Adverse drug reactions

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (577-586)

Adverse drug reactions (ADRs) associated with hospital admissions – elderly female patients are at highest risk Original ©2011 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP201514

Key words adverse drug reactions – drug-related hospitalization – risk factors – gender – patient safety

Received October 23, 2010; accepted May 16, 2011 Correspondence to C. Hofer-Dueckelmann Pharmacy Department, Landesapotheke Salzburg, Müllner Hauptstr. 50, 5020 Salzburg, Austria [email protected]

C. Hofer-Dueckelmann1, E. Prinz2, W. Beindl1, J. Szymanski3, G. Fellhofer1, M. Pichler2 and J. Schuler2 Department, Landesapotheke Salzburg, 2Department of Cardiology, Landeskrankenhaus Salzburg, Private Paracelsus Medical University, Salzburg, Austria, and 3Helios Klinikum Wuppertal, Universität Witten/Herdecke, Department of Clinical Pharmacology, Wuppertal, Germany 1Pharmacy

Abstract. Background: ADRs represent a significant problem in drug utilisation. The prevalence of admissions caused by ADRs varies depending on the observational site, studied population, data collection method and the used definitions. Women seem to be more frequently affected than men. Objective: To assess the incidence and quality of ADRs related to hospital admissions, to identify the drugs most commonly involved and to define risk factors and preventive strategies for those ADRs. Material and methods: 3,190 medical records of all newly admitted internal ward patients were assessed in a prospective observational study in an internal hospital over 6 months. Potential ADRs at hospital admission were identified following a list of suspicious symptoms and laboratory results. Cases were evaluated by means of a computer tool and data-base specialized on detecting causality and severity of ADRs. Results: 304 ADRs were identified in 242 patients (7.6%), with 60% directly leading to admission. More women than men encountered an ADR (10 vs. 6%, p < 0.005). Analyzed separately by age groups, this gender difference became significant at an age of ≥ 81 years. The most common ADRs were electrolyte imbalances and over-anticoagulation. Diuretics and vitamin K antagonists were significantly correlated with ADRs. 62% of all ADRs were severe or life-threatening. Conclusion: ADRs leading or related to hospital admission are highly prevalent. Older age and female gender are significantly associated with ADR related hospital admissons. Causative drugs are the ones prescribed most frequently. Multidisciplinary preventive strategies and surveillance methods are necessary to ensure better care and patient safety especially for elderly women.

Introduction Medication can be an important source of unintended harm to patients, which may be caused by either non-preventable adverse effects of medication use or by medication errors (potentially preventable). In a study of almost 19,000 admissions, 6.5% of patient admissions to two National Health service hospitals in the UK were related to ADRs [1]. The reported incidence is roughly compatible with pooled data from older studies, and with more recent studies [2, 3, 4, 5, 6]. Important risk factors for adverse drug events or reactions include polypharmacy, female sex, intake of drugs with a narrow therapeutic range, primarily renal elimination of drugs, age > 65 years, cognitive impairment, four or more comorbidities and use of anticoagulants or diuretics [3, 7]. In the older population, the representation of women is higher, they consume multiple medications and are more likely to have functional and cognitive disabilities due to age [8]. In a study evaluating polypharmacy and inappropriate prescribing in elderly internal-medicine patients (≥ 75 years) in Austria, 17.8% (97/543) of elderly patients suffered from an adverse drug event in which women were much more frequently affected [9]. ADRs not only increase morbidity and mortality, but according to several studies in the US, in hospitalized patients they prolong average hospital stay for 2.5 days, thus increasing costs by € 3,100 [10]. In Germany, a study on medication related hospitalization on the basis of 13 ± 10.6 days at a reimburse-

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Hofer-Dueckelmann, Prinz, Beindl et al.

ment level of € 287 per hospital day, estimated the drug related hospitalization cost at € 3,700 and the total annual economic burden for Germany at € 400 million [11]. According to the literature, about half of the ADRs are deemed possibly or definitely avoidable, but the estimates vary greatly (30 – 70%) [2, 3, 5, 12]. Since the prevalence and quality of community-acquired ADRs related to hospital admissions independent of age in Austria is unknown, the aim of this study was to analyze community-acquired ADRs that lead to hospitalization or occurred in concurrence with hospitalization in an Austrian Hospital. Furthermore, we wanted to evaluate risk factors for ADRs and to define strategies to reduce their number.

