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Aliment Pharmacol Ther 2001; 15: 171±180. Adverse drug reactions in patients with gastroenterological diseases: does age increase the risk? H. DOR MANN*, S. KREBS , U . M UTH-SELBACH , M. CRIEGEE-RIECK , M. RADESPIEL-TROÈ GERà, M. LEVY§, E. G. HAHN *, K. BRUN E & H. T. SCH NEIDER* *Department of Internal Medicine I, University of Erlangen-Nuremberg, Germany; Department of Experimental and Clinical Pharmacology and Toxicology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; àDepartment of Biometry, Epidemiology, and Medical Informatics, University of Erlangen-Nuremberg, Germany and §Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Accepted for publication 6 October 2000 SUMMARY Background: It has been claimed that the risk of adverse drug reactions increases with age. However, only limited data exist for disease-group speci®c risks and none for patients with liver and gastrointestinal diseases. Aims: To determine the incidence and characteristics of adverse drug reactions and the physicians' awareness of adverse drug reactions. Methods: During a 7-month period, a prospective survey of 532 male patients (158 aged 65 years or older; 30%) was conducted on a hepatogastroenterological ward of a tertiary-care university hospital, using intensive bedside and computer-assisted drug surveillance methods. Results: No difference was found in the overall rate of adverse drug reactions between older and younger patients (25.9% vs. 24.2%) during 6213 treatment days. However, a signi®cantly higher risk for developing adverse drug reactions could be shown for the elderly with biliary tract diseases (P < 0.01). Independently of age, patients suffering from gastric ulcers, acute episodes of pancreatitis, cholangitis or in¯ammatory bowel diseases were at high risk of adverse drug reactions. Adverse drug reaction-associated mortality was encountered in four elderly and none of the younger patients. Secondary pharmacological effects and drug toxicity were the main types of adverse drug reactions for both age groups. Although 75.3% of the adverse drug reactions were predictable, only 37.5% of all adverse drug reactions were recognized by the staff physicians. Conclusion: In hepatogastroenterological patients, advancing age was not associated with an overall increased risk of adverse drug reactions except for patients with biliary tract diseases. In the elderly, adverse drug reactions were more severe and carried higher mortality. Guidelines and educational programs should be developed to increase the awareness of adverse drug reactions and their prevention, especially in high risk patients and, thus, to improve patient outcomes. INTRODUCTION Correspondence to: Dr H. Dormann, Medizinische Klinik I mit Poliklinik, Friedrich-Alexander University Erlangen-NuÈrnberg, Krankenhausstr. 12, D-91054 Erlangen, Germany. E-mail: [email protected] Ó 2001 Blackwell Science Ltd As the elderly population increases, more patients have to be treated for conditions such as hypertension, coronary heart disease, diabetes mellitus, liver and kidney failure, arthritis and stroke. When used appropriately, pharmacotherapy may be the single most 171 172 H. DORMANN et al. important intervention in the care of the elderly.1, 2 Nonetheless, because age and morbidity lead to signi®cant changes in organ functions, pharmacokinetics and pharmacodynamics pharmacotherapy may endanger the health of an older patient by causing an adverse drug reaction.3, 4 Additional factors reported to contribute to the risk of adverse reactions in the elderly are polypragmasy, drug±drug interactions, non-compliance and selfmedication.5±8 However, the results of epidemiological studies on the relationship between age and adverse drug reactions are not equivocal.3, 9 An interpretation of the results of these studies is limited by inconsistent de®nitions and a failure to control for important age- and disease-related covariates, including the clinical status of the patient and co-morbidities.5, 10±12 In many observational studies, the rate of adverse drug reactions in the elderly was compared to younger patients without taking into account the underlying diseases and co-existing illnesses.12±15 The surveillance of adverse drug reactions according to disease groups represents a special challenge and may lead to more relevant results.16±21 Epidemiological data on adverse drug reactions in hepatogastroenterological patients is scarce, despite the number of patients admitted to these departments as a result of adverse drug reactions involving the organ systems in question.8, 19 The aim of this study was to analyse the frequency, severity and preventability of adverse drug reactions in patients with liver and gastrointestinal diseases, to characterize the mechanisms of