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

Abstract

SummaryBackgroundThe vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory 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.MethodsWe undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) 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 infarction, 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, obstruction, or bleed).FindingsMajor 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), chiefly 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 significantly 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 significantly increase major vascular events (0·93, 0·69–1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85, p=0·0187), non-significantly 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 effects 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).InterpretationThe 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.FundingUK Medical Research Council and British Heart Foundation.

Diclofenac use and cardiovascular risks: series of nationwide cohort studies

“…The discrepancy between our estimated 60% increased risk and the meta-analysis’ estimate for any stroke (1.18, 0.79 to 1.78) could be explained by our focus on ischaemic stroke 3. The incidence rate ratio for atrial fibrillation or flutter found in our study was lower than previously reported (1.73, 1.53-1.97),39 in part owing to our ability to control for healthcare seeking behaviour.…”

“…Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making. The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis found a 40% increased risk of vascular events associated with diclofenac use versus placebo or no use (incidence rate ratio 1.41, 95% confidence interval 1.12 to 1.78), driven by an increased rate of myocardial infarction (1.70, 1.19 to 2.41) 3. Also in line with our results, the meta-analysis showed that diclofenac users had an increased risk of heart failure (1.85, 1.17 to 2.94) and vascular death (1.65, 0.95 to 2.85) 3…”

Sleep Apnea, the Risk of Developing Heart Failure, and Potential Benefits of Continuous Positive Airway Pressure (CPAP) Therapy

“…Hence, we applied many of these comorbidities in our regression models, including continuous assessment of their presence. Use of NSAIDs has been associated with increased risk of HF and was therefore included in the model as well 23, 24. Although lower estimates were found (Model 2 compared with Model 1, Table 4), the IRRs were still significantly increased; thus, SA seems to be an independent risk factor for developing HF.…”

Role of chemoprophylaxis with either NSAIDs or statins in patients with Barrett’s esophagus

“…Because mortality due to cardiovascular disease is high in BE patients, "technical review on the management of Barrett's esophagus today" suggests screening for cardiovascular factors in BE patients and aspirin and statin use as warranted [45] . Because we have shown no benefit for non-aspirin NSAID use in BE patients with ischemic heart disease [53] and substantial cardiovascular side effects are expected [103,104] , use of non-aspirin NSAIDs should be withheld in patients with BE and cardiovascular co-morbidities, at least until more clinical data might justify their use.…”

“…Analyses showed that the excess risk was mainly attributable to an increase of about three quarters in the risk of major coronary events. Vascular death increased by about twothirds, heart failure risk roughly doubled, while risk for stroke was not affected [103,104] . Nitro-NSAIDs represent an NSAID subclass with lower risk for gastrointestinal bleeding [105] .…”