Arterial Thromboembolism in Patients With Atrial Fibrillation and CHA2DS2-VASc Score 1: A Nationwide Study.

BACKGROUND: Oral anticoagulation is suggested in patients with atrial fibrillation and a CHA2DS2-VASc score ≥1 (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, and sex score). To assess granular differences within CHA2DS2-VASc 1, the incidence of arterial thromboembolism according to CHA2DS2-VASc 1 subgroups was examined. METHODS: The Danish National Patient Registry and the Danish Prescription Registry were linked on a nationwide level to identify patients with atrial fibrillation from 2000 to 2021 without oral anticoagulation and categorized according to CHA2DS2-VASc score: CHA2DS2-VASc 0 (male and female subjects); CHA2DS2-VASc 1 (hypertension, heart failure, diabetes, vascular disease, and age 65-74 years); or CHA2DS2-VASc 2 (age ≥75 years without other risk factors). Female sex was not considered a risk factor in any risk group. The outcome was arterial thromboembolism (ischemic stroke, embolism of extremity, or transient cerebral ischemia). Study groups were compared using Cox regression analysis. RESULTS: We included 26 701 patients with a CHA2DS2-VASc 0 score; 22 915 with CHA2DS2-VASc 1 (1483 patients with heart failure, 9066 with hypertension, 843 with diabetes, 770 with vascular disease, and 10 753 who were 65 to 74 years of age); and 14 525 patients with CHA2DS2-VASc 2 (≥75 years of age without other risk factors). With a median of 1 year of observation time, the cumulative incidence of arterial thromboembolism was 0.6% (n=154 [95% CI, 0.6%-0.8%]), 1.4% (n=16 [95% CI, 0.8%-2.2%]), 1.9% (n=141 [95% CI, 1.6%-2.2%]), 1.7% (n=12 [95% CI, 0.9%-2.9%]), 2.0% (n=13 [95% CI, 1.1%-3.4%]), 2.3% (n=187 [95% CI, 2.0%-2.7%]), and 4.4% (n=533 [95% CI, 4.1%-4.8%]) for CHA2DS2-VASc 0, heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years (CHA2DS2-VASc 1), and age ≥75 years (CHA2DS2-VASc 2), respectively. No statistically significant difference was identified among subgroups of CHA2DS2-VASc 1 (P=0.15 for difference). CONCLUSIONS: For patients with atrial fibrillation, all subgroups of CHA2DS2-VASc 1 were associated with lower incidence of arterial thromboembolism compared with age ≥75 years without other risk factors (ie, CHA2DS2-VASc 2) and a higher incidence compared with CHA2DS2-VASc 0. No statistically significant difference was identified between the subgroups of CHA2DS2-VASc 1. These findings support current recommendations that patients within this intermediate risk group could be identified with a similar risk of arterial thromboembolism.

Long-Term Incidence of Ischemic Stroke After Transient Ischemic Attack: A Nationwide Study From 2014 to 2020.

BACKGROUND: The short-term incidence of ischemic stroke after a transient ischemic attack (TIA) is high. However, data on the long-term incidence are not well known but are needed to guide preventive strategies. METHODS: Patients with first-time TIA (index date) in the Danish Stroke Registry (January 2014-December 2020) were included and matched 1:4 with individuals from the background population and 1:1 with patients with a first-time ischemic stroke on the basis of age, sex, and calendar year. The incidences of ischemic stroke and mortality from index date were estimated by Aalen-Johansen and Kaplan-Meier estimators, respectively, and compared between groups using multivariable Cox regression. RESULTS: We included 21 500 patients with TIA, 86 000 patients from the background population, and 21 500 patients with ischemic stroke (median age, 70.8 years [25th-75th percentile, 60.8-78.7]; 53.1% males). Patients with TIA had more comorbidities than the background population, yet less than the control stroke population. The 5-year incidence of ischemic stroke after TIA (6.1% [95% CI, 5.7-6.5]) was higher than the background population (1.5% [95% CI, 1.4-1.6], P<0.01; hazard ratio, 5.14 [95% CI, 4.65-5.69]) but lower than the control stroke population (8.9% [95% CI, 8.4-9.4], P<0.01; hazard ratio, 0.58 [95% CI, 0.53-0.64]). The 5-year mortality for patients with TIA (18.6% [95% CI, 17.9-19.3]) was higher than the background population (14.8% [95% CI, 14.5-15.1], P<0.01; hazard ratio, 1.26 [95% CI, 1.20-1.32]) but lower than the control stroke population (30.1% [95% CI, 29.3-30.9], P<0.01; hazard ratio, 0.41 [95% CI, 0.39-0.44]). CONCLUSIONS: Patients with first-time TIA had an ischemic stroke incidence of 6.1% during the 5-year follow-up period. After adjustment for relevant comorbidities, this incidence was approximately 5-fold higher than what was found for controls in the background population and 40% lower than for patients with recurrent ischemic stroke.

