EPID Research Oy

Espoo, Finland

EPID Research Oy

Espoo, Finland

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Savolainen-Peltonen H.,University of Helsinki | Savolainen-Peltonen H.,Folkhalsan Research Center | Tuomikoski P.,University of Helsinki | Korhonen P.,EPID Research Oy | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2016

Context: The window of opportunity hypothesis" refers to data indicating that conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, if initiated before 60 years of age, protects the heart but endangers it if initiated later (Women's Health Initiative study). Less is known about the "window of opportunity hypothesis" with natural estradiol alone (ET) or with various progestins in combination with estradiol (EPT). Objective: We related the death risk from coronary heart disease (CHD) in users of ET or EPT to the age at the initiation of therapy and to the progestin component of EPT. Design, Patients, Interventions, and Main Outcome Measures: Altogether, 498 105 women had used ET or EPT containing medroxyprogesterone acetate, norethisterone acetate, dydrogesterone, other progestins, or tibolone during 3.7 million person-years during 1994-2009. Women were followed from the therapy initiation to death, or to the end of year 2009. The risk of CHD death in hormone users was compared with that in the age-matched background population using standardized mortality ratio with 95% confidence intervals. Results: Age younger than 60 rather than older than 60 years at the initiation of ET (standardized mortality ratio, 0.53; 95% confidence interval, 0.47-0.59 vs 0.76; 0.71-0.82), EPT with norethisterone acetate (0.45; 0.41-0.49 vs 0.74; 0.67-0.81), or tibolone (0.35; 0.26-0.47 vs 1.01; 0.67-1.46) therapy lasting for less than 5 years was associated with significantly greater decreases in the CHD death risk. A similar tendency was also seen for other EPT groups and for longer use. In all hormone users, the CHD death risk was smaller the earlier the use of ET or EPT had started (P <.05); this phenomenon was unrelated to the progestin component of EPT. Conclusions: Estradiol-based hormone therapies are accompanied with larger CHD mortality risk reductions the earlier the therapies are initiated. The progestin component of EPT does not modify this "timing effect. © 2016 by the Endocrine Society.


Mikkola T.S.,University of Helsinki | Mikkola T.S.,Folkhalsan Research Center | Tuomikoski P.,University of Helsinki | Lyytinen H.,University of Helsinki | And 6 more authors.
Menopause | Year: 2015

Objective: Data on the health benefits and risks of postmenopausal hormone therapy (HT) are derived mainly from the use of conjugated equine estrogens. Estradiol-based regimens may have a different risk-benefit profile. We evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based HT regimens in a nationwide study in Finland. Methods: A total of 489,105 women who used HT from 1994 to 2009 (3.3 million HT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed. A total of 28,734 HT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke. Mortality risk in HT users with varying duration of exposure (≤1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population. Results: Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older. Conclusions: In absolute terms, the risk reductions mean 19 fewer CHD deaths and 7 fewer stroke deaths per 1,000 women using any HT for at least 10 years. © 2015 by The North American Menopause Society.


Mikkola T.S.,University of Helsinki | Mikkola T.S.,Folkhalsan Research Center | Tuomikoski P.,University of Helsinki | Tuomikoski P.,Folkhalsan Research Center | And 8 more authors.
Human Reproduction | Year: 2016

STUDY QUESTION Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke. SUMMARY ANSWER The use of VE reduces the risk for cardiovascular mortality. WHAT IS KNOWN ALREADY A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects. STUDY DESIGN, SIZE, DURATION We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean ± SD] 65.7 ± 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294). PARTICIPANTS/MATERIALS, SETTING, METHODS The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to ≤3, >3 to ≤5, >5 to ≤10 and >10 years). MAIN RESULTS AND THE ROLE OF CHANCE The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to ≤5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to ≤10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively). LIMITATIONS, REASONS FOR CAUTION Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol. WIDER IMPLICATIONS OF THE FINDINGS In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.


Mikkola T.S.,University of Helsinki | Mikkola T.S.,Folkhalsan Research Center | Tuomikoski P.,University of Helsinki | Lyytinen H.,EPID Research Oy | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk. Objective: We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n=3177) or stroke (n= 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users. Results: Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72-0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48). Conclusions: Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT. Copyright © 2015 by the Endocrine Society.


