Anders Sundström

A signal for an abuse liability for pregabalin—results from the Swedish spontaneous adverse drug reaction reporting system

PurposePregabalin is a gamma-aminobutyric acid (GABA) analogue approved for the treatment of epilepsy, neuropathic pain and generalised anxiety disorder. As a GABA analogue, there has been some concern about an abuse liability. We aimed to investigate the possible abuse liability of pregabalin.MethodsBy applying a Bayesian data-mining algorithm to reports of possible drug abuse or addiction in the Swedish national register of adverse drug reactions (SWEDIS), we calculated the information component (IC) for pregabalin and reports of abuse and addiction.ResultsOut of 198 reports indicative of abuse or addiction to any drug, 16 concerned pregabalin. The IC became significantly elevated in the fourth quarter of 2008, rising to 3.99 (95% confidence interval 3.21–4.59) at the end of 2009.ConclusionBased on the signal from the present study, we conclude that pregabalin is likely to be associated with an abuse potential.

Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study

Objective To assess the risk of attempted suicide before, during, and after treatment with isotretinoin for severe acne. Design Retrospective cohort study linking a named patient register of isotretinoin users (1980-9) to hospital discharge and cause of death registers (1980-2001). Setting Sweden, 1980-2001. Population 5756 patients aged 15 to 49 years prescribed isotretinoin for severe acne observed for 17 197 person years before, 2905 person years during, and 87 120 person years after treatment. Main outcome measures Standardised incidence ratio (observed number divided by expected number of suicide attempts standardised by sex, age, and calendar year), calculated up to three years before, during, and up to 15 years after end of treatment. Results 128 patients were admitted to hospital for attempted suicide. During the year before treatment, the standardised incidence ratio for attempted suicide was raised: 1.57 (95% confidence interval 0.86 to 2.63) for all (including repeat) attempts and 1.36 (0.65 to 2.50) counting only first attempts. The standardised incidence ratio during and up to six months after treatment was 1.78 (1.04 to 2.85) for all attempts and 1.93 (1.08 to 3.18) for first attempts. Three years after treatment stopped, the observed number of attempts was close to the expected number and remained so during the 15 years of follow-up: standardised incidence ratio 1.04 (0.74 to 1.43) for all attempts and 0.97 (0.64 to 1.40) for first attempts. Twelve (38%) of 32 patients who made their first suicide attempt before treatment made a new attempt or committed suicide thereafter. In contrast, 10 (71%) of the 14 who made their first suicide attempt within six months after treatment stopped made a new attempt or committed suicide during follow-up (two sample test of proportions, P=0.034). The number needed to harm was 2300 new six month treatments per year for one additional first suicide attempt to occur and 5000 per year for one additional repeat attempt. Conclusions An increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin, which motivates a close monitoring of patients for suicidal behaviour for up to a year after treatment has ended. However, the risk of attempted suicide was already rising before treatment, so an additional risk due to the isotretinoin treatment cannot be established. As patients with a history of suicide attempts before treatment made new attempts to a lesser extent than did patients who started such behaviour in connection with treatment, patients with severe acne should not automatically have isotretinoin treatment withheld because of a history of attempted suicide.

The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case–control study using the General Practice Research Database

Objective  To assess whether use of tranexamic acid is associated with an increased risk of venous thromboembolism (VTE).

Generalisability of clinical registers used for drug safety and comparative effectiveness research: coverage of the Swedish Biologics Register

Objective To determine coverage and generalisability of data in the Swedish Biologics Register ARTIS. Methods Patients with adult onset rheumatoid arthritis (RA) were identified in the National Patient Register and the Swedish Rheumatology Quality Register, including the ARTIS cohort of patients exposed to biological agents. Exposure to etanercept and adalimumab between 2006 and 2008 was determined by register linkage to the Prescribed Drug Register which contains patient-level data on >99% of all etanercept and adalimumab use in Sweden. Results Of 62 897 patients with RA, 6510 had received treatment with etanercept or adalimumab according to the Prescribed Drug Register. Of these, 5673 were also registered in ARTIS, resulting in a national coverage of 87%. The regional variation was small with >85% coverage in 18 of 21 counties. In multivariable analysis, ARTIS-registered and non-registered patients did not differ by age (p=0.62), sex (p=0.84) or education level (p=0.24). Conclusion Nationwide drug dispensing and demographic data may function as quality metrics for coverage and generalisability assessments. Using such data, the coverage of ARTIS was estimated at 87% with no indications of compromised external generalisability regarding demography.

Risk of clinically relevant bleeding in warfarin‐treated patients—influence of SSRI treatment

To investigate the risk of clinically relevant bleeding in warfarin‐treated patients with or without concomitant treatment with selective serotonin reuptake inhibitors (SSRIs).

Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009

Objective: To measure small-area variations in sales per capita of tumour necrosis factor (TNF) inhibitors. Methods: For 2000–2009, sales data on etanercept, infliximab, and adalimumab were retrieved from the Swedish National Corporation of Pharmacies, which keeps data on drugs dispensed in ambulatory care and hospitals. As points of reference, data were retrieved on all drugs, non-biologic treatments for chronic inflammatory disorders (sulfasalazine, methotrexate, azathioprine), and for a biologic used in a different therapeutic area (trastuzumab). As a corollary measure to sales per capita, penetration of biologics in the rheumatoid arthritis (RA) population was calculated using nationwide registers. Small areas were defined as the 21 counties of Sweden. Results: From 2000 to 2009, annual TNF inhibitor sales increased 9-fold from 195 to 1779 million SEK (0.7–5.0% of total drug expenditure). The county variation in sales per capita, initially 6.2-fold (coefficient of variation 42%), decreased to 2.3-fold in 2009 (24%). During the same period, total drug expenditure per capita remained at a 1.2-fold county variation (4–6%). Sales per capita variations of non-biologic treatments against chronic inflammatory diseases ranged from 1.5 to 1.8 (12–16%). For trastuzumab, a 3.2-fold variation (30%) was observed in 2009. At the patient level, there was a 2-fold county variation (from 10% to 21%) in biologic penetration in RA. County-specific sales per capita were associated with mean RA duration (r = −0.52, p = 0.015) and C-reactive protein at treatment initiation (r = −0.49, p = 0.025), while pain was borderline significant (r = −0.43, p = 0.055). Conclusions: Despite universal access to treatment, substantial but decreasing small-area variations were observed. Although geographic variations are anticipated initially, their persistence calls for investigation of patient equity and treatment appropriateness as counties seem to have different initiation thresholds.

The higher proportion of men with psoriasis treated with biologics may be explained by more severe disease in men.

Objectives Moderate to severe psoriasis, once regarded as merely a skin disease, is today seen as an inflammatory systemic disease. The sex ratio of the prevalence of psoriasis is balanced. In recent years several reports have documented that men receive more systemic or UV treatment than women, and different hypotheses were made. In PsoReg, the national registry for systemic treatment of psoriasis in Sweden, we have, like other European registries, observed a predominance of men (59%), especially of men treated with biologics (63%). Biologics are a relatively new group of very effective but high-priced drugs. The objective of this study was to analyse if women are discriminated by not having the same access to the high-priced biologics. Design Population based cohort study using data from a nationwide quality register of psoriasis patients. Population 2294 patients with moderate to severe psoriasis receiving systemic treatment from a specialist in dermatology. Main Outcome Measures Time to initiation of biologic treatment. A multiple Cox proportional hazard’s regression was performed, with time to initiating a biologic treatment as the outcome in order to assess the independent role of the patient’s sex in initiating such therapy. The psoriasis severity was defined as a time-varying variable. Results Men had more severe psoriasis than women according to the Psoriasis Area and Severity Index (PASI), regardless of age at enrolment, and throughout the study period. The analysis in the multiple Cox regression show that age, psoriasis severity and psoriasis arthropathy were relevant factors for initiating biologic therapy, whereas sex is not. Conclusions Although as many women as men are believed to suffer from psoriasis, men seem to be more severely affected by psoriasis. The asymmetry in allocation of biologic therapy thereby probably reflects the differing disease activity between the sexes, and is not a discrimination against women per se.

Montelukast and psychiatric disorders in children

A signal has been raised concerning montelukast and adverse drug reactions (ADRs) in children. The purpose of the present study was to evaluate psychiatric ADRs during treatment with montelukast in children.

Duration of dual antiplatelet treatment with clopidogrel and aspirin in patients with acute coronary syndrome

AIMS Dual antiplatelet treatment (DAPT) is a cornerstone in the treatment of acute coronary syndrome (ACS) but the optimal treatment duration is unclear. We aimed to evaluate the effect of DAPT duration with clopidogrel and aspirin on the recurrence of ischaemic events and bleeding in a large, unselected ACS population. METHODS AND RESULTS We performed a prospective, observational cohort study of patients in Sweden (n = 56 440) admitted for ACS, with prescribed DAPT and hospitalized between January 2006 and July 2010. Patients were obtained from the SWEDEHEART register and data were merged with registers from the National Board of Health and Welfare. Depending on dispensed clopidogrel tablets, patients were divided into groups based on DAPT duration with clopidogrel and aspirin (3 months: 84-100 clopidogrel tablets (t); >3 months: >100 t; 6 months: 168-200 t; >6 months: >200 t). For the combined primary endpoint, defined as all-cause death, stroke, or re-infarction, only patients with an uneventful first 3-month period (no death, stroke, re-infarction, bleeding, stent thrombosis, or revascularization) were included. The incidence of the primary endpoint was 45 events per 1000 person-years in the >3 months DAPT group compared with 65 events per 1000 person-years in the 3 months DAPT group [adjusted HR 0.84, 95% CI (0.75; 0.95)]. Bleeding was more common in the >3 months treatment group (adjusted HR 1.56, 95% CI (1.18; 2.07), but the number of events was small. For >6 vs. 6 months DAPT, the adjusted HR for the combined endpoint was 0.75 with 95% CI (0.59; 0.95). CONCLUSION In this contemporary, large real-life ACS population, DAPT for more than 3 months compared with a shorter duration was associated with a lower risk of death, stroke, or re-infarction. TRIAL REGISTRATION Clinicaltrials.gov (NCT01623700).

The asian pharmacoepidemiology network (AsPEN): Promoting multi-national collaboration for pharmacoepidemiologic research in Asia

Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden Medical Research Collaborating Center, Seoul National University Hospital/Seoul National University College of Medicine, Seoul, South Korea Institute for Health, Health Care Policy and Aging Research, Rutgers University, New Brunswick, NJ, USA Department of Medicine, Division of Pharmacoepidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA Department of Medical Informatics, School of Medicine, Hamamatsu University, Shizuoka, Japan Department of Pharmacoepidemiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Institute of Clinical Pharmacy and Pharmaceutical Sciences, and Health Outcome Research Center, National Cheng Kung University, Tainan, Taiwan Department of Preventative Medicine, College of Medicine, Seoul National University, Seoul, South Korea Korea Institute of Drug Safety and Risk Management, Seoul, South Korea Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia Duke Clinical Research Institute, Durham, NC, USA Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden Karolinska University Hospital, Stockholm, Sweden Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, South Korea Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA