Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial.

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.

Duration and timing of depression and risk of family dissolution: A register-based cohort study of newly-formed Danish families.

BACKGROUND: Depression is detrimental to partnership stability. However, it remains unclear if and how the duration and timing of depression affect the risk of family dissolution. METHODS: We conducted a Danish register-based cohort study of newly-formed cohabiting and married couples in 2008 and 2009, who were followed from the second year after family formation. Depressive episodes were defined by individual-level prescription patterns of antidepressant drugs (ATC codes N06A) in either partner. Family dissolution was characterized by the discontinuation of a shared residential address. Using Longitudinal Targeted Minimum Loss-based Estimation, we estimated the risk of family dissolution after 5 years of follow-up under various lengths and timings of depressive episodes. RESULTS: There were 102,335 families included. The covariate-adjusted risk of family dissolution in families without depressive episodes was 30.0 % (95 % CI 29.6-30.4 %) and 35.5 % (95 % CI 29.5-41.5 %) in families with at least one depressive episode during follow-up. The risk of family dissolution increased with the duration of depressive episodes to 42.2 % (95 % CI 40.8-43.6 %) for five coherent years of depression. Depression shortly after family formation carried higher risk of family dissolution; this risk was 42.3 % (95 % CI 38.4-46.3 %) for depression experienced in the first year of family formation versus 32.9 % (95 % CI 31.8-34.0 %) in the fifth year of family formation. LIMITATIONS: Proxy measures of depression by antidepressant prescriptions fails to identify milder depression. Annual measures of family dissolution precluded more fine-grained analyses of time-intervals. CONCLUSIONS: Depression is disruptive to family stability, particularly with longer duration and early onset after family formation.

Hypothetical interventions on emergency ambulance and prehospital acetylsalicylic acid administration in myocardial infarction patients presenting without chest pain.

BACKGROUND: Myocardial infarction (MI) patients presenting without chest pain are a diagnostic challenge. They receive suboptimal prehospital management and have high mortality. To elucidate potential benefits of improved management, we analysed expected outcome among non-chest pain MI patients if hypothetically they (1) received emergency ambulances/acetylsalicylic acid (ASA) as often as observed for chest pain patients, and (2) all received emergency ambulance/ASA. METHODS: We sampled calls to emergency and non-emergency medical services for patients hospitalized with MI within 24 h and categorized calls as chest pain/non-chest pain. Outcomes were 30-day mortality and a 1-year combined outcome of re-infarction, heart failure admission, and mortality. Targeted minimum loss-based estimation was used for all statistical analyses. RESULTS: Among 5418 calls regarding MI patients, 24% (1309) were recorded with non-chest pain. In total, 90% (3689/4109) of chest pain and 40% (525/1309) of non-chest pain patients received an emergency ambulance, and 73% (2668/3632) and 37% (192/518) of chest pain and non-chest pain patients received prehospital ASA. Providing ambulances to all non-chest pain patients was not associated with improved survival. Prehospital administration of ASA to all emergency ambulance transports of non-chest pain MI patients was expected to reduce 30-day mortality by 5.3% (CI 95%: [1.7%;9%]) from 12.8% to 7.4%. No significant reduction was found for the 1-year combined outcome (2.6% CI 95% [- 2.9%;8.1%]). In comparison, the observed 30-day mortality was 3% among ambulance-transported chest pain MI patients. CONCLUSIONS: Our study found large differences in the prehospital management of MI patients with and without chest pain. Improved prehospital ASA administration to non-chest pain MI patients could possibly reduce 30-day mortality, but long-term effects appear limited. Non-chest pain MI patients are difficult to identify prehospital and possible unintended effects of ASA might outweigh the potential benefits of improving the prehospital management. Future research should investigate ways to improve the prehospital recognition of MI in the absence of chest pain.

Antidiabetes Agents and Incident Depression: A Nationwide Population-Based Study.

