What is the story here?
The most recent MeReC extra from the NPC reminds health professionals that certain NSAIDs, including diclofenac and the coxibs, are associated with a small increased risk of causing cardiovascular (CV) disease, in addition to their well-known gastro-intestinal (GI) risks.
What does the MeReC Extra say?
Coxibs as a class are associated with a small excess risk of thrombotic events compared with no treatment (about 3 per 1000 users treated for one year). They are contraindicated in patients with established ischaemic heart disease, cerebrovascular disease or peripheral arterial disease. For patients with risk factors for cardiovascular events, individual risk assessment is appropriate.
Some ‘traditional’ NSAIDs may also be associated with an increased risk of thrombotic events. The Commission on Human Medicines (CHM) have previously stated that diclofenac 150mg/day appears to be associated with a similar excess risk to that of coxibs: about 3 CV events per 1000 users per year.
Why is this an issue?
Prescribing data shows that only one third of NSAID prescriptions in England are for ibuprofen or naproxen. 46% of NSAID prescribing is diclofenac. Compared to no NSAID use, approximately 2500 additional or premature CV events per year could be caused by current patterns of NSAID prescribing. This may be an overestimate of risk as many patients who take short-term NSAIDs may be suffering from acute musculo-skeletal conditions rather than chronic arthritis, and might not have the same baseline risk of CV events as those patients seen in clinical trials. On the other hand, some patients will have a greater baseline risk than those included in the RCTs since patients recruited to RCTs are generally younger and have fewer co-morbidities. In addition, the absolute risk for diclofenac at doses less than150mg/day remains uncertain.
It is important to note that the risk to an individual person taking diclofenac (or a coxib) is low – it is only because NSAIDs are taken by so many people that the population effect occurs.
Does the increase in CV risk apply to all NSAIDs?
Low-dose ibuprofen (≤1200mg/day) and naproxen 1000mg/day appear to be associated with a lower CV risk than other NSAIDs.
What about NSAIDs and GI risk?
Coxibs, as a class, are associated with a lower GI risk than traditional NSAIDs. However, their GI-safety advantage is diminished when they are co-administered with aspirin. Of the traditional NSAIDs, low-dose ibuprofen is associated with a lower GI risk than diclofenac or naproxen. But use of a proton pump inhibitor (PPI) with any NSAID significantly reduces the risk of GI side effects. The benefits from gastroprotection largely depend on the individual patient’s baseline risk of GI complications – age and co-morbidities are important considerations. And there is, as yet, no good evidence that adding a PPI to a coxib is more beneficial, equivalent or a worse option than adding a PPI to a traditional NSAID.
So what should patients and prescribers do?
NSAIDs are effective medicines whose benefits outweigh the risks in the majority of people. There is no need to rush to change anyone’s medicine. A considered review of individual patient’s risk factors (in particular gastrointestinal and cardiovascular) including the patient’s personal preferences and acceptance of those risks is required.
The evidence is complex with different study designs, different interventions and controls, different doses, and sometimes conflicting results. Moreover, it has been published piecemeal over many years. And to make any sense of it readers need to be able to appreciate the fact that the risk to individuals of GI or CV serious side effects from NSAIDs can be very small to an individual, yet at a population level the same data suggests a reappraisal of current approaches would be prudent.
We suggest the first thing to do is to read the MeReC Extra carefully.
The ideal anti-inflammatory prescribing choice will vary from patient to patient, depending on individual risk factors, therapeutic response and patient preference. Patients should generally use the lowest effective dose, and the shortest duration of therapy necessary to control symptoms.
After discussion, some patients may decide to continue treatment with their current NSAID. However in some cases (especially patients with risk factors for cardiovascular disease) it may be appropriate to consider alternatives:
Patients who change from diclofenac 150mg daily to 1200mg ibuprofen daily would probably reduce both their gastrointestinal and cardiovascular risk, especially if the opportunity is taken to introduce a proton pump inhibitor (a medicine to protect the stomach against ulcers). However, 1200mg ibuprofen may not provide sufficient anti-inflammatory effect for some patients (especially those with severe inflammatory arthritis). Higher doses of ibuprofen (e.g. 2400mg daily) are not frequently used in clinical practice, and the relative risks versus diclofenac are unclear.
Patients who change from diclofenac 150mg daily to 1000mg naproxen daily would reduce their cardiovascular risk, but may slightly increase their risk of gastrointestinal complications. However, if the opportunity is taken to introduce a proton pump inhibitor, if appropriate, the gastrointestinal risks may also be reduced. Just to repeat, there is less evidence for the balance of risks with lower doses of diclofenac and naproxen.
There is a wealth of resources on the newly-published musculoskeletal pain section of NPC, including a patient decision aid which may help patients and practitioners decide on the best way forward.