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Stress ulcer prophylaxis in an evidence-based analysis of therapy
2566
World Literature Review
Stress Ulcer Prophylaxis in an Evidence-Based Analysis of Therapy American Society of Health-System Pharmacists ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis Am J Health-Syst Pharm 1999;56:347–79
ABSTRACT The American Society of Health-System Pharmacists (ASHP) therapeutic guidelines on stress ulcer prophylaxis are the first society-based published guidelines. These guidelines were promulgated following a rigorous and formal examination of the published medical literature. This evidence-based medicine approach is crucial for the development of comprehensive scientifically based clinical care. A multidisciplinary team including pharmacy specialists in critical care and drug information, consulting physicians and nurses, and an independent panel of clinical specialists appointed by ASHP prepared and reviewed the guidelines. The guidelines can aid health care professionals in identifying appropriate patients for stress ulcer prophylaxis and selecting cost-effective therapeutic options. The scope of the article includes application of guidelines for patients of all ages following a stressful event, such as trauma or surgery, which would predispose them to stress-induced bleeding. Therapeutic agents evaluated include only those available in the United States, regardless of United States Food and Drug Administration-approved labeling. The article is divided into sections with pertinent issues related to stress ulcer prophylaxis in adults and pediatrics, when plausible. The evidence-based medical guidelines were developed following a comprehensive literature review of each presented issue. Summary data from randomized controlled trials and meta-analyses are presented to validate and strengthen the authors’ line of reasoning. A summary and recommendation paragraph follows each major section. The first section evaluates the issues of frequency of bleeding, efficacy of prophylaxis, and risk factors for bleeding in general. The second major area of review includes these same topics as they relate to special populations. Other topics evaluated include the efficacy of prophylactic agents on bleeding prevention and mortality. A separate part evaluates the frequency of nosocomial pneumonia associated with stress ulcer prophylaxis. Therapeutic monitoring, other options for prophylaxis, prevention of recurrent bleeding, discontinuation of prophylaxis, and economic analysis complete the article. (Am J Gastroenterol 1999;94:2566 –2567. © 1999 by Am. Coll. of Gastroenterology)
COMMENT Publication of the ASHP therapeutic guidelines represents the first society-developed and endorsed evidence-based medicine guidelines for stress ulcer prophylaxis. Stress-
AJG – Vol. 94, No. 9, 1999
induced gastrointestinal mucosal lesions are a recognized cause of morbidity and mortality in critically ill patients. The incidence of gastrointestinal bleeding from stress ulcers in an intensive care unit (ICU) setting ranges from 5% to 25% and is dependent upon criteria and outcomes defined (i.e., overt vs occult or clinically important bleeding). The risk of clinically significant bleeding may be limited to certain patient populations (i.e., multiple trauma, thermal injury), and prophylactic therapy may be reserved for these high-risk groups. The associated mortality may be as high as 50%. Complex pathophysiological mechanisms including alterations of gastric acid and pepsin, inadequate mucosal defenses, or mucosal ischemia are believed to be the underlying causes of stress-induced gastrointestinal lesions. Pharmacological prophylaxis has been shown to ameliorate the underlying pathophysiology and decrease the incidence of stress-induced gastrointestinal lesions. The use and addition of multiple drug therapies in an ICU setting predisposes a patient to drug– drug interactions and drug-induced adverse events. Important issues to consider when evaluating the guidelines in this article and examining the issue of stress ulcer prophylaxis include: 1) the disparate results recorded in available medical literature regarding reported and actual frequency of bleeding; 2) efficacy rates of prophylaxis as evaluated by individual randomized controlled clinical trials or by meta-analyses; 3) the effect on morbidity and mortality among therapeutic modalities or no therapy; 4) evaluation and choice of appropriate candidates for therapy based on risk factors; 5) study methodology and definition of clinical endpoints; and 6) consideration of institution-specific data to determine bleeding rates for a particular patient population. This article is strengthened by an evidence-based medicine, decision-making approach. Recommendations in the