In The Lancet, researchers from the Coxib and traditional NSAID Trialists’ (CNT) Collaboration have used meta-analyses to assess the vascular and gastrointestinal (GI) effects of NSAIDs, including selective COX-2 inhibitors (coxibs) and traditional NSAIDs.
The analyses included 280 trials of NSAIDs versus placebo (n=124,513, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (n= 229,296, 165,456 person-years). The main outcomes were major vascular events (non-fatal MI, non-fatal stroke, or vascular death); major coronary events (non-fatal MI or coronary death); stroke; mortality; heart failure; and upper GI complications (perforation, obstruction, or bleed).
The following findings were reported:
• Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1.37, 95% CI, 1.14 to 1.66; p=0.0009) or diclofenac (1.41, 1.12 to 1.78; p=0.0036), due largely to an increase in major coronary events (coxibs 1.76, 1.31 to 2.37; p=0.0001; diclofenac 1.70, 1.19 to 2.41; p=0.0032).
• Ibuprofen increased major coronary events (2.22, 1.10 to 4.48; p=0.0253), but not major vascular events (1.44, 0.89 to 2.33).
• Compared with placebo, of 1000 patients on a coxib or diclofenac for a year, 3 more had major vascular events, 1 of which was fatal.
• Naproxen did not statistically significantly increase major vascular events (0.93, 0.69 to 1.27).
• Vascular death was statistically significantly increased by coxibs (1.58, 99% CI, 1.00 to 2.49; p=0.0103) and diclofenac (1.65, 0.95 to 2.85, p=0.0187), non-significantly by ibuprofen (1.90, 0.56 to 6.41; p=0.17), but not by naproxen (1.08, 0.48 to 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 GI complications (coxibs 1.81, 1.17 to 2.81, p=0.0070; diclofenac 1.89, 1.16 to 3.09, p=0.0106; ibuprofen 3.97, 2.22 to 7.10, p<0.0001; and naproxen 4.22, 2.71—6.56, p<0.0001).
The researchers note that though naproxen might not be associated with an increased risk of major vascular events, this result should be interpreted with caution because:
1. It is not known if this would be true in patients treated with aspirin, in whom naproxen will not result in any additional inhibition of COX-1 and might actually interfere with the antiplatelet effect of low-dose aspirin
2. The effects of lower naproxen doses, such as those typically used in OTC preparations are uncertain since they would be less likely to mimic the aspirin-like effect of a 500mg BD dose
3. The apparent advantage of naproxen regimens might not be preserved after longer term use.
4. Naproxen substantially increases the risk of upper GI complications (although such bleeds are less likely than vascular events to result in disability and such hazards could be mitigated with proton-pump inhibitors).
They conclude overall that their meta-analysis suggests high-dose diclofenac has vascular risks similar to coxibs, but also raises the possibility that high-dose ibuprofen has similar vascular effects. High-dose naproxen seems to be associated with less vascular hazard, although whether this is true of the lower doses most commonly used in clinical practice is unclear. They add that although NSAIDs increase vascular and GI risks to a varying extent, the analyses indicate that the effects of different regimens in particular patients can be predicted, which could help in guiding decisions about the clinical management of inflammatory disorders.
An accompanying Comment article notes that less information was available on other NSAIDs, but there is no evidence that there are any with a safer risk profile than the more studied drugs. The authors calculate that for 1000 patients at moderate risk of heart disease, one would expect about 3 major vascular events, including 1 death, due to a year of high-dose NSAIDs (except naproxen). For 1000 patients at moderate risk of GI complications, a year of high-dose NSAIDs would result in 4 to 16 GI complications. They note that someone at moderate risk for both vascular and GI complications would have a 4–19% chance of a treatment-related vascular or gastrointestinal complication over 10 years of high-dose NSAID use. In addition, though naproxen seems a good choice for patients at high risk of cardiovascular disease, the concomitant use of antiplatelets or warfarin increases bleeding risks, which can be only partially prevented by adding a proton-pump inhibitor. Furthermore, low-dose ibuprofen seems to be fairly safe for both cardiovascular and GI complications, but higher doses greatly increase the risk of both outcomes. The authors of the Comment conclude that identification of safe and effective strategies for chronic pain is needed and in the meantime, long-term use of high-dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks.
The MHRA has made a statement in response to this paper highlighting that these findings are not new and confirm the conclusions reached in October 2012 by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). It notes that NSAIDs such as ibuprofen and diclofenac are effective painkillers but a small increase in cardiovascular risk is associated with long-term at high doses. However, the short term use of ibuprofen at doses available without a prescription has not been associated with an increased risk and the current treatment advice for all NSAIDs is for people to use the lowest effective dose, for the shortest duration necessary to control symptoms. Further information on the cardiovascular safety of NSAIDs can be found on the MHRA website (link below).