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.
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
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Cites: Ann Intern Med. 2007 Jun 5;146(11):775-8617548409
Studies have raised concern on the cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs). We studied safety of NSAID therapy in a nationwide cohort of healthy individuals.
With the use of individual-level linkage of nationwide administrative registers, we identified a cohort of individuals without hospitalizations 5 years before first prescription claim of NSAIDs and without claimed drug prescriptions for selected concomitant medication 2 years previously. The risk of cardiovascular death, a composite of coronary death or nonfatal myocardial infarction, and fatal or nonfatal stroke associated with the use of NSAIDs was estimated by case-crossover and Cox proportional hazard analyses. The entire Danish population age 10 years or more consisted of 4,614,807 individuals on January 1, 1997, of which 2,663,706 (57.8%) claimed at least 1 prescription for NSAIDs during 1997 to 2005. Of these; 1,028,437 individuals were included in the study after applying selection criteria regarding comorbidity and concomitant pharmacotherapy. Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk. There was a trend for increased risk of fatal or nonfatal stroke associated with ibuprofen treatment (odds ratio, 1.29; 95% confidence interval, 1.02 to 1.63), but naproxen was not associated with increased cardiovascular risk (odds ratio for cardiovascular death, 0.84; 95% confidence interval, 0.50 to 1.42).
Individual NSAIDs have different degrees of cardiovascular safety, which must be considered when choosing appropriate treatment. In particular, rofecoxib and diclofenac were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals, whereas our results suggest that naproxen has a safer cardiovascular risk-profile.
It remains unknown whether non-electrocardiogram-gated coronary artery calcium (CAC) score in lung cancer screening provides incremental prognostic value. The aim of this study was to evaluate the prognostic value of CAC in the Danish Lung Cancer Screening Trial (DLCST), in addition to conducting a systematic review and meta-analysis including previously published studies regarding CAC in lung cancer screening.
In DLCST, we measured Agatston CAC scores in 1,945 current and former smokers. Causes of death were extracted from the Danish National Death Registry. We used Cox proportional hazards model to determine hazard ratios (HRs) of CAC scores. A weighted fixed-effects model was used for the meta-analysis.
Median follow-up in DLCST was 7.1 years, and 55% were men. Overall survival rates associated with CAC scores of 0, 1-400, and > 400 were 98%, 96%, and 92% (p 400 was 3.8 (1.0-15) (p
The majority of available data on the clinical course of patients with ventricular preexcitation in the ECG originates from tertiary centers. We aimed to investigate long-term outcomes in individuals from a primary care population with electrocardiographic preexcitation.
Digital ECGs from 328?638 primary care patients were collected during 2001 to 2011. We identified 310 individuals with preexcitation (age range, 8-85 years). Data on medication, comorbidity, and outcomes were collected from Danish nationwide registries. The median follow-up time was 7.4 years (quartiles, 4.6-10.3 years). Compared with the remainder of the population, patients with preexcitation had higher adjusted hazards of atrial fibrillation (hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.07-4.70) and heart failure (HR, 2.11; 95% CI, 1.27-3.50). Subgroup analysis on accessory pathway location revealed a higher adjusted hazard of heart failure for a right anteroseptal accessory pathway (HR, 5.88; 95% CI, 2.63-13.1). There was no evidence of a higher hazard of death among individuals with preexcitation when looking across all age groups (HR, 1.07; 95% CI, 0.68-1.68). However, a statistically significant (P=0.01) interaction analysis (
Syncope risk stratification is difficult and has not been implemented clinically.
The CHADS2 score can be applied as a risk stratification tool for predicting mortality after an episode of syncope.
All patients discharged from emergency departments with a first-time diagnosis of syncope from 2001 to 2009 where identified from nationwide registers in Denmark and matched on sex and age with a control population. Risk of all-cause or cardiovascular death was analyzed by multivariable Cox models.
A total of 37,705 patients were included. There were a total of 7761 deaths (21%), of which 52% were cardiovascular vs 27 862 (15%) deaths in the control population. The risk of cardiovascular death was significantly increased with increasing CHADS2 score (CHADS2 score: 1-2, hazard ratio [HR]: 9.11, 95% confidence interval [CI]: 8.25-10.07; CHADS2 score: 3-4, HR: 17.32, 95% CI: 15.42-19.47; CHADS2 score: 5-6, HR: 26.66, 95% CI: 21.40-33.21) relative to CHADS2 score of 0. A CHADS2 score of 0 was associated overall with very low event rates (15.1 deaths per 1000 person-years) but was associated with increased relative risk in the syncope population compared to controls. Syncope predicted 1-week, 1-year, and long-term mortality across CHADS2 scores compared to controls but did not reach significance in CHADS2 scores of 5 to 6.
Increasing CHADS2 score significantly predicts mortality in patients discharged with a diagnosis of syncope, and a CHADS2 score of 0 was associated with a very low absolute mortality. Compared to controls, syncope was associated with increased short- and long-term mortality, particularly in the lower CHADS2 scores.
It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption.
A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days.
In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption.
Comment In: Eur Heart J. 2012 Aug;33(15):1864-622368184
The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.
All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.
Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.
