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Aims Methods and results Conclusion Although body mass index (BMI) is the most commonly used anthropometric measure to assess adiposity, alternative indices such as the waist‐to‐height ratio may better reflect the location and amount of ectopic fat as well as the weight of the skeleton.The prognostic value of several alternative anthropometric measures was compared with that of BMI in 1116 patients with non‐ischaemic heart failure with reduced ejection fraction (HFrEF) enrolled in DANISH. The association between anthropometric measures and all‐cause death was adjusted for prognostic variables, including natriuretic peptides. Median follow‐up was 9.5 years (25th–75th percentile, 7.9–10.9). Compared to patients with a BMI 18.5–24.9 kg/m2 (n = 363), those with a BMI ≥25 kg/m2 had a higher risk of all‐cause and cardiovascular death, although this association was only statistically significant for a BMI ≥35 kg/m2 (n = 91) (all‐cause death: hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.28–2.48; cardiovascular death: HR 2.46, 95% CI 1.69–3.58). Compared to a BMI 18.5–24.9 kg/m2, a BMI <18.5 kg/m2 (n = 24) was associated with a numerically, but not a significantly, higher risk of all‐cause and cardiovascular death. Greater waist‐to‐height ratio (as an exemplar of indices not incorporating weight) was also associated with a higher risk of all‐cause and cardiovascular death (HR for the highest vs. the lowest quintile: all‐cause death: HR 2.11, 95% CI 1.53–2.92; cardiovascular death: HR 2.17, 95% CI 1.49–3.15).In patients with non‐ischaemic HFrEF, there was a clear association between greater adiposity and higher long‐term mortality.Clinical Trial Registration: ClinicalTrials.gov NCT00542945. [ABSTRACT FROM AUTHOR]

Aim: Blood urea nitrogen (BUN) to creatinine ratio is associated with worse outcomes in acute heart failure (HF) but little is known about its importance in chronic HF. Methods and results: We combined individual patient data from clinical trials (HF with reduced ejection fraction [HFrEF]: PARADIGM‐HF, ATMOSPHERE and DAPA‐HF, and HF with preserved ejection fraction [HFpEF]: PARAGON‐HF and I‐PRESERVE). The primary outcome examined was a composite time to first HF hospitalization or cardiovascular death; its components and all‐cause death were also examined. Each HF phenotype was categorized according to median BUN/creatinine ratio, generating four groups that is, HFpEF ≤ and >median BUN/creatinine ratio and HFrEF ≤ and >median BUN/creatinine ratio. The association between BUN/creatinine ratio and outcomes was evaluated using the Kaplan–Meier estimator and Cox proportional hazard models. Overall, 28 820 patients were analysed. The median (IQR) BUN/creatinine ratio was 20.1 (Q1–Q3 16.7–24.7) in HFpEF and 18.7 (15.2–22.8) in HFrEF. In both HFpEF and HFrEF, higher BUN/creatinine ratio was associated with older age, female sex, and diabetes, but similar estimated glomerular filtration rate (eGFR). The risk of each outcome examined was significantly higher in patients with BUN/creatinine ratio ≥median, compared to

Background A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level. Methods Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes. Results Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211–0.310), and 1 499 (34.8%) in severely frail categories (FI >0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% confidence interval {CI}]: 0.50 [0.33–0.76], 0.62 [0.45–0.85], and 0.64 [0.49–-0.83], respectively; p -interaction = 0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; p -interaction = 0.44), CV endpoint (heart failure hospitalization or CV death; p -interaction = 0.63), and all-cause mortality (p -interaction p  = .42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin versus placebo in all FI categories (16.9% vs 20.1%, 26.3% vs 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately, and severely frail categories, respectively). Conclusions The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety. [ABSTRACT FROM AUTHOR]

Aim: Chronic obstructive pulmonary disease (COPD) is common in heart failure with a mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and is associated with worse outcomes. In a pre‐specified analysis of DELIVER, we investigated the relationship between COPD status and outcomes, and the efficacy and safety of dapagliflozin, compared with placebo, according to COPD status. Methods and results: Patients with severe pulmonary disease (including COPD) were excluded from the trial. The primary outcome was a composite of cardiovascular death or worsening heart failure. Of the 6261 patients with data on baseline COPD status, 694 (11.1%) had a known history of this condition. The risk of the primary endpoint was higher in patients with mild‐to‐moderate COPD compared with those without COPD (adjusted hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.08–1.51). The benefit of dapagliflozin on the primary outcome was consistent irrespective of COPD status (no COPD: HR 0.82 [95% CI 0.72–0.93]; COPD: HR 0.82 [95% CI 0.62–1.10]; pinteraction = 0.98). Consistent effects were observed for heart failure, cardiovascular, and all‐cause hospitalization, and deaths, and composites of these. Dapagliflozin, as compared with placebo, improved the Kansas City Cardiomyopathy Questionnaire scores from baseline to 8 months to a similar extent in patients with and without mild‐to‐moderate COPD (pinteraction ≥ 0.63). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of COPD status. Conclusions: Mild‐to‐moderate COPD is common in patients with HFmrEF/HFpEF and is associated with worse outcomes. The beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, regardless of COPD status. Clinical Trial Registration: ClinicalTrials.gov NCT03619213. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments, and outcomes. We examined these differences in PARADISE‐MI. Methods and results: Overall, 23.0% were randomized in Eastern Europe/Russia, 17.5% in Western Europe, 12.2% in Southern Europe, 10.1% in Northern Europe, 12.0% in Latin America (LA), 9.3% in North America (NA), 10.0% in East/South‐East Asia and 5.8% in South Asia (SA). Those from Asia, particularly SA, were different from patients enrolled in the other regions, being younger and thinner. They also differed in terms of comorbidities (high prevalence of diabetes and low prevalence of atrial fibrillation), type of myocardial infarction (more often ST‐elevation myocardial infarction), and treatment (low rate of primary percutaneous coronary intervention). By contrast, patients from LA did not differ meaningfully from those randomized in Europe or NA. Use of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (34.8%) and beta‐blockers (65.5%) was low in SA, whereas mineralocorticoid receptor antagonist use was lowest in NA (22%) and highest in Eastern Europe/Russia (53%). Rates of the primary composite outcome of cardiovascular death or incident heart failure varied two‐fold among regions, with the lowest rate in SA (4.6/100 person‐years) and the highest in LA (9.2/100 person‐years). Rates of incident heart failure varied almost six‐fold among regions, with the lowest rate in SA (1.0/100 person‐years) and the highest in Northern Europe (5.9/100 person‐years). The effect of sacubitril/valsartan was not modified by region. Conclusion: In PARADISE‐MI, there were substantial regional differences in patient characteristics, treatments and outcomes. Although the generalizability of these findings to a 'real‐world' unselected population may be limited, these findings underscore the importance of considering both regional and within‐region differences when designing global clinical trials. [ABSTRACT FROM AUTHOR]

Purpose. Transthyretin is produced in the retina and approximately one quarter of patients with variant transthyretin amyloidosis (ATTRv) develop ocular involvement. Glaucoma is the most important ocular manifestation, leading to rapid loss of vision. The usefulness of glaucoma as a red flag for cardiac amyloidosis is unknown. Materials and Methods. On a national scale, we investigated the association between glaucoma and development of amyloidosis, compared to an age- and sex-matched population from the general population. Results. The study population included 365,496 subjects (1:1 ratio). Adjusted Cox-models showed no significant association between glaucoma and future diagnosis of amyloidosis (hazard ratio: 1.16 [0.80–1.70], p =.44). Conclusion. We conclude that while ocular involvement is a possible early manifestation of ATTRv, nationwide data suggest that glaucoma is probably not useful as a red flag for cardiac amyloidosis. [ABSTRACT FROM AUTHOR]

