based on the  demonstration of monosodium urate crystals in the synovial fluid of symptomatic individuals. Hyperuricaemia was found in 28 (26.9%) and 2 (1.9%) of SCD and control participants respectively (p<0.001). The median (range) Serum Uric Acid (SUA) was higher among patients (330 μmol/L [146 to 702 μmol/]) than in controls (232 μmol/L [143 to 440 μmol/L]), (p<0.01). Six (5.8%) cases of gout were found among the patients and none among the controls (p=0.029). The pattern of articular involvement was monoarticular in 2 (33.3%), oligoarticular in 3 (50%) and polyarticular in 1 (16.7%). One (16.7%) patient had subcutaneous tophi. Factors associated with gout in SCD were age, hyperuricaemia, more than two SCD crises in the past year and more than two hospital admissions in the past year.Conclusion: Gout as is hyperuricaemia, is more frequent in persons with SCD than in the general population. It is mostly oligoarticular and older patients with multiple attacks of painful joint swelling as well as frequent hospital admissions may be at higher risk of gout