Ellen Holm

Falls and comorbidity: The pathway to fractures

Aims: To compare nationwide time trends and mortality in hip and proximal humeral fractures; to explore associations between incidences of falls risk related comorbidities (FRICs) and incidence of fractures. Methods: The study is a retrospective cohort study using nationwide Danish administrative registries from 2000 through 2009. Individuals aged 65 years or older who experienced a hip or a proximal humeral fracture were included. Incidence of hip and of proximal humeral fractures, incidence of FRICs (ischemic heart disease, COPD, dementia, depression, diabetes, heart failure, osteoporosis, Parkinson’s disease and stroke) and incidence rate ratios (IRR) for fractures in patients with FRICs, and all-cause mortality up to 10 years after a hip or a proximal humeral fracture were analysed. Results: A total of 89,150 patients experienced hip fractures and 48,581 proximal humeral fractures. From 2000 through 2009, the incidence of hip fractures per 100,000 individuals declined by 198 (787 to 589, OR = 0.75, CI: 0.72–0.80) among males and by 483 (1758 to 1275, OR = 0.74, CI: 0.72–0.77) among females. Incidences of FRICs decreased. The absolute reduction in fractures was most pronounced for the age group above 75 years (2393 to 1884, OR = 0.81, CI: 0.78–0.83), but the relative reduction was more pronounced in the age group of 65–75 years old (496 to 342, OR = 0.70, CI: 0.66–0.74). IRRs for hip fractures and for proximal humeral fractures were significantly elevated in patients with FRICs. Conclusions: The results suggest that the overall reduction in fractures can be explained by reduction in falls related comorbidity.

Association of Selected Antipsychotic Agents With Major Adverse Cardiovascular Events and Noncardiovascular Mortality in Elderly Persons

Background Data from observational studies have raised concerns about the safety of treatment with antipsychotic agents (APs) in elderly patients with dementia, but this area has been insufficiently investigated. We performed a head-to-head comparison of the risk of major adverse cardiovascular events and noncardiovascular mortality associated with individual APs (ziprasidone, olanzapine, risperidone, quetiapine, levomepromazine, chlorprothixen, flupentixol, and haloperidol) in Danish treatment-naïve patients aged ≥70 years. Methods and Results We followed all treatment-naïve Danish citizens aged ≥70 years that initiated treatment with APs for the first time between 1997 and 2011 (n=91 774, mean age 82±7 years, 35 474 [39%] were men). Incidence rate ratios associated with use of different APs were assessed by multivariable time-dependent Poisson regression models. For the first 30 days of treatment, compared with risperidone, incidence rate ratios of major adverse cardiovascular events were higher with use of levomepromazine (3.80, 95% CI 3.43 to 4.21) and haloperidol (1.85, 95% CI 1.67 to 2.05) and lower for treatment with flupentixol (0.54, 95% CI 0.45 to 0.66), ziprasidone (0.31, 95% CI 0.10 to 0.97), chlorprothixen (0.76, 95% CI 0.61 to 0.95), and quetiapine (0.68, 95% CI 0.58 to 0.80). Relationships were generally similar for long-term treatment. The majority of agents were associated with higher risks among patients with cardiovascular disease compared with patients without cardiovascular disease (P for interaction <0.0001). Similar results were observed for noncardiovascular mortality, although differences in associations between patients with and without cardiovascular disease were small. Conclusions Our study suggested some diversity in risks associated with individual APs but no systematic difference between first- and second-generation APs. Randomized placebo-controlled studies are warranted to confirm our findings and to identify the safest agents.

Nationwide time trends and risk factors for in-hospital falls-related major injuries

Accidental falls during hospitalisation have a range of complications and more information is needed to improve prevention. We investigated patterns of in‐hospital fall‐related major injuries in the period 2000–2012 and the association between chronic conditions and in‐hospital fall‐related major injuries.

Danish register-based study on the association between specific cardiovascular drugs and fragility fractures

