Pasi Korhonen

The Finnish Cancer Registry as Follow-Up Source of a Large Trial Cohort Accuracy and Delay

We evaluated the accuracy and time to reporting of cancer diagnoses obtained through the Finnish Cancer Registry (FCR) for the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study in 1985-1997. In the ATBC Study suspect neoplasms were centrally reviewed through medical records and pathology specimens. The FCR data were compared against the reviewed data for 3600 cancers of eight sites. For most sites, 95% of the cases were reported to the FCR within 0.9 years with longer delays for lung and pancreatic cancers. Ninety-six percent of all FCR cases received the same primary site diagnosis in the ATBC review, and in 1.4% no malignancy was found. Conversely, 97% of cancers ascertained in the ATBC review had the same primary site in the FCR and 0.8% were unknown to the R egistry. The accuracy of the FCR data is high but the delay in case notification should be considered in epidemiological studies.

Polypharmacy With Antipsychotics, Antidepressants, or Benzodiazepines and Mortality in Schizophrenia

CONTEXTnPolypharmacy is widely used in the treatment of schizophrenia, although it is believed to have major adverse effects on the well-being of patients.nnnOBJECTIVEnTo investigate if the use of benzodiazepines, antidepressants, or multiple concomitant antipsychotics is associated with increased mortality among patients with schizophrenia.nnnDESIGNnRegistry-based case linkage study.nnnSETTINGnAcademic research.nnnPATIENTSnWe 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.nnnMAIN OUTCOME MEASURESnHazard 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.nnnRESULTSnCompared 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.nnnCONCLUSIONSnBenzodiazepine 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.

Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality.

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.

Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy

CONTEXTnCurrent 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.nnnOBJECTIVEnWe 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.nnnRESULTSnWithin 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).nnnCONCLUSIONSnIncreased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.

Description of long-term polypharmacy among schizophrenia outpatients

ObjectiveThis large nationwide study describes the prevalence and predictors of long-term antipsychotic polypharmacy among patients with schizophrenia.MethodsA 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 (Nxa0=xa08,037) and recent onset (Nxa0=xa08,046) schizophrenia patients. Antipsychotic polypharmacy was defined as overlapping of two or more filled prescriptions of antipsychotics for over 60xa0days.ResultsIn a total 16,083 patients with schizophrenia the prevalence of antipsychotic polypharmacy was 46.2xa0% (Nxa0=xa07,436, mean age 47.5xa0years, male 55xa0%). 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.ConclusionsAntipsychotic 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.

Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries

Objective To evaluate the association between pioglitazone use and bladder cancer risk in patients with type 2 diabetes. Design Retrospective cohort study using propensity score matched cohorts. Settings Healthcare databases from Finland, the Netherlands, Sweden, and the United Kingdom. Data comprised country specific datasets of linked records on prescriptions, hospitals, general practitioners, cancer, and deaths. Participants Patients with type 2 diabetes who initiated pioglitazone (n=56u2009337) matched with patients with type 2 diabetes in the same country exposed to diabetes drug treatments other than pioglitazone (n=317u2009109). Two matched cohorts were created, using a 1:1 fixed ratio (nearest match cohort) and a 1:10 variable ratio (multiple match cohort). Patients were matched on treatment history and propensity scores accounting for several variables associated with pioglitazone initiation. Main outcome measures Hazard ratios and 95% confidence intervals were estimated by Cox’s proportional hazards model with adjustments for relevant confounders. To assess the robustness of the findings, several sensitivity and stratified analyses were performed. Results In the cohort exposed to pioglitazone treatment, 130 bladder cancers occurred over a mean follow-up time of 2.9 years. In the nearest match and multiple match cohorts not exposed to pioglitazone treatment, 153 and 970 bladder cancers were recorded, with a mean follow‑up time of 2.8 and 2.9 years, respectively. With regards to bladder cancer risk, the adjusted hazard ratio for patients ever exposed versus never exposed to pioglitazone was 0.99 (95% confidence interval 0.75 to 1.30) and 1.00 (0.83 to 1.21) in the nearest and multiple match cohorts, respectively. Increasing duration of pioglitazone use and increasing cumulative dose were not associated with risk of bladder cancer (>48 months of pioglitazone use, adjusted hazard ratio 0.86 (0.44 to 1.66); >40u2009000 mg cumulative dose, 0.65 (0.33 to 1.26) in the nearest match cohort). Conclusions This study shows no evidence of an association between ever use of pioglitzone and risk of bladder cancer compared with never use, which is consistent with results from other recent studies that also included a long follow-up period. Trial registration Registered to the European Union electronic register of post-authorisation studies (EU PAS register no EUPAS3626).

