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

CV Effects of NSAIDs

The importance of prostanoids in maintaining CV homeostasis was primarily highlighted by the evidence that the NSAID, aspirin, at low-doses, reduces the secondary incidence of myocardial infarction and stroke by approximately one quarter.[60] Aspirin is the only NSAID that irreversibly inactivates platelet COX-1 activity through a selective acetylation of a specific serine residue (Ser529) of human COX-1, which translates into an almost complete suppression (>95%) of platelet capacity to produce TXA2 at low doses throughout the 24-h dosing interval.[60] This complete and permanent suppression of platelet COX-1 activity by aspirin is necessary to translate into cardioprotection because even tiny concentrations of TXA2 may cause platelet activation.[61] In contrast to aspirin, tNSAIDs and coxibs are associated with an increased CV risk.[4,62,63] Increased incidence of thrombotic events has been detected in placebo-controlled trials involving the COX-2 inhibitors celecoxib, rofecoxib and valdecoxib.[62–65] Importantly, results from observational studies and meta-analyses of data derived from randomized clinical trials with coxibs have shown that the CV hazard is also related to some tNSAIDs, such as diclofenac.[4,66,67] In a population-based retrospective cohort study with nested case–control analysis using data from The Health Improvement Network database in the UK, it was shown that patients taking NSAIDs, both COX-2 inhibitors and tNSAIDs, have a 35% increased risk of nonfatal myocardial infarction (MI; RR: 1.35; 95% CI: 1.23–1.48).[4] This elevation of risk increased with increasing treatment duration and daily dose. A network meta-analysis including 31 randomized controlled trials (116,429 patients) further supported evidences of the CV risk related to both COX-2 inhibitors and tNSAIDs, showing that:

  • Rofecoxib and lumiracoxib were associated with the highest risk of MI (rate ratio: 2.12 and 2.00; 95% CI: 1.26–3.56 and 0.71–6.21, respectively);

  • Ibuprofen and diclofenac were associated with the highest risk of stroke (rate ratio: 3.36 and 2.86; 95% CI: 1.00–11.6 and 1.09–8.36, respectively);

  • Etoricoxib and diclofenac were associated with the highest risk of death due to CV causes (i.e., MI, fatal arrhythmia, pulmonary embolism and stroke [rate ratio: 4.07 and 3.98; 95% CI: 1.23–15.7 and 1.48–12.7, respectively]).[67]

The highest risk of death owing to CV causes for NSAIDs, such as diclofenac, observed in this meta-analysis, could be explained by the use of supratherapeutic doses of these drugs (>100 mg/day) in some of the analyzed randomized clinical trials.

The most plausible mechanism of the CV hazard associated with NSAIDs (both coxibs and tNSAIDs) is that they cause a profound inhibition of PGI2[4,62,63] which is generated in the vasculature by COX-2.[68] PGI2 is a protective mediator for the CV system and it acts mainly through the activation of its receptor (called IP) expressed in different cell types, such as platelets, and causing the increase in the intracellular levels of cAMP.[69] The increased risk of vascular events caused by the inhibition of COX-2-dependent PGI2 might be mitigated by a concomitant suppression of platelet COX-1 activity and the generation of the pro-aggregatory mediator TXA2. However, most tNSAIDs and coxibs do not affect platelet COX-1 activity at a degree (i.e., >95%) necessary to translate into inhibition of platelet function (Figure 4).[4,70] Naproxen is different among tNSAIDs because it shares a potent COX-1 inhibition and a long half-life,[1,4] thus profoundly and persistently affecting platelet COX-1 at therapeutic doses.[71,72] This has been proposed as one of the mechanisms by which naproxen could have a better CV safety profile than other tNSAIDs.[4] However, naproxen is not cardioprotective, plausibly because it profoundly inhibits PGI2.[71,72]

Figure 4.

Mechanism of cardiovascular toxicity of NSAIDs. The cardiovascular toxicity associated with the administration of NSAID selective for COX-2 and some tNSAIDs occurs through a common mechanism involving the inhibition of COX-2-dependent prostacyclin, an atheroprotective prostanoid. Most tNSAIDs and coxibs are functionally selective for COX-2 – i.e., they cause a profound suppression of COX-2 associated with an inhibition of platelet COX-1 that is insufficient to translate into inhibition of platelet function. This feature might explain the shared cardiovascular toxicity of some tNSAIDs and coxibs.
COX: Cyclooxygenase; PGI2: Prostacyclin; tNSAID: Traditional NSAID; TXA2: Thromboxane A2.


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