Aims: The effects of adding a sodium–glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor–neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. Methods and results: The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74–1.01) for MRA non‐users versus 0.76 (95% CI 0.64–0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non‐users and users were 0.82 (95% CI 0.73–0.92) and 0.74 (95% CI 0.45–1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. Conclusions: The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes compared with sinus rhythm, and may modify the effects of therapy.Objectives: This study examined the effects of dapagliflozin according to the presence or not of AF in the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial.Methods: A total of 6,263 patients with HF with New York Heart Association functional class II-IV, left ventricular ejection fraction >40%, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomized to dapagliflozin or placebo. Clinical outcomes and the effect of dapagliflozin, according to AF status, were examined. The primary outcome was a composite of cardiovascular death or worsening HF.Results: Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% had paroxysmal AF, and 38.7% had persistent/permanent AF. The risk of the primary endpoint was higher in patients with AF, especially paroxysmal AF, driven by a higher rate of HF hospitalization: no AF, HF hospitalization rate per 100 person-years (4.5 [95% CI: 4.0-5.1]), paroxysmal AF (7.5 [95% CI: 6.4-8.7]), and persistent/permanent AF (6.4 [95% CI: 5.7-7.1]) (P < 0.001). The benefit of dapagliflozin on the primary outcome was consistent across AF types: no AF, HR: 0.89 (95% CI: 0.74-1.08); paroxysmal AF, HR: 0.75 (95% CI: 0.58-0.97); persistent/permanent AF, HR: 0.79 (95% CI: 0.66-0.95) (Pinteraction = 0.49). Consistent effects were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the KCCQ-TSS.Conclusions: In DELIVER, the beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, irrespective of type of AF at baseline. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. [DELIVER]; NCT03619213). [ABSTRACT FROM AUTHOR]

Background: Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure).Methods: Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death.Results: Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P<0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; Pinteraction=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class.Conclusions: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty.Registration: URL: https://www.Clinicaltrials: gov; Unique identifier: NCT03619213. [ABSTRACT FROM AUTHOR]

Background: Frailty is an increasingly common problem, and frail patients are less likely to receive new pharmacologic therapies because the risk-benefit profile is perceived to be less favorable than in nonfrail patients.Objectives: This study investigated the efficacy of sacubitril/valsartan according to frailty status in 4,796 patients with heart failure with preserved ejection fraction randomized in the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial.Methods: Frailty was measured by using the Rockwood cumulative deficit approach. The primary endpoint was total heart failure hospitalizations or cardiovascular death.Results: A frailty index (FI) was calculable in 4,795 patients. In total, 45.2% had class 1 frailty (FI ≤0.210, not frail), 43.5% had class 2 frailty (FI 0.211-0.310, more frail), and 11.4% had class 3 frailty (FI ≥0.311, most frail). There was a graded relationship between FI class and the primary endpoint, with a significantly higher risk associated with greater frailty (class 1: reference; class 2 rate ratio: 2.19 [95% CI: 1.85-2.60]; class 3 rate ratio: 3.29 [95% CI: 2.65-4.09]). The effect of sacubitril/valsartan vs valsartan on the primary endpoint from lowest to highest FI class (as a rate ratio) was: 0.98 [95% CI: 0.76-1.27], 0.92 [95% CI: 0.76-1.12], and 0.69 [95% CI: 0.51-0.95]), respectively (Pinteraction = 0.23). When FI was examined as a continuous variable, the interaction with treatment was significant for the primary outcome (Pinteraction = 0.002) and total heart failure hospitalizations (Pinteraction < 0.001), with those most frail deriving greater benefit.Conclusions: Frailty was common in heart failure with preserved ejection fraction and associated with worse outcomes. Compared with valsartan, sacubitril/valsartan seemed to show a greater reduction in the primary endpoint with increasing frailty, although this was not significant when FI was examined as a categorical variable. (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). [ABSTRACT FROM AUTHOR]

Introduction: It has not been established if migraine headache and migraine aura share common pathophysiological mechanisms. Sildenafil, a phosphodiesterase-5 inhibitor, causes cGMP accumulation and provokes migraine-like headache in patients with migraine without aura. We investigated if sildenafil induced aura and migraine-like headache in patients with migraine with aura. Methods: In a randomized, double-blinded, placebo-controlled crossover study, 16 patients with migraine with aura (of whom 11 patients exclusively had attacks of migraine with aura) received 100 mg sildenafil or placebo on two separate days. The development, duration, and characteristics of aura and headache were recorded using a questionnaire. The primary outcome was the incidence of migraine aura. Results: Aura symptoms were induced in three patients (19%) after sildenafil and none after placebo (P < 0.001). After administration of sildenafil, 12 patients (75%) developed headache compared with two patients (12.5%) after placebo (Fisher's exact test, P < 0.001). The headache in nine patients (56%) after sildenafil and one patient (6%) after placebo fulfilled the criteria for migraine-like attacks (Fisher's exact test, P = 0.002). All patients, who fulfilled the criteria for migraine-like attacks, reported that the attack mimicked the headache phase during their usual migraine attacks. Discussion: Sildenafil have a moderate migraine headache-inducing and a modest aura-inducing effect in patients with migraine with aura, even in those who exclusively experienced attacks of migraine with aura in their spontaneous attacks. These findings suggest that accumulation of cGMP by PDE5-inhibition do not play any significant role in the initiation of migraine aura and refute the hypothesis of sildenafil being a tool for pharmacological provocation of this phenomenon. These findings further support dissociation between the aura and the headache phase. Trial registration: ClinicalTrials.gov – NCT02795351 [ABSTRACT FROM AUTHOR]

Background: Frailty may modify the risk-benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments.Objective: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure).Design: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124).Setting: 410 sites in 20 countries.Patients: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide.Intervention: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy.Measurements: The primary outcome was worsening HF or cardiovascular death.Results: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI ≤0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI ≥0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were -3.5 (95% CI, -5.7 to -1.2), -3.6 (CI, -6.6 to -0.5), and -7.9 (CI, -13.9 to -1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class.Limitation: Enrollment criteria precluded the inclusion of very high-risk patients.Conclusion: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients.Primary Funding Source: AstraZeneca. [ABSTRACT FROM AUTHOR]

Frailty may modify the balance of risks and benefits of various therapeutic interventions in heart failure. In this study, the authors performed a post hoc analysis of the DAPA-HF trial to examine the efficacy of dapagliflozin in various frailty classes. Visual Abstract. Dapagliflozin and Frailty in HFrEF.: Frailty may modify the balance of risks and benefits of various therapeutic interventions in heart failure. In this study, the authors performed a post hoc analysis of the DAPA-HF trial to examine the efficacy of dapagliflozin in various frailty classes. Background: Frailty may modify the risk−benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. Objective: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). Design: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124) Setting: 410 sites in 20 countries. Patients: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide. Intervention: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. Measurements: The primary outcome was worsening HF or cardiovascular death. Results: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI ≤0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI ≥0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were −3.5 (95% CI, −5.7 to −1.2), −3.6 (CI, −6.6 to −0.5), and −7.9 (CI, −13.9 to −1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class. Limitation: Enrollment criteria precluded the inclusion of very high-risk patients. Conclusion: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients. Primary Funding Source: AstraZeneca. [ABSTRACT FROM AUTHOR]

Aims: The new Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation for estimating glomerular filtration rate (eGFR), based on serum creatinine, that does not incorporate race may reclassify individuals, irrespective of race, from one eGFR category to another, with implications for eligibility for treatments in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results: A total of 43 138 ambulatory patients with HFrEF from 12 clinical trials were included (mean age 64.3 years; 9580 [22.2%] women). Mean eGFR was 67 (standard deviation [SD] 21) ml/min/1.73 m2 and 70 (SD 21) ml/min/1.73 m2 using the original and new CKD‐EPI equations, respectively (mean difference 3.20 ml/min/1.73 m2, 95% confidence interval [CI] 3.17–3.23, p < 0.001). Of the 935 patients with chronic kidney disease (CKD) stages 4 or 5, identified using the original equation, 309 (33.0%) were reclassified to CKD stages 1–3 (eGFR ≥30 ml/min/1.73 m2) with the new equation. However, the opposite was observed among the 2521 Black patients (5.8%) included, with a reduction in mean eGFR from 75 to 68 ml/min/1.73 m2 using the original and new equations, respectively (mean difference 6.94 ml/min/1.73 m2, [95% CI 6.82–7.06], p < 0.001). The number of Black patients with an eGFR <30 ml/min/1.73 m2 increased from 49 (1.9%) using the original equation to 71 (2.8%) with the new equation. Conclusions: The new CKD‐EPI creatinine equation reclassified CKD stage in a large proportion of patients with HFrEF enrolled in clinical trials. As eGFR is an essential determinant of eligibility for several key pharmacological therapies in HFrEF, this reclassification could result in a substantial change in the proportion of patients considered eligible for such therapies and reduce the proportion of eligible Black patients. [ABSTRACT FROM AUTHOR]

