Incidence of thyroid dysfunction following initiation of amiodarone treatment in patients with and without heart failure: a nationwide cohort study.

AIMS: Thyroid dysfunction is considered the most frequent complication to amiodarone treatment, but data on its occurrence outside clinical trials are sparse. The present study aimed to examine the incidence of thyroid dysfunction following initiation of amiodarone treatment in a nationwide cohort of patients with and without heart failure (HF). METHODS AND RESULTS: In Danish registries, we identified all patients with first-time amiodarone treatment during the period 2000-18, without prior thyroid disease or medication. The primary outcome was a composite of thyroid diagnoses and initiation of thyroid drugs. Outcomes were assessed at 1-year follow-up, and for patients free of events in the first year, in a landmark analysis for the subsequent 5 years. We included 43 724 patients with first-time amiodarone treatment, of whom 16 939 (38%) had HF. At 1-year follow-up, the cumulative incidence and adjusted hazard ratio (HR) of the primary outcome were 5.3% and 1.37 (95% confidence interval 1.25-1.50) in patients with a history of HF and 4.2% in those without HF (reference). In the 1-year landmark analysis, the subsequent 5-year cumulative incidences and adjusted HRs of the primary outcome were 5.3% (reference) in patients with 1-year accumulated dose <27.38 g [corresponding to average daily dose (ADD <75 mg)], 14.0% and HR 2.74 (2.46-3.05) for 27.38-45.63 g (ADD 75-125 mg), 20.0% and HR 4.16 (3.77-4.59) for 45.64-63.88 g (ADD 126-175 mg), and 24.5% and HR 5.30 (4.82-5.90) for >63.88 g (ADD >175 mg). CONCLUSION: Among patients who initiated amiodarone treatment, around 5% had thyroid dysfunction at 1-year follow-up, with a slightly higher incidence in those with HF. A dose-response relationship was observed between the 1-year accumulated amiodarone dose and the subsequent 5-year cumulative incidence of thyroid dysfunction.

The effect of sodium-glucose transport protein 2 inhibitors on mortality and heart failure in randomized trials versus observational studies.

AIM: Randomized clinical trials (RCTs) allocating type 2 diabetes patients to treatment with sodium-glucose transport protein 2 (SGLT-2) inhibitors or placebo have found significant effects on the risk of heart failure and modest effects on mortality. In the wake of the first trials, a number of observational studies have been conducted, some of these reporting a mortality reduction of 50% compared to active comparators. In this review, we systematically assess and compare the results on all-cause mortality, cardiovascular mortality and heart failure hospitalization observed in RCTs with the results obtained in observational studies. METHOD: We performed a systematic bibliographical search including cardiovascular outcome trials and observational studies assessing the effect of SGLT-2 inhibitors on mortality and heart failure. RESULTS: Seven RCTs and 23 observational studies were included in the current review. The observed heterogeneity between study results for all-cause mortality (p-interaction < 0.001) and cardiovascular mortality (p-interaction < 0.001) was explained by study type, whereas this was not the case for heart failure (p-interaction = 0.18). CONCLUSION: Methodological considerations such as the omission of important confounders, immortal-time bias and residual confounding such as unmeasured social economic inequality may be the cause of the inflated results observed in observational studies and that calls for caution when observational studies are used to guide treatment of patients with type 2 diabetes.

SuPAR is associated with death and adverse cardiovascular outcomes in patients with suspected coronary artery disease.

