Influence of age, sex and seriousness on reporting of adverse drug reactions in Sweden.

PURPOSE: To investigate how reporting of adverse drug reactions (ADRs) among adults in Sweden is associated to age and sex, in addition to seriousness of the reaction and drug utilisation. METHODS: Individual case safety reports (ICSRs) reported by healthcare professionals to the national pharmacovigilance database 2008-2011 were related to defined daily dose (DDD) in the Swedish Prescribed Drug Register (SPDR) for individual's ≥20 years. Data were stratified into five age groups. Crude and adjusted (by age standardisation of prescribed drugs) reporting rate (RR) and reporting rate ratio was evaluated as well as impact of sex-dependent drugs. RESULTS: Based on 9898 included ICSRs, the crude results show that overall RR was almost similar for both serious and non-serious reports and indicates highest RR in the youngest age group. Women had higher rates than men, with predominance for non-serious reports, contrary to men who had a higher RR of serious ones. Standardisation led partly to the same result, but age-related distribution was adjusted, with highest overall RR in the oldest age groups. Sex-dependent drugs had marginal impact on the results. CONCLUSION: Age and sex have impact on spontaneous reporting of ADRs. After adjusting for dispensed drugs and by standardisation of age-related differences in prescribed drugs, results indicate that healthcare professionals more frequently reported ADRs for the oldest individuals and for women. Serious reports were more frequently reported for men. Copyright © 2017 John Wiley & Sons, Ltd.

Increased availability of paracetamol in Sweden and incidence of paracetamol poisoning: using laboratory data to increase validity of a population-based registry study.

PURPOSE: To estimate the incidence trend and outcome of paracetamol poisoning, in relation to increased availability of paracetamol from non-pharmacy outlets in 2009. METHOD: Patients' serum paracetamol results over 14 years (2000-2013) from 20 (out of 21) regions in Sweden were linked to national registers of hospital care, cause of death, and prescriptions. Paracetamol poisonings were defined by serum paracetamol levels, hospital diagnoses, or cause of death. The change in incidence of poisonings following increased availability of paracetamol was analysed by using segmental regression of time series. RESULTS: Of the 12 068 paracetamol poisonings, 85% were classified as intentional self-harm. Following increased availability from non-pharmacy outlets, there was a 40.5% increase in the incidence of paracetamol poisoning, from 11.5/100 000 in 2009 to 16.2/100 000 in 2013. Regression analyses indicated a change in the trend (p < 0.0001) but not an immediate jump in the incidence (p = 0.5991) following the increased availability. Adjusting for trends in hospital episodes for self-harm, suicides, and the sales volume of paracetamol did not influence the result. All-cause mortality at 30 days (3.2%) did not change over time. CONCLUSIONS: The incidence of paracetamol poisoning in Sweden has increased since 2009, contrasting the decreased incidence in the period of 2007-2009. The change in trend was temporally associated with the introduction of availability of paracetamol from non-pharmacy outlets but did not appear to be related to sales volume of paracetamol or general trends in self-harm or suicides. © 2017 Commonwealth of Australia. Pharmacoepidemiology and Drug Safety © 2017 John Wiley & Sons, Ltd.

Sex differences in spontaneous reports on adverse bleeding events of antithrombotic treatment.

PURPOSE: To explore if sex differences are found in spontaneously reported adverse events for clopidogrel, low-dose aspirin and warfarin treatment in routine care. METHODS: A cross-sectional analysis combining data on bleeding events from the Swedish Spontaneous Adverse Drug Event Reporting System (SWEDIS) with data from the National Prescribed Drug register. Bleeding event reports from 1999 to 2010 and 2005 to 2010 were adjusted to the number of prescriptions and the number of exposed patients respectively among women and men. Co-medication and co-prescription were analysed. RESULTS: More men were dispensed clopidogrel although the reported bleeding event risk after adjustment for number of patients exposed was higher in women (RR 1.40; 95 % CI, 1.00-1.96). The difference disappeared when adjusting for the number of prescriptions (RR 0.99; 95 % CI, 0.71-1.39). The reported bleeding event risk with low-dose aspirin was lower in women, adjusted for patients exposed (RR 0.80; 95 % CI, 0.66-0.97). For warfarin, no sex difference in bleeding event reports could be found (RR 1.01; 95 % CI, 0.87-1.17). CONCLUSIONS: This ecological comparison of bleeding reports and dispensed prescriptions showed a signal towards a higher prevalence of bleeding reports in women on clopidogrel treatment while the opposite was found for low-dose aspirin. For warfarin, no significant sex difference was seen regarding bleeding event reports, suggesting individualised dosing being an important factor. Men were more commonly prescribed antithrombotic combinations, and this was reflected by a larger proportion of bleeding reports including more than one antithrombotic agent.