Aims: Among patients with heart failure (HF) and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF). We also examined the effect of dapagliflozin on new‐onset AF. Methods and results: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had 'any AF' (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62–0.92 and 0.74, 95% CI 0.62–0.88, respectively; p for interaction = 0.88]. Consistent benefits were observed for the components of the primary outcome, all‐cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new‐onset AF compared with placebo (HR 0.86, 95% CI 0.60–1.22). However, patients with new‐onset AF had a 5 to 6‐fold higher risk of adverse outcomes when compared to those without incident AF. Conclusions: Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all‐cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new‐onset AF. [ABSTRACT FROM AUTHOR]

Aim: To determine the risk of adverse outcomes across the spectrum of glycated haemoglobin (HbA1c) levels among hospitalized COVID‐19 patients with and without diabetes. Materials and methods: Danish nationwide registries were used to study the association between HbA1c levels and 30‐day risk of all‐cause mortality and the composite of severe COVID‐19 infection, intensive care unit (ICU) admission and all‐cause mortality. The study population comprised patients hospitalized with COVID‐19 (3 March 2020 to 31 December 2020) with a positive polymerase chain reaction (PCR) test and an available HbA1c ≤ 6 months before the first positive PCR test. All patients had at least 30 days of follow‐up. Among patients with diabetes, HbA1c was categorized as <48 mmol/mol, 48 to 53 mmol/mol, 54 to 58 mmol/mol, 59 to 64 mmol/mol (reference) and >64 mmol/mol. Among patients without diabetes, HbA1c was stratified into <31 mmol/mol, 31 to 36 mmol/mol (reference), 37 to 41 mmol/mol and 42 to 47 mmol/mol. Thirty‐day standardized absolute risks and standardized absolute risk differences are reported. Results: We identified 3295 hospitalized COVID‐19 patients with an available HbA1c (56.2% male, median age 73.9 years), of whom 35.8% had diabetes. The median HbA1c was 54 and 37 mmol/mol among patients with and without diabetes, respectively. Among patients with diabetes, the standardized absolute risk difference of the composite outcome was higher with HbA1c < 48 mmol/mol (12.0% [95% confidence interval {CI} 3.3% to 20.8%]) and HbA1c > 64 mmol/mol (15.1% [95% CI 6.2% to 24.0%]), compared with HbA1c 59 to 64 mmol/mol (reference). Among patients without diabetes, the standardized absolute risk difference of the composite outcome was greater with HbA1c < 31 mmol/mol (8.5% [95% CI 0.5% to 16.5%]) and HbA1c 42 to 47 mmol/mol (6.7% [95% CI 1.3% to 12.1%]), compared with HbA1c 31 to 36 mmol/mol (reference). Conclusions: Patients with COVID‐19 and HbA1c < 48 mmol/mol or HbA1c > 64 mmol/mol had a higher associated risk of the composite outcome. Similarly, among patients without diabetes, varying HbA1c levels were associated with higher risk of the composite outcome. [ABSTRACT FROM AUTHOR]

Aims Among patients with heart failure (HF) and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on new-onset AF. Methods and results The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had 'any AF' (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62-0.92 and 0.74, 95% CI 0.62-0.88, respectively; p for interaction = 0.88]. Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new-onset AF compared with placebo (HR 0.86, 95% CI 0.60-1.22). However, patients with new-onset AF had a 5 to 6-fold higher risk of adverse outcomes when compared to those without incident AF. Conclusions Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all-cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new-onset AF. [ABSTRACT FROM AUTHOR]

Background: DANISH (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators [ICDs] in Patients With Nonischemic Systolic Heart Failure on Mortality) found that primary-prevention ICD implantation was not associated with an overall survival benefit in patients with nonischemic systolic heart failure during a median follow-up of 5.6 years, although there was a beneficial effect on all-cause mortality in patients ≤70 years. This study presents an additional 4 years of follow-up data from DANISH.Methods: In DANISH, 556 patients with nonischemic systolic heart failure were randomized to receive an ICD and 560 to receive usual clinical care and followed until June 30, 2016. In this long-term follow-up study, patients were followed until May 18, 2020. Analyses were conducted for the overall population and according to age (≤70 and >70 years).Results: During a median follow-up of 9.5 years (25th-75th percentile, 7.9-10.9 years), 208/556 patients (37%) in the ICD group and 226/560 patients (40%) in the control group died. Compared with the control group, the ICD group did not have significantly lower all-cause mortality (hazard ratio [HR] 0.89, [95% CI, 0.74-1.08]; P = 0.24). In patients ≤70 years (n = 829), all-cause mortality was lower in the ICD group than the control group (117/389 [30%] versus 158/440 [36%]; HR, 0.78 [95% CI, 0.61-0.99]; P = 0.04), whereas in patients >70 years (n = 287), all-cause mortality was not significantly different between the ICD and control group (91/167 [54%] versus 68/120 [57%]; HR, 0.92 [95% CI, 0.67-1.28]; P = 0.75). Cardiovascular death showed similar trends (overall, 147/556 [26%] versus 164/560 [29%]; HR, 0.87 [95% CI, 0.70-1.09]; P = 0.20; ≤70 years, 87/389 [22%] versus 122/440 [28%]; HR, 0.75 [95% CI, 0.57-0.98]; P = 0.04; >70 years, 60/167 [36%] versus 42/120 [35%]; HR, 0.97 [95% CI, 0.65-1.45]; P = 0.91). The ICD group had a significantly lower incidence of sudden cardiovascular death in the overall population (35/556 [6%] versus 57/560 [10%]; HR, 0.60 [95% CI, 0.40-0.92]; P = 0.02) and in patients ≤70 years (19/389 [5%] versus 49/440 [11%]; HR, 0.42 [95% CI, 0.24-0.71]; P = 0.0008), but not in patients >70 years (16/167 [10%] versus 8/120 [7%]; HR, 1.34 [95% CI, 0.56-3.19]; P = 0.39).Conclusions: During a median follow-up of 9.5 years, ICD implantation did not provide an overall survival benefit in patients with nonischemic systolic heart failure. In patients ≤70 years, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00542945. [ABSTRACT FROM AUTHOR]

Background Treatment with dabigatran, an oral direct thrombin inhibitor, reduces the virulence of Staphylococcus aureus in in vitro and in vivo models. However, it remains to be determined whether dabigatran reduces the risk of S. aureus infections in humans. We investigated the incidence rate of S. aureus bacteremia (SAB) in patients with atrial fibrillation treated with the direct thrombin inhibitor dabigatran compared with patients treated with the factor Xa-inhibitors rivaroxaban, apixaban, and edoxaban. Methods In this observational cohort study, 112 537 patients with atrial fibrillation who initiated treatment with direct oral anticoagulants (August 2011–December 2017) were identified from Danish nationwide registries. The incidence rates of SAB in patients treated with dabigatran versus patients treated with the factor Xa-inhibitors were examined by multivariable Cox regression accounting for time-dynamic changes in exposure status during follow-up. Results A total of 112 537 patients were included. During a median follow-up of 2.0 years, 186 patients in the dabigatran group and 356 patients in the factor Xa-inhibitor group were admitted with SAB. The crude incidence rate of SAB was lower in the dabigatran group compared with the factor Xa-inhibitor group (22.8 [95% confidence interval [CI], 19.7–26.3] and 33.8 [95% CI, 30.5–37.6] events per 10 000 person-years, respectively). In adjusted analyses, dabigatran was associated with a significantly lower incidence rate of SAB compared with factor Xa-inhibitors (incidence rate ratio,.76; 95% CI,.63–.93). Conclusions Treatment with dabigatran was associated with a significantly lower incidence rate of SAB compared with treatment with factor Xa-inhibitors. [ABSTRACT FROM AUTHOR]

