Search

Recently, it has become common for applied works to combine commonly used survival analysis modelingmethods, such as the multivariable Cox model and propensity score weighting, with the intention of forming a doublyrobust estimator of an exposure effect hazard ratio that is unbiased in large samples when either the Cox model orthe propensity score model is correctly specified. This combination does not, in general, produce a doubly robustestimator, even after regression standardization, when there is truly a causal effect. We demonstrate via simulationthis lack of double robustness for the semiparametric Cox model, the Weibull proportional hazards model, and asimple proportional hazards flexible parametric model, with both the latter models fit via maximum likelihood. Weprovide a novel proof that the combination of propensity score weighting and a proportional hazards survival model,fit either via full or partial likelihood, is consistent under the null of no causal effect of the exposure on the outcomeunder particular censoring mechanisms if either the propensity score or the outcome model is correctly specified andcontains all confounders. Given our results suggesting that double robustness only exists under the null, we outlinetwo simple alternative estimators that are doubly robust for the survival difference at a given time point (in the abovesense), provided the censoring mechanism can be correctly modeled, and one doubly robust method of estimationfor the full survival curve. We provide R code to use these estimators for estimation and inference in the supporting information.

Background and aims Patients with severely reduced kidney function have been excluded from randomized controlled trials and data on the safety and efficacy of direct oral anticoagulants (DOACs) according to kidney function remain sparse. The aim was to evaluate the safety and efficacy of the DOACs across subgroups of kidney function. Methods Using multiple Danish nationwide registers and laboratory databases, we included patients initiated on oral anticoagulants (OACs) with atrial fibrillation and available creatinine level and followed patients for 2 years to evaluate occurrence of stroke/thromboembolism (TE) and major bleeding. Results Among 26 686 included patients, 3667 (13.7%) had an estimated glomerular filtration rate (eGFR) of 30–49 mL/min/1.73 m2 and 596 (2.2%) had an eGFR below 30 mL/min/1.73 m2. We found no evidence of differences regarding the risk of stroke/TE between the OACs (P-value interaction >0.05 for all). Apixaban was associated with a lower 2-year risk of major bleeding compared to vitamin K antagonists (VKA) [hazard ratio 0.79, 95% confidence interval (CI) 0.67–0.93], and the risk difference was significantly larger among patients with reduced kidney function (P-value interaction 0.018). Rivaroxaban was associated with a higher risk of bleeding compared to apixaban (hazard ratio 1.78, 95%CI 1.32–2.39) among patients with eGFR 30–49 mL/min/1.73 m2. Conclusions Overall, we found no differences regarding the risk of stroke/TE, but apixaban was associated with a 21% lower relative risk of major bleeding compared to VKA. This risk reduction was even greater when comparing apixaban to VKA among patients with eGFR 15–30 mL/min/1.73 m2, and when comparing apixaban to dabigatran and rivaroxaban among patients with eGFR 30–49 mL/min/1.73 m2., BACKGROUND AND AIMS: Patients with severely reduced kidney function have been excluded from randomized controlled trials and data on safety and efficacy of direct oral anticoagulants (DOACs) according to kidney function remain sparse. The aim was to evaluate safety and efficacy of the DOACs across subgroups of kidney function.METHODS: Using multiple Danish nationwide registers and laboratory databases, we included patients initiated on oral anticoagulants (OACs) with atrial fibrillation and available creatinine level and followed patients for 2 years to evaluate occurrence of stroke/thromboembolism (TE) and major bleeding.RESULTS: Among 26,686 included patients, 3667 (13.7%) had an estimated glomerular filtration rate (eGFR) of 30-49 mL/min/1.73m2 and 596 (2.2%) had an eGFR below 30 mL/min/1.73m2. We found no evidence of differences regarding the risk of stroke/TE between the OACs (p-value interaction>0.05 for all). Apixaban was associated with a lower 2-year risk of major bleeding compared to VKA (risk ratio 0.79, 95% confidence interval (CI) 0.67-0.93), and the risk difference was significantly larger among patients with reduced kidney function (p-value interaction 0.018). Rivaroxaban was associated with higher risk of bleeding compared to apixaban (risk ratio 1.78, 95%CI 1.32-2.39) among patients with eGFR 30-49 mL/min/1.73m2.CONCLUSIONS: Overall, we found no differences regarding the risk of stroke/TE, but apixaban was associated with a 21% lower relative risk of major bleeding compared to VKA. This risk reduction was even greater when comparing apixaban and rivaroxaban among patients with eGFR 15-30 mL/min/1.73m2, and when comparing apixaban to dabigatran and rivaroxaban among patients with eGFR 30-49 mL/min/1.73m2.