BACKGROUND: The inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with presence and severity of coronary artery disease (CAD) and incident death and myocardial infarction (MI). We sought to validate this finding in a further cohort of patients with suspected CAD. METHODS: Plasma suPAR was available in 1635 patients (73% with CAD) undergoing coronary angiography at a single regional Danish hospital between 2003 and 2005. Patients were followed for adverse cardiovascular outcomes of death, cardiac death and MI over a median follow-up of 4.2 years. RESULTS: In multivariate Cox models, adjusted for established cardiovascular risk factors, the biomarkers C-reactive protein, troponin-T and N-terminal-pro brain natriuretic peptide and the number of stenotic vessels, suPAR was independently associated with the combined endpoint of death/MI, hazard ratio (HR) 1.88; cardiovascular death, HR 2.01; and non-fatal MI, HR 1.53; (all p ≤ .037) per doubling of suPAR concentration. A plasma cutoff for suPAR ≥ 3.5 ng/mL was also significantly associated with death/MI, HR 1.51; p = .005. The C-statistic for the multivariate model predicting death/MI improved from 0.712 to 0.730 (p for difference .008) after inclusion of suPAR. However, suPAR was not associated with presence or extent of CAD (p > .05). CONCLUSION: These results validate previous findings that demonstrate suPAR to be an independent predictor of death/MI in patients with suspected or known CAD, however suPAR was not associated with presence or extent of CAD in our cohort. Probably because suPAR reflects end organ damage rather than the degree of atherosclerosis. BRIEF SUMMARY: We demonstrate that the inflammatory biomarker soluble urokinase plasminogen activator receptor is an independent predictor of death/myocardial infarction in patients with suspected or known coronary artery disease, but is not associated with the presence or severity of coronary artery disease.

Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality.

IMPORTANCE: It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2. OBJECTIVE: To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: To examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020. EXPOSURES: ACEI/ARB use was defined as prescription fillings 6 months prior to the index date. MAIN OUTCOMES AND MEASURES: In the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis. RESULTS: In the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]). CONCLUSIONS AND RELEVANCE: Prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

Heart failure and the prognostic impact and incidence of new-onset of diabetes mellitus: a nationwide cohort study.

BACKGROUND: Prevalent diabetes at the time of heart failure (HF) diagnosis is associated with a higher risk of death, but the incidence and prognostic importance of new-onset diabetes in patients with established HF remains unknown. METHODS: Patients with a first hospitalization for HF in the period 2003-2014 were included and stratified according to history of diabetes. Annual incidence rates of new-onset diabetes were calculated and time-dependent multivariable Cox regression models were used to compare the risk of death in patients with prevalent and new-onset diabetes with patients without diabetes as reference. The model was adjusted for age, sex, duration of HF, educational level and comorbidity. Covariates were continuously updated throughout follow-up. RESULTS: A total of 104,522 HF patients were included in the study, of which 21,216 (19%) patients had diabetes at baseline, and 8164 (10%) developed new-onset diabetes during a mean follow-up of 3.9 years. Patients with new-onset diabetes and prevalent diabetes were slightly younger than patients without diabetes (70 vs. 74 and 77, respectively), more likely to be men (62% vs. 60% and 54%), and had more comorbidities expect for ischemic heart disease, hypertension and chronic kidney disease which were more prevalent among patients with prevalent diabetes. Incidence rates of new-onset diabetes increased from around 2 per 100 person-years in the first years following HF hospitalization up to 3 per 100 person-years after 5 years of follow-up. A total of 61,424 (59%) patients died during the study period with event rates per 100 person-years of 21.5 for new-onset diabetes, 17.9 for prevalent diabetes and 13.9 for patients without diabetes. Compared to patients without diabetes, new-onset diabetes was associated with a higher risk of death (adjusted HR 1.47; 95% CI 1.42-1.52) and prevalent diabetes was associated with an intermediate risk (HR 1.19; 95% CI, 1.16-1.21). CONCLUSION: Following the first HF hospitalization, the incidence of new-onset diabetes was around 2% per year, rising to 3% after 5 years of follow-up. New-onset diabetes was associated with an increased risk of death, compared to HF patients with prevalent diabetes (intermediate risk) and HF patients without diabetes.

Cardiac systolic dysfunction in past illicit users of anabolic androgenic steroids.

