El Cóndor Pasa: Reflections on the Condor Trial
2011; Elsevier BV; Volume: 140; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2011.01.011
ISSN1528-0012
Autores Tópico(s)Asthma and respiratory diseases
ResumoChan FK, Lanas A, Scheiman J, et al. (Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China). Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376:173–179. There are not many middle-aged men or women who do not recognize, whistle along with, and reminisce with El cóndor pasa (the condor flies by), possibly the best-known Peruvian song worldwide because of a cover version by Simon and Garfunkel in 1970 on their Bridge Over Troubled Water album. This cover version called El cóndor pasa (If I Could) came to my mind while reading the CONDOR randomized trial of celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis by Francis Chan and others, published in the Lancet (Lancet 2010;376:173–179). Why was such a trial conducted and why is it important? We all know that nonsteroidal anti-inflammatory drug (NSAID) use is associated not only with gastroduodenal ulcerations and complications (J Rheumatol Suppl 1999;56:18–24), but also with injury to the small bowel and colon, leading to overt bleeding, ulceration, occult blood loss, or development of anemia (Curr Pharm Res 2003;9:2253–2266). It is estimated that the rate of “lower” bleeding events is about one-third of that of “upper” gastrointestinal bleeding, but its importance has been relatively neglected (Gastroenterology 2003;124:288–292). We also know that cyclooxygenase-2 (COX-2)–selective NSAIDs are associated with fewer mucosal lesions of the small bowel than are nonselective NSAIDs plus a proton pump inhibitor (PPI; Clin Gastroenterol Hepatol 2005;3:133–141) and that COX-2–selective NSAIDs and nonselective NSAIDs plus a PPI have similar upper gastrointestinal outcomes because of the PPI effect on gastric pH (Clin Gastroenterol Hepatol 2009;7:725–735). The eminent investigators of this industry-sponsored trial hypothesized that the risk of adverse clinical outcomes across “the entire” gastrointestinal tract might be lower with the sponsor's selective COX-2 anti-arthritic drug celecoxib in terms of non–acid-dependent damage than a representative, widely used and generally as effective but non-selective drug, diclofenac. Therefore, they aimed to compare the risk of gastrointestinal events associated with celecoxib versus slow-release diclofenac plus the widely used PPI omeprazole. This was a 6-month, double-blind, triple dummy, randomized trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk that took place at 196 centers in 32 countries. All patients tested negative for Helicobacter pylori and were aged ≥60 years (adjusted relative risk for upper gastrointestinal bleeding, 3.1–5.6) or ≥18 years with previous gastroduodenal ulceration (adjusted relative risk for upper gastrointestinal bleeding, 6.1–13.5; Lancet 1994;343:769–772). Using a computer-generated randomization schedule, they assigned patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or slow-release diclofenac 75 mg twice a day plus omeprazole 20 mg once a day. Both patients and investigators were masked to treatment allocation and the analysis was by intention to treat. Patients were excluded if they had concomitant use of antiplatelet or anticoagulant drugs; ischemic heart disease; heart failure; peripheral arterial disease; cerebrovascular disease; gastrointestinal hemorrhage; active gastroduodenal ulceration; inflammatory bowel disease; gastric surgery besides a patch repair; erosive esophagitis; gastric-outlet obstruction; active malignant disease; alcohol or substance misuse; allergy to diclofenac, celecoxib, omeprazole, or sulphonamides; serum alanine aminotransferase and aspartate aminotransferase levels >1.5 times; serum creatinine >1.2 times the upper limit of normal; or a hemoglobin 10%. During the independent adjudication, if the source of bleeding was identified, the event was adjudicated as clinically significant anemia of “defined” gastrointestinal origin. Without a source found, and if no clinical or laboratory evidence of a nongastrointestinal source of anemia was identified, the event was adjudicated as clinically significant anemia of “presumed” occult gastrointestinal origin, including “possible” small bowel blood loss. As a brief synopsis, 4484 patients were randomly allocated to treatment (2238 celecoxib; 2246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. Of these, 20 (0.9%) patients receiving celecoxib and 81 (3.8%) receiving diclofenac plus omeprazole met criteria for the primary end point (hazard ratio, 4.3; 95% confidence interval [CI], 2.6–7.0 in favor of celecoxib; P < .0001). Using a Cox proportional hazard model, the proportion of patients reaching the primary end point during the 6-month study period was 0.9% (95% CI, 0.5–1.3) in the celecoxib group and 3.8% (95% CI, 2.9–4.3) in the diclofenac plus omeprazole group (difference, 2.9%; 95% CI, 2.0%–3.8%; P < .0001). Importantly, the main driving force behind the primary end point was a hemoglobin decrease of ≥20 g/L. Hidden in a table is the fact that there were 20 diclofenac plus omeprazole users versus 5 celecoxib ones who developed clinically significant anemia owing to gastroduodenal ulcer or erosions that goes against the hypothesis that acid-dependent gastroduodenal events may be prevented by PPI. In terms of adverse events and withdrawals, abdominal symptoms were slightly less frequent with celecoxib (16%) than with diclofenac plus omeprazole (19%), whereas the risk of serious adverse events was similar in both groups (3%). One hundred fourteen (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (P = .0006). The authors highlight their study's limitations: Its short follow-up (6 months); the exclusion of patients taking aspirin; its applicability only to arthritis patients at high risk for gastroduodenal complications; the lack of direct confirmation of the source of blood loss; the lack of power (by design) to assess differences in cardiovascular outcomes, and the fact that, unfortunately, it is only relevant to patients requiring anti-inflammatory therapy who are at increased GI and not CV risk and they are not receiving aspirin or other antiplatelet agents or anticoagulants. CONDOR's message is that the risk of clinical outcomes throughout the entire gastrointestinal tract—practically addressed using clinically significant upper or lower gastrointestinal events—was lower in patients treated with a COX-2–selective NSAID (celecoxib) than in those receiving a nonselective NSAID (diclofenac) plus a PPI (omeprazole). The authors suggest that these findings should encourage a re-review of approaches to reduce the risks of NSAID treatment in arthritis patients and the restandardization of important clinical end points in future research in the field. The US Food and Drug Administration is planning to do exactly this soon and we will all see if el cóndor pasa or el cóndor no pasa. In the meantime, as a clinician it would be very nice to know every time where the bleeding comes from, using capsule endoscopy and/or double-balloon enteroscopy. And pursuing the exact origin(s) of bleeding and characterizing it better would make me sing along to Simon and Garfunkel: “Yes I would. If I only could, I surely would.”
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