article are categorized by strength and level of evidence. For example, randomized controlled trials hold more strength than expert opinion. Also, in the evaluation of available literature and guideline development, the authors: 1) employed an acceptable definition for clinically important bleeding as gastroduodenal bleeding associated with clinically important complications; 2) considered the importance of published literature rates versus institution-specific bleeding frequency rates; and 3) considered the importance of patient risk factors in choosing appropriate patients for prophylaxis. An exhaustive evaluation of each criterion is beyond the scope of this column. The review encompasses general ICU patients and special populations including head, spinal, and thermal injury, and those undergoing renal or hepatic transplantation separately. In the evaluation of available literature with respect to the frequency of bleeding and efficacy of prophylaxis, the authors appropriately emphasize the disparate results demonstrated among studies. For example, frequency of bleeding
AJG – September, 1999
varied significantly by year ranging from 33% before 1978 to 6% between 1984 and 1994. Controversy surrounding this issue has led some experts to believe that the temporal decrease in the frequency results from the appropriate and effective use of prophylactic drug therapy. Others believe that improvements in patient care and available technology are responsible for the decline. The authors cite the necessity for evaluating institution-specific data if available or using these guidelines as a proxy. Individual trials evaluated examining the efficacy of prophylaxis versus no prophylaxis demonstrate conflicting results. In an effort to overcome the limitations of individual studies, several meta-analyses are reviewed. Four metaanalysis studies are evaluated citing differences in ICU population studied, agents evaluated, methodology, evaluative criteria, and investigation and definition bleeding. An evaluation of primary risk factors is presented from metaanalysis and a recent large sample retrospective study. Study type, patient population, and sample size should be considered when reviewing the need for stress ulcer prophylaxis. A review of medications, their pharmacological effects, and efficacy is presented. The available literature suggests that, in general, there are no significant differences among the agents used in the prophylaxis of clinically important bleeding. However, using this evidence-based medicine approach, the authors identify problems and weaknesses with recent meta-analysis of this topic including limited sample size, ability to detect statistical differences, and reported differences in bleeding frequencies in randomized controlled trials available for review. As previously mentioned, health care professionals must take into consideration the definition for overt or clinically important bleeding and the population being studied. A review of the adverse effect profiles expected with the use of prophylactic therapy, including antacids, histamine
World Literature Review
2567
type 2 (H2) receptor antagonists, sucralfate, and proton pump inhibitors is presented. A comprehensive review of nosocomial pneumonia associated with stress ulcer prophylaxis is also provided. Risk factors are identified and ranked according to available evidence. Enhanced diagnostic techniques, pneumonia rates, and methodological differences in studies are considered. The importance of a pharmacoeconomic analysis for developing and implementing institution-specific guidelines is outlined. Two cost-effectiveness studies are reviewed. A template for evaluating the cost-effectiveness of stress ulcer prophylaxis regimens is presented. Finally, a useful algorithm for stress ulcer prophylaxis in an adult population is presented. The routine use of H2 receptor antagonists, sucralfate, or antacids has become a standard practice in many ICU settings in an effort to prevent stress ulcers and associated gastrointestinal bleeding. The risk of developing stressrelated mucosal injury with clinically significant gastrointestinal bleeding may be confined to a specific high-risk population. The frequency of occurrence varies among studies and by institution. Stress ulcer prophylactic agents have been shown to decrease the incidence of bleeding, associated morbidity and mortality, and are advocated in high-risk patients. The ASHP stress ulcer prophylaxis guidelines present an excellent evidence-based medicine review of available literature for both adult and pediatric populations. These guidelines should be used as a model for adaptation by an institution especially when institution-specific data are lacking. Paul F. Souney, R.Ph, M.S. Adjunct Professor of Clinical Pharmacy Massachusetts College of Pharmacy and AHS Boston, Massachusetts