Background: Illicit use of anabolic androgenic steroids (AAS) is associated with left ventricle (LV) systolic dysfunction and increased LV mass (LVM), but whether these findings persist in former AAS users has yet to be elucidated. The objective was to assess LV systolic function, LVM and myocardial fibrosis in current and former illicit AAS users compared with non-users. Methods: Community-based cross-sectional study among men, aged 18­50 years, involved in recreational resistance training. We included 37 current and 33 former illicit AAS users, geometric mean (95%CI), 30 (21; 44) months since AAS cessation, and 30 non-users as controls. We assessed myocardial function and structure using advanced echocardiography and cardiac MRI with late-gadolinium enhancement. Results: Mean (SE) LV global longitudinal strain (GLS) was impaired in former AAS users compared with non-users, −16.7 (0.5) versus −18.2 (0.4) %, P < .05. Mean (SE) LV ejection fraction (EF) was decreased, 51 (1) versus 58 (1) %, P < .001 and LV GLS impaired, −14.5 (0.4)%, P < .001, in current AAS users compared with non-users. Measures of LVM were increased in current AAS users compared with the other two groups, P < .001. Plasma total testosterone was independently associated with reduced LVEF (P = .049) and increased LVM/body surface area (P = .005) in multivariate linear regressions. Focal myocardial fibrosis was not detected in any participants and diffuse myocardial fibrosis, assessed using post-contrast T1-mapping time, did not differ among the three groups. Conclusions: Past illicit AAS use is associated with impaired LV GLS, suggesting subclinical cardiac systolic dysfunction years after AAS cessation.

Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids.

OBJECTIVE: Abuse of anabolic androgenic steroids (AAS) is prevalent among young men, but information regarding effects on insulin sensitivity and fat distribution is limited. The objective was to investigate insulin sensitivity in relation to fat distribution and adipocytokines among current and former AAS abusers compared with controls. DESIGN: Cross-sectional study among men involved in recreational strength training. Current and former AAS abusers (n=37 and n=33) and controls (n=30) volunteered from the community. METHODS: We assessed insulin sensitivity by Matsuda index (oral glucose tolerance test). Using overnight fasting blood samples, adiponectin and leptin were measured. Body composition and fat distribution, including visceral adipose tissue (VAT), were assessed by dual energy X-ray absorptiometry. RESULTS: Current and former AAS abusers displayed lower Matsuda index than controls (%-difference (95%CI) from controls, -26% (-45; -1) and -39% (-55; -18)). Testosterone was markedly higher among current AAS abusers and subnormal among former AAS abusers compared with controls. Current AAS abusers displayed higher mean VAT than controls (388 (17) vs 293 (12) cm3 , P<.001) whereas body fat %, adiponectin and leptin concentrations were lower. In contrast, former AAS abusers showed highest leptin concentrations and body fat %. Multivariate linear regressions identified VAT as independent predictor of lower Matsuda index among current AAS abusers compared with controls; while body fat % independently predicted lower Matsuda index among former AAS abusers. CONCLUSIONS: Both current and former AAS abusers displayed lower insulin sensitivity which could be mediated by higher VAT and total body fat %, respectively.

Hyperprolactinemia and the Association with All-Cause Mortality and Cardiovascular Mortality.

Hyperprolactinemia has been suspected to increase mortality risk, but the available data are conflicting. The objective of this study was to estimate the association between hyperprolactinemia and all-cause and cardiovascular mortality among patients referred for assessment of prolactin. For this study, adults with no prio pituitary disease who underwent prolactin assessment at 3 university Hospitals in Denmark between 2001 and 2011 were included in a retrospective cohort study. A total of 3 633 patients with a median follow-up time of 5.3 years (IQR 2.7-5.7) were included. Mean (SD) age 39.7 (15.5) years and 78% female. 373/3 633 (10.3%) had hyperprolactinemia and during follow-up 330/3 633 (9.1%) patients died of any cause, and 113/3 633 (3.1%) patients died of cardiovascular causes. In males, hyperprolactinemia was associated with age-adjusted incidence rate ratio (IRR) of 1.86 for all-cause mortality (95% CI 1.22-2.82) and 2.55 (95% CI 1.43-4.55) for cardiovascular mortality. The IRR for all-cause mortality was reduced to 1.37 (0.90-2.08) when adjusted for the use of antipsychotic medication. The association between hyperprolactinemia and cardiovascular mortality remained after adjusting for confounders, for example, chronic renal failure, diabetes, and antipsychotic medication. In females, hyperprolactinemia was not associated with all-cause mortality (IRR 1.45; CI 0.86-2.47) or cardiovascular mortality (IRR 0.58; CI 0.14-2.39). In conclusion, hyperprolactinemia was associated with increased cardiovascular mortality in male patients. This association was not found in female patients. Focus on increased cardiovascular risk in males with hyperprolactinemia is warranted.