Methods Patient selection and data collection An observational study was conducted covering two 3-month periods from May 15, 2007 until August 15, 2007 and from January 4, 2008 until April 24, 2008 (with a break of 3 weeks). All patients newly admitted to the departments of gastroenterology, nephrology and cardiology at the County Hospital of Salzburg, Austria, were eligible for the study. Most acute medical admissions at this hospital are transferred to these two departments, which comprise seven wards with 166 internal beds and one intensive care unit with 13 beds. The County Hospital of Salzburg serves a population of about 250,000 with a total annual activity of 94,000 admissions. Newly admitted patients were identified from the admission books by two trained study nurses on the wards every day. The study nurses documented all data on drug prescriptions from patients with and without ADRs. If a patient had multiple admissions or multiple ADRs, the most severe ADR episode was used for assessment of severity and analysed at patient level. Demographic (age, sex), clinical (height, weight, reason for admission) and social data, as well as patients´ premedication and laboratory results (serum creatinine, creatinine clearance, glucose, hemoglobin, sodium, po-

tassium, urea, bilirubin, ALT, INR, TSH, leucocytes, platelet count) were collected from medical charts and entered into a standardized case report form. To assess patients’ cognitive abilities and the need for nursing care, the study nurses interviewed the participating patients themselves or their care givers and the medical staff. Renal failure was defined as a glomerular filtration rate of ≤ 30 ml/min, as estimated by the Cockroft Gault equation.

ADR definition and detection For the purpose of this study, an ADR was defined according to the definition of Edwards and Aranson as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product” [13]. Only community-acquired ADRs identified on admission were included. Patients with a suspected ADR related to deliberate non-compliance or intentional overdose of drugs (suicide-intention) were excluded from the study. Possible symptoms of ADRs were predefined by the study team. Suspect events that could be caused by drugs were either recorded from the reports of the treating physicians, by the ward nurses, by an active search in the charts by study nurses and by checking all discharge letters by members of the study group. Objective markers of suspicious ADRs (e.g. laboratory results) were identifiable from the patient notes and the hospital computer system, while subjective markers of ADRs, (e.g. headache, nausea or rash) were identified in patient charts, talking with the ward team or the affected patient. Potential ADRs were allocated to hospital admissions.

ADR analysis Suspected ADRs were documented in a database developed by the Philipp Klee-Institute for Clinical Pharmacology at the HELIOS Clinic Wuppertal [14]. This software based on the experience of the “German Network of Regional Pharmacovigilance Cen-

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ADRs and elderly female patients

Table 1. Patient characteristics. Number of patients Age (years) (mean ± SD) Female gender BMI (kg/m2) (mean ± SD)) Renal function ml/min (mean GFR ± SD) Number of drugs on admission Mean ± SD median and range Number of drugs at discharge Mean ± SD median and range D in number of drugs admission/discharge mean ± SD median and range Number of diuretics/patient (mean no. ± SD) Vit K antagonists (no. of patients (%)) No need for care (no. of patients (%)) Mild dementia (no. of patients (%)) Moderate or severe dementia (no. of patients (%)) Days in hospital mean and SD median and range Death during hospital stay (no. of patients (%))

tres” is specialized in structured documentation and coding of ADRs and assessment of their causality, severity and preventability [11]. Occurrence, description and progression of ADRs as well as symptoms, consequences and therapy were recorded. ADRs were classified according to the effect on an organ or metabolic system (e.g., electrolyte imbalance, coagulation system). Consequently, the same drug – or a drug as part of a drug-drug interaction – could be classified into different categories (e.g., digitoxin to nausea or bradycardia). Suspected ADR cases were evaluated by a clinical pharmacist (CHD) and a doctor (EP). Causality assessment was based on the Naranjo Score, a rating of doubtful-possibleprobable-highly probable likelihood that a clinical status is the result of an ADR rather than of other factors such as progression of the disease [15]. We included only ADRs which were highly probable, probable and possible related to drug therapy in this study. Assessment of severity of ADRs was based on the cancer therapy classification program CTCAE [common terminology criteria for adverse events], which is graded from 1 to 5 (mild/moderate/severe/lifethreatening/death) to differentiate ADRs that manifest no clinical signs, for example, sus-