Use of inotropic agents in advanced heart failure: pros and cons.

BACKGROUND: Use of inotropic agents in advanced heart failure (HF) has over time been evaluated in several randomized, controlled clinical trials (RCTs). However, the evidence for both efficacy and safety is conflicting. SUMMARY: In this narrative review, the evidence for and role of inotropes in advanced HF are outlined. Readers are provided with a comprehensive overview of key-findings from 23 important RCTs comparing orally or intravenously administered inotropes. Clinically relevant pros and cons of inotropic regimens are summarized to guide the clinician in the management of advanced HF patients in different settings (e.g., out-patient, in-patient, and intensive care unit). Finally, future perspectives and potential new agents are discussed. KEY MESSAGES: Long-term use of inotropes in advanced HF is controversial and should only be considered in selected patients (e.g., as palliative or bridging strategy). However, short-term use continues to play a large role in hospitalized patients with cardiogenic shock or severe decompensated acute HF.

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.

Long-term cardiovascular outcomes among immigrants and non-immigrants in cardiac resynchronization therapy: a nationwide study.

AIMS: To date, potential differences in outcomes for immigrants and non-immigrants with a cardiac resynchronization therapy (CRT), in a European setting, remain underutilized and unknown. Hence, we examined the efficacy of CRT measured by heart failure (HF)-related hospitalizations and all-cause mortality among immigrants and non-immigrants. METHODS AND RESULTS: All immigrants and non-immigrants who underwent first-time CRT implantation in Denmark (2000-2017) were identified from nationwide registries and followed for up to 5 years. Differences in HF related hospitalizations and all-cause mortality were evaluated by Cox regression analyses. From 2000 to 2017, 369 of 10 741 (3.4%) immigrants compared with 7855 of 223 509 (3.5%) non-immigrants with a HF diagnosis underwent CRT implantation. The origins of the immigrants were Europe (61.2%), Middle East (20.1%), Asia-Pacific (11.9%), Africa (3.5%), and America (3.3%). We found similar high uptake of HF guideline-directed pharmacotherapy before and after CRT and a consistent reduction in HF-related hospitalizations the year before vs. the year after CRT (61% vs. 39% for immigrants and 57% vs. 35% for non-immigrants). No overall difference in 5-year mortality among immigrants and non-immigrants was seen after CRT [24.1% and 25.8%, respectively, P-value = 0.50, hazard ratio (HR) = 1.2, 95% confidence interval (CI): 0.8-1.7]. However, immigrants of Middle Eastern origin had a higher mortality rate (HR = 2.2, 95% CI: 1.2-4.1) compared with non-immigrants. Cardiovascular causes were responsible for the majority of deaths irrespective of immigration status (56.7% and 63.9%, respectively). CONCLUSION: No overall differences in efficacy of CRT in improving outcomes between immigrants and non-immigrants were identified. Although numbers were low, a higher mortality rate among immigrants of Middle Eastern origin was identified compared with non-immigrants.

Long-term Risk of Death and Hospitalization in Patients With Heart Failure and Takotsubo Syndrome: Insights From a Nationwide Cohort.

