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Gabexate mesilate in acute pancreatitis: miracle or mirage?
Commentary
” Sort P, Navasa M, Arroyo V. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis in cirrhosis. N Engl J Med 1999;341:403-9. ” Sort P Cardenas A, Navasa M. Circulatory dysfunction induced by spontaneous bacterial peritonitis: mechanism and prevention. 103-108 In: Treatment of liver diseases. Arroyo V, Bosch J, Bruguera M, Rod& J, Sanchez-Tapias JM, editors. Barcelona: Masson; 1999. p. 109-16. 26 Goulis J, Patch D, Burroughs AK. Bacterial infection in the
Gabexate E.L. Bradley
See relatedarticle
mesilate
in acute pancreatitis:
miracle
or miraae?
III
on pages
49-57
1
Despite prodigious efforts by the investigative community, the ultimate pathogenesis of acute pancreatitis remains elusive. Until such time as the primary initiating events can be recognized and specifically targeted, therapeutic intervention in pancreatitis must necessarily remain empiric. Moreover, given the existing state of our knowledge, the principal investigative approach is one of post-hoc analysis; i.e., the therapeutic efficacy of a specific approach is either supported or denied from observable results attributed to that intervention. However, such post-hoc analysis remains particularly vulnerable to unrecognized or uncontrolled variables. The theory of acute pancreatitis as an autodigestive phenomenon, arising from overwhelming activation of intrinsic pancreatic enzymes, is a case in point. Although innumerable observations of inappropriate enzyme activation exist in patients with acute pancreatitis, it has not been possible to determine whether enzyme activation is cause or effect. Furthermore, until recently, it has not been possible to study the potential therapeutic effects of blocking these enzymes. The current study by Drs. Pezzilli, Miglioli, and the Italian Acute Pancreatitis Study Group (GISPAC) (Digest Liver Dis 2001;33:49-57) ’ is an excellent example of how far clinical proteinase inhibitor research has come. In a five-year, randomized, parallel, unblinded study of 388 patients with documented acute pancreatitis collected from 42 centres in Italy, they demonstrate quite conclusively that the study antiproteinase agent, gabexate mesilate, given intravenously for seven days in a dosage of 900 mglday “is as effective as 1500 mg/day in preventing complications within 30
I!J .L
pathogenesis of variceal bleeding. Lancet 1999;353: 139-42. 27 Salmeron JM, Navasa M, Rod& J. General management of patients with spontaneous bacterial peritonitis. In: Conn HO, Rod& J, Navasa M, editors. Spontaneous bacterial peritonitis: The disease, pathogenesis and treatment. New York: Marcel Dekker, Inc; 2000. p. 205-l 8. z Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, Inadomi JM. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis. A consensus document. International Ascites Club. J Hepatol 2000;32: 142-53.
days”. Since the authors set out to determine an optimum dosage regimen for gabexate mesilate, their goal has been achieved. Criticisms of this commendable report are few, but perhaps important. As in any clinical study of acute pancreatitis, it is difficult for well-intentioned investigators to control treatment variables, such as the use and effects of endoscopic retrograde cholangiopancreatography (ERCP), antibiotics, whether nutritional supplemention was used and whether it was enteral or parenteral, ICU protocols specific to certain institutions, etc. Uncontrolled variables are magnified with increasing numbers of participating investigators and institutions, and 42 centres seems excessive. Furthermore, while the stated evaluation criteria of 30-day morbidity/mortality rates and adverse drug effects are objective criteria, the “need for surgery” is quite subjective, and can vary widely among surgeons. Although these criticisms are relatively minor, and do not detract significantly from this exemplary study, more important considerations surround the criteria for inclusion into the study population of “severe acute pancreatitis”. The Glasgow Severity Score was employed in this study, and the bar for declaration of severity was set at 3 or more criteria. Unfortunately, the Glasgow Scale, like the Ranson criteria, overweights age as a severity criterion. In the current study, over 70% of patients were older than 55 years, and, therefore, received more than one-third of their severity rating from one criterion alone. If this is a valid criticism, then the overall severity of acute pancreatitis in this patient population should be low. Evidence for this contention does exist, as the overall mortality in this series was only 1.8%, considerably less than the average 10% mortality cus-
--_ss-.