Objective To determine whether drugs used in treatment of cardiovascular diseases (CVD-drugs), including hypertension, increase the risk of fragility fractures in individuals above the age of 65 years. Design Retrospective nationwide cohort study. Setting Danish nationwide national registers. Participants All individuals in Denmark ≥65 years who used specified CVD-drugs in the study period between 1999 and 2012. Main outcomes measures Time-dependent exposure to CVD-drugs (nitrates, digoxin, thiazides, furosemide, ACE inhibitors, angiotensin receptor antagonists, β-blockers, calcium antagonists and statins) was determined by prescription claims from pharmacies. The association between use of specific CVD-drugs and fragility fractures was assessed using multivariable Poisson regression models, and adjusted incidence rate ratios (IRRs) were calculated. Results Overall, 1 586 554 persons were included, of these 16.1% experienced a fall-related fracture. The multivariable Poisson regression analysis showed positive associations between fracture and treatment with furosemide, thiazide and digoxin. IRRs during the first 14 days of treatment were for furosemide IRR 1.74 (95% CI 1.61 to 1.89) and for thiazides IRR 1.41 (1.28 to 1.55); IRR during the first 30 days of treatment with digoxin was 1.18 (1.02 to 1.37). Conclusions Use of furosemide, thiazides and digoxin was associated with elevated rates of fragility fractures among elderly individuals. This may warrant consideration when considering diuretic treatment of hypertension in elderly individuals.

Antidepressants and the risk of hyponatremia: a Danish register-based population study

Objective To examine the association between classes of antidepressants and hyponatremia, and between specific antidepressants and hyponatremia. Design Retrospective register-based cohort study using nationwide registers from 1998 to 2012. Setting The North Denmark Region. Participants In total, 638 352 individuals were included. Primary and secondary outcome measures Plasma sodium was obtained from the LABKA database. The primary outcome was hyponatremia defined as plasma sodium (p-sodium) below 135 mmol/L and secondary outcome was severe hyponatremia defined as p-sodium below 130 mmol/L. The association between use of specific antidepressants and hyponatremia was analysed using multivariable Poisson regression models. Results An event of hyponatremia occurred in 72 509 individuals and 11.36% (n=6476) of these events happened during treatment with antidepressants. Incidence rate ratios and CIs for the association with hyponatremia in the first p-sodium measured after initiation of treatment were for citalopram 7.8 (CI 7.42 to 8.20); clomipramine 4.93 (CI 2.72 to 8.94); duloxetine 2.05 (CI 1.44 to 292); venlafaxine 2.90 (CI 2.43 to 3.46); mirtazapine 2.95 (CI 2.71 to 3.21); and mianserin 0.90 (CI 0.71 to 1.14). Conclusions All antidepressants except mianserin are associated with hyponatremia. The association is strongest with citalopram and lowest with duloxetine, venlafaxine and mirtazapine.

Antipsychotics and associated risk of out-of-hospital cardiac arrest

Antipsychotic drugs have been associated with sudden cardiac death, but differences in the risk of out–of–hospital cardiac arrest (OHCA) associated with different antipsychotic drug classes are not clear. We identified all OHCAs in Denmark (2001–2010). The risk of OHCA associated with antipsychotic drug use was evaluated by conditional logistic regression analysis in case–time–control models. In total, 2,205 (7.6%) of 28,947 OHCA patients received treatment with an antipsychotic drug at the time of the event. Overall, treatment with any antipsychotic drug was associated with OHCA (odds ratio (OR) = 1.53, 95% confidence interval (CI): 1.23–1.89), as was use with typical antipsychotics (OR = 1.66, CI: 1.27–2.17). By contrast, overall, atypical antipsychotic drug use was not (OR = 1.29, CI: 0.90–1.85). Two individual typical antipsychotic drugs, haloperidol (OR = 2.43, CI: 1.20–4.93) and levomepromazine (OR = 2.05, CI: 1.18–3.56), were associated with OHCA, as was one atypical antipsychotic drug, quetiapine (OR = 3.64, CI: 1.59–8.30).

Diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone.

Background: Hyponatremia is a frequent condition in elderly patients. In diagnostic workup, a 24-hour urine sample is used to measure urinary osmolality and urinary sodium concentration necessary to confirm the diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This study was undertaken to test the hypothesis that a spot urine sample would be sufficient for urinalysis. Methods: In nine patients with SIADH, morning spot and 24-hour urine samples were examined for osmolality and sodium concentration. Levels of arginine vasopressin, atrial natriuretic and brain natriuretic peptides, renin, and aldosterone were measured in the supine and upright positions of patients and compared with nine healthy age-matched control patients. Results: The patients had low plasma osmolality (median 266 mOsm/kg) and measurable levels of arginine vasopressin (median 1.8 pg/mL). Values of osmolality in the spot urine (median 298 mOsm/kg) and in the 24-hour urine (median 215 mOsm/kg) did not differ significantly; neither did sodium concentration (medians 80 mmol/L in the spot urine versus 45 mmol/L in the 24-hour urine). Patients had significantly elevated plasma levels of brain natriuretic peptide (P = 0.007), elevated mean arterial blood pressure (P = 0.03), and lower plasma levels of creatinine (P = 0.002) compared to the controls. Conclusion: A spot urine sample seems to be sufficient to confirm the diagnosis of SIADH.