Gastrointestinal toxicity and cardiovascular toxicity are the two most important safety concerns for NSAIDs and COX-ll inhibitors. These issues have been extensively reviewed on a Europe-wide basis. Data from MHRA Safety Updates and communications are summarised below. Most data relates to the COX-ll inhibitors, celecoxib and etoricoxib and the traditional NSAIDs, naproxen, ibuprofen and diclofenac.

Cardiovascular risk with NSAIDs and COX-ll inhibitors

Choice of therapy

• COX-ll inhibitors are associated with an increased risk of thrombotic events of approximately three cases per 1,000 users treated for one year. Diclofenac is associated with a similar CV risk to the COX-ll inhibitors. Naproxen and low dose ibuprofen are associated with a lower risk of thrombotic events than diclofenac and COX-ll inhibitors.
• For patients with established cardiovascular disease and those at increased risk of developing cardiovascular disease, low dose ibuprofen or naproxen is a more appropriate choice.
• Patients with significant risk factors for cardiovascular disease (e.g. hypertension, diabetes, smoking, elevated cholesterol levels) should only be treated with COX-ll inhibitors after careful consideration. Note that etoricoxib is contra-indicated in patients with poorly controlled hypertension.
• The greatest concern relates to chronic use of high doses (especially for diclofenac and COX-ll inhibitors).
• Co-prescription with aspirin should be avoided unless absolutely necessary.

Who is at risk?

• A small increase in thrombotic cardiovascular risk (e.g. myocardial infarction or stroke) applies to all users of NSAIDs or COX-ll inhibitors irrespective of their baseline risk, but the absolute increase in risk for healthy users is very low.

Risks associated with individual drugs

• MHRA Drug Safety Update (June 2013) Diclofenac is now contraindicated in patients with established:
• ischaemic heart disease
• peripheral arterial disease
• cerebrovascular disease
• congestive heart failure (New York Heart Association [NYHA] classification II–IV)
  • Patients with these conditions should be switched to an alternative treatment at their next routine appointment
  • Diclofenac treatment should only be initiated after careful consideration for patients with significant risk factors for cardiovascular events (eg, hypertension, hyperlipidaemia, diabetes mellitus, smoking)
• Naproxen has a lower thrombotic risk than COX-ll inhibitors and overall data do not suggest an increased risk of cardiovascular events.
• For ibuprofen, no significant risk has been identified for doses up to 1200mg daily. However, high doses (over 1200mg) may be associated with a small increase in risk.
• COX-ll inhibitors are associated with a small increased risk of thrombotic events compared with most traditional NSAIDs. Diclofenac 150mg daily has a similar thrombotic risk to etoricoxib.
• Less evidence is available for other NSAIDs, but they may be associated with a small increase in absolute risk of thrombotic events.
• Celecoxib and etoricoxib are contra-indicated in ischaemic heart disease, peripheral arterial disease, cerebrovascular disease and congestive heart failure (NYHA class II-IV).
• Etoricoxib is associated with more frequent and severe effects on blood pressure than some other NSAIDs and COX-ll inhibitors. Etoricoxib is contra-indicated in patients whose blood pressure is persistently above 140/90mmHg and has not been adequately controlled. In all patients, blood pressure should be monitored within 2 weeks of starting treatment and regularly thereafter.
• Fluid retention and oedema may occur with any NSAID or COX-ll inhibitor and this may precipitate congestive heart failure in at-risk patients (see also renal adverse effects). NSAIDs are contra-indicated in severe heart failure. COX-ll inhibitors are contra-indicated in NYHA class II-IV heart failure.

Gastrointestinal risk with NSAIDs and COX-ll inhibitors

• The risk of gastrointestinal toxicity with NSAIDs increases with an increase in dose.
• Low dose ibuprofen has the lowest gastrointestinal risk of the formulary NSAIDs. Naproxen and diclofenac are associated with an intermediate risk of gastrointestinal events with naproxen having a slightly higher risk than diclofenac.
• COX-ll inhibitors are associated with a lower gastrointestinal risk relative to most NSAIDs at equivalent doses. However, evidence for a reduction in the most clinically important gastrointestinal risks (e.g. bleeding from ulcer) with etoricoxib is weak.
• It has been estimated that 1 in 70 patients who take a non-selective NSAID for at least 2 months will develop a symptomatic gastric ulcer and 1 in 150 will experience a bleed or perforation (Tramer et al. Pain 2000;85 (1-2):169-182 [PubMed LINK]).

When to prescribe a PPI

• Local advice is to consider co-prescription of a PPI with a NSAID or COX-ll inhibitor based upon assessment of the patient's baseline risk factors for an adverse GI event. Patients at higher risk who should receive a PPI include those:
  • Aged over 65 years
  • Past history of relevant GI pathology
  • Concomitant use of other medications which increase the likelihood of upper GI complications (e.g. steroids, anticoagulants)
  • Serious co-morbidity (cardiovascular disease, renal or hepatic impairment, diabetes, hypertension)
• Gastroprotection with NSAIDs or COX-ll inhibitors
  • Omeprazole capsules 20mg daily

Renal adverse effects of NSAIDs and COX-2 inhibitors

All NSAIDs and COX-ll inhibitors can have effects on the kidney, particularly at high doses, which increase the risk of fluid retention, high blood pressure and (rarely) heart failure in at-risk patients. In people with CKD the chronic use of NSAIDs may be associated with progression of kidney disease; acute use is associated with a reversible decrease in GFR. These drugs may rarely precipitate renal failure; the risk of renal failure is highest in those with existing renal impairment. Contributing factors include current administration of ACE inhibitors, ARBs and diuretics.

NSAIDs and COX-II inhibitors should be used in the lowest effective dose for the shortest possible duration in all patients.

• NSAIDs or COX II inhibitors should be avoided if possible in patients who have renal impairment and/or patients taking ACE inhibitors or ARBs.
• If these drugs are clinically essential in patients with renal impairment or those taking concomittant ACE inhibitors or ARBs, monitor renal function every week until the patient stops the drug or shows stability in renal function, in which case monitoring may become less frequent.
• Annual monitoring is recommended for patients without renal disease who take NSAIDs or COX II inhibitors on a continuous basis.

Patients taking NSAIDs and COX-ll inhibitors who develop diarrhoea and vomiting are at increased risk of becoming dehydrated leading to renal problems. At risk patients may be advised to stop their NSAIDs or COX-ll inhibitors if they become unwell.

Use traditional NSAIDs for pre- and post-op pain control. Intra-operative parecoxib may be used where appropriate, but the patient should receive traditional NSAIDs in the post-operative period. Patients at high risk of GI toxicity should receive prophylactic cover with omeprazole. In those few patients unable to take oral or rectal NSAIDs post-op, parecoxib can be continued if it essential for pain management.