adverse drug reactions, investigate the awareness of physicians to adverse drug reactions and to look for the factors associated with adverse drug reactions in elderly patients. MATERIALS AND METHODS Study design A prospective, 7-month pharmacoepidemiological survey was carried out in the hepatogastroenterological ward of the Erlangen±Nuremberg University Hospital between June 1998 and January 1999. This 29-bed ward admits only male patients with gastrointestinal, pancreatic, liver and infectious diseases. The patients were categorized according to their age (< 65 and ³ 65 years), organ-related diagnosis and gastrointestinal diseases. All patients were prospectively monitored by a pharmacoepidemiological team for the occurrence of adverse drug reactions. These were characterized according to their probability, severity, preventability, predictibility, the awareness of physicians and their outcome. Because some patients had several adverse drug reactions simultaneously or successively, the total number of reactions is greater than the total number of patients having the reaction. For analysis of patient-related factors only the ®rst observed adverse reaction was analysed for each patient during a hospital stay. For an analysis of adverse drug reactions-related factors (e.g. severity, type of adverse drug reactions), all adverse drug reactions were taken into consideration. The study was approved by the institutional Ethics Review Board. Organ related diagnosis and gastrointestinal disease In this study all investigated patients were categorized according to their main diagnosis or their major illness, into the organ-speci®c groups of bowel diseases, diseases of the biliary tract, liver diseases, pancreatic diseases, lung diseases or other diseases. The acute illness which had to be treated ®rst determined the category into which patients were assigned. In the category `other diseases', the patients' main illness was of metabolic, endocrinological or other non-gastrointestinal nature, such as cardiovascular (n 8), neurological (n 3), alcohol intoxication (n 4), deep vein thrombosis (n 2) or malaria tropica (n 1). However, each of these patients suffered at least from one gastrointestinal illness as a secondary disease. For example, patients admitted to the hospital for bleeding of oesophageal varices due to portal hypertension were assigned to the bowel disease group. Each patient could only be assigned to one organ-related diagnosis. Because many patients had other gastrointestinal diseases besides one major illness, all available gastrointestinal diagnosis were included in a second classi®cation in order to identify the occurrence of adverse drug reactions in these disease groups. One patient could be present in more than one gastrointestinal disease group, e.g. a patient with liver cirrhosis and oesophageal varices was categorized to both the cirrhosis and the oesophageal varices group. Procedures for identifying adverse drug reactions Adverse drug reactions were de®ned according to the WHO de®nition: `A response to a drug which is noxious Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 AGE AND ADVERSE DRUG REACTIONS and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modi®cation of physiological function'.22 Three methods were used for identifying adverse drug reactions. 1 Patients were screened on a daily basis for the occurrence of potential adverse drug reactions, by physicians who were part of the pharmacoepidemiological team. 2 Additionally, all charts were reviewed three times a week by the pharmacoepidemiological team, consisting of a physician, a clinical pharmacologist and a pharmacist. 3 Absolute values of laboratory tests which might indicate potential adverse drug reactions were de®ned and used as automatic laboratory signals. A specially developed computer monitoring system generated a daily list of alerts (automatically generated laboratory signals), including patients' data and date of event. The alerts were assessed by the pharmacoepidemiological team, regardless of whether or not they were associated with an adverse drug reaction.16, 23 CLASSIFICATION OF ADVERSE DRUG REACTIONS Probability and severity The evaluation of the probability that a medication caused an adverse drug reaction is usually based on clinical judgement. Because of the lack of objective criteria for establishing causality, this method may generate large inter- and intraraters variability in 173 assessment. To minimize bias, we used the Naranjo algorithm score, shown to have a high coef®cient of reliability (R 0.92) to evaluate the probability of an event being an adverse drug reaction.24 All potential adverse drug reactions detected by the pharmacoepidemiological team were evaluated independently by a physician, a clinical pharmacologist and a