BACKGROUND: Data concerning the long-term risk of heart failure (HF) in patients with takotsubo syndrome (TTS) are sparse. We compared the rates of death and hospitalization due to HF with matched individuals from the background population and patients with ST-segment elevation myocardial infarction (STEMI). METHODS: In this nationwide observational cohort study, all patients with first-time TTS (2011-2018) who were alive at discharge were identified by using data from Danish nationwide registries. These were matched for age and sex with individuals from the background population (1:4 matching) and with patients with STEMI who were alive at discharge (1:3 matching). RESULTS: A total of 881 patients with TTS who were alive at discharge were identified (median age 70 years; 89.4% men). During a mean follow-up of 2.9 years, the incidence rates of death, HF hospitalization, and TTS recurrence in survivors of TTS were 6.9, 0.9 and 1.1 events per 100 person-years. The corresponding absolute 3-year risks were 9.3%, 1.8% and 2.5%, respectively. Survivors of TTS had higher associated rates of death compared with the background population (hazard ratio [HR] 2.05 [95% CI, 1.62-2.60]) and survivors of STEMI (HR 1.69 [1.34-2.13]). Similarly, survivors of TTS had higher associated rates of hospitalization due to HF compared with the background population (HR 4.24 [1.88-9.53]), but lower rates compared with survivors of STEMI (HR 0.34 [0.20-0.56]). Propensity-score matched analyses yielded similar results. CONCLUSIONS: Survivors of TTS had significantly higher associated mortality rates than the background population and survivors of STEMI. Survivors of TTS had lower HF hospitalization rates than survivors of STEMI, but the rates were higher than those of the background population.

Natriuretic peptide plasma concentrations and risk of cardiovascular versus non-cardiovascular events in heart failure with reduced ejection fraction: Insights from the PARADIGM-HF and ATMOSPHERE trials.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. OBJECTIVE: To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. METHODS: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. RESULTS: A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. CONCLUSIONS: The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Incidence of heart valve disease in women treated with the ergot-derived dopamine agonist bromocriptine.

BACKGROUND: Ergot-derived dopamine agonists are thought to induce fibrotic changes in cardiac valve leaflets. We sought to determine the incidence of heart valve disease in women treated with bromocriptine compared with age and sex matched controls from the background population. METHODS: In nationwide Danish registries we identified female patients treated with bromocriptine in the period 1995-2018. Patients were included at date of second redeemed prescription and were matched 1:5 with controls from the background population based on age, sex and year of inclusion by use of incidence density sampling. The outcomes were hospital admission for or outpatient diagnosis of heart valve disease, and death as competing risk. Incidence rates, cumulative incidence curves, and adjusted cox-proportional hazard models adjusted for cardiovascular risk factors were used to assess outcomes in bromocriptine users versus controls. RESULTS: A total of 3035 female bromocriptine users and 15,175 matched controls were included. Median age at inclusion was 32 years (Q1-Q3, 28-37 years). Both bromocriptine users and controls had few comorbidities and low use of concomitant pharmacotherapy. Within 10 years of follow-up, 11 patients (0.34%, 95% CI 0.13-0.55%) and 44 controls (0.29%, 95% CI 0.20-0.37) met the primary endpoint of heart valve disease, p = 0.63. The adjusted cox regression analysis yielded a hazard ratio of 0.96 (95% confidence interval (CI) 0.55-1.69, p = 0.89). CONCLUSIONS: Treatment initiation with ergot-derived dopamine agonist bromocriptine in younger women with few comorbidities, was associated with a low absolute long-term risk of heart valve disease, not significantly different from the risk in age and sex matched population controls. Thus, indicating a low clinical yield of pre-treatment echocardiographic screening in this patient population in accordance with current guidelines.

Nursing Home Admission and Initiation of Domiciliary Care After Ischemic Stroke - The Importance of Time to Thrombolysis.

OBJECTIVES: There is a paucity of data on the risk of nursing home admission or domiciliary care initiation according to time to intravenous thrombolysis for ischemic stroke. We investigated the association between time to intravenous thrombolysis and the composite of nursing home admission or domiciliary care initiation in patients with acute ischemic stroke. MATERIALS AND METHODS: In this nationwide cohort study, all stroke patients treated with intravenous thrombolysis (2011-2015) and alive at discharge were identified from the Danish Stroke Registry and other nationwide registries. The composite of nursing home admission or domiciliary care initiation one year post-discharge according to time to thrombolysis was examined with multivariable Cox regression. RESULTS: The study population comprised 4,349 patients (median age 67 years [25th-75th percentile 57-75], 65.2% men). The median National Institutes of Health Stroke Scale score at presentation was 5, and the median time from symptom-onset to initiation of thrombolysis was 143 min. The absolute 1-year risk of the composite endpoint was 14.0% (95%CI, 11.5-16.8%) in the ≤90 min group, 16.6% (15.1-18.1%) in the 91-180min group, and 16.0% (14.0-18.2%) in the 181-270 min group. Compared with thrombolysis ≤90 min, time to thrombolysis between 91-180 min and 181-270 min was associated with a significantly higher risk of the composite endpoint (hazard ratio 1.31 [1.04-1.65] and 1.47 [1.14-1.91], respectively). CONCLUSIONS: In patients admitted with ischemic stroke, increasing time to thrombolysis was associated with a greater risk of the composite of nursing home admission or domiciliary care initiation. Continued efforts to shorten the time delay from symptom-onset to initiation of thrombolysis are warranted.