Objective: Timely evaluation and initiation of treatment is the key for improving stroke outcomes, although minimizing the time from symptom onset to the first contact with healthcare professionals remains a challenge. We aimed to identify patient‐related factors associated with early hospital arrival. Materials and methods: In this cross‐sectional survey, we included patients with stroke or transient ischemic attack admitted directly to one of two noncomprehensive stroke units or transferred to the units from comprehensive stroke centers in the Capital Region of Denmark. Patient‐reported factors associated with early hospital arrival were analyzed using multivariable logistic regression analysis adjusted for age, sex, education, living arrangement, brain location of the stroke, stroke severity, patient‐perceived symptom severity, history of prior stroke, stroke risk factors, and knowledge of stroke symptoms. Results: In total, 479 patients with acute stroke were included (median age 74 (25th–75th percentile, 64–80), 40% women), of whom 46.4% arrived within 180 min of symptom onset. Factors associated with early hospital arrival were patients or bystanders choosing emergency medical service (EMS) for the first contact with a medical professional (adjusted odds ratio (OR), 3.41; 95% confidence interval, CI [1.57, 7.35]) or the patient's perceived symptom severity above the median score of 25 on a 100‐point verbal scale (adjusted OR, 2.44; 95% CI [1.57, 3.82]). Living alone reduced the likelihood of early arrival (adjusted OR, 0.53; 95% CI [0.33, 0.86]). Conclusions: Only when patients perceived symptoms as severe or when EMS was selected as the first contact, early arrival for stroke treatment was ensured. [ABSTRACT FROM AUTHOR]

Aims: We examined the efficacy and safety of dapagliflozin, compared with placebo, according to aetiology in patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF). Methods and results: Aetiology was investigator‐reported and categorized as ischaemic or non‐ischaemic. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. A total of 4744 patients were randomized in DAPA‐HF, of whom 2674 (56.4%) patients had an ischaemic aetiology. Participants with an ischaemic aetiology had a higher risk of cardiovascular mortality [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.13–1.63], but lower risk of HF hospitalization (HR 0.83, 95% CI 0.70–0.98) than non‐ischaemic patients. Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in both patients with ischaemic and non‐ischaemic aetiology (HR 0.77, 95% CI 0.65–0.92, and HR 0.71, 95% CI 0.58–0.87, respectively; P for interaction = 0.55). Consistent benefits were observed for the components of the primary outcome and all‐cause mortality. Dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement of Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS) of ≥5 points (P for interaction = 0.32) and decreased the proportion with a deterioration in KCCQ‐TSS of ≥5 points (P for interaction = 0.76), irrespective of aetiology. Study drug discontinuation and serious adverse events were similar according to treatment groups, irrespective of aetiology. Conclusions: Dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, similarly in patients with ischaemic and non‐ischaemic aetiology. In addition, dapagliflozin was safe and well‐tolerated, irrespective of aetiology. [ABSTRACT FROM AUTHOR]

Aims: To examine the rates of all-cause mortality and heart failure (HF) readmission in patients hospitalized with decompensated HF according to HF duration - new-onset HF and worsening of chronic HF.Methods and Results: In this nationwide observational cohort study, 17 176 patients were included at first hospital admission for HF in the period 2013-2015 using data from Danish nationwide registries. In total, 8860 (51.6%) patients were admitted with new-onset HF and 8316 (48.4%) with worsening of chronic HF. Patients with worsening of chronic HF were characterized by a greater comorbidity burden compared with patients with new-onset HF. The rates of outcomes were examined by multivariable Cox regression models, adjusted for age, sex, and comorbidity. Worsening of chronic HF was associated with a higher rate of the composite endpoint of all-cause mortality or HF readmission [hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.31-1.43], all-cause mortality (HR 1.22, 95% CI 1.16-1.28), and HF readmission (HR 1.81, 95% CI 1.69-1.93) compared with new-onset HF. There was an interaction between atrial fibrillation (AF), HF duration, and outcome: in worsening of chronic HF, the rate of the composite endpoint was higher in patients with AF compared with those without (HR 1.12, 95% CI 1.07-1.19), whereas in new-onset HF, the rate of the composite endpoint was lower in patients with AF compared with those without (HR 0.91, 95% CI 0.85-0.96) (P-value for interaction <0.001).Conclusions: Among patients hospitalized with decompensated HF, worsening of chronic HF was associated with poorer outcomes compared with new-onset HF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Drs Wong and Demers are of course correct that there is an association between frailty and age, but it is also well recognized that frailty can develop at any age. Article Information Disclosures J.H.B. reports advisory board honoraria from Bayer, consultant fees from Novartis, and travel grants from AstraZeneca. [Extracted from the article]

View large Download slide View large Download slide OBJECTIVES Hospitalizations are a major burden for both patients and society and are potentially preventable. However, data on the burden and causes for hospitalizations after coronary artery bypass grafting (CABG) are sparse. We examined hospitalizations within 1 year after CABG and associated factors. METHODS Using the Danish nationwide registries, we identified 36 475 patients who underwent first-time isolated CABG (1998–2014) and were discharged alive. Subsequent hospitalizations were classified as cardiovascular or non-cardiovascular according to discharge diagnosis codes. Factors associated with any hospitalization were identified using the Cox regression. RESULTS Thirty-day hospitalization risks for all-cause, cardiovascular and non-cardiovascular reasons were 16.7%, 12.4% and 4.2%, respectively. The corresponding 1-year hospitalization risks were 40.2%, 28.6% and 11.5%. Among patients who survived the first year, 7877 (22.1%) patients were admitted once, 3198 (9.0%) patients were admitted twice and 2844 (8.0%) patients were admitted 3 or more times within the first year. Ischaemic heart disease (15.6%), angina pectoris (9.8%), atrial fibrillation (AF) (8.7%) and heart failure (8.0%) were the most frequent reasons for hospitalization. Factors associated with any hospitalization were lower income level, a history of stroke, heart failure, AF, diabetes, malignancy, chronic renal failure, chronic obstructive pulmonary disease, longer length of stay, postoperative AF and stroke. CONCLUSIONS Within 1-year post-CABG, 40% of patients had at least 1 hospitalization, and approximately 70% of all hospitalizations were attributed to a cardiovascular cause. Lower socioeconomic status, preoperative comorbidities, postoperative complications during index admission and a longer length of stay were associated with hospitalization. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing surgical aortic valve replacement (SAVR) are considered at high risk of infective endocarditis (IE). However, data on the risk of IE following transcatheter aortic valve replacement (TAVR) are sparse and limited by the lack of long-term follow-up as well as a direct comparison with patients undergoing SAVR.Objectives: This study sought to investigate the long-term incidence of IE in patients undergoing TAVR and to compare the long-term risk of IE with patients undergoing isolated SAVR.Methods: In this nationwide observational cohort study, all patients undergoing TAVR and isolated SAVR from January 1, 2008, to December 31, 2016, with no history of IE and alive at discharge were identified using data from Danish nationwide registries.Results: A total of 2,632 patients undergoing TAVR and 3,777 patients undergoing isolated SAVR were identified. During a mean follow-up of 3.6 years, 115 patients (4.4%) with TAVR and 186 patients (4.9%) with SAVR were admitted with IE. The median time from procedure to IE hospitalization was 352 days (25th to 75th percentile: 133 to 778 days) in the TAVR group and 625 days (25th to 75th percentile: 209 to 1,385 days) in the SAVR group. The crude incidence rates of IE were 1.6 (95% confidence interval [CI]: 1.4 to 1.9) and 1.2 (95% CI: 1.0 to 1.4) events per 100 person-years in TAVR and SAVR patients, respectively. The cumulative 1-year risk of IE was 2.3% (95% CI: 1.8% to 2.9%) and 1.8% (95% CI: 1.4% to 2.3%) in TAVR and SAVR patients, respectively. Correspondingly, the cumulative 5-year risk of IE was 5.8% (95% CI: 4.7% to 7.0%) and 5.1% (95% CI: 4.4% to 6.0%), respectively. In multivariable Cox proportional hazard analysis, TAVR was not associated with a statistically significant different risk of IE compared with SAVR (hazard ratio: 1.12; 95% CI: 0.84 to 1.49).Conclusions: The 5-year incidence of IE following TAVR was 5.8% and not significantly different than the incidence following SAVR. [ABSTRACT FROM AUTHOR]

