Download Adverse drug reactions in patients with gastroenterological diseases

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 ˆ 8), neurological (n ˆ 3),
alcohol intoxication (n ˆ 4), deep vein thrombosis
(n ˆ 2) or malaria tropica (n ˆ 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 ˆ 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 ˆ 16) in the
younger and to 6.3% (n ˆ 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 ˆ 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 ˆ 70; ³ 65 years, n ˆ 40)
followed by toxicity (< 65 years, n ˆ 39; ³ 65 years,
n ˆ 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 ˆ 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 ˆ 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.
ACKNOWLEDGEMENTS
This study was supported by grants from BMBF no. 01
EC 9403/7 and ELAN No.98.07.30±1.
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