Add-on therapy in metformin-treated patients with type 2 diabetes at moderate cardiovascular risk: a nationwide study.

BACKGROUND: In randomised clinical trials, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduced cardiovascular events in patients with type 2 diabetes (T2D) at high cardiovascular risk, as compared to standard care. However, data comparing these agents in patients with T2D who are at moderate risk is sparse. METHODS: From Danish national registries, we included patients with T2D previously on metformin monotherapy, who started an additional glucose-lowering agent [GLP-1 RA, SGLT-2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea (SU), or insulin] in the period 2010-2016. Patients with a history of cardiovascular events [heart failure (HF), myocardial infarction (MI) or stroke] were excluded. Patients were followed for up to 2 years. Cause-specific adjusted Cox regression models were used to compare the risk of hospitalisation for HF, a composite endpoint of major adverse cardiovascular events (MACE) (MI, stroke or cardiovascular death), and all-cause mortality for each add-on therapy. Patients who initiated DPP-4 inhibitors were used as reference. RESULTS: The study included 46,986 T2D patients with a median age of 61 years and of which 59% were male. The median duration of metformin monotherapy prior to study inclusion was 5.3 years. Add-on therapy was distributed as follows: 13,148 (28%) GLP-1 RAs, 2343 (5%) SGLT-2 inhibitors, 15,426 (33%) DPP-4 inhibitors, 8917 (19%) SUs, and 7152 (15%) insulin. During follow-up, 623 (1.3%, range 0.8-2.1%) patients were hospitalised for HF-hazard ratios (HR) were 1.11 (95% CI 0.89-1.39) for GLP-1 RA, 0.84 (0.52-1.36) for SGLT-2 inhibitors, 0.98 (0.77-1.26) for SU and 1.54 (1.25-1.91) for insulin. The composite MACE endpoint occurred in 1196 (2.5%, range 1.5-3.6%) patients, yielding HRs of 0.82 (0.69-0.97) for GLP-1 RAs, 0.79 (0.56-1.12) for SGLT-2 inhibitors, 1.22 (1.03-1.49) for SU and 1.23 (1.07-1.47) for insulin. 1865 (3.9%, range 1.9-9.0%) died from any cause during follow-up. HRs for all-cause mortality were 0.91 (0.78-1.05) for GLP-1 RAs, 0.79 (0.58-1.07) for SGLT-2 inhibitors, 1.13 (0.99-1.31) for SU and 2.33 (2.08-2.61) for insulin. CONCLUSION: In a nationwide cohort of metformin-treated T2D patients and no history of cardiovascular events, the addition of either GLP-1 RA or SGLT-2 inhibitor to metformin treatment was associated with a similar risk of hospitalisation for HF and death, and a lower risk of MACE for GLP-1 RA when compared with add-on DPP-4 inhibitors. By contrast, initiation of treatment with SU and insulin were associated with a higher risk of MACE. Additionally, insulin was associated with an increased risk of all-cause mortality and hospitalisation for HF.

Incidence of Hospitalization for Heart Failure and Case-Fatality Among 3.25 Million People With and Without Diabetes Mellitus.