Dosage of angiotensin-II receptor blockers in heart failure patients following changes in Danish drug reimbursement policies.

PURPOSE: National reimbursement policies in Denmark were changed in November 2010 favouring a shift in angiotensin-II receptor blocker (ARB) treatment to generic losartan for heart failure (HF) patients. We examined how changes in reimbursement policies affected the fraction of HF patients up-titrated to optimal or suboptimal ARB dosage. METHODS: A historical cohort study was performed including HF patients with at least one prescription of ARB in the months of May-Jul 2010 (baseline). Patients were considered up-titrated at doses 100, 16 or 160 mg for losartan, valsartan and candesartan, respectively. Individual-level linkage of nationwide registries of hospitalization and drug dispensing in Denmark was used to describe patterns of ARB prescriptions and estimate dosage before and after November 2010. Logistic regression models were used to assess the probability for being up-titrated in the period. RESULTS: Of 6036 individuals included (mean age 73.5 [standard deviation 11.2] years; 51% males), 3346 (55.4%) used losartan, 541 (9.0%) valsartan and 2149 (35.6%) candesartan at inclusion, respectively. 2887 (47.8%) were up-titrated at baseline (May-Jul 2010), followed by 2878 (48.2%) in the three months before the policy change (Aug-Oct 2010), and 2492 (43.7%) in the first months after the policy change (Feb-Apr 2011). Odds ratios for being up-titrated according to time period were 1.02 [0.95-1.09] in Aug-Oct 2010 (before policy change) and 0.84 [0.78-0.90] in Feb-Apr 2011 (after policy change), compared with May-Jul 2010 (reference). CONCLUSION: Probability of being up-titrated in ARB treatment was reduced 20% following changes in drug reimbursement policies.

Cancer risk in patients treated with denosumab compared with alendronate: A population-based cohort study.

BACKGROUND: Antiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian cancer incidence and emerging data suggest that denosumab stimulates germ cell proliferation in the gonads. This study aims to determine the association between the use of denosumab and the risk of reproductive cancers compared with the use of alendronate. RESEARCH DESIGN AND METHODS: Using a cohort study design, we used the Danish nationwide registries to identify a population of subjects ≥50 years of age during 2010-2017 who started denosumab after being on alendronate treatment for at least six months. The cohort was matched 1:2 with patients who had been treated with alendronate alone for at least six months. The risk of reproductive cancers and the risk difference between groups were estimated using the Longitudinal Targeted Maximum Likelihood Estimation (L-TMLE) method. RESULTS: We identified 6054 Danish individuals who underwent treatment with denosumab. These individuals were matched with 12,108 receiving alendronate. The absolute risk of reproductive cancer was 1.05 % (95 % CI 0.75-1.34) after three years for denosumab users and was not different 0.03 % (-0.34-0.39) than for alendronate users. In supplemental analyses, there was no increased risk of non-reproductive cancers associated with the use of denosumab (risk difference of 0.54 % (-0.41-1.19). Analysis comparing denosumab users with the general population gave similar results. CONCLUSION: There was no difference in the risk of cancer following treatment with denosumab compared to treatment with alendronate assessed after a short follow-up of 3 years.

Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study.