Validation of myocarditis diagnoses in the Swedish patient register for analyses of potential adverse reactions to COVID-19 vaccines.

Background: Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain. Methods: Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation. Results: Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed (definite, probable or possible myocarditis according to Brighton Collaboration diagnosis criteria, positive predictive value 0.96 [95% CI 0.93-0.98]). Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation. Conclusion: This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Reclassification had only a minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination.

A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose.

We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7)) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78)) at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31)) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3 x 10(-10)) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.

The largest prospective warfarin-treated cohort supports genetic forecasting.

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis.

PURPOSE: To quantify the influence of common cytochrome P450 2C9 (CYP2C9) polymorphisms on warfarin dose requirements. METHODS: A systematic review and a meta-analysis, calculating the warfarin dose reduction associated with the five most common variant CYP2C9 genotypes. RESULTS: Thirty-nine studies (7,907 patients) were included in the meta-analysis. Compared to the CYP2C9*1/*1 genotype, the CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 required warfarin doses that were 19.6 (95% confidence interval 17.4, 21.9), 33.7 (29.4, 38.1), 36.0 (29.9, 42.0), 56.7 (49.1, 64.3), and 78.1% (72.0, 84.3) lower, respectively. The impact of CYP2C9 genotype tended to be larger in patients without interacting drugs. CONCLUSIONS: Previous studies have rarely been powered to determine the quantitative influence of specific CYP2C9 genotypes on warfarin dose requirements. The results from our pooled analysis are likely to be the most accurate to date and the methodology could serve as a model for future pharmacogenetic meta-analyses.

Utility of registries for post-marketing evaluation of medicines. A survey of Swedish health care quality registries from a regulatory perspective.

AIM: The aim of this study was to describe content and procedures in some selected Swedish health care quality registries (QRs) of relevance to regulatory decision-making. METHODS: A workshop was organized with participation of seven Swedish QRs which subsequently answered a questionnaire regarding registry content on drug treatments and outcomes. Patient populations, coverage, data handling and quality control, as well as legal and ethical aspects are presented. Scientific publications from the QRs are used as a complementary measure of quality and scientific relevance. RESULTS: The registries under study collect clinical data of high relevance to regulatory and health technology agencies. Five out of seven registries provide information on the drug of interest. When applying external quality criteria, we found a high degree of fulfillment, although information on medication was not sufficient to answer all questions of regulatory interest. A notable strength is the option for linkage to the Prescribed Drug Registry and to information on education and socioeconomic status. Data on drugs used during hospitalization were also collected to some extent. Outcome measures collected resemble those used in relevant clinical trials. All registries collected patient-reported outcome measures. The number of publications from the registries was substantial, with studies of appropriate design, including randomized registry trials. CONCLUSIONS: Quality registries may provide a valuable source of post-marketing data on drug effectiveness, safety, and cost-effectiveness. Closer collaboration between registries and regulators to improve quality and usefulness of registry data could benefit both regulatory utility and value for health care providers.

Adverse Drug Reactions in a Tertiary Care Emergency Medicine Ward - Prevalence, Preventability and Reporting.