BACKGROUND: Recent clinical trials of new glucose-lowering treatments have drawn attention to the importance of hospitalization for heart failure as a complication of diabetes mellitus. However, the epidemiology is not well described, particularly for type 1 diabetes mellitus. We examined the incidence and case-fatality of heart failure hospitalizations in the entire population aged ≥30 years resident in Scotland during 2004 to 2013. METHODS: Date and type of diabetes mellitus diagnosis were linked to heart failure hospitalizations and deaths using the national Scottish registers. Incidence rates and case-fatality were estimated in regression models (quasi-Poisson and logistic regression respectively). All estimates are adjusted for age, sex, socioeconomic status, and calendar-year. RESULTS: Over the 10-year period of the study, among 3.25 million people there were 91, 429, 22 959, and 1313 incident heart failure events among those without diabetes mellitus, with type 2, and type 1 diabetes mellitus, respectively. The crude incidence rates of heart failure hospitalization were therefore 2.4, 12.4, and 5.6 per 1000 person-years for these 3 groups. Heart failure hospitalization incidence was higher in people with diabetes mellitus, regardless of type, than in people without. Relative differences were smallest for older men, in whom the difference was nonetheless large (men aged 80, rate ratio 1.78; 95% CI, 1.45-2.19). Rates declined similarly, by 0.2% per calendar-year, in people with type 2 diabetes mellitus and without diabetes mellitus. Rates fell faster, however, in those with type 1 diabetes mellitus (2.2% per calendar-year, rate ratio for type 1/calendar-year interaction 0.978; 95% CI, 0.959-0.998). Thirty-day case-fatality was similar among people with type 2 diabetes mellitus and without diabetes mellitus, but was higher in type 1 diabetes mellitus for men (odds ratio, 0.96; 95% CI, 0.95-0.96) and women (odds ratio, 0.98; 95% CI, 0.97-0.98). Case-fatality declined over time for all groups (3.3% per calendar-year, odds ratio per calendar-year 0.967; 95% CI, 0.961-0.973). CONCLUSIONS: Despite falling incidence, particularly in type 1 diabetes mellitus, heart failure remains ≈2-fold higher than in people without diabetes mellitus, with higher case-fatality in those with type 1 diabetes mellitus. These findings support the view that heart failure is an under-recognized and important complication in diabetes mellitus, particularly for type 1 disease.

Risk of stroke subsequent to infective endocarditis: A nationwide study.

BACKGROUND: The aim of the study was to investigate the associated risk of stroke after discharge of infective endocarditis (IE) in patients with stroke during IE admission compared with patients without stroke during IE admission. METHODS: Using Danish nationwide registries, we identified nonsurgically treated patients with IE discharged alive in the period from 1996 to 2016. The study population was grouped into (1) patients with stroke during IE admission and (2) patients without stroke during IE admission. Multivariable adjusted Cox proportional-hazard analysis was used to compare the associated risk of stroke between groups. RESULTS: We identified 4,284 patients with IE, of whom 239 (5.6%) had a stroke during IE admission. We identified differentials in the associated risk of stroke during follow-up between groups (P = .006 for interaction with time). The associated risk of stroke was higher in patients with stroke during IE admission with a 1-year follow-up, HR = 3.21 (95% CI 1.66-6.20), compared with patients without stroke during IE admission. From 1 to 5 years of follow-up, we identified no difference in the associated risk of stroke between groups, HR = 0.91 (95% CI 0.33-2.50). CONCLUSIONS: Patients with nonsurgically treated IE with a stroke during IE admission were at significant higher associated risk of subsequent stroke within the first year of follow-up as compared with patients without a stroke during IE admission. This risk difference was not evident beyond 1 year of discharge. These findings underline the need for identification of causes and mechanisms of recurrent strokes after IE to develop preventive means.

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.

Geographic variations in the PARADIGM-HF heart failure trial.

AIMS: The globalization of clinical trials has highlighted geographic variations in patient characteristics, event rates, and treatment effects. We investigated these further in PARADIGM-HF, the largest and most globally representative trial in heart failure (HF) to date. METHODS AND RESULTS: We looked at five regions: North America (NA) 602 (8%), Western Europe (WE) 1680 (20%), Central/Eastern Europe/Russia (CEER) 2762 (33%), Latin America (LA) 1433 (17%), and Asia-Pacific (AP) 1487 (18%). Notable differences included: WE patients (mean age 68 years) and NA (65 years) were older than AP (58 years) and LA (63 years) and had more coronary disease; NA and CEER patients had the worst signs, symptoms, and functional status. North American patients were the most likely to have a defibrillating-device (54 vs. 2% AP) and least likely prescribed a mineralocorticoid receptor antagonist (36 vs. 65% LA). Other evidence-based therapies were used most frequently in NA and WE. Rates of the primary composite outcome of cardiovascular (CV) death or HF hospitalization (per 100 patient-years) varied among regions: NA 13.6 (95% CI 11.7-15.7) WE 9.6 (8.6-10.6), CEER 12.3 (11.4-13.2), LA 11.2 (10.0-12.5), and AP 12.5 (11.3-13.8). After adjustment for prognostic variables, relative to NA, the risk of CV death was higher in LA and AP and the risk of HF hospitalization lower in WE. The benefit of sacubitril/valsartan was consistent across regions. CONCLUSION: There were many regional differences in PARADIGM-HF, including in age, symptoms, comorbidity, background therapy, and event-rates, although these did not modify the benefit of sacubitril/valsartan. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Atrial fibrillation and risk of stroke: a nationwide cohort study.

