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Non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat pain, fever, and inflammation. Historically, NSAIDs have been categorized as traditional NSAIDs and newer cyclooxygenase (COX)-2 inhibitors (coxibs). However, traditional NSAIDs also inhibit the COX-1 and COX-2 enzyme isoforms to a varying degree. This diversity of COX-1 and COX-2 selectivity within the class of traditional NSAIDs has proven clinically important, with evidence accumulating on the cardiovascular risks associated with selective COX-2 inhibition. Thus, the relative COX-2 selectivity of traditional NSAIDs correlates with their cardiovascular risk profile, being more favourable for non-selective NSAIDs, such as naproxen and low-dose ibuprofen, and less favourable for more COX-2 selective agents, such as diclofenac. To enhance clinically relevant terminology, we advocate categorizing all non-aspirin NSAIDs—including traditional NSAIDs—according to their relative COX-1 and COX-2 selectivity as either COX-1 inhibitors, non-selective NSAIDs, or COX-2 inhibitors. We further recommend subcategorizing COX-2 inhibitors as newer COX-2 inhibitors (coxibs) or older COX-2 inhibitors. Finally, we recommend examining the effects of the individual NSAIDs included in each of the proposed categories. Adhering to these recommendations will align future studies, advance interpretation of COX-specific adverse cardiovascular effects, and provide better guidance to clinicians prescribing NSAIDs.
Résumé
Les anti-inflammatoires non stéroïdiens (AINS) différents de l'aspirine sont fréquemment utilisés pour traiter la douleur, la fièvre et l'inflammation. Les AINS étaient d'habitude classés en deux catégories : les AINS classiques et les nouveaux inhibiteurs de la cyclooxygénase (COX)-2. Or, les AINS classiques inhibent aussi, à divers degrés, les isoformes enzymatiques COX-1 et COX-2. Cette sélectivité variable envers la COX-1 et la COX-2 au sein de la classe des AINS classiques s'est avérée pertinente sur le plan clinique, puisque de plus en plus de données font état des risques cardiovasculaires associés à l'inhibition sélective de la COX-2. Par conséquent, la sélectivité relative des AINS classiques pour la COX-2 est corrélée avec leur profil de risque cardiovasculaire, qui est plus favorable dans le cas des AINS non sélectifs tels que le naproxène et l'ibuprofène à faible dose, et moins favorable avec les agents plus sélectifs de la COX-2 tels que le diclofénac. Afin que la terminologie reflète mieux des aspects pertinents sur le plan clinique, nous préconisons de classer tous les AINS différents de l'aspirine, y compris les AINS classiques, selon leur sélectivité relative à l’égard de la COX-1 et de la COX-2, en trois catégories : inhibiteurs de la COX-1, AINS non sélectifs, et inhibiteurs de la COX-2. Nous recommandons également des sous-catégories d'inhibiteurs de la COX-2 : nouveaux inhibiteurs de la COX-2 (coxibs) et anciens inhibiteurs de COX-2. Enfin, nous recommandons d’évaluer les effets de chaque AINS inclus dans chaque catégorie proposée. Le respect de ces recommandations permettra d'harmoniser les futures études, de mieux interpréter les effets indésirables cardiovasculaires propres aux inhibiteurs de la COX et de mieux orienter les décisions des cliniciens en matière de prescription d'AINS.
Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin and non-aspirin NSAIDs.
Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999-2012.
NSAIDs function by inhibiting the cyclooxygenase (COX) enzymes catalyzing the conversion of arachidonic acid into thromboxane A2 and different prostaglandins with diverse biological effects.
The 2 major COX enzyme isoforms are COX-1, which is continuously expressed in most tissues, and COX-2, which is upregulated in response to inflammatory processes.
Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.
The analgesic and antipyretic effects of NSAIDs derive mainly from inhibition of COX-2 and the resulting decrease in proinflammatory prostaglandins E2 and I2 (prostacyclin),
The increased risk of gastrointestinal complications associated with COX-1 inhibition promoted the development of newer COX-2 inhibitors (also known as coxibs) in the late 1990s.