BACKGROUND: The cardiovascular risk after the first myocardial infarction (MI) declines rapidly during the first year. We analyzed whether the cardiovascular risk associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with the time elapsed following first-time MI. METHODS AND RESULTS: We identified patients aged 30 years or older admitted with first-time MI in 1997 to 2009 and subsequent NSAID use by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. We calculated the incidence rates of death and a composite end point of coronary death or nonfatal recurrent MIs associated with NSAID use in 1-year time intervals up to 5 years after inclusion and analyzed risk by using multivariable adjusted time-dependent Cox proportional hazards models. Of the 99 187 patients included, 43 608 (44%) were prescribed NSAIDs after the index MI. There were 36 747 deaths and 28 693 coronary deaths or nonfatal recurrent MIs during the 5 years of follow-up. Relative to noncurrent treatment with NSAIDs, the use of any NSAID in the years following MI was persistently associated with an increased risk of death (hazard ratio 1.59 [95% confidence interval, 1.49-1.69]) after 1 year and hazard ratio 1.63 [95% confidence interval, 1.52-1.74] after 5 years) and coronary death or nonfatal recurrent MI (hazard ratio, 1.30 [95% confidence interval,l 1.22-1.39] and hazard ratio, 1.41 [95% confidence interval, 1.28-1.55]). CONCLUSIONS: The use of NSAIDs is associated with persistently increased coronary risk regardless of time elapsed after first-time MI. We advise long-term caution in the use of NSAIDs for patients after MI.

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Glucose Monitoring Metrics in Individuals With Type 1 Diabetes Using Different Treatment Modalities: A Real-World Observational Study.

OBJECTIVE: This study aimed to investigate the association between continuous glucose monitoring (CGM)-derived glycemic metrics and different insulin treatment modalities using real-world data. RESEARCH DESIGN AND METHODS: A cross-sectional study at Steno Diabetes Center Copenhagen, Denmark, included individuals with type 1 diabetes using CGM. Data from September 2021 to August 2022 were analyzed if CGM was used for at least 20% of a 4-week period. Individuals were divided into four groups: multiple daily injection (MDI) therapy, insulin pumps with unintegrated CGM (SUP), sensor-augmented pumps with low glucose management (SAP), and automated insulin delivery (AID). The MDI and SUP groups were further subdivided based on CGM alarm features. The primary outcome was percentage of time in range (TIR: 3.9-10.0 mmol/L) for each treatment group. Secondary outcomes included other glucose metrics and HbA1c. RESULTS: Out of 6,314 attendees, 3,184 CGM users were included in the analysis. Among them, 1,622 used MDI, 504 used SUP, 354 used SAP, and 561 used AID. Median TIR was 54.0% for MDI, 54.9% for SUP, 62,9% for SAP, and 72,1% for AID users. The proportion of individuals achieving all recommended glycemic targets (TIR >70%, time above range <25%, and time below range <4%) was significantly higher in SAP (odds ratio [OR] 2.4 [95% CI 1.6-3.5]) and AID (OR 9.4 [95% CI 6.7-13.0]) compared with MDI without alarm features. CONCLUSIONS: AID appears superior to other insulin treatment modalities with CGM. Although bias may be present because of indications, AID should be considered the preferred choice for insulin pump therapy.

In Ischemic Heart Disease, Reduced Sensitivity to Pressure at the Sternum Accompanies Lower Mortality after Five Years: Evidence from a Randomized Controlled Trial.

Background: Autonomic nervous system dysfunction (ANSD) is associated with negative prognosis of ischemic heart disease (IHD). Elevated periosteal pressure sensitivity (PPS) at the sternum relates to ANSD and sympathetic hyperactivity. Two previous observational case-control studies of the effect of reduction of PPS suggested lower all-cause mortality from IHD and stroke. We now used a specific daily, adjunct, non-pharmacological program of reduction of elevated PPS to test the hypothetical association between the intervention and reduced all-cause mortality in patients with stable IHD in a randomized controlled trial (RCT). Methods: We completed active (n = 106) and passive interventions (n = 107) and compared the five-year mortalities. We also compared the five-year individual all-cause mortality of each participant to approximately 35.000 members of the general population of Denmark. Pooling the mortality data from the active group of the RCT with the two preliminary studies, we registered the mortality following active intervention of 1.168 person-years, compared to 40 million person-years of the pooled general population. Results: We recorded fewer deaths of the active RCT intervention group than of the corresponding control group from the general population (p = 0.01), as well as of the passive RCT intervention group (p = 0.035). The meta-analysis of the three studies together demonstrated reduced 4.2-year all-cause mortality of 60% (p = 0.007). Conclusions: The test of the hypothetical effect of an intervention aimed at the attenuation of ANSD accompanied by a lowered PPS revealed reduced all-cause mortality in patients with stable IHD.

Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study.

BACKGROUND: Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI). METHODS AND RESULTS: Patients ≥30 years of age who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years. Of the 83 677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (hazard ratio, 1.55; 95% confidence interval, 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment). CONCLUSIONS: Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.

The burden of cardiovascular outcomes in heart failure patients with new-onset, prevalent, and without type 2 diabetes.

BACKGROUND: The prognostic importance of new-onset type 2 diabetes (T2D) in heart failure (HF) remains unknown. We aimed to describe the cardiovascular outcome profile in HF patients with new-onset, no and prevalent T2D. METHODS: We constructed a cohort of patients with first HF admission between 1998 and 2016 from nationwide Danish registers. Outcomes were ischemic event, HF event, and death from other causes. The landmarking approach and the Aalen Johansen estimator were used together to estimate 5-year absolute and 5-year relative risk of the outcomes in HF patients with new-onset, no and prevalent T2D. Risk among subgroups were investigated by stratification. RESULTS: A total of 139 264 HF patients were included between 1998 and 2016, of which 29 078 patients had prevalent T2D. A total of 11 819 developed new-onset T2D. The 5-year risks of ischemic event in new-onset, no, and prevalent T2D were: 17.9% [17.2; 18.6], 18.8% [18.6; 19.0], and 26.1% [25.6; 26.7]. The 5-year risks of HF event were: 31.5% [30.6; 32.3], 30.7% [30.5; 31.0], and 33.6% [33.0; 34.2]. For other causes of death, the 5-year risks were: 20.9% [20.2; 21.7], 18.6% [18.4; 18.8], and 18.9% [18.4; 19.3]. The 5-year risk ratios of HF event or death from other causes versus ischemic event were: 2.9 [2.8; 3.1], 2.6 [2.6; 2.7], and 2.0 [2.0; 2.1] in patients with new-onset, no, and prevalent T2D. CONCLUSIONS: In patients with new-onset T2D, death from other causes were more likely to occur than an ischemic event, whereas in patients with prevalent T2D and no T2D, ischemic events were more common.

Impact of socioeconomic position on initiation of SGLT-2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes - a Danish nationwide observational study.

BACKGROUND: Low socioeconomic position may affect initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucacon-like-peptide-1 receptor agonists (GLP-1RA) among patients with type 2 diabetes (T2D). We examined the association between socioeconomic position and initiation of SGLT-2i or GLP-1RA in patients with T2D at time of first intensification of antidiabetic treatment. METHODS: Through nationwide registers, we identified all Danish patients on metformin who initiated second-line add-on therapy between December 10, 2012, and December 31, 2020. For each time period (2012-2014, 2015-2017, and 2018-2020), we used multivariable multinomial logistic regression to associate disposable income, as proxy for socioeconomic position, with the probability of initiating a specific second-line treatment at time of first intensification. We reported probabilities standardised to the distribution of demographics and comorbidities of patients included in the last period (2018-2020). FINDINGS: We included 48915 patients (median age 62 years; 61·7% men). In each time period, high-income patients were more often men and had less comorbidities as compared with low income-patients. In each time period, the standardised probability of initiating a SGLT-2i or a GLP-1RA was significantly higher in the highest income group compared with the lowest: 11·4% vs. 9·5% (probability ratio [PR] 1·21, 95 % confidence interval [CI] 1·01-1·44) in 2012-2014; 22·6% vs. 19.6% (PR 1·15, CI 1·05-1·27) in 2015-2017; and 65·8% vs. 54·8% (PR 1·20, CI 1·16-1·24) in 2018-2020. The differences by income were consistent across multiple subgroups. INTERPRETATION: Despite a universal healthcare system, low socioeconomic position was consistently associated with a lower probability of initiating a SGLT-2i or a GLP-1RA. These disparities may widen the future socioeconomic gap in cardiovascular outcomes. FUNDING: The work was funded by unrestricted grants from 'Region Sjaelland Den Sundhedsvidenskabelige Forskningsfond' and 'Murermester Lauritz Peter Christensen og hustru Kirsten Sigrid Christensens Fond'.