BACKGROUND: Ex vivo lung perfusion (EVLP) is a method for the evaluation and reconditioning of high-risk donor lungs to increase the pool of potential donor lungs.METHODS: We reviewed all consecutive patients who received lung transplants from May 2012 to May 2017 with follow-up until July 2021. EVLP was used in lungs initially rejected due to inadequate oxygenation but without other contraindications. Lungs with improved oxygenation levels above the threshold were transplanted. The primary endpoint was the time to graft failure, which was defined as the time from surgery to death or re-transplantation, whichever occurred first. The secondary outcome was freedom from chronic lung allograft dysfunction.RESULTS: A total of 157 patients underwent transplantation during the study period. Thirty-nine patients received EVLP-treated donor lungs. Restricted mean graft survival time up to 7 years is 5.14 years for non-EVLP and 4.19 for EVLP, the difference being -0.95 (confidence interval [CI]-1.93 to 0.04, p = .059). The hazard ratio is 1.66 (CI 1.00-2.75, p = .046). Chronic lung allograft dysfunction was the highest contributor to mortality in both groups. There were significant differences in freedom from chronic lung allograft dysfunction at 12 and 24 months of follow-up (p = .005 and p = .030, respectively). Subgroup analyses revealed that the first patients who received EVLP in 2012-2013 had a substantially worse 5-year graft survival than those who received EVLP more recently in 2016-2017 (14.3% vs. 60.0%). For the latter, the 5-year graft survival was observed to be remarkably close to the non-EVLP group (60.8%).CONCLUSION: Long-term survival was significantly lower, and lung function was poorer among recipients in the EVLP group than in the non-EVLP group. However, the outcome of patients who received EVLP-treated lungs was observed to improve steadily after the first 2 years after EVLP was introduced in Denmark.

Aim To investigate the association between previous periodontal treatment and recurrent events after first-time myocardial infarction (MI). Materials and Methods From the Danish nationwide registries, patients with first-time MI between 2000 and 2015 were divided into three groups according to oral health care within 1 year prior to first-time MI. A multiple logistic regression model provided adjusted odds ratios (ORs) with 95% confidence intervals (CIs) to assess the 3-year risk of major adverse cardiovascular events (MACE). Results A total of 103,949 patients were included. Patients with treated periodontitis (PD) prior to first-time MI had an adjusted 3-year risk of MACE similar to patients presumed periodontally healthy (OR 0.97 [95% CI 0.92–1.03]). Patients with no prior dental visits were significantly older, had more comorbidities and showed significantly increased adjusted 3-year risks of MACE (OR 1.47 [95% CI 1.42–1.52]), cardiovascular death (OR 1.71 [95% CI 1.64–1.78]) and heart failure (OR 1.13 [95% CI 1.07–1.20]) compared with patients presumed periodontally healthy. Conclusions Patients with treated PD 1 year prior to first-time MI had a similar risk of recurrent cardiovascular events as patients presumed periodontally healthy. No dental visit prior to first-time MI was an independent risk factor for recurrent events., Aim: To investigate the association between previous periodontal treatment and recurrent events after first-time myocardial infarction (MI). Materials and Methods: From the Danish nationwide registries, patients with first-time MI between 2000 and 2015 were divided into three groups according to oral health care within 1 year prior to first-time MI. A multiple logistic regression model provided adjusted odds ratios (ORs) with 95% confidence intervals (CIs) to assess the 3-year risk of major adverse cardiovascular events (MACE). Results: A total of 103,949 patients were included. Patients with treated periodontitis (PD) prior to first-time MI had an adjusted 3-year risk of MACE similar to patients presumed periodontally healthy (OR 0.97 [95% CI 0.92–1.03]). Patients with no prior dental visits were significantly older, had more comorbidities and showed significantly increased adjusted 3-year risks of MACE (OR 1.47 [95% CI 1.42–1.52]), cardiovascular death (OR 1.71 [95% CI 1.64–1.78]) and heart failure (OR 1.13 [95% CI 1.07–1.20]) compared with patients presumed periodontally healthy. Conclusions: Patients with treated PD 1 year prior to first-time MI had a similar risk of recurrent cardiovascular events as patients presumed periodontally healthy. No dental visit prior to first-time MI was an independent risk factor for recurrent events.

