Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

Paola Patrignani; Stefania Tacconelli; Annalisa Bruno; Carlos Sostres; Angel Lanas

Expert Rev Clin Pharmacol. 2011;4(5):605-621.

Expert Commentary

The beneficial therapeutic use of NSAIDs as anti-inflammatory and analgesic agents is associated with increased risk of GI and CV serious adverse events.^[2–5] The integration of previously segregated fields of basic and clinical scientific research predicted and explained the efficacy and hazards from NSAIDs. Both beneficial and adverse effects are associated to the same mechanism of action – that is, the inhibition of COX activity.^[1] The main clinically relevant GI side effects include GI bleeding, perforation and obstruction, while the major CV side effect is an increased risk of nonfatal MI.^[2–5] The therapeutic effects of NSAIDs and coxibs are due to the inhibiton of COX-2 in inflammatory sites and spinal cord.^[7,14] By contrast, the GI toxicity of tNSAIDs is dependent on the inhibition of COX-1 both in the GI mucosa and in platelets.^[7,14,15] Interestingly, it has been shown that drugs which suppress profoundly both COX-isozymes are those at higher GI risk^[3] and this finding supports the results obtained in animal models showing that also COX-2-dependent PGE2 may play a protective role by facilitating ulcer healing.^[30–32] Recent studies of pharmacoepidemiology have shown that the administration of tNSAIDs and coxibs is associated with an increased risk of nonfatal MI.^[4] Importantly, this study has shown that one determinant of the risk is the extent of inhibition of COX-2 and as a consequence the degree of reduction of vascular PGI₂.^[4] Both the CV and GI risks are related to drug exposure thus supporting the recommendation that these drugs should be administered at lowest effective dose and for a short period of chronic administration.

The individual risk factors, both CV and GI, of patients have to be taken into consideration for the choice of NSAIDs. Patients with GI risk factors who require NSAIDs should receive the safest NSAIDs, such as coxibs, diclofenac, aceclofenac and ibuprofen, at the lowest possible dose for the shorter period of time. Moreover, the use of co-therapy with gastroprotectants is recommended. The co-therapy of NSAIDs with anticoagulants, antiplatelet agents or corticosteroids should be avoided.

Patients with low CV risk can be given a tNSAID or a coxib and, in particular, coxibs should be used in preference to tNSAIDs only in patients who may be at 'high risk' of developing serious GI adverse effects, in association with a PPI. In patients at high risk of CV events, coxibs should be avoided and if aspirin is indicated for CV prevention, the choice of the tNSAID should aim to minimize the possible interference of these drugs with the antiplatelet effect of aspirin.^[165–167] Thus, ibuprofen should be avoided and naproxen should be given 2 h after low-dose aspirin (studies have been performed only with immediate-release aspirin).

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Table 1. Suggested strategies for analgesic/anti-inflammatory treatment and cardiovascular prevention among patients with inflammatory disease and different levels of risk of vascular events.
Risk of vascular event^†	Pharmacological strategies
Low (<1% per year)	tNSAID or coxib depending on GI risk
Intermediate (1–3% per year)	tNSAID (low-dose ibuprofen or naproxen + PPI); if aspirin is indicated, naproxen + PPI and aspirin, given 2 h before^‡
High (>3% per year)	Naproxen + PPI and aspirin, given 2 h before^‡

^†Vascular event is defined as the combined outcome of a nonfatal myocardial infarction, nonfatal stroke or vascular death [168].
^‡Recent findings suggest that the possible interference of naproxen on the antiplatelet effect of aspirin can be minimized by the administration of aspirin 2 h before naproxen [167]. By contrast, ibuprofen should be avoided if aspirin is indicated [165,166].
GI: Gastrointestinal; PPI: Proton pump inhibitor; tNSAID: Traditional NSAID.