Background: The long-term risk of thromboembolism in patients developing new-onset post-operative atrial fibrillation (POAF) following noncardiac surgery is unknown, and data on stroke prophylaxis in this setting are lacking.Objectives: The purpose of this study was to assess the long-term risk of thromboembolism in patients developing new-onset POAF following noncardiac surgery relative to patients with nonsurgical, nonvalvular atrial fibrillation (NVAF).Methods: Using Danish nationwide registries, the authors identified all patients who developed POAF following noncardiac surgery from 1996 to 2015. These were matched by age, sex, heart failure, hypertension, diabetes, previous thromboembolism, ischemic heart disease, and year of diagnosis to patients with nonsurgical NVAF in a 1:4 ratio. Comparative long-term risk of thromboembolism was examined by multivariable Cox regression models.Results: In patients undergoing noncardiac surgery, 6,048 (0.4%) developed POAF during hospitalization, with the highest incidences following thoracic/pulmonary, vascular, and abdominal surgery. A total of 3,830 patients with POAF were matched with 15,320 patients with NVAF. Oral anticoagulation therapy was initiated within 30 days post-discharge in 24.3% and 41.3% of these patients, respectively (p value <0.001). The long-term risk of thromboembolism was similar in patients with POAF and NVAF (31.7 events vs. 29.9 events per 1,000 person years; hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.85 to 1.07). Anticoagulation therapy during follow-up was associated with a comparably lowered risk of thromboembolic events in patients with POAF (HR: 0.52; 95% CI: 0.40 to 0.67) as well as NVAF (HR: 0.56; 95% CI: 0.51 to 0.62) compared with no anticoagulation therapy.Conclusions: New-onset POAF following noncardiac surgery was associated with a long-term risk of thromboembolism similar to NVAF. [ABSTRACT FROM AUTHOR]

Whether migraine headache and migraine aura share common pathophysiological mechanisms remains to be understood. Cilostazol causes cAMP accumulation and provokes migraine-like headache in migraine patients without aura. We investigated if cilostazol induces aura and migraine-like headache in patients with migraine with aura and alters peripheral endothelial function and levels of endothelial markers. In a randomized, double-blinded, placebo-controlled crossover study, 16 patients with migraine with aura (of whom 12 patients exclusively had attacks of migraine with aura) received 200 mg cilostazol (Pletal®) or placebo on two separate days. The development, duration, and characteristics of aura and headache were recorded using a questionnaire. Peripheral endothelial function was assessed by digital pulse amplitude tonometry using EndoPAT2000, and endothelial markers (VCAM1, E-selectin, and VEGFA) were measured. After administration of cilostazol, 14 patients (88%) experienced headache compared with six patients (38%) after placebo (P = 0.009). The headache in 12 patients (75%) after cilostazol and one patient (6%) after placebo fulfilled the criteria for migraine-like attacks (P = 0.0002). Patients reported that the attack mimicked the headache phase during their usual migraine attacks. However, aura symptoms were elicited in one patient after cilostazol and one patient after placebo. Further, endothelial function, as assessed by peripheral arterial tonometry, and endothelial markers were not significantly altered by cilostazol. Accumulation of cAMP by cilostazol induces migraine-like headache, but not aura, in patients with migraine with aura, even in those who exclusively reported attacks of migraine with aura in their spontaneous attacks. These findings further support dissociation between the aura and the headache phase with a yet unknown trigger for the aura and link between aura and headache. In addition, cilostazol administration did not significantly alter endothelial function, as assessed by peripheral arterial tonometry, or the endothelial markers, VCAM1, E-selectin, and VEGFA. However, post hoc analyses showed that our study was statistically underpowered for these outcomes. [ABSTRACT FROM AUTHOR]

Background Returning to the workforce after coronary artery bypass grafting (CABG) holds important socioeconomic consequences not only for patients, but the society as well. Yet data on this issue are limited. We examined return to the workforce and associated factors in patients of working age undergoing CABG. Methods and results Using Danish nationwide administrative registries, we identified 6031 patients of working age (18–60 years) undergoing isolated CABG (1998–2011) who were part of the workforce 30 days prior to admission and alive at discharge. One year after discharge for CABG, 4827 (80.0%) patients had returned to the workforce, 614 (10.2%) were on paid sick leave, 267 (4.4%) received disability pension, 250 (4.1%) were on early retirement, 57 (0.9%) had died, and 16 (0.3%) had emigrated. Factors associated with return to the workforce were identified using multivariable logistic regression. Younger age (18–45 versus 56–60 years; odds ratio, 1.89; 95% confidence interval, 1.48–2.42), male sex (1.51, 1.24–1.84), and higher level of education (higher educational level versus basic school; 1.53, 1.05–2.23) and income (highest quartile versus lowest; 3.01, 2.42–3.75) were associated with return to the workforce. Urgency of surgery (emergency versus elective; 0.65, 0.49–0.88), cardiovascular comorbidity, a history of chronic kidney disease (0.49, 0.29–0.84) and liver disease (0.47, 0.28–0.80), as well as additional hospital admissions within the first year post-discharge (> 2 versus none; 0.25, 0.19–0.32) were associated with a lower likelihood of returning to the workforce. Conclusion One year after discharge for CABG, four out of five patients were part of the workforce and mortality was low. Younger age, male sex, higher socioeconomic status, and absence of major comorbidities were associated with return to the workforce. [ABSTRACT FROM AUTHOR]

Objectives: Beta-blockers relieve the autonomic symptoms of exam-related anxiety and may be beneficial in exam-related and performance anxiety, but knowledge on related psychiatric outcomes is unknown. We hypothesized that beta-blocker therapy for exam-related anxiety identifies young students at risk of later psychiatric events.Methods: Using Danish nationwide administrative registries, we studied healthy students aged 14-30 years (1996-2012) with a first-time claimed prescription for a beta-blocker during the exam period (May-June); students who were prescribed a beta-blocker for medical reasons were excluded. We matched these students on age, sex, and time of year to healthy and study active controls with no use of beta-blockers. Risk of incident use of antidepressants, incident use of other psychotropic medications, and suicide attempts was examined by cumulative incidence curves for unadjusted associations and multivariable cause-specific Cox proportional hazard analyses for adjusted hazard ratios (HRs).Results: We identified 12,147 healthy students with exam-related beta-blocker use and 12,147 matched healthy students with no current or prior use of beta-blockers (median age, 19 years; 80.3% women). Among all healthy students, 0.14% had a first-time prescription for a beta-blocker during the exam period with the highest proportion among students aged 19 years (0.39%). Eighty-one percent of the students filled only that single prescription for a beta-blocker during follow-up. During follow-up, 2225 (18.3%) beta-blocker users and 1400 (11.5%) nonbeta-blocker users were prescribed an antidepressant (p < 0.0001); 1225 (10.1%) beta-blocker users and 658 (5.4%) nonbeta-blocker users were prescribed a psychotropic drug (p < 0.0001); and 16 (0.13%) beta-blocker users and 6 (0.05%) nonbeta-blocker users attempted suicide (p = 0.03). Exam-related beta-blocker use was associated with an increased risk of antidepressant use (adjusted HRs, 1.68 [95% confidence intervals (CIs), 1.57-1.79], p < 0.0001), other psychotropic medication use (HR, 1.93 [95% CI, 1.76-2.12] p < 0.0001), and suicide attempts (HR, 2.67 [95% CI, 1.04-6.82] p = 0.04).Conclusion: In healthy students, use of beta-blockers during the exam period was associated with an increased risk of psychiatric outcomes and might identify psychologically vulnerable students who need special attention. [ABSTRACT FROM AUTHOR]

B This article refers to 'Concentration-dependent clinical and prognostic importance of high-sensitivity cardiac troponin T in heart failure and a reduced ejection fraction and the influence of empagliflozin: the EMPEROR-Reduced trial' by M. Packer I et al i ., published in this issue on pages 1529-1538.. b Measurements of troponin, in its cardiac-specific isoforms, was initially introduced to diagnose myocardial infarction in patients with suspected acute coronary syndrome. Among patients treated with placebo, there was a linear relationship between the logarithm of hs-cTnT and the risk of cardiovascular death or hospitalization for heart failure. With the use of high-sensitivity assays, circulating troponin can be measured in most patients with heart failure and reduced ejection fraction (HFrEF), and it is now clear that the level of troponin is also predictive of outcomes in these patients.1-3 Despite this, troponin is currently not routinely measured in patients with heart failure. [Extracted from the article]