pharmacist. When the three reviewers disagreed, they met and reached consensus. Only possible, probable and de®nite adverse drug reactions were taken into consideration. Adverse drug reactions which were classi®ed as doubtful were not taken into consideration. The severity of the adverse drug reaction was assessed using a modi®ed severity algorithm score (Table 1).16 Predictability All adverse drug reactions were classi®ed according to their predictability at the time of detection. The rationale for classifying adverse drug reactions into such groups, which may re¯ect mechanistic homogeneity, is to help improve the clinicians' understanding of the diagnosis or therapy of the problems in question. According to the classi®cation system modi®ed by DeSwarte and Blaiss and deShazo, predictable adverse drug reactions are related to the pharmacological characteristics of administered drugs, e.g. toxicity, interactions, secondary effects, and may theoretically be avoidable.25, 26 In contrast, unpredictable adverse drug reactions are based on idiosyncratic or allergic mechanisms or intolerance. Table 1. Adverse drug reaction severity score Did the adverse drug reaction impair the patient's quality of life? Was the (immediate) discontinuance of the drug necessary or recommended? Was the use of a different drug or other therapy necessary or recommended? Did the adverse drug reaction prolong treatment or lead to hospitalization? Did the adverse drug reaction cause temporary malfunctioning of an organ (system)? Did the adverse drug reaction cause permanent malfunctioning of an organ (system)? Did the adverse drug reaction cause temporary inability to work? Did the adverse drug reaction lead to permanent inability to work? Was the adverse drug reaction potentially dangerous? Was the adverse drug reaction (potentially) life-threatening? Was the adverse drug reaction fatal? Yes No Unknown + + + + + + + + + + + )1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 2 1 2 1 2 3 The severity of the adverse drug reactions is classi®ed according to the total score. A score of 1±4 indicates a mild reaction, a score of 5±8 a moderate reaction and a score of > 8 a severe adverse drug reaction. Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 174 H. DORMANN et al. The adverse drug reactions were further classi®ed by mechanisms as type A or type B reactions. Type A reactions are related to pharmacological characteristics and are often dose-dependent. Adverse drug reactions classi®ed as type B are idiosyncratic or allergic in nature.27, 28 irreversible injury; category 2 necessitated aggressive therapy (e.g. critical care unit); category 3 necessitated another drug or antidote treatment; category 4 restitutio ad integrum occurred after discontinuance of the medication; category 5 had no effect on outcome. Statistics Preventability To assess the preventability of each adverse drug reactions, we adapted the criteria developed by Schumock et al.29 The pharmacoepidemiological team in cooperation with the staff physicians conducted a retrospective review of all patient charts. To minimize bias, a pharmacist, a clinical pharmacologist and the staff physicians independently reviewed each adverse drug reactions to determine preventibility. If their conclusions differed, the staff physician served as arbitrator. Mean values were given with standard deviation. Where appropriate, median values were given with interquartile range. Relative frequencies of unpaired samples were compared using Fisher's exact test. The two-tailed Mann±Whitney U-test was used for a comparison of unpaired samples of rank-scaled data or data where normality could not be assumed. P-values equal to or smaller than 0.05 were considered signi®cant. A correction for multiple comparisons was made using Bonferroni's adjustment. All calculations were carried out using SPSS for Windows Version 9 (SPSS Inc., Chicago, USA). Physicians' awareness of adverse drug reactions The awareness of physicians to veri®ed adverse drug reactions were grouped by the pharmacoepidemiological team into two main categories. If no evidence that the physician has recognized an adverse drug reactions was found in the chart, it was categorized as `not recognized'. If reactions from the physicians, such as chart notes, dose reductions, discontinuation of the drug, additional laboratory studies or other diagnostic measures could be detected and the relation to drug therapy was evident, the adverse drug reactions was categorized as `recognized'. Medical outcome The medical outcomes of the adverse drug reactions were grouped into ®ve categories: category 1 led to RESULTS Incidence, probability and number of adverse drug reactions (Table 2) During the 7-month study period, 532 patients on one hepatogastroenterological ward were kept under intensive