BACKGROUND: Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated.OBJECTIVE: To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors.DESIGN: Case-crossover design.SETTING: Nationwide study of Danish patients from 2000 to 2018.PATIENTS: Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors.MEASUREMENTS: Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event.RESULTS: From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome).LIMITATION: An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use.CONCLUSION: From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medi

BACKGROUND: There is no practical dementia risk score in the clinical setting.OBJECTIVE: To derive and validate a score obtained by a rapid and simple assessment, which guides primary care providers in predicting the risk of dementia among older adults.DESIGN: A total of 4178 participants from three longitudinal cohorts (mean age at baseline = 76.8 [SD = 7.6] years), without baseline dementia, followed annually for a median of 10 years (IQR: 5 to16 years, Reverse Kaplan-Meier).PARTICIPANTS: To derive the score, we used data from 1,780 participants from the Rush Memory and Aging Project (93% White). To validate the score, we used data from 1,299 participants from the Religious Order Study (92% White), and to assess generalizability, 679 participants from the Minority Aging Research Study (100% Black).MEASUREMENTS: Clinician-based dementia diagnosis at any time after baseline and predictive variables associated with dementia risk that can be collected in a primary care setting: demographics, clinical indicators, medical history, memory complaints, cognitive and motor tests, and questions to assess functional disability, depressive symptoms, sleep, social isolation, and genetics (APOE e4 and AD polygenic risk score).RESULTS: At baseline, age, memory complaint, the ability to handle finances, the recall of the month, recall of the room, and recall of three words, were associated with the cumulative incidence of dementia, in the derivation cohort. The discrimination of the RADaR (Rapid Risk Assessment of Dementia) was good for the derivation and external-validation cohorts (AUC3 years = 0.82-0.86), compared to the overall discrimination of age alone (AUC3 years = 0.73), a major risk factor for dementia. Adding genetic data did not increase discrimination.LIMITATIONS: Participants were volunteers, may not represent the general population.CONCLUSIONS: The RADaR, derived from community-dwelling older persons, is a brief an

BACKGROUND: Acute kidney injury (AKI) has been associated with cardiovascular disease, but this is sparsely studied in non-selected populations and with little attention to the effect in age and renal function. Using nationwide administrative data, we investigated the hypothesis of increased one-year risk of cardiovascular event or death associated with AKI.METHODS: In a cohort study, we identified all admissions in Denmark between 2008 and 2018. AKI was defined as ≥1.5 times increase from baseline to peak creatinine during admission, or dialysis. We excluded patients with age <50 years, estimated glomerular filtration rate (eGFR) <15ml/min/1.73m 2, renal transplantation, index-admission due to cardiovascular disease or death during index-admission. The primary outcome was cardiovascular risk within one year from discharge, which was a composite of the secondary outcomes ischemic heart disease, heart failure or stroke. To estimate risks, we applied multiple logistic regression fitted by inverse probability of censoring weighting and stratified estimations by eGFR and age. We adjusted for proteinuria in the subcohort with measurements available. RESULTS: Among 565,056 hospital admissions, 39,569 (7.0%) cases of AKI were present. In total, 18,642 patients sustained a cardiovascular outcome. AKI was significantly associated with cardiovascular outcome with an adjusted OR [CI] of 1.33 [1.16-1.53], 1.43 [1.33-1.54], 1.23 [1.14-1.34], 1.38 [1.18-1.62] for eGFR ≥90, 60-89, 30-59 and 15-29ml/min/1.73m 2, respectively. When omitting the outcome heart failure, these results were 1.24 [1.06-1.45], 1.22 [1.11-1.33], 1.05 [0.95-1.16], 1.25 [1.02-1.54]. Results did not change substantially in strata of age groups, in AKI stages and in the subcohort adjusted for proteinuria. CONCLUSION: Non-selected patients aged 50 years or above with AKI during admission had significantly higher one-year risk of cardiovascular event or death, especially, but not onl