with ADR 242 73 ± 14.1 58% 26.9 ± 5.4

without ADR 2,948 66 ± 15.8 45% 26.9 ± 5.5

p-value

48.4 ± 18.7

59.3 ± 15.9

8.5 ± 3.9 8 (1 – 24)

5.5 ±3.9 5 (0 – 22)

< 0.0005

8.2 ± 3.5 8 (0 – 18) –0.24 ± 3.27 0 (–14 – 14) 1.26 ± 0.87 89 (37%) 152 (64%) 61 (26%) 26 (11%) 9.6 ± 6.3 8.0 (1 – 33) 9 (4%)

6.7 ± 3.6 7 (0 – 24) 1.26 ± 2.85 1 (–13 – 18) 0.48 ± 0.66 367 (13%) 2349 (83%) 344 (12%) 136 (5%) 7.0 ± 6.5 5.0 (1 – 80) 128 (4%)

< 0.0005

< 0.0005 < 0.0005 n.s. < 0.0005

< 0.0005 < 0.0005 < 0.0005 < 0.0005 < 0.0005 n.s.

pected drug-induced abnormalities in blood test results from those which caused clinical symptoms. To assess the clinical relevance, every ADR was categorized as either (a) an accompanying event when the patient was admitted for other reasons, or (b) leading to hospital admission when the ADR was causative for the admission. All detected ADRs were screened for causative drug interactions. This assessment was based on the Medis® software. Medis® software lists all available drugs in Austria with their known ADRs and drug-drug interactions and is based on the information on drug-drug interactions in the ABDA database [16, 17].

Statistics Standard methods of descriptive statistics were applied to summarize the data. T-tests were used to compare means, χ2-tests were used to compare proportions. Odds ratios (ORs) for an ADE were estimated by logistic regression and due to the relative low frequency of ADRs can be used as a good approximation to the relative risk. All calculations were done using SPSS 16. All numbers are given in means.

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Table 2. Sex differences in 242 patients with ADR. Characteristics of patients in the ADR group

Men

Women

Number (%)

101 (42%)

141 (58%)

Mean age

75.3 ± 13.2

69.8 ± 14.7

BMI (kg/m2)

26.8 ± 5.9

26.9 ± 4.6

Renal function ml/min (GFR)

48.8 ± 18.5

48.1 ± 18.9

8.3 ± 3.6

8.6 ± 4.1

Number of drugs on admission Mean number of discharge diagnoses

5.65

4.45

Severity of ADR (mean and SD)

2.61 ± 0.89

2.75 ± 0.98

Number of diuretics/patient (mean and SD) median and range Vitamin K antagonists (no. of patients)

1.29 ± 0.98 1 (0 – 4) 34

1.23 ± 0.8 1 (0 – 3) 55

Figure 1. Representation of females in ADR group vs. control group without ADR: Only in females of ≥ 81 years there is a significant higher percentage of ADRs.

Results During the 6-month screening period, 3,190 patients were admitted to two internal wards. 1,735 (54% of patients) were men, 1,455 (46%) were women. Mean age was 66.5 ± 15.8 years. There was a significant age difference between men and women. Mean age in men was 64.3 ± 15.1 years and 69.1 ± 16.3 years respectively in women (p < 0.0005). In total, 304 ADRs were identified in 246 admissions of 242 patients. Thus, 4 of the