and computer-assisted drug surveillance for a total of 6213 treatment days (mean 11.7 11.5 days, min 1, max 81 hospitalized days per patient). Of these patients, 158 (29.7%) were aged 65 years or older. The age distribution is shown in Figure 1. In total, adverse drug reactions were detected in 25.9% of the elderly (78 adverse drug reactions in 41 out of 158 patients ³ 65 years) and in 24.2% of the younger patients (173 adverse drug reactions in 90 out of Age group < 65 ³ 65 Total number of patients Mean age in years s.d. in years No of patients with at least one adverse drug reaction No of adverse drug reactions taken into consideration Possible adverse drug reactions Probable adverse drug reactions De®nite adverse drug reactions Patients with one adverse drug reaction Patients with two or more adverse drug reactions 374 48 11 90 (24%) 173 47 (27.1%) 107 (61.8%) 17 (10.9%) 51 (13.7%) 39 (10.5%) 158 74 6 41 (26)* 78 22 (28.2%) 52 (66.7%) 4 (5.1%) 26 (16.5%)** 15 (9.5%)*** Table 2. Number and probability of ADRs in different age groups *P = 0.66; **P = 0.42; ***P = 0.87. Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 AGE AND ADVERSE DRUG REACTIONS 374 patients < 65 years). Neither the overall rate of patients with adverse drug reactions nor the total number of adverse drug reactions differed signi®cantly between the elderly (mean 1.65 0.96) and the younger patients (mean 2.03 1.55). Drug-induced hospitalizations amounted to 4.3% (n 16) in the younger and to 6.3% (n 10) in men aged 65 years or older. Adverse drug reactions, organ-related diagnosis and gastrointestinal diseases (Tables 3 and 4) The highest rate of adverse drug reactions was found in patients with diseases of the biliary tract (30%) in the 175 elderly and with bowel diseases (29%) in younger patients. The risk for adverse drug reactions in elderly patients with biliary diseases was nearly twice as high as in younger people within the same organ-related diagnosis (P < 0.013). Nearly every third elderly patient with diseases of the biliary tract experienced at least one adverse drug reaction. In this group, antibiotics and diuretics were the major cause of adverse drug reactions. They affected the gut, led to nausea, emesis or diarrhoea, changes in the vitamine K-dependant coagulatory system and often caused electrolyte disturbances and liver disorders. Antibiotics and diuretics also played a major role in the liver disease group and were responsible for disorders similar to those shown in patients with biliary diseases. Younger patients with liver diseases had a nearly threefold higher risk of developing at least one adverse drug reactions than elderly patients (P < 0.06). In patients with bowel or pancreatic diseases, the rates of adverse drug reactions did not differ signi®cantly between the age groups. Analgetics, gastrointestinal therapeutics and diuretics represent the main agents which led to adverse drug reactions in this twoorgan-related diagnosis. When all adverse drug reactions were examined by the organ systems affected, gastrointestinal complications followed by liver disorders, electrolyte disturbances, thrombocytopenia and decrease in prothrombin time were the most frequent. Nearly all the analysed gastrointestinal diseases showed no statistically signi®cant differences between younger and older patients, except for patients with acute pancreatitis (P < 0.03). Independently of age, the highest adverse drug reaction prevalence was found in patients with gastric ulcers (67%), followed by patients with an acute episode of chronic pancreatitis (63%), cholangitis (58%) and in¯ammatory bowel diseases (48%). The prevalence of adverse drug reactions in other investigated gastrointestinal diseases are shown in Table 4. Severity of adverse drug reactions Figure 1. Age distribution of the study population. (A) < 65 years; (B) ³ 65 years. Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 Out of 173 adverse drug reactions in the younger men, 86 (49.7%) were judged to be mild, 72 (41.6%) moderate and seven (4.0%) severe, compared to 34 (43.6%), 34 (43.6%) and seven (8.9%) out of 78 adverse drug reactions in the elderly, respectively. Overall, the severity of adverse drug reactions increased 176 H. DORMANN et al. Table 3. Age, organ-related diagnosis (ORD) and adverse drug reactions (ADR) < 65 years ADR Total no. patients Bowel Biliary tract* Liver** Pancreas Lung Others 206 74 72 93 29 56 Total 530 No. ADRs ³ 65 years No. ADR positive patients (%) of patients No. ADRs positive patients No. ADRs (%) of patients 78 15 31 29 4 16 41 7 12 17 3 10 29 16 21 22 20 27 35 16 8 6 4 9 18 9 1 3 4 6 27 30 6 20 29 46 173 90 78 41 *P < 0.013; **P < 0.06. Two missing. Table 4. Age, gastrointestinal diagnosis (GID) and adverse drug reaction (ADR) positive patients < 65 years ³ 65 years ADR