Lars Hougaard Nielsen

Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9

Objective To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose. Design National historical registry based cohort study. Setting Four registries in Denmark. Participants Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009. Main outcome measures Relative and absolute risks of first time venous thromboembolism. Results Within 8 010 290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10 000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year. Conclusion After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.

Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10

Objective To assess the risk of venous thrombosis in current users of non-oral hormonal contraception. Design Historical national registry based cohort study. Setting Four national registries in Denmark. Participants All Danish non-pregnant women aged 15-49 (n=1 626 158), free of previous thrombotic disease or cancer, were followed from 2001 to 2010. Main outcome measures Incidence rate of venous thrombosis in users of transdermal, vaginal, intrauterine, or subcutaneous hormonal contraception, relative risk of venous thrombosis compared with non-users, and rate ratios of venous thrombosis in current users of non-oral products compared with the standard reference oral contraceptive with levonorgestrel and 30-40 µg oestrogen. Diagnoses were confirmed by at least four weeks of anticoagulation therapy after the diagnosis. Results Within 9 429 128 woman years of observation, 5287 first ever venous thrombosis events were recorded, of which 3434 were confirmed. In non-users of hormonal contraception the incidence rate of confirmed events was 2.1 per 10 000 woman years. Compared with non-users of hormonal contraception, and after adjustment for age, calendar year, and education, the relative risk of confirmed venous thrombosis in users of transdermal combined contraceptive patches was 7.9 (95% confidence interval 3.5 to 17.7) and of the vaginal ring was 6.5 (4.7 to 8.9). The corresponding incidences per 10 000 exposure years were 9.7 and 7.8 events. The relative risk was increased in women who used subcutaneous implants (1.4, 0.6 to 3.4) but not in those who used the levonorgestrel intrauterine system (0.6, 0.4 to 0.8). Compared with users of combined oral contraceptives containing levonorgestrel, the adjusted relative risk of venous thrombosis in users of transdermal patches was 2.3 (1.0 to 5.2) and of the vaginal ring was 1.9 (1.3 to 2.7). Conclusion Women who use transdermal patches or vaginal rings for contraception have a 7.9 and 6.5 times increased risk of confirmed venous thrombosis compared with non-users of hormonal contraception of the same age, corresponding to 9.7 and 7.8 events per 10 000 exposure years. The risk was slightly increased in women using subcutaneous implants but not in those using the levonorgestrel intrauterine system.

Hormone therapy and risk of myocardial infarction: a national register study.

AIM To assess the risk of myocardial infarction (MI) as a result of hormone therapy (HT), with focus on the influence of age, duration of HT, various regimens and routes, progestagen type, and oestrogen dose. METHODS AND RESULTS All healthy Danish women (n = 698,098, aged 51-69) were followed during 1995-2001. On the basis of a central prescription registry, daily updated national capture on HT was determined. National Registers identified 4947 MI incidents. Poisson regression analyses estimated rate ratios (RRs). Overall, we found no increased risk [RR 1.03 (95% CI: 0.95-1.11)] of MI with the current HT compared with women who never used HT; age-stratified RR among women aged 51-54, 55-59, 60-64, and 65-69 years were 1.24 (1.02-1.51), 0.96 (0.82-1.12), 1.11 (0.97-1.27), and 0.92 (0.80-1.06), respectively. An increasing risk with longer duration was found for younger women, which was not observed with older age groups. In all age groups, the highest risk of MI was found with continuous HT regimen. No increased risk was found with unopposed oestrogen, cyclic combined therapy, or tibolone. Significantly lower risk was found with dermal route than oral unopposed oestrogen therapy (P = 0.04). No associations were found with progestagen type or oestrogen dose. CONCLUSION In a National cohort study, we found that HT regimen and route of application could modify the influence of HT on the risk of MI.

Consumer reporting of adverse drug reactions: a retrospective analysis of the Danish adverse drug reaction database from 2004 to 2006.

AbstractBackground: Reporting adverse drug reactions (ADRs) has traditionally been the sole province of healthcare professionals. Since 2003 in Denmark, consumers have been able to report ADRs directly to the authorities. The objective of this study was to compare ADRs reported by consumers with ADRs reported from other sources, in terms of their type, seriousness and the suspected medicines involved. Methods: The number of ADRs reported to the Danish ADR database from 2004 to 2006 was analysed in terms of category of reporter, seriousness, category of ADRs by system organ class (SOC) and the suspected medicines on level 1 of the anatomical therapeutic chemical (ATC) classification system. ADR reports from consumers were compared with reports from other sources (physicians, pharmacists, lawyers, pharmaceutical companies and other healthcare professionals). Chi-square and odds ratios (ORs) were calculated to investigate the dependence between type of reporter and reported ADRs (classified by ATC or SOC). Findings: We analysed 6319 ADR reports corresponding to 15 531 ADRs. Consumers reported 11% of the ADRs. Consumers’ share of’serious’ ADRs was comparable to that of physicians (approximately 45%) but lower than that of pharmacists and other healthcare professionals. When consumer reports were compared with reports from other sources, consumers were more likely to report ADRs from the following SOCs: ‘nervous system disorders’ (OR =1.27; 95% CI 1.05, 1.53); ‘psychiatric disorders’ (OR =1.70; 95% CI 1.31, 2.20) and ‘reproductive system and breast disorders’ (OR = 2.02; 95% CI 1.13, 3.61) than other sources. Compared with other sources, consumers reported fewer ADRs from the SOCs ‘blood and lymphatic system disorders’ (OR = 0.22; 95% CI 0.08, 0.59) and ‘hepatobiliary system disorders’ (OR = 0.14; 95% CI 0.04, 0.57). Consumers were more likely to report ADRs from the ATC group N (nervous system) [OR = 2.72; 95% CI 2.34, 3.17], ATC group P (antiparasitic products) [OR = 2.41; 95% CI 1.32, 4.52] and ATC group S (sensory organs) [OR = 4.79; 95% CI 2.04, 11.23] than other sources. Consumers reported fewer ADRs from the ATC group B (blood and blood-forming organs) [OR = 0.04; 95% CI 0.006, 0.32] and the ATC groups J (anti-infective for systemic use) [OR=0.44; 95% CI 0.33, 0.58], L (antioneoplastic and immunomodulating agents) [OR= 0.19; 95% CI 0.12,0.30] and V (various) [OR = 0.03; 95% CI 0.004, 0.21] than other sources. In the SOC ‘nervous system disorders’, consumers reported seven categories of ADRs that were not reported by the other sources. Conclusion: This study showed that compared with other sources, consumers reported different categories of ADRs for different types of medicines. Consumers should be actively included in systematic drug surveillance systems, including clinical settings, and their reports should be taken as seriously as reports from other sources.