Commentary
tomarily seen in mixed populations of acute pancreatitis at other centres around the world. Although the authors might like to attribute this inordinately low mortality to the effects of gabexate mesilate, it is at least equally likely that the reduced mortality was due to patient selection secondary to age-overweighting. Further supporting this contention of a population of mild acute pancreatitis is the observation that the incidence of significant complications (renal failure, pulmonary insufficiency, liver failure, or infections) was only 18.5%, also considerably less than that required for the definition of a “severe” population by the Atlanta Criteria. If this study population was, indeed, composed of patients with mild acute pancreatitis, then it is possible that the principal conclusion from this study that there was no difference observed between the study dosages might not be applicable to more severe populations. Perhaps the most important consideration regarding acceptance of antiproteinase therapy is not the optimum dosage of gabexate mesilate as addressed by the GISPAC study, but rather whether or not antiproteinase therapy offers any reliably demonstrable therapeutic advantage to patients with acute pancreatitis. Since the GISPAC study only compared the efficacy of two treatment arms (dosage 1 versus dosage 2), and did not include untreated controls, the current study cannot address this critical question. I would submit that it is possible that the failure to find a significant difference in morbidity or mortality between the dosage regimens in the GISPAC study could be interpreted with equal logical rectitude that NEITHER dosage of gabexate mesilate was effective!
In my opinion, a careful review of the previous literature does not permit unreserved acceptance of gabexate mesilate as standard of care therapy for acute pancreatitis. Even though two recent metanalyses have suggested slight advantages for gabexate mesilate administration to patients with acute pancreatitis with regard to the incidence of complications, this issue is perhaps best characterized as far from settled. Metanalyses, although useful as guidelines, are never substitutes for properly controlled clinical studies. Before we can accept gabexate mesilate as necessary in the treatment of acute pancreatitis, appropriately designed placebo-controlled clinical studies will be required. Although some may view this opinion as far too conservative, the rationale has been formed in the crucible of experience, most notably by the initial promise and subsequent failure of many putative therapies for acute pancreatitis (somatostatin and lexlpafant come quickly to mind). That being said, if there is no place for unbridled enthusiasm, most certainly there is no role for undue pessimism. Careful scientific evaluation is always in order. Address for correspondence: Prof. E.L. Bradley 111, 1600 Baywood Way, Sarosota, Fax: +I-941-360-9287, E-mail: [email protected]
FL 34231,
USA.
References I R. Pezzilli, M. Miglioli, and the Italian Acute Pancreatitis Study Group (GISPAC). Multicentre comparative study of two schedules of gabexate mesilate in the treatment of acute pancreatitis. Digest Liver Dis 2001;33:49-57.
13
” Sort P, Navasa M, Arroyo V. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis in cirrhosis. N Engl J Med 1999;341:403-9. ” Sort P Cardenas A, Navasa M. Circulatory dysfunction induced by spontaneous bacterial peritonitis: mechanism and prevention. 103-108 In: Treatment of liver diseases. Arroyo V, Bosch J, Bruguera M, Rod& J, Sanchez-Tapias JM, editors. Barcelona: Masson; 1999. p. 109-16. 26 Goulis J, Patch D, Burroughs AK. Bacterial infection in the
Gabexate E.L. Bradley
See relatedarticle
mesilate
in acute pancreatitis:
miracle
or miraae?
III
on pages
49-57
1
Despite prodigious efforts by the investigative community, the ultimate pathogenesis of acute pancreatitis remains elusive. Until such time as the primary initiating events can be recognized and specifically targeted, therapeutic intervention in pancreatitis must necessarily remain empiric. Moreover, given the existing state of our knowledge, the principal investigative approach is one of post-hoc analysis; i.e., the therapeutic efficacy of a specific approach is either supported or denied from observable results attributed to that intervention. However, such post-hoc analysis remains particularly vulnerable to unrecognized or uncontrolled variables. The theory of acute pancreatitis as an autodigestive phenomenon, arising from overwhelming activation of intrinsic pancreatic enzymes, is a case in point. Although innumerable observations of inappropriate enzyme activation exist in patients with acute pancreatitis, it has not been possible to determine whether enzyme activation is cause or effect. Furthermore, until recently, it has not been possible to study the potential therapeutic effects of blocking these enzymes. The current study by Drs. Pezzilli, Miglioli, and the Italian Acute Pancreatitis Study Group (GISPAC) (Digest Liver Dis 2001;33:49-57) ’ is an excellent example of how far clinical proteinase inhibitor research has come. In a five-year, randomized, parallel, unblinded study of 388 patients with documented acute pancreatitis collected from 42 centres in Italy, they demonstrate quite conclusively that the study antiproteinase agent, gabexate mesilate, given intravenously for seven days in a dosage of 900 mglday “is as effective as 1500 mg/day in preventing complications within 30
I!J .L
pathogenesis of variceal bleeding. Lancet 1999;353: 139-42. 27 Salmeron JM, Navasa M, Rod& J. General management of patients with spontaneous bacterial peritonitis. In: Conn HO, Rod& J, Navasa M, editors. Spontaneous bacterial peritonitis: The disease, pathogenesis and treatment. New York: Marcel Dekker, Inc; 2000. p. 205-l 8. z Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, Inadomi JM. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis. A consensus document. International Ascites Club. J Hepatol 2000;32: 142-53.