OBJECTIVE: Diabetes is associated with an increased risk of depression. Some antidiabetes agents, specifically metformin and pioglitazone, have been suggested to have beneficial effects on depression, but associations between antidiabetes drugs and depression have not been systematically investigated. RESEARCH DESIGN AND METHODS: We combined four Danish population-based registers to investigate whether the 20 most widely used orally administered antidiabetes drugs were associated with an altered risk of incident depression. Analyses of insulin were included for comparisons. All persons in Denmark in 2005 were included in the study and followed until 2015. Two different outcome measures of incident depression were included: 1) a diagnosis of depressive disorder at a psychiatric hospital as an inpatient or outpatient and 2) a combined measure of a diagnosis of depression or use of antidepressants. Data were analyzed using Cox regression models. RESULTS: A total of 360,205 individuals using orally administered antidiabetes drugs and 64,582 using insulin at any time during the study period were included in the analyses. Continued use of metformin and combinations of drugs including metformin were associated with decreased rates of incident depression. Pioglitazone was not associated with a decreased rate of incident depression. No other antidiabetes drugs or insulin showed significant associations with depression. CONCLUSIONS: Real-life population-based data suggest a positive effect of metformin on depression rates. This evidence should be used in guiding prescriptions for patients with type 2 diabetes who are at risk for developing depression, including those with prior depression or anxiety and patients with a family history of depression.

Antihypertensive Drugs and Risk of Depression: A Nationwide Population-Based Study.

Hypertension, cardiovascular diseases, and cerebrovascular diseases are associated with an increased risk of depression, but it remains unclear whether treatment with antihypertensive agents decreases or increases this risk. The effects of individual drugs are also unknown. We used Danish population-based registers to systematically investigate whether the 41 most used individual antihypertensive drugs were associated with an altered risk of incident depression. Analyses of diuretics were included for comparisons. Participants were included in the study in January 2005 and followed until December 2015. Two different outcome measures were included: (1) a diagnosis of depressive disorder at a psychiatric hospital as an inpatient or outpatient and (2) a combined measure of a diagnosis of depression or use of antidepressants. Continued use of classes of angiotensin agents, calcium antagonists, and ß-blockers was associated with significantly decreased rates of depression, whereas diuretic use was not. Individual drugs associated with decreased depression included 2 of 16 angiotensin agents: enalapril and ramipril; 3 of 10 calcium antagonists: amlodipine, verapamil, and verapamil combinations; and 4 of 15 ß-blockers: propranolol, atenolol, bisoprolol, and carvedilol. No drug was associated with an increased risk of depression. In conclusion, real-life population-based data suggest a positive effect of continued use of 9 individual antihypertensive agents. This evidence should be used in guiding prescriptions for patients at risk of developing depression including those with prior depression or anxiety and patients with a family history of depression.

Prevalent cohort studies and unobserved heterogeneity.

Consider lifetimes originating at a series of calendar times [Formula: see text]. At a certain time [Formula: see text] a cross-sectional sample is taken, generating a sample of current durations (backward recurrence times) of survivors until [Formula: see text] and a prevalent cohort study consisting of survival times left-truncated at the current durations. A Lexis diagram is helpful in visualizing this situation. Survival analysis based on current durations and prevalent cohort studies is now well-established as long as all covariates are observed. The general problems with unobserved covariates have been well understood for ordinary prospective follow-up studies, with the good help of hazard rate models incorporating frailties: as for ordinary regression models, the added noise generates attenuation in the regression parameter estimates. For prevalent cohort studies this attenuation remains, but in addition one needs to take account of the differential selection of the survivors from initiation [Formula: see text] to cross-sectional sampling at [Formula: see text]. This paper intends to survey the recent development of these matters and the consequences for routine use of hazard rate models or accelerated failure time models in the many cases where unobserved heterogeneity may be an issue. The study was inspired by concrete problems in the study of time-to-pregnancy, and we present various simulation results inspired by this particular application.