p value for significant differences 0.003

0.038

242 ADR patients were admitted twice. Incidence of ADRs was 7.6%. 191 patients experienced a single ADR whereas 51 had more than one. According to the classification of Rawlins and Thompson [18], 95% were Type A reactions. The occurrence of an ADR was significantly correlated with age, impaired renal function and the number of drugs on admission and at discharge (Table 1). Patients with an ADR were prescribed diuretics and vitamin K antagonists significantly more frequently than patients without an ADR. They were more often in need of care (36% vs. 17%), more frequently had an impaired mental status and stayed significantly longer in hospital than patients without an ADR. Women were significantly more frequently affected from ADRs than men (141/1,455 = 10% vs. 101/1,735 = 6%; p < 0,0005; OR 1,7; 95% CI: 1.3 – 2.3). In general, women in the ADR group were significantly younger and had less comorbidities than men with ADRs (Table 2). Analyzed separately by age group, the OR was only significant in the group of patients ≥ 81 years. Here, 65/403 = 16% of female admissions had an ADR compared to 21/226 = 9% of male admissions (p = 0.018; OR = 1.9, 95% CI: 1.1 – 3.2). Comparing the ADR group with the control group without an ADR, there was also a significantly higher percentage of female patients in the ADR group. However, when analysis was stratified by age (≤ 70, 71 – 80, ≥ 81), the difference became only significant in females of ≥ 81 years. Again, in this high age group, females were significantly overrepresented compared to subjects without an ADR (76% vs. 62%, p = 0,017) (Figure 1).

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Table 3. Observed adverse drug reactions. Involved organ system or symptom1

n (%)

Electrolytes, Metabolic/laboratory

91 (30)

Leading to admission 50

Drug-drug interaction 49

m

f

32%

42%

Hyponatremia E 87.1

44 (15)

23

27

14%

22%

Hypokalemia E 87.6

21 (7)

8

11

8%

9%

Hyperkalemia E 87.5

10 (3)

7

5

3%

5% 1%

Hypoglycemia E 16.0

4 (1)

4

2

2%

Others E 87.8

12 (4)

8

4

5%

5%

Coagulation system

70 (23)

16

37

28%

30%

Over-anticoagulation Z 92.1

51 (17)

2

28

9%

7%

Hemorrhage/Bleeding D 68.3

19 (6)

14

9

19%

23%

Renal/Genitourinary

41 (14)

34

36

21%

14%

Worsening of renal function N14.-

26 (9)

20

22

13%

9%

Acute renal failure N 17.-

15 (5)

14

14

8%

5%

Cardiac arrhythmia R OO.-, I47.-- I49.Cardiac general I.27.-, I15.-, I42.9, I 95.2 Gastrointestinal K 25.-, K59.0, K59.9 K63., R11 Neurology F11.-, F 13.-, F 19.Constitutional symptoms R 61,9 R53. Based on cardiac glycoside overdosing R 53.Pulmonary/Upper respiratory J 84.1, R05.Blood/Bone marrow D59.0, D 70, D 72 Allergy/Immunology T 88.6, L27.-, L50.0, R 06.0, T 78.3 Musculoskeletal/Soft tissue G 72.0 Infection D 72.8

39 (13)

31

20

21%

13%

11 (4)

10

2

5%

4%

13 (4)

12

3

6%

5%

9 (3)

6

5

3%

4%

7 (2)

1

0

3%

3%

6 (2)

0

0

3%

2%

7 (2)

0

0

4%

2%

6 (2)

4

3

2%

3%

5 (2)

3

0

3%

1%

2 (1)

0

1

1%

1%

Endocrine E 05.8 Total 1

2 (1)

2

2

2%

0%

1 (0)

0

0

1%

0%

304 (100)

169

158

132

172

Numbers refer to International Classification of Diseases (ICD)-10 code.

The most common ADRs in this setting were electrolyte imbalances, over-anticoagula tion, cardiac arrhythmias, followed by worsening of renal function and dehydration, and hemorrhage (Table 3). The most common causative drugs were diuretics, vitamin K antagonists, ACE-inhibitors and non-steroidalantiinflammatory drugs (NSAR), followed by beta-blockers and cardiac glycosides (Table 4). Renal failure as well as cardiac arrhythmia due to ADRs were more commonly found in men, whereas drug induced bradycardia and hyponatremia occurred significantly more often in women (p = 0.053). In addition, coagulation problems were seen more often in women.