days”. Since the authors set out to determine an optimum dosage regimen for gabexate mesilate, their goal has been achieved. Criticisms of this commendable report are few, but perhaps important. As in any clinical study of acute pancreatitis, it is difficult for well-intentioned investigators to control treatment variables, such as the use and effects of endoscopic retrograde cholangiopancreatography (ERCP), antibiotics, whether nutritional supplemention was used and whether it was enteral or parenteral, ICU protocols specific to certain institutions, etc. Uncontrolled variables are magnified with increasing numbers of participating investigators and institutions, and 42 centres seems excessive. Furthermore, while the stated evaluation criteria of 30-day morbidity/mortality rates and adverse drug effects are objective criteria, the “need for surgery” is quite subjective, and can vary widely among surgeons. Although these criticisms are relatively minor, and do not detract significantly from this exemplary study, more important considerations surround the criteria for inclusion into the study population of “severe acute pancreatitis”. The Glasgow Severity Score was employed in this study, and the bar for declaration of severity was set at 3 or more criteria. Unfortunately, the Glasgow Scale, like the Ranson criteria, overweights age as a severity criterion. In the current study, over 70% of patients were older than 55 years, and, therefore, received more than one-third of their severity rating from one criterion alone. If this is a valid criticism, then the overall severity of acute pancreatitis in this patient population should be low. Evidence for this contention does exist, as the overall mortality in this series was only 1.8%, considerably less than the average 10% mortality cus-
--_ss-.
Commentary
tomarily seen in mixed populations of acute pancreatitis at other centres around the world. Although the authors might like to attribute this inordinately low mortality to the effects of gabexate mesilate, it is at least equally likely that the reduced mortality was due to patient selection secondary to age-overweighting. Further supporting this contention of a population of mild acute pancreatitis is the observation that the incidence of significant complications (renal failure, pulmonary insufficiency, liver failure, or infections) was only 18.5%, also considerably less than that required for the definition of a “severe” population by the Atlanta Criteria. If this study population was, indeed, composed of patients with mild acute pancreatitis, then it is possible that the principal conclusion from this study that there was no difference observed between the study dosages might not be applicable to more severe populations. Perhaps the most important consideration regarding acceptance of antiproteinase therapy is not the optimum dosage of gabexate mesilate as addressed by the GISPAC study, but rather whether or not antiproteinase therapy offers any reliably demonstrable therapeutic advantage to patients with acute pancreatitis. Since the GISPAC study only compared the efficacy of two treatment arms (dosage 1 versus dosage 2), and did not include untreated controls, the current study cannot address this critical question. I would submit that it is possible that the failure to find a significant difference in morbidity or mortality between the dosage regimens in the GISPAC study could be interpreted with equal logical rectitude that NEITHER dosage of gabexate mesilate was effective!
In my opinion, a careful review of the previous literature does not permit unreserved acceptance of gabexate mesilate as standard of care therapy for acute pancreatitis. Even though two recent metanalyses have suggested slight advantages for gabexate mesilate administration to patients with acute pancreatitis with regard to the incidence of complications, this issue is perhaps best characterized as far from settled. Metanalyses, although useful as guidelines, are never substitutes for properly controlled clinical studies. Before we can accept gabexate mesilate as necessary in the treatment of acute pancreatitis, appropriately designed placebo-controlled clinical studies will be required. Although some may view this opinion as far too conservative, the rationale has been formed in the crucible of experience, most notably by the initial promise and subsequent failure of many putative therapies for acute pancreatitis (somatostatin and lexlpafant come quickly to mind). That being said, if there is no place for unbridled enthusiasm, most certainly there is no role for undue pessimism. Careful scientific evaluation is always in order. Address for correspondence: Prof. E.L. Bradley 111, 1600 Baywood Way, Sarosota, Fax: +I-941-360-9287, E-mail: [email protected]
FL 34231,
USA.
References I R. Pezzilli, M. Miglioli, and the Italian Acute Pancreatitis Study Group (GISPAC). Multicentre comparative study of two schedules of gabexate mesilate in the treatment of acute pancreatitis. Digest Liver Dis 2001;33:49-57.
13