This commentary refers to 'Effect of longterm beta-blocker treatment followingmyocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study', by A. Holt et al., doi:10.1093/eurheartj/ehaa1058. and the discussion piece 'Long-term beta-blocker treatment in stable patients aftermyocardial infarction: a potential impact due to changes in the diagnosis of myocardial infarction?', by J.G. van der Stouwe et al., doi:10.1093/eurheartj/ehab257.

Objective Gastrointestinal bleeding (GIB) risk in relation to concomitant treatment with non-vitamin K oral anticoagulants (NOAC) and oral glucocorticoids is insufficiently explored. We aimed to investigate the short-term risk following coexposure. Methods This is a register-based, nationwide Danish study including patients with atrial fibrillation on NOACs during 2012–2018. Patients were defined as exposed to oral glucocorticoids if they claimed a prescription within 60 days prior to GIB. We investigated the associations between GIB and oral glucocorticoid exposure, reporting HRs via a nested case–control design and absolute risk via a cohort design. Matching terms were age, sex, calendar year, follow-up time and NOAC agent. Results 98 376 patients on NOACs (median age: 75 years (IQR: 68–82), 44% female) were included, and 16% redeemed at least one oral glucocorticoid prescription within 3 years. HRs of GIB were increased comparing exposed with non-exposed patients (<20 mg daily dose, HR 1.54 (95% CI 1.29 to 1.84); ≥20 mg daily dose, HR 2.19 (95% CI 1.81 to 2.65)). 60-day standardised absolute risk of GIB following first claimed oral glucocorticoid prescription increased compared with non-exposed: 60-day absolute risk: 0.71% (95% CI 0.58% to 0.85%) vs 0.38% (95% CI 0.32% to 0.43%). The relative risk was elevated as well: risk ratio of 1.89 (95% CI 1.43 to 2.36). Conclusions Concomitant treatment with NOACs and oral glucocorticoids was associated with a short-term rate and risk increase of GIB compared with patients only on NOACs. This could have implications for clinical management, necessitating closer monitoring or other risk mitigation strategies during episodes of cotreatment with oral glucocorticoids.

Comparing areas under the ROC curve (AUCs) is a popular approach to compare prognostic biomarkers. The aim of this paper is to present an efficient method to control the family-wise error rate when multiple comparisons are performed. We suggest to combine the max-t test and the closed testing procedures. We build on previous work on asymptotic results for ROC curves and on general multiple testing methods to efficiently take into account both the correlations between the test statistics and the logical constraints between the null hypotheses. The proposed method results in an uniformly more powerful procedure than both the single-step max-t test procedure and popular stepwise extensions of the Bonferroni procedure, such as Bonferroni-Holm. As demonstrated in this paper, the method can be applied in most usual contexts, including the time-dependent context with right censored data. We show how the method works in practice through a motivating example where we compare several psychometric scores to predict the t-year risk of Alzheimer's disease. The example illustrates several multiple testing settings and demonstrates the advantage of using the proposed methods over common alternatives. R code has been made available to facilitate the use of the methods by others.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer.METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively.CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.