No. ADR positive patients % of patients No. ADR positive patients % of patients P two-tailed Gastric ulcers Acute episode of chronic panceatitis Cholangitis Liver cirrhosis In¯ammatory bowel disease Hepatitis Carcinoma total Ulcera duodeni Chronic pancreatitis Oesophageal varices Biliary duct stenosis Acute pancreatitis 5 11 6 24 12 7 27 5 4 8 9 3 71 61 55 50 48 37 36 33 31 29 28 6 5 1 5 6 2 0 12 3 0 2 6 3 63 100 63 55 50 0 25 43 0 40 33 38 1.0 1.0 1.0 1.0 1.0 0.5 0.2 1.0 0.5 0.6 0.8 0.03 (P < 0.06) with advancing age. In the organ-related diagnosis groups, there were no signi®cant age-related differences in the severity of adverse drug reactions, with the exception of patients with bowel and pancreatic diseases. The mean severity value in the younger patients with this organ-related diagnosis was 4.7 2.0 and 4.7 2.4 in contrast to the elderly, with 5.6 2.3 and 8.0 1.7 (P < 0.05 and P < 0.04), respectively. Adverse drug reactions related to mortality occurred only in patients ³ 65 years (n 4). In two of these four cases, mortality was associated with drug interactions between antibiotics and theophylline and between digitoxin, a calcium channel blocker and loop diuretics. In two additional cases, severe hyperkalemia secondary to acute renal failure during anti-neoplastic and analgesic therapy increased the mortality in the elderly. Mechanisms of adverse drug reactions (Table 5) All adverse drug reactions were classi®ed according to their proposed pathogenetic mechanisms into six categories. For both age groups, the leading mechanisms of adverse drug reactions were secondary pharmacological effects (< 65 years, n 70; ³ 65 years, n 40) followed by toxicity (< 65 years, n 39; ³ 65 years, n 17). Drug allergy was observed in 26 younger and four older patients. The latter was the only statistically signi®cant difference between older and younger patients (P < 0.03). Drug±drug interactions were rare in both age groups. Statistically signi®cant differences between the age groups could be calculated for type A and type B reactions. In the elderly, more type A reactions (91.1%) Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 AGE AND ADVERSE DRUG REACTIONS 177 *P < 0.03. able adverse drug reactions, as were 67 (85.9%) of the adverse drug reactions in the elderly (P < 0.006). Of the adverse drug reactions in younger men, 74 (42.8%) were classi®ed as preventable, 76 (43.9%) as non-preventable and 12 (6.9%) as tolerated because of a positive bene®t to risk ratio. In older patients, 46 (58.9%) were classi®ed as preventable, 24 (30.8%) as non-preventable and four (5.1%) as tolerated. The absolute number of preventable adverse drug reactions was signi®cantly higher in patients older than 65 years of age (P < 0.01). occurred (P < 0.01), whereas in the younger, more type B reactions (22.5%) were observed (P < 0.01). DISCUSSION Table 5. Types of adverse drug reactions (% of total number of adverse drug reactions) See pharmacological effect Toxicity Sub-supratherapeutic drug level Drug allergy* Idiosyncratic Drug±drug interaction not classi®ed < 65 years ³ 65 years 40.5 22.5 5.2 15.0 7.5 2.3 7.0 51.3 21.8 8.8 5.1 3.8 3.8 5.1 Medical outcome of adverse drug reactions In 53 (30.6%) of the younger patients, the adverse drug reactions had to be treated with other drugs and in 31 (17.9%) cases it was necessary to discontinue the medication. In 19 cases (10.9%), the adverse drug reactions required treatment on a critical care unit or led to irreversible injuries. In 21 cases (12.1%), medication was not changed despite the occurrence of an adverse drug reaction. In the elderly experiencing adverse drug reactions, medication discontinuation was the most frequent outcome (n 21; 26.9%) and additional drugs to treat adverse drug reactions were necessary in 18 cases (23.1%). Irreversible injury or transfer to a critical care unit occurred more frequently in the elderly (n 14; 17.9%). In six cases (7.7%), medication was continued despite the association with adverse drug reactions in the elderly. Adverse therapeutic interventions such as treatment on a critical care unit and medication discontinuation together was statistically signi®cantly higher in the elderly (P < 0.01). Awareness of the attending physicians A total of 144 (63.5%) of adverse drug reactions were not noticed at all by the staff physicians. Only 67 (38.7%) in the younger patients and 27 (34.6%) adverse drug reactions in the elderly were recognized as such by the staff physicians (P < 0.32). Predictability and preventability Out of 173 adverse drug reactions in patients younger than 65 years, 122 (70.5%) were judged to be predictÓ 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 Keeping in mind that medications are the most common and most useful therapeutic intervention in the elderly population, and that