Background An increased risk of ischemic stroke is repeatedly reported in young subjects with migraine with aura ( MA). Such may be caused by changes in endothelial function. The present review evaluates current evidence on endothelial function in MA patients. Methods A systematic search of electronic databases ( Medline, Embase, Cochrane library) was performed, and a search in associated reference lists of identified studies was done. Results In total, 27 studies met inclusion criteria for this review. Six studies assessed endothelial function by flow-mediated dilation; four reported no differences compared with healthy subjects, one study reported an increase and one study a decrease in migraineurs. Peripheral arterial tonometry was applied in one study where no changes were detected between groups. Likewise, applying venous occlusion plethysmography elicited comparable responses. Arterial function was investigated in six studies; increased augmentation index and decreased arterial distensibility were reported in migraineurs, whereas findings regarding pulse wave velocity were dissimilar. However, when investigating levels of endothelial progenitor cells, two studies reported reduced levels in migraineurs, and several studies on endothelial markers in the areas of inflammation, oxidative stress, and coagulation found increased endothelial activation in migraineurs, particularly in MA. One study, assessing cerebral endothelial function using transcranial Doppler sonography, reported lower cerebrovascular reactivity to L-arginine in the posterior cerebral arteries in migraineurs. Conclusion Endothelial dysfunction appears not to be of importance in MA patients. However, the studies were few with a wide variety of techniques applied in small groups of patients. Endothelial biomarkers were increased in patients indicating a possible subtle change in the endothelium. Further investigations on larger groups of patients combining testing of endothelial dysfunction as well as biomarkers are warranted to identify whether or not endothelial changes may play a role in the increased risk of stroke in young MA patients. [ABSTRACT FROM AUTHOR]

Aims: Multimorbidity, the coexistence of two or more chronic conditions, is synonymous with heart failure (HF). How risk related to comorbidities compares at individual and population levels is unknown. The aim of this study is to examine the risk related to comorbidities, alone and in combination, both at individual and population levels. Methods and results: Using two clinical trials in HF – the Prospective comparison of ARNI (Angiotensin Receptor–Neprilysin Inhibitor) with ACEI (Angiotensin‐Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and morbidity in HF trial (PARADIGM‐HF) and the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure trials (ATMOSPHERE) – we identified the 10 most common comorbidities and examined 45 possible pairs. We calculated population attributable fractions (PAF) for all‐cause death and relative excess risk due to interaction with Cox proportional hazard models. Of 15 066 patients in the study, 14 133 (93.7%) had at least one and 11 867 (78.8%) had at least two of the 10 most prevalent comorbidities. The greatest individual risk among pairs was associated with peripheral artery disease (PAD) in combination with stroke (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.28–2.33) and anaemia (HR 1.71; 95% CI 1.39–2.11). The combination of chronic kidney disease (CKD) and hypertension had the highest PAF (5.65%; 95% CI 3.66–7.61). Two pairs demonstrated significant synergistic interaction (atrial fibrillation with CKD and coronary artery disease, respectively) and one an antagonistic interaction (anaemia and obesity). Conclusions: In HF, the impact of multimorbidity differed at the individual patient and population level, depending on the prevalence of and the risk related to each comorbidity, and the interaction between individual comorbidities. Patients with coexistent PAD and stroke were at greatest individual risk whereas, from a population perspective, coexistent CKD and hypertension mattered most. [ABSTRACT FROM AUTHOR]

Chronic inflammation is increasingly recognized as a risk factor for VTE, but unlike other inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis, data on the risk of VTE in patients with sarcoidosis are sparse. Do patients with sarcoidosis have a higher long-term risk of VTE (pulmonary embolism or DVT, and each of these individually) compared with the background population? Using Danish nationwide registries, patients aged ≥ 18 years with newly diagnosed sarcoidosis (two or more inpatient/outpatient visits, 1996-2020) without prior VTE were matched 1:4 by age, sex, and comorbidities with individuals from the background population. The primary outcome was VTE. We included 14,742 patients with sarcoidosis and 58,968 matched individuals (median age, 44.7 years; 57.2% male). The median follow-up was 8.8 years. Absolute 10-year risks of outcomes for patients with sarcoidosis vs the background population were the following: VTE, 2.9% vs 1.6% (P <.0001), pulmonary embolism, 1.5% vs 0.7% (P <.0001), and DVT, 1.6% vs 1.0% (P <.0001), respectively. In multivariable Cox regression, sarcoidosis was associated with an increased rate of all outcomes in the first year after diagnosis (VTE: hazard ratio [HR], 4.94; 95% CI, 3.61-6.75) and after the first year (VTE: HR, 1.65; 95% CI, 1.45-1.87) compared with the background population. These associations persisted when excluding patients with a history of cancer and censoring patients with incident cancer during follow-up. Three-month mortality was not significantly different between patients with VTE with and without sarcoidosis (adjusted HR, 0.84; 95% CI, 0.61-1.15). In this nationwide cohort study, sarcoidosis was associated with a higher long-term risk of VTE compared with a matched background population. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: Current guidelines recommend implantable cardioverter‐defibrillator (ICD) therapy in patients with heart failure, a left ventricular ejection fraction of ≤35%, and New York Heart Association (NYHA) class II–III. However, the evidence regarding the benefit of primary prevention ICD is less consistent in patients with NYHA class III. We investigated the long‐term effects of primary prevention ICD implantation according to NYHA class in an extended follow‐up study of the DANISH trial. Methods and results: The DANISH trial randomized 1116 patients with non‐ischaemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Outcomes were analysed according to NYHA class at baseline (NYHA class II and III/IV). The primary outcome was all‐cause mortality. Of the 1116 patients randomized in the DANISH trial, 597 (53.5%) were in NYHA class II at baseline, 505 (45.3%) in NYHA class III, and 14 (1.3%) in NYHA class IV. During a median follow‐up of 9.5 years, NYHA class III/IV, compared with NYHA class II, were associated with a greater long‐term rate of all‐cause mortality (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.20–1.93) and cardiovascular death (HR 1.95 [1.47–2.60]). ICD implantation, compared with usual care, did not reduce the long‐term rate of all‐cause mortality (all participants: HR 0.89 [95% CI 0.74–1.08]; NYHA class II: HR 0.85 [0.64–1.13]; NYHA class III/IV: HR 0.89 [0.69–1.14]; pinteraction = 0.78) or cardiovascular death (all participants: HR 0.87 [95% CI 0.70–1.09]; NYHA class II: HR 0.78 [0.54–1.12]; NYHA class III/IV: HR 0.89 [0.67–1.19]; pinteraction = 0.58), irrespective of NYHA class. Similarly, NYHA class did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (all participants: HR 0.60 [95% CI 0.40–0.92]; NYHA class II: HR 0.73 [0.40–1.36]; NYHA class III/IV: HR 0.52 [0.29–0.94]; pinteraction = 0.39). Conclusions: In patients with non‐ischaemic HFrEF, ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce sudden cardiovascular death, regardless of baseline NYHA class. Clinical Trial Registration: ClinicalTrials.gov NCT00542945. [ABSTRACT FROM AUTHOR]

Aim: Although education in self‐management is thought to be an important aspect of the care of patients with heart failure, little is known about whether self‐rated knowledge of self‐management is associated with outcomes. The aim of this study was to assess the relationship between patient‐reported knowledge of self‐management and clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results: Using individual patient data from three recent clinical trials enrolling participants with HFrEF, we examined patient characteristics and clinical outcomes according to responses to the 'self‐efficacy' questions of the Kansas City Cardiomyopathy Questionnaire. One question quantifies patients' understanding of how to prevent heart failure exacerbations ('prevention' question) and the other how to manage complications when they arise ('response' question). Self‐reported answers from patients were pragmatically divided into: poor (do not understand at all, do not understand very well, somewhat understand), fair (mostly understand), and good (completely understand). Cox‐proportional hazard models were used to evaluate time‐to‐first occurrence of each endpoint, and negative binomial regression analysis was performed to compare the composite of total (first and repeat) heart failure hospitalizations and cardiovascular death across the above‐defined groups. Of patients (n = 17 629) completing the 'prevention' question, 4197 (23.8%), 6897 (39.1%), and 6535 (37.1%) patients had poor, fair, and good self‐rated knowledge, respectively. Of those completing the 'response' question (n = 17 637), 4033 (22.9%), 5463 (31.0%), and 8141 (46.2%) patients had poor, fair, and good self‐rated knowledge, respectively. For both questions, patients with 'poor' knowledge were older, more often female, and had a worse heart failure profile but similar treatment. The rates (95% confidence interval) per 100 person‐years for the primary composite outcome for 'poor', 'moderate' and 'good' self‐rated knowledge in answer to the 'prevention' question were 12.83 (12.11–13.60), 12.08 (11.53–12.65) and 11.55 (11.00–12.12), respectively, and for the 'response' question were 12.88 (12.13–13.67), 12.22 (11.60–12.86) and 11.56 (11.07–12.07), respectively. The lower event rates in patients with 'good' self‐rate knowledge were accounted for by lower rates of cardiovascular (and all‐cause) death and not hospitalization for worsening heart failure. Conclusions: Poor patient‐reported 'self‐efficacy' may be associated with higher rates of mortality. Evaluation of knowledge of 'self‐efficacy' may provide prognostic information and a guide to which patients may benefit from further education about self‐management. [ABSTRACT FROM AUTHOR]

