NSAIDs and cardiovascular risk—Reply

We do not agree with Kotob and associates and their interpretation of the clinical trials of COX-2 inhibitors. In our view, none of the published studies provide useful information regarding potential effects of low-dose aspirin on cardiovascular risk. In the APPROVe trial (Bresalier et al., 2005xCardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. Bresalier, R.S., Sandler, R.S., Quan, H., Bolognese, J.A., Oxenius, B., Horgan, K., Lines, C., Riddell, R., Morton, D., Lanas, A. et al. N. Engl. J. Med. 2005; 352: 1092–1102Crossref | PubMed | Scopus (1851)See all ReferencesBresalier et al., 2005), aspirin use was not prespecified; interpretation of outcomes in patients taking aspirin is therefore severely confounded by perceived risk.As noted, in the retrospective analysis of patients taking celecoxib with aspirin in the CLASS trial, there was no GI benefit (Silverstein et al., 2000xGastrointestinal 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. Silverstein, F.E., Faich, G., Goldstein, J.L., Simon, L.S., Pincus, T., Whelton, A., Makuch, R., Eisen, G., Agrawal, N.M., Stenson, W.F. et al. JAMA. 2000; 284: 1247–1255Crossref | PubMedSee all ReferencesSilverstein et al., 2000). However, over the full 12 month duration of CLASS, there was no significant GI protection with celecoxib for the entire study population, irrespective of aspirin use. In TARGET (Schnitzer et al., 2004xComparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomized controlled trial. Schnitzer, T.J., Burmester, G.R., Mysler, E., Hochberg, M.C., Doherty, M., Ehrsam, E., Gitton, X., Krammer, G., Mellein, B., Matchaba, P. et al. Lancet. 2004; 364: 665–674Abstract | Full Text | Full Text PDF | PubMed | Scopus (540)See all ReferencesSchnitzer et al., 2004), the only COX-2 inhibitor trial in which aspirin use was prespecified, the GI benefit was attenuated but perhaps not abolished with coincident aspirin. Furthermore, the relative risk of cardiovascular events between lumaricoxib and naproxen was substantially narrowed in aspirin users (Farkouh et al., 2004xComparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Farkouh, M.E., Kirshner, H., Harrington, R.A., Ruland, S., Verheugt, F.W., Schnitzer, T.J., Burmester, G.R., Mysler, E., Hochberg, M.C., Doherty, M. et al. Lancet. 2004; 364: 675–684Abstract | Full Text | Full Text PDF | PubMed | Scopus (434)See all ReferencesFarkouh et al., 2004). While this finding is potentially consistent with protection, none of the published trials including TARGET have sufficient power to truly assess the impact of aspirin on cardiovascular risk in COX-2 users (Topol and Falk, 2004xA coxib a day won't keep the doctor away. Topol, E.J. and Falk, G.W. Lancet. 2004; 364: 639–640Abstract | Full Text | Full Text PDF | PubMed | Scopus (88)See all ReferencesTopol and Falk, 2004).Thus, in the absence of any relevant evidence from the randomized controlled clinical trials, we stand by our conclusions (Francois et al., 2005xProstacyclin protects against elevated blood pressure and cardiac fibrosis. Francois, H., Athirakul, K., Howell, D., Dash, R., Mao, L., Kim, H.S., Rockman, H.A., Fitzgerald, G.A., Koller, B.H., and Coffman, T.M. Cell Metab. 2005; 2: 201–207Abstract | Full Text | Full Text PDF | PubMed | Scopus (101)See all ReferencesFrancois et al., 2005), with the caveat that the applicability of our studies in mice to human complications of COX-2 inhibition remains to be established.