According to the Naranjo score, causality was considered definite in 40 (13%) ADRs. In 226 cases (74%), it was probable, and possible in 38 cases (12%). Concerning severity, 62% of all ADRs were either severe, life-threatening or fatal (Table 5). There were 4 fatal events: One was irreversible renal injury and asystole due to hyperkalemia (9.8 mmol/l (3.6 – 5.0)) because of a combination therapy of spironolactone 100 mg once daily (o.d.), hydrochlorothiazide/amilorid 50/5 mg o.d., frusemide 30 mg o.d. and enalapril 10 mg o.d. in a 73-year-old man. The second one was an incessant supra ventricular tachycardia with pulmonary ede-

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Table 4. Drugs responsible for ADR. Causative drugs Diuretics

Number of ADRs 175

High-ceiling

71

Low-ceiling

66

Potassium-sparing

38

Vitamin K antagonists

66

ACE-inhibitor/AT-II blocker

52

Non steroidal anti- inflammatory drugs (NSAID) Betablocker

29

Cardiac glycoside

27

Serotonin reuptake inhibitor (SSRI) Antiplatelet drugs

16

28

13

Amiodaron

11

Statins

10

Antidepressants

9

Immunosuppressants

9

Opioids

9

Corticosteroids

7

Benzodiazepines

6

Antibiotics

6

Other

53

ma and acute renal failure in a 75-year-old female patient caused by an unintentional theophylline overdose (450 mg o.d., reduced to 300 mg o.d.) resulting in a blood-level of 27.3 mg/l (10 – 20), aggravated by a possible interaction with moxifloxacin 400 mg o.d.. The third case was a drug-induced white cell aplasia following administration of thiamazole 20 mg o.d. resulting in urosepsis and pneumonia in a 75-year-old female patient. The fourth one was an acute renal failure with lactic acidosis (lactate 13.5 mmol/l (0.5 – 2.2)) as a consequence of furosemide 30 mg od, dexibuprofen 200 mg 3 times a day and metformin 850 mg twice daily in an 80-year-old lady. In 146 first admissions (60%), the ADR was the reason for hospital admission, whereas in 96 cases it occurred concomitantly (Table 5). If an ADR was the reason for admission, its severity was significantly higher. Women were more often admitted because of an ADR and had a significantly higher percentage of life-threatening and fatal ADRs than men (23 vs. 12%, p = 0.031). Severe ADRs that were not the reason for admission were mainly hyponatremia, hypokalemia, hyperkalemia and overanticoagulation. Although they were

not directly responsible for the admission, they may nevertheless have contributed to it. Within the most common ADRs, coagulation problems and hypokalemia occurred more often as concomitant ADR, whereas hyponatremia, cardiac arrhythmia, worsening of renal function and hemorrhage more frequently were the reasons for admission. In 158/304 detected ADRs (52%), a drug-drug interaction was involved (Table 3, 6). The drugs most commonly included were ACE-inhibitors, diuretics, vitamin K antagonists, serotonin reuptake inhibitors (SSRI) and non steroidal anti-inflammatory drugs (NSAIDs). The majority of clinically relevant drug-drug interactions were pharmacodynamic interactions which were aggravating or impairing drug effects. Only 4% accounted for pharmacokinetic drugdrug interactions (bioavailability, distribution, metabolism, elimination).

Discussion In this study, we identified an ADR on hospital admission in 7.6% of all newly admitted patients to two internal medicine departments. In 4.6% of the observed patients, the ADRS was the reason for admission. Women encountered ADRS significantly more often than men. These data are in accordance with numbers from several other studies [1, 2, 3, 4, 5, 6]. There is a range from 0.2 to 13.8%, depending on the observational site, studied population, data collection methods and the used definitions [19, 20]. The occurrence of an ADR was significantly correlated with higher age, female gender, impaired renal function, the need for nursing care, impaired cognitive abilities and the number of prescribed drugs. Whereas gender, age, renal and cognitive function is mostly unchangeable, the number of drugs is potentially variable. In a study evaluating polypharmacy and inappropriate prescribing in elderly patients, 36% of patients were taking unnecessary drugs, 30% drugs to avoid in the elderly and in 8% there were duplications [9]. Thus, reducing the number of drugs seems to be a strategy for minimizing ADRs. However, in many cases this is not easily done, as polypharmacy is strongly associated with poly-