drugs may cause undesired effects in a varying proportion of patients depending on the underlying diseases, it is desirable to have information on the clinically relevant aspects of increasing age, gastrointestinal diseases and adverse drug reactions.1, 30 Even though normal physiological changes associated with aging may place the elderly at an increased risk of adverse drug reactions in some situations, it may also decrease the risk in other cases.31±33 The present analysis revealed an overall incidence of adverse drug reactions in 25.4% of patients hospitalized in the study unit, comprised of hepato-gastroenterological patients. Among hospitalized patients, incidence rates of adverse drug reactions or adverse drug events range from 2% to 33% in various study populations (Table 6). This range is a result of differences in de®nitions of methodology, clinical settings and detection systems used for identifying potential adverse drug reactions. The relatively high incidence rates in our study population, especially in some organ-related diagnosis/ gastrointestinal diseases, may in part be explained by the underlying gastrointestinal diseases and the use of an intensive drug surveillance method.16, 23 Furthermore, the relatively high incidence rates may have been in¯uenced by gastrointestinal diseases leading to alterations in pharmakokinetics and dynamics, thus making drug therapy far more complex. On the other hand, the liver and the gut may be affected by adverse drug reactions in many cases and may lead to hospitalization in gastroenterological departments more frequently than in other sub-specialities of internal medicine.19 178 H. DORMANN et al. Table 6. ADRs. their predictability, preventability and recognition by the physicians Source Population Gonzalez-Martin14 Medicine Dormann GI-ward A-Livshits23 Harb35 Lindley36 Leach37 Tegeder20 Gray12 Dormann16 Fattinger38 Moore39 Bates40 Smith41 Carbonin5 Foreman15 Classen42 Evans43 Medicine HIV Geriatric Geriatric Medicine Medicine Medicine Medicine Medicine Mixed Medicine Geriatric Geriatric Mixed Mixed Age group/ mean age ³ 65 < 65 ³ 65 < 65 67 * * * 51 ³ 70 50.8 62 55.8 * * 67.1 74.4 54 * Patients ADR/ADE positive patients % 41 90 38 79 77 94 16 23 45 461 31 247 140 532 1 648 1691 33 24 26 24 25 20 19 18 16 15 12 11 9 7 7 6 2 2 2 201 532 153 390 416 521 98 157 379 4331 329 4031 20 695 9148 64 36 653 79 719 ADR/ADE 33 24 78 173 40 118 77 117 18 28 46 461 31 247 1420 532 1 701 Type A in % 91 78 68 83 54à REC 36 40 34 77 28* 95 * Value not known. à Preventable adverse drug reaction/adverse drug event. Population: Mixed = medicine, surgery, intensive care units; Medicine = different medical wards or departments; Geriatric = Geriatric ward; GI-ward = Hepatogastroenterological patients; HIV = Patients with human immunde®ciency virus. ADR: adverse drug reaction; ADE: adverse drug event; Type A or preventable adverse drug reactions; REC: recognized by the physician. Additional studies should be carried out to compare gastroenterological departments with other sub-specialities in internal medicine. As shown in Table 6, the detection rate of adverse drug reactions or adverse drug events drops to levels as low as 2% in large heterogeneous study populations. Such data do not permit a structured analysis of risk factors in the study populations and thus do not give detailed information about the risk pro®le of patients to clinicians. In our study population the highest incidence of adverse drug reactions was observed in patients with gastric ulcers induced by NSAIDs or a combined NSAID±corticosteroid therapy. This was followed by antibiotics and analgesics as the main source for adverse drug reactions in patients with an acute episode of chronic pancreatitis and by antibiotics and diuretic agents as the leading cause of adverse drug reactions in patients with cholangitis. Half of the patients with in¯ammatory bowel diseases suffered from at least one adverse drug reaction. Whereas a link between the organ-related diagnosis or the gastrointestinal diseases and the occurrence of adverse drug reactions can be noted in Tables 3 and 4, no signi®cant age effect on the overall incidence of adverse drug reactions was detected with the exception of elderly patients with a major illness of the biliary tract or suffering from acute pancreatitis. As older patients with hepatic diseases tended to develop fewer adverse drug reactions than younger patients, the role of an age-related decline in hepatic metabolism has to be reconsidered. Drug absorption, volume of distribution, metabolism and elimination and receptor sensitivity have been shown to change with advancing age.3, 4 The question arises to what extent age may present an independent risk factor for adverse drug reactions. To gain more insight, we analysed the mechanisms