World Literature Review
Stress Ulcer Prophylaxis in an Evidence-Based Analysis of Therapy American Society of Health-System Pharmacists ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis Am J Health-Syst Pharm 1999;56:347–79
ABSTRACT The American Society of Health-System Pharmacists (ASHP) therapeutic guidelines on stress ulcer prophylaxis are the first society-based published guidelines. These guidelines were promulgated following a rigorous and formal examination of the published medical literature. This evidence-based medicine approach is crucial for the development of comprehensive scientifically based clinical care. A multidisciplinary team including pharmacy specialists in critical care and drug information, consulting physicians and nurses, and an independent panel of clinical specialists appointed by ASHP prepared and reviewed the guidelines. The guidelines can aid health care professionals in identifying appropriate patients for stress ulcer prophylaxis and selecting cost-effective therapeutic options. The scope of the article includes application of guidelines for patients of all ages following a stressful event, such as trauma or surgery, which would predispose them to stress-induced bleeding. Therapeutic agents evaluated include only those available in the United States, regardless of United States Food and Drug Administration-approved labeling. The article is divided into sections with pertinent issues related to stress ulcer prophylaxis in adults and pediatrics, when plausible. The evidence-based medical guidelines were developed following a comprehensive literature review of each presented issue. Summary data from randomized controlled trials and meta-analyses are presented to validate and strengthen the authors’ line of reasoning. A summary and recommendation paragraph follows each major section. The first section evaluates the issues of frequency of bleeding, efficacy of prophylaxis, and risk factors for bleeding in general. The second major area of review includes these same topics as they relate to special populations. Other topics evaluated include the efficacy of prophylactic agents on bleeding prevention and mortality. A separate part evaluates the frequency of nosocomial pneumonia associated with stress ulcer prophylaxis. Therapeutic monitoring, other options for prophylaxis, prevention of recurrent bleeding, discontinuation of prophylaxis, and economic analysis complete the article. (Am J Gastroenterol 1999;94:2566 –2567. © 1999 by Am. Coll. of Gastroenterology)
COMMENT Publication of the ASHP therapeutic guidelines represents the first society-developed and endorsed evidence-based medicine guidelines for stress ulcer prophylaxis. Stress-
AJG – Vol. 94, No. 9, 1999
induced gastrointestinal mucosal lesions are a recognized cause of morbidity and mortality in critically ill patients. The incidence of gastrointestinal bleeding from stress ulcers in an intensive care unit (ICU) setting ranges from 5% to 25% and is dependent upon criteria and outcomes defined (i.e., overt vs occult or clinically important bleeding). The risk of clinically significant bleeding may be limited to certain patient populations (i.e., multiple trauma, thermal injury), and prophylactic therapy may be reserved for these high-risk groups. The associated mortality may be as high as 50%. Complex pathophysiological mechanisms including alterations of gastric acid and pepsin, inadequate mucosal defenses, or mucosal ischemia are believed to be the underlying causes of stress-induced gastrointestinal lesions. Pharmacological prophylaxis has been shown to ameliorate the underlying pathophysiology and decrease the incidence of stress-induced gastrointestinal lesions. The use and addition of multiple drug therapies in an ICU setting predisposes a patient to drug– drug interactions and drug-induced adverse events. Important issues to consider when evaluating the guidelines in this article and examining the issue of stress ulcer prophylaxis include: 1) the disparate results recorded in available medical literature regarding reported and actual frequency of bleeding; 2) efficacy rates of prophylaxis as evaluated by individual randomized controlled clinical trials or by meta-analyses; 3) the effect on morbidity and mortality among therapeutic modalities or no therapy; 4) evaluation and choice of appropriate candidates for therapy based on risk factors; 5) study methodology and definition of clinical endpoints; and 6) consideration of institution-specific data to determine bleeding rates for a particular patient population. This article is strengthened by an evidence-based medicine, decision-making approach. Recommendations in the article are categorized by strength and level of evidence. For