Safety of Short-Term Administration of Celecoxib in Decompensated Cirrhosis *
Authors: Joan Clària, Vicente Arroyo
Journal: Hepatology (2005)

We thank Drs. Campbell and Makar for their interest in our paper.1 We also thank them for their comments recognizing the tightly controlled conditions of our study and the relevance of our conclusions indicating that naproxen, but not celecoxib, administered during a short period of time adversely affects renal function and the renal response to furosemide in patients with cirrhosis and ascites and increased activity of the renin-angiotensin system. We agree with these authors that our investigation did not offer information about the safety of celecoxib administered for therapeutic purposes in patients with decompensated cirrhosis and that further studies using selective cyclooxygenase-2 inhibitors for a longer period of time and providing data at the patient level are required to warrant the safety of these drugs in clinical practice. The exclusion from analysis of 7 patients found to have hepatorenal syndrome (HRS) at baseline, despite a normal serum creatinine value (<1.5 mg/dL), reflects the difficulties in performing renal physiological studies in patients with decompensated cirrhosis. HRS is defined as a glomerular filtration rate (GFR) lower than 40 mL/min,2 and we found a GFR below this level in all 7 patients as measured by the technetium 99m-diethylenetriaminepentaacetic acid clearance, which is a sensitive technique for assessing GFR. Three major reasons justified the exclusion of these patients. First, HRS is considered to be secondary to an imbalance between an increased activity of endogenous vasoconstrictors systems (renin-angiotensin and sympathetic nervous systems) and a deficient renal synthesis of prostaglandins (PGs).3 Contrary to what occurs in patients without renal failure, in whom GFR and renal plasma flow are critically dependent on renal synthesis of PGs, patients with HRS have extremely low urinary excretion of PGs.3 Therefore, testing the renal effects of anti-inflammatory drugs in patients who already have a renal impairment in PG excretion is not a good approach. Second, since the diagnosis of HRS based on GFR was not done at randomization (it was based on serum creatinine concentration), keeping the patients with GFR lower than 40 mL/min within the study might have introduced bias in the homogeneity of the groups. Finally, PG inhibition by short-term administration of anti-inflammatory drugs produces between a 20% and 30% decrease in GFR.3 If baseline values of GFR are very low, as occurs in HRS, the clearance technique is not sensitive enough to detect small changes in GFR. In our study, no patient treated with celecoxib developed a significant (greater than 20%) decrease in GFR. We have no explanation for the differences between our results and those of Guevara et al.4 Although they administered celecoxib for a longer period of time (1.5 days more) than us, we do not think this accounts for the observed differences. However, the study of Guevara et al.4 was a pilot study, whereas ours was a randomized, double-blind, placebo, naproxen investigation. Joan Clària*, Vicente Arroyo*, * Liver Unit-Institut de Malalties Digestives, Hospital Clínic, Barcelona, Spain