Tuomikoski P.,University of Helsinki | Lyytinen H.,University of Helsinki | Korhonen P.,EPID Research Oy | Hoti F.,EPID Research Oy | And 6 more authors.
Maturitas | Year: 2015

Objective: The Women's Health Initiative (WHI) study clarified the indications and contraindications for postmenopausal hormone therapy (HT). We studied the impact of the WHI results on the risk of fatal stroke in HT users in Finland. Study design: Retrospective analysis setting: Nationwide registers on postmenopausal HT use and causes of death between 1995 and 2009. Population: Women ≥40 years (n = 290,272) using systemic estradiol-based postmenopausal HT. Methods: Follow-up started from the first HT purchase during the pre-WHI era (1995-2001) and post-WHI era (2002-2009). Main outcome measures: Stroke deaths in HT users were compared with that in the age-matched background population and expressed as standardized mortality ratio (SMR) with 95% confidence intervals. Results: Overall, 311 HT users died due to stroke. The exposure to HT ≤1 year was associated with a similarly reduced 22% (0.67-0.91) risk of stroke death in the pre-WHI era and in the post-WHI era 27% (0.55-0.94). The risk reductions for HT exposure of 1-8 years in the pre-WHI era (47%, 0.42-0.65) did not differ from that in the post-WHI era (32%, 0.48-0.94). The discontinuation of HT was accompanied by a significant 33% (1.02-1.72) increase in stroke death risk in the pre-WHI era and a non-significant 32% (0.84-1.99) increase in the post-WHI era within the first post-treatment year, but no longer after 1-8 years. Conclusions: The change in prescribing policy after the WHI study did not affect the risk of fatal stroke in Finnish HT users. © 2015 Elsevier Ireland Ltd. All rights reserved.


PubMed | EPID Research Oy, University of Helsinki and Nordic School of Public Health
Type: Journal Article | Journal: Maturitas | Year: 2015

The Womens Health Initiative (WHI) study clarified the indications and contraindications for postmenopausal hormone therapy (HT). We studied the impact of the WHI results on the risk of fatal stroke in HT users in Finland.Retrospective analysis setting: Nationwide registers on postmenopausal HT use and causes of death between 1995 and 2009.Women 40 years (n=290,272) using systemic estradiol-based postmenopausal HT.Follow-up started from the first HT purchase during the pre-WHI era (1995-2001) and post-WHI era (2002-2009).Stroke deaths in HT users were compared with that in the age-matched background population and expressed as standardized mortality ratio (SMR) with 95% confidence intervals.Overall, 311 HT users died due to stroke. The exposure to HT 1 year was associated with a similarly reduced 22% (0.67-0.91) risk of stroke death in the pre-WHI era and in the post-WHI era 27% (0.55-0.94). The risk reductions for HT exposure of 1-8 years in the pre-WHI era (47%, 0.42-0.65) did not differ from that in the post-WHI era (32%, 0.48-0.94). The discontinuation of HT was accompanied by a significant 33% (1.02-1.72) increase in stroke death risk in the pre-WHI era and a non-significant 32% (0.84-1.99) increase in the post-WHI era within the first post-treatment year, but no longer after 1-8 years.The change in prescribing policy after the WHI study did not affect the risk of fatal stroke in Finnish HT users.


Suokas J.T.,Finnish National Institute for Health and Welfare | Suokas J.T.,University of Helsinki | Suvisaari J.M.,Finnish National Institute for Health and Welfare | Haukka J.,EPID Research Oy | And 6 more authors.
Social Psychiatry and Psychiatric Epidemiology | Year: 2013

Objective: This large nationwide study describes the prevalence and predictors of long-term antipsychotic polypharmacy among patients with schizophrenia. Methods: A register-based longitudinal study of all people in Finland, who had at least one hospitalization due to schizophrenia during the years 2000-2007 and who were alive on March 1, 2007. Entry to the cohort was defined from the first hospitalization for schizophrenia during the years 2000-2007, and the date of assessment of antipsychotic polypharmacy was March 1, 2007. We studied separately chronic (N = 8,037) and recent onset (N = 8,046) schizophrenia patients. Antipsychotic polypharmacy was defined as overlapping of two or more filled prescriptions of antipsychotics for over 60 days. Results: In a total 16,083 patients with schizophrenia the prevalence of antipsychotic polypharmacy was 46.2 % (N = 7,436, mean age 47.5 years, male 55 %). The longer the duration of schizophrenia, the more common the antipsychotic polypharmacy. Long index hospitalization and being male significantly associated with antipsychotic polypharmacy among all schizophrenia patients. Especially, in chronic schizophrenia patients, the previous use of benzodiazepine like agents was associated with antipsychotic polypharmacy, but the use of antidepressants associated with less frequent antipsychotic polypharmacy. Conclusions: Antipsychotic polypharmacy was widely prevalent among patients with schizophrenia and it was associated with long hospitalizations and long duration of illness. Benzodiazepine use was associated with increased risk and antidepressant use with decreased risk of antipsychotic polypharmacy when the effect of other clinical and socioeconomic factors was adjusted. Research is needed of risks and benefits of antipsychotic polypharmacy and augmentation of antipsychotic with other psychoactive drugs. © 2012 Springer-Verlag.