Multivariate Latent Risk: A Credibility Approach

We investigate a concept of multivariate pricing, which includes claim history for more than one line of business and is a generalization of the Buhlmann-Straub model. The multivariate credibility model is extended to allow for the age of claims to influence the estimation of future claims. The model is applied to data from a portfolio of commercial lines of business.

Clopidogrel discontinuation after myocardial infarction and risk of thrombosis: a nationwide cohort study

AIMS The benefit of extending clopidogrel treatment beyond the 12-month period recommended in current guidelines after myocardial infarction (MI) is debated. We analysed the risk of adverse cardiovascular outcomes after discontinuation of 12 months of clopidogrel treatment. METHODS AND RESULTS This Danish retrospective nationwide study included all patients treated with clopidogrel after discharge from a first-time MI during 2004-09. The risk of death or recurrent MI after the discontinuation of clopidogrel was studied by multivariable Poisson regression models. Patients treated with and without percutaneous coronary intervention (PCI) were analysed separately. The follow-up was 18 months. Of the 29,268 patients included, 3214 (11.0%) experienced death or recurrent MI. There were 9819 (33.6%) patients treated only medically and 19,449 (66.4%) patients treated with PCI. Twelve months after the index MI, for patients treated only medically, the risk of death or recurrent MI in the first 90-day period of clopidogrel discontinuation was 1.07 (0.65-1.76; P= 0.79) [adjusted incidence rate ratio (IRR) and 95% confidence interval] compared with the next 90-day period of discontinuation. For patients treated with PCI, the corresponding IRR was 1.59 (1.11-2.30; P= 0.013). The risk of recurrent MI yielded an IRR of 0.77 (0.36-1.67; P= 0.51) for patients treated only medically and 1.87 (1.11-3.15; P= 0.019) for PCI-treated patients. CONCLUSION Discontinuation of clopidogrel 12 months after MI is associated with an increased risk of death or recurrent MI in the first 90 days of discontinuation compared with the next 90-day period of discontinuation for patients treated with PCI, but not for patients not treated with PCI.

Estimating the effect of current, previous and never use of drugs in studies based on prescription registries†

Many studies which investigate the effect of drugs categorize the exposure variable into never, current, and previous use of the study drug. When prescription registries are used to make this categorization, the exposure variable possibly gets misclassified since the registries do not carry any information on the time of discontinuation of treatment.

Risk of Stroke With Various Types of Menopausal Hormone Therapies: A National Cohort Study

Background and Purpose— Double-blind randomized studies on the effects of oral postmenopausal hormone therapies were stopped mainly because of increased risk of stroke. We aimed to assess the risk of all strokes and various subtypes associated with hormone therapy and explore the influence of regimens and routes of administration. Methods— A national historical cohort of women aged 51 to 70 years from 1995 to 2010 was established by linking 5 Danish registries. The National Registry of Medicinal Product Statistics provided information on hormone therapy exposure and the National Patient or Cause of Death Registries supplied data regarding stroke diagnoses (ischemic/hemorrhagic/subarachnoid hemorrhage). Multiply adjusted rate ratios with time-varying covariates were fitted in Poisson regression models. Results— Of the 980 003 included women, 20 199 suffered a stroke (78% ischemic, 12% hemorrhagic, and 10% subarachnoid hemorrhage). In total, 36% of women used hormone therapy. Current use conferred a relative rate of 1.16 (95% confidence interval, 1.12–1.22). Compared with never users, the increased rate ratio of all stroke with continuous, cyclic combined estrogen/progestin, and estrogen only oral therapies were 1.29 (95% confidence interval, 1.21–1.37), 1.11 (95% confidence interval, 1.04–1.20), and 1.18 (95% confidence interval, 1.10–1.26), respectively. The increased risk was because of ischemic stroke, but not hemorrhagic stroke. Transdermal application of hormone therapy was not associated with risk of stroke. Vaginal estrogen was associated with a decreased risk of stroke. Conclusions— In a national setting, we found an increased risk of stroke, based on ischemic stroke, with oral hormone therapies that was comparable to findings from randomized studies. We found no risk of stroke with transdermal application and a reduced risk with vaginal estrogen.