PURPOSE: To identify the prevalence and preventability of adverse drug reactions (ADRs) in an emergency ward setting in a tertiary hospital in Sweden and to what extent the detected ADRs were reported to the Medical Product Agency (MPA). METHODS: In this prospective cross sectional observational study, 706 patients admitted to one of the Emergency Wards, at the Karolinska University Hospital in Solna, Stockholm during September 2008 -September 2009, were included. The electronic patient records were reviewed for patients' demographic parameters, prevalence of possible ADRs and assessment of their preventability. In addition, the extent of formal and required ADR reporting to national registers was studied. RESULTS: Approximately 40 percent of the patient population had at least one possible ADR (n = 284). In the multivariable regression model, age and number of drugs were significantly associated with risk of presenting with an ADR (p<0.01 and p<0.001, respectively). Sex was not identified as a significant predictor of ADRs (p = 0.27). The most common ADRs were cardiovascular, followed by electrolyte disturbances, and hemorrhage. In 18 percent of the patient population ADRs were the reason for admission or had contributed to admission and 24% of these ADRs were assessed as preventable. The under-reporting of ADRs to the MPA was 99%. CONCLUSIONS: ADRs are common in Emergency Medicine in tertiary care in Sweden, but under-reporting of ADRs is substantial. The most frequent ADRs are caused by cardiovascular drugs, and significantly associated with age and number of drugs. However, only a minority of the detected serious ADRs contributing to admission could have been avoided by increased risk awareness.

Several-fold increase in risk of overanticoagulation by CYP2C9 mutations.

OBJECTIVE: Our objective was to prospectively study the impact of CYP2C9 polymorphism (*2 and *3) on the risk of overanticoagulation during the induction phase of warfarin therapy. METHODS: Blood samples for genotyping were collected from 219 patients requiring warfarin therapy, and clinical data were prospectively collected during the first 3 weeks of medication. Patients were divided into 3 groups according to CYP2C9 genotype, as follows: *1 (homozygous), *2 (*1/*2 and *2/*2), and *3 (any genotype containing the *3 allele). RESULTS: During the first week of treatment, the relative risk of achieving at least 1 international normalized ratio (INR) value above the therapeutic interval (2-3) was 2.8 (95% confidence interval, 1.2-6.7) and 6.1 (2.7-13.6) in the *2 and *3 groups, respectively (with *1 used as control). During the second week, the corresponding values were 2.1 (1.2-3.7) and 3.5 (2.1-5.8), respectively. By the third week, the genetic impact was no longer evident, presumably as a result of successful dose individualization. Increased INR levels (compared with the *1 group) were already demonstrated in the *2 group on the fourth treatment day. CONCLUSIONS: The CYP2C9*2 and *3 single-nucleotide polymorphisms significantly increase the risk of overanticoagulation during the first 2 weeks of warfarin treatment, with increased INR levels evident after only 4 days' treatment in *2 carriers. Our prospective data are consistent with results from previous retrospective studies and indicate that CYP2C9 genotyping may be a means of improving safety during warfarin induction.

Incidence and predictors of severe bleeding during warfarin treatment.

BACKGROUND: Optimal warfarin prescription requires correct, individualized assessment of the warfarin-related bleeding risk, which randomised controlled trials may underestimate . Observational studies have reported a range of bleeding risks that differ 40-fold. This variation may be caused by time trends, variation in bleeding definition and study subject selection. We investigated the incidence of, and risk factors for severe bleeding in un-selected warfarin-treated patients from Sweden. METHODS: Between 2001 and 2005, 40 centres recruited warfarin-naïve patients commencing warfarin therapy and followed them prospectively with continuous registration of clinical data. The primary outcome was severe bleeding, according to the WHO universal definition of severe adverse drug reactions. The influence of potential risk factors was investigated by means of a Cox proportional-hazards model. RESULT: A total of 1523 patients contributed 1276 warfarin-exposed patient-years. The incidence of first-time severe bleeding was 2.3 per 100 patient-years (95% confidence interval 1.4 to 3.1). Male sex and use of drugs potentially interacting with warfarin were the only independent risk factors of severe bleeding, with hazard ratios of 2.8 and 2.3, respectively. Age, target International Normalized Ratio (INR), time spent outside target INR range, and warfarin dose requirement were not significantly associated with bleeding risk. CONCLUSIONS: The risk of severe bleeding in a large naturalistic, prospective cohort of first-time warfarin users was lower than reported in some previous reports. Male gender was an independent predictor of severe bleeding as was the receipt of warfarin-interacting medications at the onset of anticoagulation therapy. Further studies are required to evaluate the effect these findings may have on the quality of current risk-benefit analysis involved in warfarin prescription.