Genetic susceptibility to adverse drug effects - Epidemiology ...

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Age- and gender specific incidence of hospitalization for digoxin intoxication in the period January 2001–December 2004 were included in the study (n= 2,987,580). A digoxin-related admission was defined as a hospitalization with the ICD-code 972.1 as the main diagnosis or one of the secondary diagnoses or the code E942.1 as a secondary diagnosis (usually diagnosis of the cause leading to main diagnosis). Digoxin use. Data on the use of digoxin were obtained from the Stichting Farmaceutische Kengetallen (SFK)[Foundation for Pharmaceutical Statistics] database, which extrapolates drug figures for The Netherlands based on filled prescriptions from 90% of all community pharmacies. As community pharmacies deliver 90% of all outpatient prescriptions, this database covers more than 80% of such prescriptions in The Netherlands. Due to different anonymization procedures in the hospitals as well as in the SFK database, it was not possible to link individual prescription data to admission data. Prescription data were only available as the number of prescriptions per age group (eight fixed age groups) stratified by gender and by year. The range of the age categories was chosen on the basis of distribution of overall drug use over age and on the relevance of specific age groups (less drug use in age groups 20-55 results in wide age-ranges, special interest in children results in smaller age-ranges). This resulted in age groups with different age-ranges instead of more conventional age groups with equal age range. Since there were no data on drug regimens and digoxin dosages can vary greatly among patients, the data did not allow for the calculation of the incidence rate in terms of person-years of use. Analyses. We calculated the proportion of acute admissions that were attributable to digoxin intoxication according to the coded discharge diagnoses. Since digoxin prescription rates vary across different patient groups, the proportion of admissions may not reflect the actual risk of digoxin intoxication. Therefore, we also calculated incidence rates of digoxin intoxication by dividing the number of admissions for digoxin intoxication by the number of filled digoxin prescriptions. Using similar methods, we calculated age- and gender-specific incidence rates. Descriptive statistical methods were used for subgroup comparisons and consisted of Student’s t-tests (unpaired) and Chi-squared tests. The relative mortality risk during admission for digoxin intoxication versus other reasons for admission was estimated by using age- and gender-adjusted logistic regression analysis. The association between the length of hospital stay and admission for digoxin intoxication was studied by using age- and gender-adjusted linear regression analysis. All analyses were carried out in SPSS 11.0 for Windows. The age adjusted relative risk (RR) of admission with digoxin intoxication per 100,000 prescriptions in females versus males, was computed using Mantel-Haenzel methods across the eight age strata. 21
Chapter 2 Table 1 Characteristics of all acute admissions (N= 2,987,580) Characteristic Mean age (years) 49.1 Age in years (no. of patients) 0-10 380,827 11-20 128,653 21-40 641,91 41-54 383,175 55-64 349,304 65-69 203,664 70-74 242,968 >=75 657,079 Female sex (%) 53.5 % Top 10 most frequent main diagnoses (% admissions) Chest pain 5.8 Myocardial infarction 3.0 Heart failure 2.7 Stroke 2.0 Pneumonia 1.9 Atrial fibrillation 1.9 Abdominal pain 1.7 Chronic obstructive pulmonary disease 1.4 Fetal distress 1.3 Acute appendicitis 1.3 Digoxin intoxication (% admissions) 0.04 a Mean duration of admission (days) 8.8 Died during admission,= (% [No] admissions) 4.9 (147,379) a N= 1286, mean age 77.4 years Results Of all 9,729,819 admissions over the years 2001-2004, 30.7% (n= 2,987,580) were acute admissions. The baseline characteristics of the study population are shown in table 1. The mean age of acutely admitted patients was 49.1 years and 53.5% were female. The most frequent main diagnoses were of a cardiovascular nature including chest pain, myocardial infarction, heart failure and stroke (13.5% of all acute admissions). The mean duration of admission was 8.8 days and 4.9% of all acute admissions ended in death. Digoxin intoxication was reported in 0.04% (n= 1286) of acute admissions. Patients with digoxin intoxication were significantly older (77.4 versus 49.1 years, p< 0.001) and more often female (68.0% versus 53.5%, p
Page 1 and 2: Genetic susceptibility to adverse d
Page 3 and 4: The work presented in this thesis w
Page 5: Promotiecommissie Promotoren: Prof.
Page 10: 1 General Introduction
Page 13 and 14: Chapter 1 genome. Every SNP represe
Page 15 and 16: Chapter 1 References 1. 2. 3. 4. 5.
Page 18: 2 Quantifying the risk of adverse d
Page 21: Chapter 2 Introduction The cardiac
Page 25 and 26: Chapter 2 digoxin treatment appears
Page 27 and 28: Chapter 2 References 1. 2. 3. 4. 5.
Page 30: 3 Common variants in the ABCB1 gene
Page 33 and 34: Chapter 3.1 Introduction The ATP-Bi
Page 35 and 36: Chapter 3.1 Co-variables. Covariate
Page 37 and 38: Chapter 3.1 Table 3 Frequencies of
Page 39 and 40: Chapter 3.1 Table 5 Risk of serum d
Page 41 and 42: Chapter 3.1 Table 6 Other studies o
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4 Common variants in the NOS1AP gen
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Chapter 4.1 Introduction Sudden car
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Chapter 4.1 Assessment of QTc inter
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Chapter 4.1 Table 1 Baseline charac
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Chapter 4.1 Table 3 Number of indiv
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Chapter 4.1 ditional GG haplotype c
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Chapter 4.1 References 1. 2. 3. 4.
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4.2 Common NOS1AP variants potentia
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Common NOS1AP variants potentiate d
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Chapter 4.3 Introduction In the pas
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Chapter 4.3 Figure 1 Flowdiagram of
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Chapter 4.3 Table 1 Characteristics
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Chapter 4.3 Table 2 Cardiovascular
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Chapter 4.3 Table 3 Drugs, NOS1AP a
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Chapter 4.3 found indication that t
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Chapter 4.3 References 1. 2. 3. 4.
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4.4 Common variation in the NOS1AP
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Common variants in the NOS1AP gene
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5 Effect of ABCB1 and NOS1AP genoty
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Effect of ABCB1 and NOS1AP genotype
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6 General discussion Despite all re
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General discussion ening properties
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General discussion or the excess [C
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General discussion continuously mon
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General discussion cardiovascular d
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General discussion for non-cardiova
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General discussion 25. 26. 27. 28.
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General discussion QTc interval in
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General discussion 169
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7.1 Summary Despite all research ef
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Summary reduced mortality in patien
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Chapter 7.2 steeds aanzienlijk is e
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8 Dankwoord Een proefschrift schrij
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Dankwoord Bijzondere dank aan alle
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10 Bibliography Manuscripts based o
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Bibliography Van der Hooft CS, Diel
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