example, randomized controlled trials hold more strength than expert opinion. Also, in the evaluation of available literature and guideline development, the authors: 1) employed an acceptable definition for clinically important bleeding as gastroduodenal bleeding associated with clinically important complications; 2) considered the importance of published literature rates versus institution-specific bleeding frequency rates; and 3) considered the importance of patient risk factors in choosing appropriate patients for prophylaxis. An exhaustive evaluation of each criterion is beyond the scope of this column. The review encompasses general ICU patients and special populations including head, spinal, and thermal injury, and those undergoing renal or hepatic transplantation separately. In the evaluation of available literature with respect to the frequency of bleeding and efficacy of prophylaxis, the authors appropriately emphasize the disparate results demonstrated among studies. For example, frequency of bleeding
AJG – September, 1999
varied significantly by year ranging from 33% before 1978 to 6% between 1984 and 1994. Controversy surrounding this issue has led some experts to believe that the temporal decrease in the frequency results from the appropriate and effective use of prophylactic drug therapy. Others believe that improvements in patient care and available technology are responsible for the decline. The authors cite the necessity for evaluating institution-specific data if available or using these guidelines as a proxy. Individual trials evaluated examining the efficacy of prophylaxis versus no prophylaxis demonstrate conflicting results. In an effort to overcome the limitations of individual studies, several meta-analyses are reviewed. Four metaanalysis studies are evaluated citing differences in ICU population studied, agents evaluated, methodology, evaluative criteria, and investigation and definition bleeding. An evaluation of primary risk factors is presented from metaanalysis and a recent large sample retrospective study. Study type, patient population, and sample size should be considered when reviewing the need for stress ulcer prophylaxis. A review of medications, their pharmacological effects, and efficacy is presented. The available literature suggests that, in general, there are no significant differences among the agents used in the prophylaxis of clinically important bleeding. However, using this evidence-based medicine approach, the authors identify problems and weaknesses with recent meta-analysis of this topic including limited sample size, ability to detect statistical differences, and reported differences in bleeding frequencies in randomized controlled trials available for review. As previously mentioned, health care professionals must take into consideration the definition for overt or clinically important bleeding and the population being studied. A review of the adverse effect profiles expected with the use of prophylactic therapy, including antacids, histamine
World Literature Review
2567
type 2 (H2) receptor antagonists, sucralfate, and proton pump inhibitors is presented. A comprehensive review of nosocomial pneumonia associated with stress ulcer prophylaxis is also provided. Risk factors are identified and ranked according to available evidence. Enhanced diagnostic techniques, pneumonia rates, and methodological differences in studies are considered. The importance of a pharmacoeconomic analysis for developing and implementing institution-specific guidelines is outlined. Two cost-effectiveness studies are reviewed. A template for evaluating the cost-effectiveness of stress ulcer prophylaxis regimens is presented. Finally, a useful algorithm for stress ulcer prophylaxis in an adult population is presented. The routine use of H2 receptor antagonists, sucralfate, or antacids has become a standard practice in many ICU settings in an effort to prevent stress ulcers and associated gastrointestinal bleeding. The risk of developing stressrelated mucosal injury with clinically significant gastrointestinal bleeding may be confined to a specific high-risk population. The frequency of occurrence varies among studies and by institution. Stress ulcer prophylactic agents have been shown to decrease the incidence of bleeding, associated morbidity and mortality, and are advocated in high-risk patients. The ASHP stress ulcer prophylaxis guidelines present an excellent evidence-based medicine review of available literature for both adult and pediatric populations. These guidelines should be used as a model for adaptation by an institution especially when institution-specific data are lacking. Paul F. Souney, R.Ph, M.S. Adjunct Professor of Clinical Pharmacy Massachusetts College of Pharmacy and AHS Boston, Massachusetts