of adverse drug reactions in elderly patients and compared them to younger patients. Generally, type A reactions were observed more frequently in the elderly, whereas a larger rate of type B reactions was observed in the younger compared to the elderly patients. Interestingly, secondary pharmacological effects and toxicity were the leading types of adverse drug reactions in both age groups, independent of the organ-related diagnosis. The low rate of drug allergies in the elderly may in part be explained by the fact that the elderly were known on the Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 AGE AND ADVERSE DRUG REACTIONS ward in many cases, and drugs which had led to allergies in the past, were avoided in therapy. The ®nding that in the elderly, more dose-dependant adverse drug reactions occurred, and that medication discontinuation was the most frequent outcome, may re¯ect changes in pharmacokinetics with increasing age. The most striking age-related ®nding in this study was the difference in the severity score of adverse drug reactions. This is in line with the ®nding that adverse drug reactions are associated with increased mortality in the elderly. The severity of adverse drug reactions and the more severe outcome in the elderly may be in part be due to the decreased capacity of the older patients to tolerate and recover from an adverse drug reaction, rather than the particular adverse drug reaction itself.3 Another remarkable ®nding is that 62.5% of the adverse drug reactions, including 71% of the severe adverse drug reactions, were not recognized as such by the attending physician. This result was disappointing, but not unexpected (Table 6). Interestingly, 75.3% of the adverse drug reactions were predictable in this study, although not all of these may be avoidable under clinical conditions. In previously published studies, the incidence of predictable adverse drug reactions varied considerably and ranged up to 80%.16, 20, 27 Of the adverse drug reactions in this study, 48% were considered preventable. The difference between predictable and preventable adverse drug reactions may be the result of the discrepancy between theoretical de®nitions and clinical conditions. Altogether, elderly patients had to endure signi®cantly more predictable and preventable adverse drug reactions. As predictable and preventable adverse drug reactions are untoward and often expected consequences of therapy by knowledge of the pharmacology of the drug in question, adverse drug reactions may be avoided if they are part of the considerations involved in planning and consequently monitoring the therapy. Computer monitoring systems have already proven to be a valid tool in increasing the awareness of the attending physicians for adverse drug reactions and to minimize the rate of predictable or potentially preventable adverse drug reactions.16, 23 Drug therapeutic monitoring is of particular importance due to the lack of information about speci®c drug dosages for the elderly. The pharmaceutical industry should include more elderly patients in pre-clinical studies to provide clinicians with more detailed information on the relationship between drugs and aging. Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 171±180 179 In some studies, the number of drugs, diagnosis or coexisting illnesses were correlated with the number of adverse drug reactions or the risk of developing adverse drug reactions.5, 6 An evaluation of the absolute number of coexisting illnesses is dif®cult; a distinction has to be made between acute and chronic diagnosis. In this study, therapeutic and gender bias were minimized as only male patients treated by the same group of physicians and nurses on one hepatogastroenterological ward were included. Patient-speci®c physiological and functional characteristics expressed by the organrelated diagnosis or the gastrointestinal diseases are probably more important in predicting both adverse and bene®cial outcomes associated with drug therapies, than any other measure.34 In conclusion, age could not be identi®ed as a risk factor for developing adverse drug reactions in elderly hepatogastroenterological patients, except in patients with biliary tract diseases and acute pancreatitis. Nevertheless, age was associated with a higher severity and adverse drug reaction-related mortality. The high rates of predictable and preventable adverse drug reactions are disappointing. Our goal should be to detect patients at high risk of adverse drug reactions (e.g. gastric ulcers, acute episodes of chronic pancreatitis, cholangitis, in¯ammatory bowel diseases), to develop guidelines and educational programs to increase adverse drug reaction awareness and prevention and, thus to improve patient outcomes. 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