Aim: Patients with heart failure (HF) often suffer from a range of comorbidities, which may affect their health status. The aim of this study was to assess the impact of different comorbidities on health status in patients with HF and reduced (HFrEF) and preserved ejection fraction (HFpEF). Methods and results: Using individual patient data from HFrEF (ATMOSPHERE, PARADIGM‐HF, DAPA‐HF) and HFpEF (TOPCAT, PARAGON‐HF) trials, we examined the Kansas City Cardiomyopathy Questionnaire (KCCQ) domain scores and overall summary score (KCCQ‐OSS) across a range of cardiorespiratory (angina, atrial fibrillation [AF], stroke, chronic obstructive pulmonary disease [COPD]) and other comorbidities (obesity, diabetes, chronic kidney disease [CKD], anaemia). Of patients with HFrEF (n = 20 159), 36.2% had AF, 33.9% CKD, 33.9% diabetes, 31.4% obesity, 25.5% angina, 12.2% COPD, 8.4% stroke, and 4.4% anaemia; the corresponding proportions in HFpEF (n = 6563) were: 54.0% AF, 48.7% CKD, 43.4% diabetes, 53.3% obesity, 28.6% angina, 14.7% COPD, 10.2% stroke, and 6.5% anaemia. HFpEF patients had lower KCCQ domain scores and KCCQ‐OSS (67.8 vs. 71.3) than HFrEF patients. Physical limitations, social limitations and quality of life domains were reduced more than symptom frequency and symptom burden domains. In both HFrEF and HFpEF, COPD, angina, anaemia, and obesity were associated with the lowest scores. An increasing number of comorbidities was associated with decreasing scores (e.g. KCCQ‐OSS 0 vs. ≥4 comorbidities: HFrEF 76.8 vs. 66.4; HFpEF 73.7 vs. 65.2). Conclusions: Cardiac and non‐cardiac comorbidities are common in both HFrEF and HFpEF patients and most are associated with reductions in health status although the impact varied among comorbidities, by the number of comorbidities, and by HF phenotype. Treating/correcting comorbidity is a therapeutic approach that may improve the health status of patients with HF. [ABSTRACT FROM AUTHOR]

Background: Whether continued follow-up in specialized heart failure (HF) clinics after optimization of guideline-directed therapy improves long-term outcomes in patients with HF with reduced ejection fraction (HFrEF) is unknown. Methods and results: 921 medically optimized HFrEF patients enrolled in the NorthStar study were randomly assigned to follow up in a specialized HF clinic or primary care and followed for 10 years using Danish nationwide registries. The primary outcome was a composite of HF hospitalization or cardiovascular death. We further assessed the 5-year adherence to prescribed neurohormonal blockade in 5-year survivors. At enrollment, the median age was 69 years, 24,7% were females, and the median NT-proBNP was 1139 pg/ml. During a median follow-up time of 4.1 (Q1-Q3 1.5–10.0) years, the primary outcome occurred in 321 patients (69.8%) randomized to follow-up in specialized HF clinics and 325 patients (70.5%) randomized to follow-up in primary care. The rate of the primary outcome, its individual components, and all-cause death did not differ between groups (primary outcome, hazard ratio 0.96 [95% CI, 0.82–1.12]; cardiovascular death, 1.00 [0.81–1.24]; HF hospitalization, 0.97 [0.82–1.14]; all-cause death, 1.00 [0.83–1.20]). In 5-year survivors (N = 660), the 5-year adherence did not differ between groups for angiotensin-converting enzyme inhibitors (p = 0.78), beta-blockers (p = 0.74), or mineralocorticoid receptor antagonists (p = 0.47). Conclusions: HFrEF patients on optimal medical therapy did not benefit from continued follow-up in a specialized HF clinic after initial optimization. Development and implementation of new monitoring strategies are needed. [ABSTRACT FROM AUTHOR]

Background: Data on long‐term cardiovascular outcomes in primary Sjögren's syndrome (PSS) are scarce. Objectives: We aim to investigate the long‐term rate of incident heart failure (HF) and other adverse cardiovascular endpoints in patients with PSS compared with the general population and to investigate mortality in individuals with incident HF with or without a history of PSS. Methods: Using Danish nationwide registries, PSS patients (diagnosed 1996–2018) without a history of other autoimmune diseases were each matched with four individuals from the general population by sex, age, and comorbidities. Multivariable Cox regression was used to estimate the rate of cardiovascular outcomes. In addition, the rate of death from any cause was compared between PSS patients with incident HF and four age‐ and sex‐matched HF patients without PSS. Results: In total, 5092 patients with newly diagnosed PSS were matched with 20,368 individuals from the general population (median age 57 years, 87.3% women, median follow‐up 7.4 years). The cumulative incidence of HF at 10 years was 4.0% for PSS patients and 2.8% for matched individuals. After adjustment, patients with PSS had a higher associated rate of incident HF (hazard ratios [HR] 1.42 [95% CI, 1.20–1.68]) and other cardiovascular outcomes, compared with the background population. PSS patients with incident HF had a similar rate of death from all‐cause mortality compared with HF patients without PSS (HR 0.94 [0.74–1.19]). Conclusions: Patients with PSS had a higher associated rate of incident HF and other cardiovascular outcomes compared with the general population. In individuals with incident HF, a history of PSS was not associated with increased mortality. [ABSTRACT FROM AUTHOR]

Background : Autoimmune diseases, including systemic lupus erythematosus, have been associated with a substantial risk of cardiovascular morbidity and mortality. However, data on the long-term risk of incident heart failure and other adverse cardiovascular outcomes among patients diagnosed with cutaneous lupus erythematosus (CLE) are limited. Methods: In this cohort study, all patients ≥ 18 years with newly diagnosed CLE between 1996 and 2018 were identified through Danish nationwide registries and matched 1:4 by age, sex, and comorbidity with individuals without CLE. Incident adverse cardiovascular outcomes, including heart failure, were compared between the matched groups, overall, and according to sex. Results: Of 2085 patients diagnosed with CLE, 2062 patients were matched with 8248 control subjects from the Danish background population (median age 50 years [25th–75th percentile: 37–62 years]; 22.3% men). The median follow-up was 6.2 years. The 10-year cumulative incidences and adjusted hazard ratios (HR) of outcomes were as follows: heart failure: 3.29% (95% CI, 2.42–4.36%) for CLE patients versus 2.59% (2.20–3.02%) for the background population, HR 1.67 (95% CI, 1.24–2.24); atrial fibrillation or flutter: 5.15% (3.99–6.52%) versus 3.84% (3.37–4.36%), HR 1.40 (1.09–1.80); the composite of ICD implantation, ventricular arrhythmia, or cardiac arrest: 0.72% (0.34–1.40%) versus 0.44% (0.29–0.64%), HR 1.71 (0.85–3.45); the composite of pacemaker implantation, atrioventricular block, or sinoatrial dysfunction: 0.91% (0.48–1.59%) versus 0.54% (0.37–0.76%), HR 1.32 (0.72–2.41); myocardial infarction: 3.05% (2.18–4.15%) versus 1.59% (1.29–1.93%), HR 2.15 (1.53–3.00); ischemic stroke: 3.25% (2.38–4.32%) versus 2.50% (2.13–2.93%), HR 1.56 (1.16–2.10); and venous thromboembolism: 2.74% (1.94–3.75%) versus 2.05% (1.71–2.44%), HR 1.60 (1.16–2.21). Sex did not modify the association between CLE and adverse cardiovascular outcomes (Pinteraction ≥ 0.12 for all outcomes). Conclusions: Patients with CLE had a higher associated risk of adverse cardiovascular outcomes compared with the background population, irrespective of sex. Key Points • Findings: In this nationwide cohort study, including 2062 patients with cutaneous lupus erythematosus and 8248 matched controls, cutaneous lupus erythematosus was associated with an increased long-term risk of heart failure, cardiac arrhythmias, and thromboembolic events, irrespective of sex. [ABSTRACT FROM AUTHOR]