Comparison of Survival After Aortic Valve Replacement With Mitroflow or Perimount Prostheses.

Bioprosthetic aortic valves degenerate over time, and differences between brands could be expected. We compared 2 brands implanted in 3 different centers serving 3.3 million people. Between 2000 and 2014, we identified 1241 bioprosthetic aortic valve replacements using Mitroflow (Sorin, Milan, Italy) and 3212 using Perimount (Edwards Lifesciences, Irvine, CA) covering 88% of all aortic valve replacements in the region. Average differences in t-year mortality were derived from Cox regression. The complete case analyses included 881 Mitroflow replacements and 2488 Perimount replacements. The median follow-up time and 25/75 percentiles were 5.0 years (3.3-7.2) and 8.4 years (5.1-10.6) for Perimount and Mitroflow, respectively. Multiple Cox regression analyses demonstrated significantly higher mortality with Mitroflow valves compared with Perimount (hazard ratio 1.27; 95% CI: 1.1-1.5; P < 0.001). Average risk of death within 5 years was 25.0% with Mitroflow and 20.4% with Perimount. Average difference in 5-year mortality based on Cox regression was 4.60% in favor of Perimount (95% CI: 1.02-8.02%; P = 0.01) and the number needed to harm was 21.9 (95% CI: 12.7-80.5) within 5 years. Propensity matching confirmed 2-year survival differences 4.6% in favor of Perimount (95% CI: 1.2-7.9%; P = 0.004), and further confirmed in a series of subgroups and a double robust analysis that takes into account both propensity for treatment and covariate relation to outcome. Mitroflow valves were associated with a significantly increased risk of death when compared to Perimount valves.

The CPC Risk Calculator: A New App to Predict Prostate-specific Antigen Recurrence During Follow-up After Radical Prostatectomy.

BACKGROUND: It can be challenging to predict the risk of biochemical recurrence (BR) during follow-up after radical prostatectomy (RP) in men who have undetectable prostate-specific antigen (PSA), even years after surgery. OBJECTIVE: To establish and validate a contemporary nomogram that predicts the absolute risk of BR every year after RP in men with undetectable PSA while accounting for competing risks of death. DESIGN, SETTING, AND PARTICIPANTS: A total of 3746 patients from Rigshospitalet (Copenhagen, Denmark) and Stanford Urology (Stanford, CA, USA) who underwent RP between 1995 and 2013 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to BR was defined as the first PSA result ≥0.2 ng/ml. BR risk was computed using multiple cause-specific Cox regression including preoperative PSA, pT category, RP Gleason score (GS), and surgical margin (R) status. Death without BR was considered a competing event. The nomogram presents the future risk of BR for a man who is alive and without BR at the time of follow-up. Validation assessed the discrimination and accuracy using time-dependent area under the curve and Brier scores. RESULTS AND LIMITATIONS: The nomogram predicts risk of BR up to 12 yr after RP at an individual level. As example, the risk of BR for a man with pT3a, R-, GS 3 + 4, and preoperative PSA ≤10 ng/ml followed for 5 yr with undetectable PSA is 18% for the next 5 yr. External validation demonstrated both high accuracy and discrimination. The CPC Risk Calculator is available as a free Android and iOS App. Declining discrimination and accuracy after 7 yr of follow-up is the main limitation. CONCLUSIONS: This nomogram can be used as a tool to inform men with undetectable PSA during follow-up after RP about their future risk of BR, and may aid in decisions on the necessity for further follow-up. The nomogram is the first to be available as a free app. PATIENT SUMMARY: We developed an easily interpretable nomogram to evaluate the risk of prostate-specific antigen elevation (cancer recurrence) following complete removal of the prostate (radical prostatectomy). The tool can aid both physicians and patients in evaluating the future risk of cancer recurrence during follow-up after surgery. The model is available as a free mobile app that can be downloaded from the App Store.