AIM: Although the relation between stroke risk factors and stroke in patients with atrial fibrillation (AF) has been extensively examined, only few studies have explored the association of AF and the risk of ischaemic stroke/systemic thromboembolism/transient ischaemic attack (stroke/TE/TIA) in the presence of concomitant stroke risk factors. METHODS AND RESULTS: From nationwide registries, all persons who turned 50, 60, 70, or 80 from 1997 to 2011 were identified. Persons receiving warfarin were excluded. The absolute risk of stroke/TE/TIA was reported for a 5-year period, as was the absolute risk ratios for AF vs. no AF according to prior stroke and the number of additional risk factors. The study cohort comprised of 3 076 355 persons without AF and 48 189 with AF. For men aged 50 years, with no risk factors, the 5-year risk of stroke was 1.1% (95% confidence interval 1.1-1.1); with AF alone 2.5% (1.8-3.2); with one risk factor and no prior stroke or AF 2.5% (2.3-2.7); and with one factor, no prior stroke and AF 2.9% (1.4-4.3). In men aged 50 years with prior stroke as the only risk factor, 5-year risk was 10.2% (9.1-11.3). In men aged 70 years, the corresponding risks were 4.8% (4.7-4.9), 6.8% (5.7-7.9), 6.6% (6.3-6.8), 8.7 (7.4-9.9), and 19.1% (18.1-20.1), respectively. In women aged 50 years, the risk was of 0.7% (0.7-0.7), 2.1% (0.9-3.2), 1.6% (1.4-1.8), 4.1% (0.6-7.6), and 7.2% (6.3-8.2), respectively, and in women aged 70 years 3.4% (3.3-3.5), 8.2% (7.0-9.5), 4.6% (4.4-4.8), 9.1% (7.5-10.6), and 15.4% (14.5-16.4), respectively. CONCLUSIONS: Stroke/TE/TIA risk was particularly increased when prior stroke/TE/TIA was present. Atrial fibrillation is associated with an increase in risk of stroke/TE/TIA in the absence of other risk factors but only a moderate increase in risk when other risk factors are present.

Comparison of antiplatelet regimens in secondary stroke prevention: a nationwide cohort study.

BACKGROUND: In patients with ischemic stroke of non-cardioembolic origin, acetylsalicylic acid, clopidogrel, or a combination of acetylsalicylic acid and dipyridamole are recommended for the prevention of a recurrent stroke. The purpose of this study was to examine the risk of bleeding or recurrent stroke associated with these three treatments. METHODS: Patients who were discharged with first-time ischemic stroke from 2007-2010, with no history of atrial fibrillation were identified from Danish nationwide registries. Hazard ratios (HRs) and 1-year risks of recurrent ischemic stroke and bleeding were calculated for each antiplatelet regimen. RESULTS: Among patients discharged after first-time ischemic stroke, 3043 patients were treated with acetylsalicylic acid, 12,295 with a combination of acetylsalicylic acid and dipyridamole, and 3885 with clopidogrel. Adjusted HRs for clopidogrel versus the combination of acetylsalicylic acid and dipyridamole were 1.02 (95% confidence interval [CI]: 0.89-1.17) for ischemic stroke and 1.06 (95% CI: 0.83-1.35) for bleeding. Adjusted HRs for acetylsalicylic acid versus the combination of acetylsalicylic acid and dipyridamole were 1.48 (95% CI: 1.31-1.67) for stroke and 1.47 (95% CI: 1.18-1.82) for bleeding. Clopidogrel versus acetylsalicylic acid yielded HRs of 0.69 (95% CI: 0.59-0.81) and 0.72 (95% CI: 0.55-0.96) for stroke and bleeding, respectively. The 1-year predicted risks associated with acetylsalicylic acid, the combination of acetylsalicylic acid and dipyridamole, and clopidogrel were 11.1 (95% CI: 10.2-12.2), 7.7 (95% CI: 7.3-8.3), and 8.0 (95% CI: 6.9-8.7) for ischemic stroke, respectively; while, the risks for bleeding were 3.4 (95% CI: 2.8-3.9), 2.4 (95% CI: 2.1-2.7), and 2.4 (95% CI: 1.9-2.9), respectively. CONCLUSION: Clopidogrel and the combination of acetylsalicylic acid and dipyridamole were associated with similar risks for recurrent ischemic stroke and bleeding; whereas acetylsalicylic acid was associated with higher risks for both ischemic stroke and bleeding. The latter finding may partially be explained by selection bias.

Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease: a nationwide study.

AIMS: Inflammation is considered to play a role in the development of atrial fibrillation (AF). Hence inflammatory bowel disease (IBD) may be associated with AF. We therefore examined the incidence of AF and stroke in patients with IBD. METHODS AND RESULTS: From Danish nationwide registries 1996-2011, we identified 24 499 patients with new-onset IBD and 236 275 age- and sex-matched controls. Poisson regression analyses with continuously updated covariates were used to estimate incidence rate ratios (IRRs) of AF and stroke. Disease activity stages of flare (new disease activity), persistent activity, and remission were defined by corticosteroid prescriptions, IBD hospital admissions, and biological treatment. Inflammatory bowel disease patients had a mean age of 43.9 years, 53.9% were women, and mean follow-up was 6.8 years. Among IBD patients, 685 had AF and 549 had a stroke, corresponding to incidence rates per 1000 person-years of 4.16 vs. 2.70 for AF and 3.33 vs. 2.44 for stroke, compared with matched controls. Overall IBD-associated risk of AF corresponded to IRR 1.26 (1.16-1.36), but was driven by increased AF incidence during IBD flares [IRR 2.63 (2.26-3.06)] and persistent activity [IRR 2.06 (1.67-2.55)], whereas no increased AF risk was observed in remission periods [IRR 0.97 (0.88-1.08)]. Likewise increased stroke risk was exclusively found during active IBD [IRRs: 1.57 (1.27-1.93), 1.71 (1.32-2.21), and 1.04 (0.93-1.15) for flares, persistent activity, and remission, respectively]. CONCLUSION: Active IBD is associated with increased risk of AF and stroke. These findings may be relevant to clinical practice.

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.

Comparative outcomes in patients with preexisting heart failure to those without heart failure after out-of-hospital cardiac arrest: A nationwide registry study.

BACKGROUND: The knowledge of prognosis following out-of-hospital cardiac arrest (OHCA) in patients with heart failure heart failure (HF) is sparse. The objective of this study was to compare the outcome after OHCA among patients with and without HF. METHODS: We studied 45,293 patients who were included for the Danish cardiac arrest registry between 2001 and 2014. Patients were stratified into two groups based on the presence of HF prior to cardiac arrest. The primary outcome was 30-day survival and secondary outcome was anoxic brain damage or permanent nursing home admission at 1-year among 30-day survivors. RESULTS: Among the final 28,955 patients included, 6675 (23%) patients had prior HF and 22,280 (77%) patients had no prior HF. At 30 days, 616 (9.2%) patients survived among the patients with HF and 1916 (8.6%) among the patients without HF. There was a significant interaction between atrial fibrillation (AF) and HF for primary outcome and therefore it was assessed separately between the two study groups stratified based on AF. Among patients without AF a significantly higher odds of 30-day survival were observed among patients with HF (OR 2.69, 95% CI 2.34-3.08, P < 0.001), but no difference was observed among the patients from two study groups with no AF. No significant difference in risk for secondary outcome was observed among the two study groups. In multivariable average treatment effect modeling, all the results largely remain unchanged. CONCLUSIONS: Outcome following OHCA among patients with and without HF is found to be similar in this large Danish OHCA registry.