Solveig Sakshaug

Resting heart rate and physical activity as risk factors for lone atrial fibrillation: a prospective study of 309 540 men and women

Objective To study the impact of resting heart rate and leisure time physical activity at middle age on long term risk of drug treated lone atrial fibrillation (AF). Design Longitudinal cohort study of 309 540 Norwegian men and women aged 40–45 years examined during 1985–1999 followed from 2005 through 2009. Setting Data from a national health screening programme were linked to the Norwegian Prescription Database (NorPD). Patients The cohort comprised 162 078 women and 147 462 men; 575 (0.4%) men and 288 women (0.2%) received flecainide and 568 men and 256 women sotalol and were defined as patients with AF. Interventions No interventions. Main outcome measures The outcome was lone fibrillation defined by having at least one prescription of flecainide or sotalol registered in NorPD between 2005 and 2009. Cox proportional hazard regression models were used to assess time to first prescription. Results The risk for being prescribed these drugs increased with decreasing baseline resting heart. Adjusted hazard ratio (HR) per 10 beats/min decrease in resting heart rate for flecainide prescription was 1.26 in men (95% CI 1.17 to 1.35) and 1.15 (95% CI 1.05 to 1.27) in women. Similar effects were seen for sotalol in men, but not in women. Men who reported intensive physical activity were more often prescribed flecainide than those in the sedentary group (adjusted HR=3.14, 95% CI 2.17 to 4.54). Conclusions This population based study supports the hypothesis that the risk of drug treated lone AF increases with declining resting heart rate in both sexes, and with increasing levels of self-reported physical activity in men.

Combination of prescribing restrictions and policies to engineer low prices to reduce reimbursement costs

Objectives: To primarily document the influence of recent changes in the pricing policies for generics and originators in Norway, coupled with prescribing restrictions for both the proton pump inhibitors (PPIs) and statins, on subsequent prescribing efficiency, to provide possible examples to other countries. Second, to review the impact of prescribing restrictions on ezetimibe utilization in Norway compared with other European countries, again to provide guidance. Methods: A retrospective observational study using data from the Norwegian Drug Wholesales Statistics to evaluate changes in utilization patterns for the PPIs and statins from 2001 to 2009, and the Norwegian Prescription Database for expenditure data from January 2004 to 2009. Reforms validated with key personnel at the Norwegian Medicines Agency. Results: Atorvastatin utilization as measured by defined daily doses decreased after prescribing restrictions. This, coupled with increased utilization of generic simvastatin at only 15% of prepatent loss prices in recent years, led to a 55% decrease in statin expenditure in Norway between 2004 and 2009 despite appreciably increased utilization. Utilization of esomeprazole also fell following prescribing restrictions, but to a lesser extent. This reduction, coupled with low prices for generics as a result of recent pricing policies, resulted in PPI expenditure decreasing by 27% during the same period despite again appreciably increased utilization. Conclusions: Policies to reduce the price of generics have been successfully introduced in Norway despite its small population size versus a number of other Western European countries. Prescribing restrictions have also been successfully introduced, mirroring the influence with multifaceted reforms in other European countries. The same applies to ezetimibe with utilization at only 1.9% of total statin and ezetimibe utilization in 2009. However, the difference in subsequent utilization patterns for atorvastatin versus esomeprazole makes it a challenge for health authorities to predict the ultimate impact of such measures. This requires further research.

Breast cancer incidence trends in Norway-explained by hormone therapy or mammographic screening?

A decline in breast cancer incidence has been observed in several countries after 2002. Reduced use of menopausal hormonal therapy (HT), as a consequence of the publication of results from the Womens Health Initiative, has been argued to be the main reason. In Norway, the governmentally funded Norwegian Breast Cancer Screening Program (NBCSP) was implemented during the same time period as the increased use of HT. This study investigated trends in breast cancer incidence by use of HT and introduction of the screening program. We obtained rates of breast cancer from the Cancer Registry of Norway and sales data of HT preparations from the Norwegian Institute of Public Health. Mammography rates were estimated from published reports. Breast cancer incidence rates increased steadily from 1956 to the end of the 20th century, particularly in women aged 55–69 during 1996–2002 residing in the counties where the NBCSP was first introduced. The rates declined after 2002–2003. HT use increased in 1987–2001, peaking around year 2000. In particular, sales of combined estrogen and progestogen preparations declined after 2002. Among women aged 55–59, rates of hormone receptor positive breast cancers peaked in 2000–2003. No such trend was seen in other age groups. In conclusion, the interpretation of breast cancer incidence trends in Norway from 1987 to 2009 is complicated because the NBCSP was introduced during a period with increasing HT use. Both factors likely contributed to the observed trends, and the role of each may vary across age groups.

