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. 

In This Article

Managing CV Toxicity

The CV toxicity associated with the use of NSAIDs is an important clinical issue which led to the withdrawal from the market of the coxibs, rofecoxib and valdecoxib. However, both observational studies and meta-analyses of data derived from randomized clinical trials showed that also some tNSAIDs, such as diclofenac, were associated with an increased CV risk.[4,63,120]

The most plausible mechanism underlying the CV risk of and NSAIDs (both coxibs and tNSAIDs) has been identified, that is, the profound inhibition of COX-2-dependent PGI2 in the presence of incomplete and intermittent inhibition of platelet COX-1.[4,63] The use of a biomarker strategy of COX inhibition has allowed the understanding that the extent of patient exposure (magnitude and duration) is an important determinant of enhanced risk of nonfatal MI.[4] Since a linear relationship exists between the degree of inhibition of COX-2 and the degree of inhibition of PGI2in vivo,[4] reduction of the dose should translate into a reduction of the CV risk.

Importantly, it has been shown that it is necessary to block COX-2 by 80% in whole blood to translate into an analgesic effect in vivo.[163] However, we have found that NSAIDs are administered to patients at doses which are not bioequivalent. In particular, tNSAIDs with short half-lifes (such as diclofenac) are usually administered at supratherapeutic doses (almost completely suppressing whole blood COX-2 activity). This may represent an important determinant which explains the differences in CV toxicity among NSAIDs.[4] In fact, whole blood COX-2 inhibition by NSAIDs (tNSAIDs and coxibs) higher than that necessary for a therapeutic effect (i.e., >80%) seems associated with a CV risk.[4] Thus, a rational selection of the dose based on the use of a biomarker predictive of efficacy, such as whole blood COX-2, might be useful to reduce the CV risk of NSAIDs. The use of this biochemical marker together with genetic biomarkers (still to be identified) might allow the selection of patients uniquely susceptible to developing CV risk through inhibition of COX-2-dependent-PGI2 when exposed to NSAIDs.

On the basis of evidences derived from the results of clinical studies, it is possible to suggest strategies for analgesic/anti-inflammatory treatment and CV prevention among patients with inflammatory disease and different levels of risk of vascular events (Table 1).[164] Patients with low CV risk (<1% per year) can be administered with a tNSAID or a coxib and the choice between the two classes of NSAIDs will be dependent on the GI risk of patients. In particular, the choice of NSAID for chronic and disabling inflammatory joint diseases like RA and OA is governed not only by GI risk but also by age, diagnosis, degree of severity, tolerability and relative efficacy in the given clinical situation. However, in these patients, coxibs are not recommended for routine use. They should be used in preference to tNSAIDs only in patients who may be at 'high risk' of developing serious GI adverse effects. In conditions where inflammation of joints is minimal, as it occurs in OA patients, analgesics such as paracetamol should be preferred. In patients with and intermediate risk (1–3% per year), the choice will be to administer a tNSAID, such as low-dose ibuprofen or naproxen (+PPI) which have been shown to be associated with reduced incidence of vascular events.[4] If aspirin is indicated, ibuprofen should be avoided due to the demonstration of the capacity of ibuprofen to interfere with the antiplatelet effect of aspirin.[165,166] By contrast, we have recently shown that the sequential administration of aspirin 2 h before naproxen should minimize the interference of the tNSAID with aspirin effect on platelet COX-1.[167] In patients at high risk of a vascular event (>3%) with a low-dose aspirin indication, the choice is naproxen + PPI and aspirin, given 2 h before, or acetaminophen and aspirin.[4,168]


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