Box 1. Prevention strategies in patients with gastrointestinal risk factors who need NSAIDs.
General rules Use the lowest effective dose for the shortest period of time Avoid concomitant therapy with corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents Use 'safer' NSAIDs (coxibs, diclofenac, aceclofenac and ibuprofen) Less use of NSAIDs with the highest gastrointestinal toxicity (ketorolac, piroxicam, and ketoprofen) Eradicate Helicobacter pyloriinfection in patients with prior ulcer history Use of prevention strategies No CV risk factors No gastrointestinal risk factors: use tNSAIDs (no need for prevention strategies) One or more gastrointestinal risk factors: coxib (standard dose) alone or nonselective NSAID + PPI or misoprostol If history of ulcer bleeding: coxib + PPI. Eradicate H. pyloriinfection. Avoid nonselective NSAIDs Previous CV events or risk for CV events >10% in 10 years (treatment with low-dose aspirin) One or more gastrointestinal risk factors: nonselective NSAID (naproxen) + PPI or coxib + PPI In Europe, if previous CV event exists, the European Medicine Agency contraindicates use of coxibs Avoid combining with ibuprofen since it may interfere with low-dose aspirin If history of ulcer bleeding: avoid tNSAIDs or coxib. Eradicate H. pyloriinfection If strictly necessary, celecoxib low dose + PPI. If previous CV event in Europe, coxib contraindicated
CV: Cardiovascular; PPI: Proton pump inhibitor; tNSAID: Traditional NSAID.

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Key Issues

Conventional medical treatment for rheumatoid arthritis and osteoarthritis requires the use of NSAIDs because they provide unmistakable and significant health benefits in the treatment of pain and inflammation.
NSAIDs share both beneficial and adverse effects due to the same mechanism of action, i.e. the inhibition of cyclooxygenase (COX) activity. Their beneficial therapeutic use as antiinflammatory and analgesic agents is associated with increased risk of gastrointestinal (GI) and cardiovascular (CV) serious adverse events (i.e., upper GI bleeding and nonfatal myocardial infarction [MI]).
The risk of nonfatal MI was increased by 35% with current use of NSAIDs, but there was no increase in the risk of fatal MI. The excess risk increased with increasing treatment duration and daily dose.
The increased incidence of thrombotic events associated with profound inhibition of COX-2-dependent prostacyclin (PGI2) can be mitigated, even if not obliterated, by a complete suppression of platelet COX-1 activity.
Degree of inhibition of COX-2 for NSAIDs functionally selective for COX-2 is relevant to CV hazard and relates to drug potency (exposure). It has been proposed that the assessment of whole blood COX-2 ex vivomay represent a valid surrogate end point to predict CV risk for functionally selective COX-2 inhibitors.
NSAIDs injure the GI tract by causing topical injury to the mucosa and by systemic effects associated with mucosal prostanoid depletion derived from COX inhibition. The main clinically relevant GI side effects include GI bleeding, perforation and obstruction.
Management of patients with GI risk factors who require NSAIDs includes the use of the lowest possible dose for the shorter period of time, the use of the safest NSAIDs, the use of co-therapy with with gastroprotectants and the avoidance of co-therapy of NSAIDs with anticoagulants, antiplatelet agents or corticosteroids. Reduced incidence of GI ulcers complications compared with traditional NSAIDs (tNSAIDs) has been demonstrated for COX-2 inhibitors. COX-2 plays an important role in the healing of pre-existing ulcers. This is supported by clinical data showing that coxibs are still associated with a small risk of upper GI bleeding, though smaller than that caused by tNSAIDs.
Despite upper GI bleeding risk being multifactorial, drugs with a long half-life or slow-release formulation and/or associated with profound and coincident inhibition of both COX isozymes – which translates into deficiency of prostanoid generation in the GI tract – were associated with a greater risk of upper GI complications.
The development of biomarkers predictive of the impact of NSAIDs on COX-1 and COX-2 activities in vitro, ex vivoand in vivohas been essential to read out the clinical consequences of selective and nonselective inhibition of COX isozymes in humans. Reduction of the dose is recommended and presumably will limit, but not delete, CV or GI risk by NSAIDs and coxibs.
The use of pharmacogenomic tools to define the role of genetic factors in individual responses to drugs, in association with pharmacoepidemiological methods, represents a very promising approach to predict CV and GI risks for coxibs and tNSAIDs and to create personalized drugs with better efficacy and safety.

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Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

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