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Table 5. Severity of ADR according to CTCAE. ADR All Reason for admission

Mild (%) 31 (13)

Moderate (%) 62 (26)

6 (4)

31 (21)

morbidity. Since polypharmacy is a result of treatment according to current guidelines in many patients, only prioritization of medication could help to reduce the number of drugs. As far as we know, the effect of this concept is not yet proven. In our study, the use of vitamin K antagonists and diuretics was associated with the incidence of ADRs. Vitamin K antagonists have a narrow therapeutic range which is a wellknown risk factor, whereas diuretics are very commonly prescribed drugs that may lead to electrolyte imbalances especially in long term treatment and in the elderly. Another drug group frequently involved in ADRs were ACE-inhibitors causing electrolyte imbalances and renal dysfunctions. Regular monitoring of laboratory values in primary care might have prevented some of these admissions. According to a systematic review, the most frequent drug therapy problem and error of omission reported for preventable adverse drug events requiring hospital admission in ambulatory care was inadequate monitoring (45.4%; range 22.2 – 69.8%) [21]. In general, the side effect profile and possible interactions between drugs should be brought much more into the attention of health care providers and patients. Not only efficacy but also safety is pivotal for treatment success. Since many of the causative drugs identified in this study are prescribed very often, a general warning for their use is not helpful. Nevertheless, since the most common ADRs are electrolyte imbalances and overanticoagulation which can be easily detected by blood testing, close monitoring of highly susceptible patients seems prudent. In more than half of the ADRs, a drugdrug interaction was involved. Often, an ADR was aggravated in case two or more drugs had the same side effects due to a pharmacodynamic interaction, e.g., hydrochlorothiazide plus loop diuretics, oral anticoagulants and selective serotonin reuptake inhibitors or beta-blocker and heart glycosides. As in other studies, these data suggest

Severe (%) Life-threatening (%) 106 (44) 39 (16) 69 (47)

36 (25)

Fatal (%) 4 (2)

Total

4 (3)

146

242

that drug-drug interactions may play a major role in inducing a severe ADR and that a drug-drug interaction needs to be carefully evaluated, particularly in elderly subjects who need polypharmacy [12, 20]. Only a few interactions had a pharmacodynamic and pharmacokinetic background like amiodarone and beta-blockers, both inducing bradycardia and interacting in metabolism by CYP 450. However, pure pharmacokinetic interactions had less clinical significance in the investigated population. This might be different in other populations like HIV or transplant patients. Although females had less comorbidities, they took more drugs and experienced more ADRs than men, especially at an age of ≥ 81 years. This is a very concerning finding without easy explanation. Extensive reviews and textbooks of sexand age-related changes in pharmacokinetics and pharmacodynamics, the pathophysiology of disease and patterns of drug usage have been published, and yet potentially preventable ADRs are more frequent in older women [8, 22, 23, 24]. Women have a smaller body size and lower weight with consequent changes in apparent volume of distribution [21]. Gastric emptying time, plasma protein levels, cytochrome P 450 activity, drug transporter function and excretion activity vary between men and women [23]. However, we found neither a significant difference in BMI nor in renal function between men and women suffering an ADR in the studied population. It is recommended to reduce the doses of CYP2D6 substrates like carvedilol, metoprolol or paroxetin by approximately 20% in older patients and by another 10 – 20% in women compared with men [8]. In this study, women were more susceptible than men to ADRs with diuretics and beta-blockers. However, numbers are too small to analyze the gender-specificity in detail for each single ADR. A multicenter prospective study also observed a higher incidence of cardio-

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Table 6. Incidence of drug-drug-interactions. Drugs

Number

ACE-inhibitor + diuretic(s)

25

HCT + furosemide

18

SSRI + OAC

12

Furosemide + Spironolactone

10

ACE-inhibitor + NSAID+ diuretic(s)

9

SSRI + diuretics

9

Beta-blocker + cardiac glycoside

8

NSAID + OAC

7

OAC + various drugs (pharmacokinetic) NSAID + acetylsalicylic acid

6

Beta-blocker + amiodarone

5

ACE-inhibitor + NSAID

4

Drugs for dementia + benzodiazepine + opioids Immunosuppressants

4

NSAID + diuretic(s)

