While no analgesic therapy is risk-free, adverse cardiovascular and gastrointestinal events associated with nonsteroidal anti-inflammatory drugs (NSAIDs), including the newer generation selective-COX-2 inhibitor (coxib) NSAIDs, need to be fully appreciated for the sake of patient safety. A newly reported, and largest of its kind, meta-analysis of randomized, controlled trials (RCTs) provides further confirmation that these analgesic agents pose noteworthy risks of heart problems, stomach disorders, and death — all of which call for their more cautious use in patients with chronic pain conditions.
In the new study, Colin Baigent, MD, of the University of Oxford, and colleagues in the Coxib and traditional NSAID Trialists’ (CNT) Collaboration incorporated 280 trials of NSAIDs versus placebo (124,513 participants) and 474 trials comparing one NSAID versus another NSAID (229,296 participants) [CNT Collaboration 2013]. The coxibs examined included celecoxib, rofecoxib, etoricoxib, and lumiracoxib, while the traditional NSAIDs studied were primarily diclofenac, ibuprofen, and naproxen.
In trials providing individual participant baseline data, mean age was 61 years, roughly two-thirds were female, and 79% were white. About a fifth of patients were concurrently using low-dose aspirin prophylaxis, 17% also were taking a proton-pump inhibitor, and 13% were current smokers. Overall, the indication for NSAID therapy was rheumatoid arthritis or osteoarthritis in approximately four-fifths of participants, and most trials of traditional NSAIDs involved high-dose daily regimens — diclofenac 150 mg/d, ibuprofen 2400 mg/d, naproxen 1000 mg/d.
The main outcomes of concern in the meta-analysis were major vascular events — including nonfatal MI, nonfatal stroke, or vascular death — as well as major coronary events (nonfatal myocardial infarction or coronary death), stroke, heart failure, and upper gastrointestinal complications (perforation, obstruction, or bleed). Key findings of the study, published online ahead of print in The Lancet, included the following:
- Coxib therapy significantly increased occurences of major vascular events by about one-third (Rate Ratio [RR]=1.37, p=0.001), as did diclofenac (RR=1.41, p=0.004). These effects were chiefly due to increases in major coronary events (coxibs RR=1.76, p<0.001; diclofenac RR=1.70, p=0.003).
- Ibuprofen also significantly increased major coronary events (RR=2.22, p=0.025), but not major vascular events (p nonsignificant).
- Naproxen did not significantly increase major vascular or coronary events (p nonsignificant).
- Vascular-related deaths were increased significantly by coxibs (RR=1.58, p=0.010) and diclofenac (RR=1.65, p=0.019), but not by ibuprofen (p nonsignificant) or by naproxen (p nonsignificant).
- The Rate Ratios for heart failure requiring hospitalization were roughly doubled by all NSAIDs, and all NSAID regimens significantly increased upper GI complications: coxibs RR=1.81, p=0.007; diclofenac RR=1.89, p=0.011; ibuprofen RR=3.97, p<0.001; and naproxen RR=4.22, p<0.001.
- There was no evidence of increased stroke risk with any of the NSAIDs studied, but few strokes were recorded in the data and this may not be a reliable assessment.
The researchers conclude that significant vascular risks associated with high-dose diclofenac, and possibly ibuprofen in some cases, are comparable to coxibs; whereas, high-dose naproxen therapy is associated with less vascular risk than other NSAIDs. In addition, all NSAIDs appeared to double the risk of heart failure and to produce a 2- to 4-fold increased risk of serious upper gastrointestinal complications such as bleeding ulcers.
This study, funded by the UK Medical Research Council and British Heart Foundation, represents a massive research effort and results are consistent with those of other meta-analyses of RCTs as well as observational trials examining the safety of traditional NSAIDs and coxibs. This also has been a topic of numerous Pain-Topics UPDATES [see article series here].
It is important to note that a focus of this meta-analysis by the CNT Collaboration was on high-dose prescribing of diclofenac, ibuprofen, and naproxen, which leaves uncertainty about the risks associated with lower doses of these agents available in over-the-counter formulations. And, while there was clear evidence that all NSAIDs increase risks of gastrointestinal adverse effects early in therapy, more definitive conclusions about adverse cardiovascular events during short-term therapy at any dose need further elaboration.
Several other points are worth mentioning. First, data on coxibs included rofecoxib and lumiracoxib, which were discontinued due to cardiovascular-risk concerns, and this may have skewed outcomes for this class of agents. Second, as in most other studies, aspirin was not included among NSAIDs studied and, while this agent is not a prescription product, it is widely used by patients for pain and prophylaxis. Third, although naproxen consistently exhibits a low risk of cardiovascular events, it is unknown whether this would hold true in patients taking lower-dose naproxen or in those taking concomitant low-dose prophylactic aspirin (the two agents may interact to cancel each other’s cardio-protective effects).
In balance, it should be noted that, while the events of concern in the CNT Collaboration study were statistically significant and clinically serious, the incidence rates and absolute excess risks were of small size. For example, compared with placebo, therapy with a coxib or high-dose diclofenac for 1 year was associated with about 3 additional major vascular events per 1000 person-years (0.3% incidence rate), with 1 such event causing death (0.1% incidence rate).
Writing in an associated commentary article, Marie Griffin from Vanderbilt University Medical Center, Nashville, TN, observes from study data that, for 1,000 persons at a predicted moderate risk of gastrointestinal complications, 1 year of high-dose NSAID therapy may result in 4 to 16 added GI adverse events [Griffin 2013]. Patients at moderate risk of both GI and vascular complications could have up to a 19% chance of experiencing one or both of those events during 10 years of therapy, she adds. Therefore, in large populations of patients at risk, relatively small annual adverse-effect incidence rates can add up to significantly large occurrences of morbidity and/or mortality over time.
Griffin concludes, “Identification of safe and effective strategies for chronic pain is sorely needed. 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.” Still, NSAIDs at high doses are generally contraindicated in patients at high risk of heart failure or with chronic kidney disease, and lower-dose NSAID therapy may be inadequate for many patients with chronic pain conditions. Alternative approaches must be considered.
> CNT (Coxib and traditional NSAID Trialists’) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. The Lancet. 2013(May 30); online ahead of print [abstract here].
> Griffin MR. High-dose non-steroidal anti-inflammatories: painful choices. The Lancet. 2013(May 30); online ahead of print [abstract here].
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