Coronary Heart Disease Mortality and Hormone Therapy Before and After the Women's Health Initiative

OBJECTIVE: To assess whether coronary heart disease mortality in Finnish hormone therapy (HT) users differed before and after 2002 when the Womens Health Initiative study was published. METHODS: The risks of coronary heart disease death in HT users in relation to the age-matched background population were compared between the pre– (1995–2001) and post– (2002–2009) Womens Health Initiative eras. We used a nationwide register on HT (ie, estradiol with or without progestin) reimbursement and linked them to causes of death in 290,272 women aged 40 years or older. RESULTS: Exposure to HT for 1 year or less was accompanied by a 29% reduction (0.71; 0.63–0.80; three per 10,000 fewer deaths) and an exposure of 1–8 years with a 43% reduction (0.57; 0.48–0.66; three per 10,000 fewer deaths) in the risk of coronary heart disease death in the pre–Womens Health Initiative era. In the post–Womens Health Initiative era, HT use of 1 year or less was associated with an 18% reduction (0.82; 0.76–1.00; one per 10,000 fewer deaths) and an exposure of 1–8 years with a 54% reduction (0.46; 0.32–0.64; two per 10,000 fewer deaths) in coronary heart disease mortality. Discontinuation of HT was associated with an increased risk of cardiac death of 42% (1.42; 1.17–1.71; seven per 10,000 extra deaths) in the pre–Womens Health Initiative era and 31% (1.31; 0.92–1.82; two per 10,000 extra deaths) in the post–Womens Health Initiative era during the first posttreatment year. This risk increase vanished in further follow-up during both eras. CONCLUSION: Changes in HT use after the Womens Health Initiative failed to affect coronary heart disease mortality of HT users in this nationwide study. LEVEL OF EVIDENCE: II

Evaluation of the incidence and risk of hypoglycemic coma associated with selection of basal insulin in the treatment of diabetes: a Finnish register linkage study†

Long‐acting basal insulin analogs have demonstrated positive effects on the balance between effective glycemic control and risk of hypoglycemia versus neutral protamine Hagedorn (NPH) insulin in randomized controlled trials. Evidence of severe hypoglycemic risk with insulin detemir, insulin glargine, or NPH insulin is presented from a nationwide retrospective database study.

Vaginal estradiol use and the risk for cardiovascular mortality

STUDY QUESTIONnDoes the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke.nnnSUMMARY ANSWERnThe use of VE reduces the risk for cardiovascular mortality.nnnWHAT IS KNOWN ALREADYnA 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.nnnSTUDY DESIGN, SIZE, DURATIONnWe 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).nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnThe 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).nnnMAIN RESULTS AND THE ROLE OF CHANCEnThe 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).nnnLIMITATIONS, REASONS FOR CAUTIONnOur 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.nnnWIDER IMPLICATIONS OF THE FINDINGSnIn 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.nnnSTUDY FUNDING/COMPETING INTERESTSnThis work was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, 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.

Quality of warfarin therapy and risk of stroke, bleeding, and mortality among patients with atrial fibrillation: results from the nationwide FinWAF Registry

The most important management strategy in atrial fibrillation (AF) patients is preventing stroke with oral anticoagulants. Warfarin is still used as a first‐line anticoagulant, although non‐vitamin K antagonist oral anticoagulants are currently recommended to manage AF. Using a large, unselected national sample of AF patients, we evaluated the relationships between quality of warfarin therapy and the risks of thromboembolism, bleeding complications, and mortality.