Aspects of statin prescribing in Norwegian counties with high, average and low statin consumption – an individual-level prescription database study

BackgroundA previous study has shown that variations in threshold and intensity (lipid goal attainment) of statins for primary prevention contribute to regional differences in overall consumption of statins in Norway. Our objective was to explore how differences in prevalences of use, dosing characteristics, choice of statin and continuity of therapy in individual patients adds new information to previous results.MethodsData were retrieved from The Norwegian Prescription Database. We included individuals from counties with high, average, and low statin consumption, who had at least one statin prescription dispensed during 2004 (N = 40 143).1-year prevalence, prescribed daily dose (PDD), statin of choice, and continuity of therapy assessed by mean number of tablets per day.ResultsThe high-consumption county had higher prevalence of statin use in all age groups.Atorvastatin and simvastatin were dispensed in 79–87% of all statin users, and the proportion was significantly higher in the high-consumption county.The estimated PDDs were higher than the DDDs, up to twice the DDD for atorvastatin. The high-consumption county had the highest PDD for simvastatin (25.9 mg) and atorvastatin (21.9 mg), and more users received tablets in the upper range of available strengths. Continuity of therapy was similar in the three counties.ConclusionAlthough differences in age-distribution seems to be an important source of variation in statin consumption, it cannot account for the total variation between counties in Norway. Variations in prevalences of use, and treatment intensity in terms of PDD and choice of statin also affect the total consumption. The results in this study seems to correspond to previous findings of more frequent statin use in primary prevention, and more statin users achieving lipid goal in the highest consuming county.

Body mass index, triglycerides, glucose, and blood pressure as predictors of type 2 diabetes in a middle-aged Norwegian cohort of men and women.

Background Obesity, hypertension, and hypertriglyceridemia are important risk factors for type 2 diabetes (T2D). We wanted to assess the risk associated with these three factors alone and in combination, and the relative importance of these and several other risk factors (eg, nonfasting glucose) as predictors of T2D. Methods Risk factors in a Norwegian population (n = 109,796) aged 40–45 years were measured in health studies in 1995–1999. Blood glucose-lowering drugs dispensed in 2004–2009 were used to estimate the incidence of T2D. Groups based on combinations of body mass index (BMI), diastolic blood pressure, and triglycerides were defined by using the 50% and 90% quantiles for each variable for men and women. The relative importance of BMI, triglycerides, total cholesterol, high-density lipoprotein cholesterol, glucose, blood pressure, and year of birth for predicting T2D was assessed using deviance from univariate and multivariate logistic regression models. Height, weight, and blood pressure were measured. All biomarkers were measured in nonfasting blood samples. Results In the various groups of BMI, triglycerides, and diastolic blood pressure, the incidence of T2D ranged from 0.5% to 19.7% in men and from 0.15% to 21.8% in women. BMI was the strongest predictor of incident T2D, followed by triglyceride levels in women and glucose levels in men. The inclusion of risk factors other than BMI, glucose, triglycerides, and blood pressure in multivariate models only marginally improved the prediction. Conclusion BMI was the strongest predictor of type 2 diabetes. At defined levels of BMI, the incidence of T2D varied substantially with triglyceride levels and blood pressure. Thus, controlling triglycerides and blood pressure in middle-aged individuals should be targeted to prevent later onset of T2D.

Trends in prescription of strong opioids for 41–80 year old Norwegians, 2005–2010

The use of strong opioids is affected by various influences such as increasing emphasis on adequate pain control and increasing measures to counteract opioid abuse. This study will examine trends of analgesic strong opioid use in an older population.

Postmenopausal hormone therapy and the risk of breast cancer in Norway

There is convincing evidence that combined estrogen–progestin therapy (EPT) increases the risk of breast cancer. However, the effect of different formulations, preparations and routes of administration is largely unknown. Estrogen only‐therapy (ET) is, in general, not associated or weakly associated with breast cancer risk. We investigated the effect of hormone therapy (HT) with ET, EPT, and tibolone on risk of invasive breast cancer. Information on HT use was obtained from the Norwegian Prescription Database, and breast cancer incidence from the Cancer Registry of Norway. Poisson regression was used to estimate the incidence rate ratios (RR). We analyzed data from 686,614 Norwegian women, aged 45–79 years in January 2004, followed until December 2008, of whom 178,383 (26%) were prescribed HT. During the average 4.8 years of follow‐up, 7,910 invasive breast cancers were registered. Compared with nonusers, current users of estradiol–norethisterone acetate (NETA)(EPT) had a RR of 2.74 (95% CI: 2.55–2.95). Users of the high dose estradiol–NETA formulation Kliogest® had a RR of 3.26 (95% CI: 2.84–3.73), while users of the low dose Activelle® had a RR of 2.76 (95% CI: 2.51–3.04). Current users of tibolone had a RR of 1.91 (95% CI: 1.61–2.28). Current users of ET with oral or transdermal estradiol had a RR of 1.40 (95% CI: 1.16–1.68), and 1.40 (95% CI: 1.00–1.95), respectively. The increased incidence rates approximates one extra invasive breast cancer case diagnosed for every 259 women using estradiol–NETA for one year, and one extra case for every 475 women using tibolone. In conclusion, use of estradiol–NETA and tibolone preparations is associated with an increased breast cancer risk.