Comment In: Ann Intern Med. 2012 Jan 17;156(2):JC1-722250169
Comment In: Eur Heart J. 2011 Aug;32(15):1832-421471136
New-onset atrial fibrillation is associated with cardiovascular events leading to death in a first time myocardial infarction population of 89,703 patients with long-term follow-up: a nationwide study.
New-onset atrial fibrillation (AF) is reported to increase the risk of death in myocardial infarction (MI) patients. However, previous studies have reported conflicting results and no data exist to explain the underlying cause of higher death rates in these patients.
All patients with first acute MI between 1997 and 2009 in Denmark, without prior AF, were identified from Danish nationwide administrative registers. The impact of new-onset AF on all-cause mortality, cardiovascular death, fatal/nonfatal stroke, fatal/nonfatal re-infarction and noncardiovascular death, were analyzed by multiple time-dependent Cox models and additionally in propensity score matched analysis. In 89 703 patients with an average follow-up of 5.0 ± 3.5 years event rates were higher in patients developing AF (n=10 708) versus those staying in sinus-rhythm (n=78 992): all-cause mortality 173.9 versus 69.4 per 1000 person-years, cardiovascular death 137.2 versus 50.0 per 1000 person-years, fatal/nonfatal stroke 19.6/19.9 versus 6.2/5.6 per 1000 person-years, fatal/nonfatal re-infarction 29.0/60.7 versus 14.2/37.9 per 1000 person-years. In time-dependent multiple Cox analyses, new-onset AF remained predictive of increased all-cause mortality (HR: 1.9 [95% CI: 1.8 to 2.0]), cardiovascular death (HR: 2.1 [2.0 to 2.2]), fatal/nonfatal stroke (HR: 2.3 [2.1 to 2.6]/HR: 2.5 [2.2 to 2.7]), fatal/nonfatal re-infarction (HR: 1.7 [1.6 to 1.8]/HR: 1.8 [1.7 to 1.9]), and non- cardiovascular death (HR: 1.4 [1.3 to 1.5]) all P
Cites: Am J Ther. 2004 Jan-Feb;11(1):33-4314704594
Cites: J Am Coll Cardiol. 1997 Aug;30(2):406-139247512
To study the relationship between body mass index (BMI) and central obesity and mortality in elderly patients with coronary artery disease (CAD).
We identified 7057 patients 65 years or older from 5 cohort studies assessing mortality risk using either waist circumference (WC) or waist-hip ratio (WHR) in patients with CAD from January 1, 1980, to December 31, 2008. Normal weight, overweight, and obesity were defined using standard BMI cutoffs. High WHR was defined as 0.85 or more for women and 0.90 or more for men. High WC was defined as 88 cm or more for women and 102 cm or more for men. Separate models examined WC or WHR in combination with BMI (6 categories each) as the primary predictor (referent = normal BMI and normal WC or WHR). Cox proportional hazards models investigated the relationship between these obesity categories and mortality.
Patients' mean age was 73.0±6.0 years (3741 [53%] women). The median censor time was 7.1 years. A normal BMI with central obesity (high WHR or high WC) demonstrated highest mortality risk (hazard ratio [HR], 1.29; 95% CI, 1.14-1.46; HR, 1.29; 95% CI, 1.12-1.50, respectively). High WHR was also predictive of mortality in the overall (HR, 2.14; 95% CI, 1.93-2.38) as well as in the sex-specific cohort. In the overall cohort, high WC was not predictive of mortality (HR, 1.04; 95% CI, 0.97-1.12); however, it predicted higher risk in men (HR, 1.12; 95% CI, 1.01-1.24).
In older adults with CAD, normal-weight central obesity defined using either WHR or WC is associated with high mortality risk, highlighting a need to combine measures in adiposity-related risk assessment.
Familial hypercholesterolemia (FH) is a common genetic disorder causing accelerated atherosclerosis and premature cardiovascular disease. The aim of this study was to examine the prevalence and prognostic significance of possible FH in patients with myocardial infarction (MI).
By individual-level linkage of data from the Eastern Danish Heart Registry and national administrative registries, a study population of patients referred for coronary angiography due to MI was selected. The study population was divided into "unlikely FH" and "possible FH" based on the Dutch Lipid Clinic Network criteria, which included a plasma low-density lipoprotein cholesterol (LDL-C) and age for onset of cardiac disease. A score of =3 points was used as the cutpoint between the 2 groups. Among the study population of 13,174 MI patients, 1,281 (9.7%) had possible FH. These patients were younger (59.1 vs 65.7 years, P = .0001), had similar levels of comorbidities, and were treated more aggressively with cholesterol-lowering drugs compared with patients with unlikely FH. During a median of 3.3 years of follow-up, the unadjusted and adjusted event rates of recurrent MI were higher in patients with possible FH compared with unlikely FH (16% vs 11%, adjusted hazard ratio 1.28, 95% CI 1.09-1.51, P = .003.). Differences in adjusted all-cause mortality were not statistically significant (17% vs 23%, adjusted hazard ratio 0.89 [0.74-1.04], P = .1).
We found that MI patients with possible FH have higher risk of recurrent MI but similar risk of mortality compared with unlikely FH patients. Further studies on secondary prevention are warranted.