These agents were anticipated to provide comparative analgesic, antipyretic, and anti-inflammatory effects as the existing (traditional) NSAIDs but with fewer gastrointestinal side effects.
which was biologically explained by an altered equilibrium between the prothrombotic thromboxane A2 and the antithrombotic prostacyclin in favour of platelet aggregation,
Consequently, studies have typically applied the same categorization without distinguishing between the COX-1 and COX-2 selectivity of individual traditional NSAIDs.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT).
This diversity of COX-1 and COX-2 selectivity within the class of traditional NSAIDs has proved clinically important, with evidence accumulating on the cardiovascular risks associated with selective COX-2 inhibition.
Hence, the relative COX-2 selectivity of traditional NSAIDs also correlates with their cardiovascular risk profile, being more favourable for non-selective NSAIDs, such as naproxen and low-dose ibuprofen (< 1200 mg per day), and less favourable for older COX-2 inhibitors: in particular, diclofenac.
Cardiovascular risk of nonsteroidal anti-inflammatory drugs and classical and selective cyclooxygenase-2 inhibitors: a meta-analysis of observational studies.
Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.
Cardiovascular risk of nonsteroidal anti-inflammatory drugs and classical and selective cyclooxygenase-2 inhibitors: a meta-analysis of observational studies.
to increase the risk of adverse cardiovascular events more than other traditional NSAIDs and similar to several coxibs. To illustrate, the NSAID Trialists Collaboration summarized data from 754 randomized clinical trials and found a similarly increased rate of adverse cardiovascular events associated with diclofenac (1.41-fold) and coxibs (1.37-fold) but no increased rate associated with naproxen.
Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.
Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology.
have acknowledged the link between the COX-2 selectivity of individual NSAIDs and their associated cardiovascular risk. Consequently, both societies recommend using non-selective NSAIDs (naproxen ≤ 500 mg per day or ibuprofen ≤ 1200 mg per day) before COX-2 inhibitors (diclofenac or coxibs) to treat musculoskeletal symptoms in patients with—or at high risk of —adverse cardiovascular events.
Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Figure 1Recommended categorization of non-aspirin nonsteroidal anti-inflammatory drugs. The upper dashed line indicates a 2-fold increase in COX-1 selectivity; the lower dashed line indicates a 2-fold increase in COX-2 selectivity. COX, cyclooxygenase; IC50, half-maximal inhibitory concentration; NSAIDs, non-aspirin nonsteroidal anti-inflammatory drugs. Constructed from previously published data.
To enhance clinically relevant terminology that correlates with thromboembolic risk, we advocate categorizing all non-aspirin NSAIDs—including traditional NSAIDs—according to their relative COX-1 and COX-2 selectivity as either COX-1 inhibitors (flurbiprofen, ketoprofen, fenoprofen, oxaprozin, and tolmetin), non-selective NSAIDs (ibuprofen, naproxen, indomethacin, dexibuprofen, piroxicam, ketorolac, nabumetone, and sulindac), or COX-2 inhibitors. Furthermore, we recommend subcategorizing COX-2 inhibitors as newer COX-2 inhibitors (coxibs) (celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib, and parecoxib) or older COX-2 inhibitors (diclofenac, etodolac, meloxicam, salsalate, mefenamic acid, and nimesulide). Figure 1 depicts the recommended categorization. The proposed cutoff to separate non-selective NSAIDs from COX-2 inhibitors is based on a 2-fold increase in relative COX-2 selectivity: that is, a 50% lower half maximal inhibitory concentration of the COX-2 enzyme isoform compared with the COX-1 enzyme isoform. Likewise, the proposed cutoff to separate non-selective NSAIDs from COX-1 inhibitors is based on a 2-fold increase in relative COX-1 selectivity. Finally, we recommend examining the effects of the individual NSAIDs included in each of the proposed categories.
Adhering to these recommendations will align future studies, advance the interpretation of COX-specific adverse cardiovascular effects, and provide better guidance to clinicians prescribing NSAIDs. Moreover, it will prevent repeating design flaws of previous randomized clinical trials that combined non-selective NSAIDs (ibuprofen and naproxen) and older COX-2 inhibitors (diclofenac) in the same comparison group
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT).
Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison.
Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999-2012.
Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT).
Cardiovascular risk of nonsteroidal anti-inflammatory drugs and classical and selective cyclooxygenase-2 inhibitors: a meta-analysis of observational studies.
Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison.
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