3

OAC + antiplatelet drugs

2

5

4

vascular ADRs in female subjects, the risk increasing with age and the numbers of drugs prescribed [24]. In our study, probably, their old age, social status and need for care were responsible for the high incidence of ADRs in women of ≥ 81 years often living alone in deprived circumstances with nobody looking after them regularily. The current challenge is to determine the relative importance of factors influencing both drug clearance rates and drug responses in older patients and in women [8]. Health care authorities and drug companies have to care more for these risk groups. In contrast to the past, Phase II – IV clinical trials should include a significant share of such patients at risk. All health care providers have the responsibility to document and report clinically important ADRs to national pharmacovigilance centers. Still, voluntary reporting leads to a massive under-reporting and team work in a multidisciplinary team is needed to improve preventive strategies and surveillance methods for ADRs. Participation of a pharmacist in the physician ward rounds on a general medicine unit contributes to a significant reduction in preventable adverse drug events by recommending medication, doses and monitoring parameters [25]. According to a recent study, the addition of pharmacists to health care teams would lead to major reductions in morbidity and health care costs by reducing the number of drug-

related readmissions [26]. Furthermore, patient counseling for a safer medicine therapy should be an essential part of drug prescribing, dispensing and administration to make patients aware of symptoms of ADRs and ensure safer treatment [19]. A study evaluating the safety of anticoagulation therapy in older patients found that the poor quality of patient education about oral anticoagulation was the most significant risk factor for bleeding complications and for the ineffectiveness of anticoagulation [27]. Education and interventions to improve clinical dosing regimens in older patients and women, especially older women, are needed and should be an obvious aim of clinical pharmacology education and quality improvement initiatives [8]. Strategies that improve the awareness for risks and their management in dealing with drugs that cause the major problems should be developed for ambulatory care and each single hospital to progress in patient safety.

Limitations Our data and findings should be interpreted in the context of several important limitations. The major limitation of this study is its monocentric and time limited study design. Thus, the variety of drugs and patients was limited. Results might have been different including oncology, psychiatric, neurologic or surgical wards as well as patients in nursing homes. Furthermore, due to the fact that we analyzed records and data exclusively in internal medical departments, patients with many comorbidities and a substantial number of prescribed drugs are overrepresented in our sample. In many cases, it is difficult to differentiate between an “adverse event” and an ADR. While an “adverse event” is an adverse outcome that occurs while a patient is taking a drug, but is not or not necessarily attributable to it, an ADR is an adverse outcome that can be attributed to a causal relationship with drug intake [13]. The drug assessment process is difficult to standardize and our decision making process can be criticized. The decisions were done on the basis of predefined parameters by a pharmacist and a clinician. From our experience, the multidisciplinary approach is the most practicable and

585


valuable way to assess a medication portfolio and clinical events.

[4]

Conclusion

[5]

ADRs leading to or related with hospital admission are highly prevalent in an Austrian internal medicine hospital. Women are significantly more often affected than men, especially at an age of ≥ 81 years. The most common ADRs were electrolyte imbalances, over-anticoagulation, bleeding complications, renal insufficiency, dehydration and syncope and arrhythmia. ADRs occur with drugs that are widely used and significantly prolong patients´ stay in hospital. Thus, multidisciplinary preventive strategies and surveillance methods need to be improved and a special care for elderly female patients is required from health care providers and health authorities to ensure patient safety.

[6]

[7]

[8] [9]

[10] [11]

Acknowledgments This study was supported by grants from the local health insurance company (Salzburger Gebietskrankenkasse) and the Austrian Pharmacists’ Society (Österreichische Apothekerverband). All statistical analyses were performed by Dr. Mynda Schreuer. The funding institutions had no influence on the analysis or interpretation of the data. The author wants to thank Andrea Zarbl and Elisabeth Wagner for their excellent job as study nurses and Prof. Petra Thürmann and Prof. Michael Wolzt for their support.

[12]

[13] [14]

[15]

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