Objective To investigate the long-term rates of heart failure (HF) and other adverse cardiovascular outcomes, including arrhythmias, myocardial infarction, ischaemic stroke, venous thromboembolism, pulmonary hypertension and pericarditis, in SSc patients according to gender and age. Methods Using Danish nationwide registries, SSc patients (diagnosed from 1996 to 2018) were matched with four controls from the background population by gender, age and comorbidities. Cox regression was used to compare the rates of cardiovascular outcomes between SSc patients and controls and the rate of mortality between SSc patients developing HF and HF patients without SSc, according to gender and age (above/below median). Results In total, 1569 SSc patients were matched with 6276 non-SSc controls (median age 55 years, 80.4% women, median follow-up 7.3 years). SSc had a higher rate of HF in both women [HR 2.99 (95% CI 2.18, 4.09)] and men [HR 3.01 (1.83, 4.95)] (P interaction = 0.88), with similar trends for other cardiovascular outcomes. SSc had a higher rate of HF in patients <55 years of age [HR 4.14 (95% CI 2.54, 6.74)] and ≥55 years [HR 2.74 (1.98, 3.78)] (P interaction = 0.22), with similar trends for other cardiovascular outcomes. SSc patients with new-onset HF had a higher rate of mortality than HF patients without a history of SSc, irrespective of gender (P interaction = 0.53) and age (P interaction = 0.43). Conclusions SSc was associated with higher rates of HF and other cardiovascular outcomes than matched controls, irrespective of gender and age. Among patients with new-onset HF, a history of SSc was associated with higher mortality. [ABSTRACT FROM AUTHOR]

Aims: Despite landmark heart failure (HF) with reduced ejection fraction (HFrEF) trials showing effect of mineralocorticoid receptor antagonists (MRA) on the risk of death and HF hospitalization, it has been suggested that MRAs are underutilized or frequently withdrawn. This study sought to identify temporal trends in the initiation of MRAs and the subsequent risk of withdrawal and adherence of MRAs in HF patients treated with a renin-angiotensin system inhibitor and a beta-blocker in Denmark from 2003-2017.Methods and Results: From nationwide registries, we identified patients receiving a diagnosis of HF. Use of MRA was identified by at least one prescription within 6 months after the diagnosis. The absolute risk of withdrawal with treatment was assessed with cumulative incidence, accounting for the competing risk of death. To estimate adherence, we calculated the proportion of days covered. We included 51 512 patients with incident HF. During the study period, 20 779 (40.3%) patients initiated MRA therapy. The incidence of withdrawal of MRA was 49.2% throughout the study period; 48.0% of the HF patients were adherent to the treatment. Among patients withdrawing treatment with MRA, the cumulative incidence of reinitiating was 36.6%.Conclusions: In a nationwide cohort of patients with HF, approximately half of the patients received MRA as third-line therapy within the first 6 months after diagnosis and approximately half of these withdrew MRA within 5 years. These findings warrant an increasing focus on retention to MRA treatment in a real-life setting. [ABSTRACT FROM AUTHOR]

Aims Despite landmark heart failure (HF) with reduced ejection fraction (HFrEF) trials showing effect of mineralocorticoid receptor antagonists (MRA) on the risk of death and HF hospitalization, it has been suggested that MRAs are underutilized or frequently withdrawn. This study sought to identify temporal trends in the initiation of MRAs and the subsequent risk of withdrawal and adherence of MRAs in HF patients treated with a renin-angiotensin system inhibitor and a beta-blocker in Denmark from 2003-2017. Methods and results From nationwide registries, we identified patients receiving a diagnosis of HF. Use of MRA was identified by at least one prescription within 6 months after the diagnosis. The absolute risk of withdrawal with treatment was assessed with cumulative incidence, accounting for the competing risk of death. To estimate adherence, we calculated the proportion of days covered. We included 51 512 patients with incident HF. During the study period, 20 779 (40.3%) patients initiated MRA therapy. The incidence of withdrawal of MRA was 49.2% throughout the study period; 48.0% of the HF patients were adherent to the treatment. Among patients withdrawing treatment with MRA, the cumulative incidence of reinitiating was 36.6%. Conclusions In a nationwide cohort of patients with HF, approximately half of the patients received MRA as third-line therapy within the first 6 months after diagnosis and approximately half of these withdrew MRA within 5 years. These findings warrant an increasing focus on retention to MRA treatment in a real-life setting. [ABSTRACT FROM AUTHOR]

Background and Objectives Male sex has been associated with severe coronavirus disease 2019 (COVID-19) infection. We examined the association between male sex and severe COVID-19 infection and if an increased risk remains after adjustment for age and comorbidities. Methods Nationwide register-based follow-up study of COVID-19 patients in Denmark until 16 May 2020. Average risk ratio comparing 30-day composite outcome of all-cause death, severe COVID-19 diagnosis or intensive care unit (ICU) admission for men versus women standardized to the age and comorbidity distribution of all patients were derived from multivariable Cox regression. Included covariates were age, hypertension, diagnoses including obesity, alcohol, sleep apnea, diabetes, chronic obstructive pulmonary disease, previous myocardial infarction (MI), ischemic heart disease (IHD), heart failure (HF), atrial fibrillation (AF), stroke, peripheral artery disease, cancer, liver, rheumatic, and chronic kidney disease (CKD). Results Of 4842 COVID-19 patients, 2281 (47.1%) were men. Median age was 57 [25%–75% 43–73] for men versus 52 [38–71] for women (P <.001); however, octogenarians had equal sex distribution. Alcohol diagnosis, diabetes, hypertension, sleep apnea, prior MI and IHD (all P <.001) as well as AF, stroke, and HF (all P =.01) were more often seen in men, and so was CKD (P =.03). Obesity diagnosis (P <.001) were more often seen in women. Other comorbidity differences were insignificant (P >.05). The fully adjusted average risk ratio was 1.63 [95% CI, 1.44–1.84]. Conclusions Men with COVID-19 infection have >50% higher risk of all-cause death, severe COVID-19 infection, or ICU admission than women. The excess risk was not explained by age and comorbidities. [ABSTRACT FROM AUTHOR]

Aims: Out-of-hospital cardiac arrest (OHCA) is highly prevalent among patients with myocardial infarction and cardiogenic shock (MI-CS). We aimed to examine the prognostic importance of OHCA in patients with MI-CS.Methods: Using Danish nationwide registries, we identified first-time hospitalized MI-CS patients (2010-2015) by OHCA status. Cumulative incidence curves and adjusted Cox regression models were used to compare in-hospital mortality, and among hospital survivors we compared 5-year rates of heart failure hospitalization and mortality.Results: We identified 3107 MI-CS patients of whom 979 presented with OHCA (32%). OHCA patients were younger (median age: 65 vs. 74 years) and had less comorbidity. In-hospital mortality was 57% in those with OHCA compared with 67% in those without, but after adjustment the hazard ratio (HR) was 0.99 [95% CI: 0.87-1.11]. Hospital survivors consisted of 1375 MI-CS patients including 531 OHCA patients (39%). Five-year mortality was 22% for OHCA patients and 42% for patients without OHCA (adjusted HR: 0.90 [95% CI: 0.70-0.1.17]). The HR for five-year cardiovascular mortality was 0.80 [95% CI: 0.62-0.98]. Lastly, 5-year rate of heart failure hospitalization was 17% for patients with OHCA compared with 34% in those without (HR: 0.44 [95% CI: 0.34-0.57]).Conclusion: Among patients hospitalized with MI-CS, OHCA did not influence all-cause in-hospital or long-term mortality but was a marker for reduced long-term rates of heart failure hospitalization and cardiovascular mortality. Future randomized studies are needed to improve prognosis of MI-CS, however, the importance of OHCA must be considered. [ABSTRACT FROM AUTHOR]