Socioeconomic position and first-time major cardiovascular event in patients with type 2 diabetes: a Danish nationwide cohort study.

AIMS: The association between socioeconomic position and cardiovascular disease has not been well studied in patients with type 2 diabetes. We aimed to examine the association between socioeconomic position and first-time major adverse cardiovascular events (MACE) in patients with type 2 diabetes. METHODS AND RESULTS: Through the Danish nationwide registers, we identified all residents with newly diagnosed type 2 diabetes between 2012 and 2017. Based on sex-stratified multivariable cause-specific Cox regression models, we calculated the standardized absolute 5-year risk of the composite outcome of first-time myocardial infarction, stroke, or cardiovascular mortality (MACE) according to income quartiles. A total of 57 106 patients with type 2 diabetes were included. During 155 989 person years, first-time MACE occurred in 2139 patients. Among both men and women, income was inversely associated with the standardized absolute 5-year risk of MACE. In men, the 5-year risk of MACE increased from 5.7% [95% confidence interval (CI) 4.9-6.5] in the highest income quartile to 9.3% (CI 8.3-10.2) in the lowest income group, with a risk difference of 3.5% (CI 2.4-4.7). In women, the risk of MACE increased from 4.2% (CI 3.4-5.0) to 6.1% (CI 5.2-7.0) according to income level, with a risk difference of 1.9% (CI 0.8-2.9). CONCLUSION: Despite free access to medical care in Denmark, low-socioeconomic position was associated with a higher 5-year risk of first-time MACE in patients with incident type 2 diabetes. Our results suggest prevention strategies could be developed specifically for patients with low-socioeconomic position.

Prediabetes Defined by First Measured HbA1c Predicts Higher Cardiovascular Risk Compared With HbA1c in the Diabetes Range: A Cohort Study of Nationwide Registries.

OBJECTIVE: To assess the risk of major adverse cardiovascular events (MACE), all-cause mortality, and initiation of medical treatment in subjects with prediabetes according to first-time measured HbA1c. RESEARCH DESIGN AND METHODS: Through registry databases, we identified 326,305 Danish patients with a first HbA1c between 40 and 51 mmol/mol (5.8-6.8%) from 2011 to 2017. After exclusion of patients with prior disease, 84,678 patients were followed 12 months after first HbA1c measurement. Cox regression models were used to estimate hazard ratios (HRs) of MACE and standardized absolute risks. Cumulative incidences were used to analyze initiation of glucose-lowering, antihypertensive, cholesterol-lowering, and antithrombotic medication. RESULTS: The 12-month risk of MACE and all-cause mortality increased gradually with increasing HbA1c until 47 mmol/mol (6.5%). In comparisons of subjects with HbA1c 40-41 mmol/mol (5.8-5.9%), subjects with HbA1c 46-47 mmol/mol (6.4-6.5%) had a 0.79% (95% CI 0.33-1.24) higher standardized absolute risk and an HR of 2.21 (95% CI 1.67-2.92) of MACE. Patients with HbA1c 48-49 mmol/mol (6.5-6.6%) had a 0.09% (95% CI -0.35 to 0.52) lower absolute risk and an HR of 1.33 (95% CI 0.87-2.05) of MACE. Initiation of medication was significantly lower among patients with HbA1c of 46-47 mmol/mol (6.4-6.5%) than among patients with HbA1c of 48-49 mmol/mol (6.5-6.6%). CONCLUSIONS: In the Danish population screened for diabetes with HbA1c, the highest risk of MACE and all-cause mortality was found in subjects with HbA1c just below the diagnostic threshold for diabetes. Our results highlight the need for increased focus on the treatment of cardiovascular risk factors for subjects with prediabetes.