PubMed | EPID Research Oy, Finnish National Institute for Health and Welfare and University of Helsinki
Type: Journal Article | Journal: Human reproduction (Oxford, England) | Year: 2016

Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke.The use of VE reduces the risk for cardiovascular mortality.A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects.We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean SD] 65.7 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294).The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to 3, >3 to 5, >5 to 10 and >10 years).The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to 5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to 10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively).Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol.In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur.This work was supported by unrestricted grants from the Pivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Lkaresllskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation and a special governmental grant for health sciences research. The funding sources had no role in the study design, data handling or manuscript preparation. EPID Research is a company that performs financially supported studies for several pharmaceutical companies. Dr Korhonen, Dr Hoti and MSc Vattulainen, employed by Epid Research, report financial activities from several other pharmaceutical companies outside the submitted work. Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr Tuomikoski has been a speaker and/or received consulting fees from Orion and Mylan. The remaining authors report no conflict of interest.


Tiihonena J.,University of Eastern Finland | Tiihonena J.,Kuopio University Hospital | Tiihonena J.,National Health Research Institute | Tiihonena J.,Karolinska Institutet | And 7 more authors.
Archives of General Psychiatry | Year: 2012

Context: Polypharmacy is widely used in the treatment of schizophrenia, although it is believed to have major adverse effects on the well-being of patients. Objective: To investigate if the use of benzodiazepines, antidepressants, or multiple concomitant antipsychotics is associated with increased mortality among patients with schizophrenia. Design: Registry-based case linkage study. Setting: Academic research. Patients: We linked national databases of mortality and medication prescriptions among a complete nationwide cohort of 2588 patients hospitalized in Finland for the first time with a diagnosis of schizophrenia between January 1, 2000, and December 31, 2007. Main Outcome Measures: Hazard ratios (HRs) were computed for all-cause mortality during the use of antipsychotics, antidepressants, or benzodiazepines in outpatient care, adjusting for the effects of sociodemographic and clinical variables, geographic location, and current and past pharmacological treatments. Results: Compared with antipsychotic monotherapy, concomitant use of 2 or more antipsychotics was not associated with increased mortality (HR, 0.86; 95% CI, 0.51-1.44). Similarly, antidepressant use was not associated with a higher risk for mortality (HR, 0.57; 95% CI, 0.28-1.16) and was associated with markedly decreased suicide deaths (HR, 0.15; 95% CI, 0.03-0.77). However, benzodiazepine use was associated with a substantial increase in mortality (HR, 1.91; 95% CI, 1.13-3.22), and this was attributable to suicidal deaths (HR, 3.83; 95% CI, 1.45-10.12) and to nonsuicidal deaths (HR, 1.60; 95% CI, 0.86-2.97). In total, 826 of 904 patients (91.4%) who used benzodiazepines had purchased prescriptions that contained more than 28 defined daily doses, violating treatment guidelines. Conclusions: Benzodiazepine use was associated with a marked increase in mortality among patients with schizophrenia, whereas the use of an antidepressant or several concomitant antipsychotics was not. Antidepressant use was associated with decreased suicide deaths. The literature indicates that long-term use of benzodiazepines among patients with schizophrenia is more prevalent in other countries (eg, the United States) compared with Finland, which suggests that benzodiazepine use may contribute to mortality among this patient population worldwide. © 2012 American Medical Association.


Korhonen P.,EPID Research Oy | Kuoppamaki M.,Orion Corporation | Prami T.,EPID Research Oy | Hoti F.,EPID Research Oy | And 7 more authors.
Movement Disorders | Year: 2015

Background: The association between Parkinson's disease (PD) and prostate cancer, both common in elderly men, is disputable. In the STRIDE-PD study, prostate cancer developed in 9 patients (3.7%) receiving levodopa/carbidopa with entacapone, a catechol-O-methyltransferase inhibitor, versus 2 cases (0.9%) without entacapone. The current pharmacoepidemiological study aimed to determine whether entacapone increases prostate cancer incidence or mortality in PD patients and whether cumulative exposure affects these rates. Methods: We performed a retrospective cohort study using population-wide health care registers with patient-level linkage. Prostate cancer incidence and mortality were modeled by Cox's proportional hazards models. Results and Conclusions: Use of entacapone with l-dopa/dopa decarboxylase inhibitor caused no increased risk of prostate cancer incidence (hazard ratio [HR]: 1.05; 95% confidence interval: 0.76-1.44) or mortality (0.93; 0.43-1.98). The HR for cumulative entacapone use of >360 days versus never-use was 0.82 (0.56-1.18) for prostate cancer incidence and 1.27 (0.60-2.72) for prostate cancer mortality. © 2015 International Parkinson and Movement Disorder Society.

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