Menopausal hormone therapy and risk of melanoma: Do estrogens and progestins have a different role?

The association between use of menopausal hormone therapy (HT) and occurrence of skin malignant melanoma (SMM) is controversial. We investigated the issue in a nationwide cohort of 684,696 Norwegian women, aged 45–79 years, followed from 2004 to 2008. The study was based on linkage between Norwegian population registries. Multivariable Poisson regression models were used to estimate the effect of HT use, different HT types, routes of administration and doses of estrogen and progestin on the risk of SMM. During the median follow‐up of 4.8 years, 178,307 (26%) women used HT, and 1,476 incident SMM cases were identified. Current use of HT was associated with increased risk of SMM (rate ratios (RR) = 1.19; 95% confidence interval (CI) 1.03–1.37). Plain estrogen therapy was associated with an increased risk of SMM (RR 1.45; 95% CI 1.21–1.73), both for oral (RR 1.45; 95% CI 1.09–1.93) and vaginal (RR 1.44; 95% CI 1.14–1.84) formulations, while combined estrogen and progestin therapy (EPT) was not (RR 0.91; 95% CI 0.70–1.19). We performed a dose–response analysis of estrogen and progestin in women using tablets, and found that use of estrogens was associated with increased risk (RR 1.24; 95% CI 1.00–1.53 per 1 mg/day) and use of progestins with decreased risk (RR 0.71; 95% CI 0.57–0.89 per 10 mg/month) of SMM. In conclusion, estrogens were associated with increased risk of SMM, while combinations of estrogens and progestins were not. Our results suggest that estrogens and progestins might affect the risk of SMM in opposite ways.

Long-term Use of Z-Hypnotics and Co-Medication with Benzodiazepines and Opioids.

Benzodiazepine‐like drugs (z‐hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z‐hypnotics are recommended for short‐term treatment not exceeding 4 weeks. We aimed to study the use of z‐hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co‐medication with benzodiazepines and opioids in long‐term users. Data were obtained from the Norwegian Prescription Database. New users in 2009 were followed through 2013. Recurrent z‐hypnotic use was defined as new fillings at least once in each of the four 365‐day follow‐up periods. Age groups of 18–39, 40–64 and 65+ years were analysed separately for men and women. In 2013, 354,571 (8.9%) of the population filled at least one prescription of z‐hypnotics and the prevalence was relatively stable over time. Among the 92,911 new users of z‐hypnotics in 2009, 13,996 (16.8%) received z‐hypnotics all four 365‐day periods of follow‐up. In these long‐term recurrent users, the treatment intensity was high already the second year, with mean annual amounts of 199 and 169 DDDs per patient in men and women, respectively. The interquartile differences were greatest in the youngest age group. 27.9% of the long‐term recurrent users of z‐hypnotics used benzodiazepines the fourth year and 33.9% used opioids. The proportions with co‐medication increased with level of z‐hypnotic treatment intensity. Overall, many z‐hypnotic users had medicines dispensed for longer periods than recommended, and co‐medications with drugs that may reinforce the central depressing and intoxicating effects were common.

Postmenopausal Hormone Therapy and Breast Cancer Prognostic Characteristics: A Linkage between Nationwide Registries

Background: The effects of use of different types of hormone therapy on breast cancer risk according to prognostic factors are largely unknown. Methods: We linked data from the Norwegian Prescription Database and the Cancer Registry of Norway during 2004 to 2009 on all women ages 45 to 79 years (N = 686,614). We estimated rate ratios and 95% confidence intervals for breast cancer in relation to hormone therapy using Poisson regression. Results: During an average 4.8 years of follow-up, 7,910 invasive breast cancers were diagnosed. Compared with nonusers of hormone therapy, users of estradiol and tibolone were more likely to be diagnosed with grade I, lymph node–negative, and estrogen receptor–positive (ER+)/progesterone receptor–positive (PR+) tumors. However, compared with nonusers, users of the most common estrogen and progestin combinations [estradiol–norethisterone acetate (NETA) preparations (Kliogest, Activelle or Trisekvens)] were at a 4- to 5-fold elevated risk of grade I tumors, 3-fold elevated risk of lymph node–negative tumors, and 3- to 4-fold elevated risk of ER+/PR+ tumors. Importantly, estradiol–NETA users were also at a 2- to 3-fold increased risk of medium differentiated (grade II) tumors and tumors with lymph node involvement. Conclusions: Use of oral estradiol, tibolone, and estradiol–NETA predominantly increases the risk of breast cancer with favorable prognosis characteristics. However, use of estradiol–NETA preparations also increases the risk of breast cancers with less favorable characteristics. Impact: The hormone therapy preparations most commonly used in the Nordic countries are associated with both breast cancers with good and less favorable prognosis characteristics. Cancer Epidemiol Biomarkers Prev; 25(11); 1464–73. ©2016 AACR.