Søren Lund Kristensen

Background and Aims: Hydralazine-isosorbide dinitrate (H-ISDN) has shown benefit in earlier randomized trials of patients with reduced left ventricular ejection fraction (LVEF) and chronic heart failure. This trial tested if H-ISDN could reduce worsening heart failure or mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF) receiving contemporary treatment. Methods: The Hydralazine-Isosorbide Dinitrate in Patients With Chronic Heart Failure Trial (H-HeFT) was a multicentre, randomized (1:1), double-blind, placebo-controlled trial in patients with HFrEF at 23 Danish hospitals (New York Heart Association class II–IV, elevated N-terminal pro-B-type natriuretic peptide and LVEF ≤40%). Target treatment was hydralazine 75 mg/isosorbide dinitrate 40 mg three times a day (t.i.d). The primary endpoint was a composite of hospitalization with worsening heart failure, an urgent outpatient visit resulting in intravenous/metolazone therapy for heart failure, heart transplantation, left ventricular assist device implantation, or death. Secondary endpoints included components of the primary outcome. Results: Overall, 592 predominantly White patients (median age 72 years, 18% women) were randomized with a mean follow-up of 3.7 years. The primary outcome occurred in 90 of 294 patients (30.6%) in the H-ISDN group and in 91 of 298 patients (30.5%) in the placebo group [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.67–1.21; P = .48]. There were 57 deaths in the H-ISDN group vs 72 in the placebo group (HR 0.72; 95% CI 0.51–1.02); worsening heart failure events occurred in 52 vs 47 patients (HR 1.01; 95% CI 0.68–1.50). Conclusions: Hydralazine-isosorbide dinitrate did not change the incidence of the composite endpoint of heart failure events or death in patients with heart failure and LVEF ≤40%.

Aim: Amiodarone increases the risk of thyroid dysfunction, but the prognostic significance of this complication in patients with heart failure (HF) is uncertain. This study investigates the association between amiodarone‐related thyroid dysfunction and risk of HF hospitalization or death in a nationwide cohort. Methods: Cases and controls were identified from a source population of all HF patients who initiated treatment with amiodarone from 1996 to 2021. Patients diagnosed with and/or treated for thyroid dysfunction within 3 years of starting amiodarone were classified as cases and comprised the study population together with controls matched 1:2 based on age, sex, calendar year, and HF duration. The primary outcome was a composite of HF hospitalization and death within 1 year from onset of thyroid dysfunction, analyzed using Kaplan–Meier curves and Cox regression models adjusted for comorbidities. Results: Of 21,947 HF patients who initiated amiodarone, 2972 (14%) developed thyroid dysfunction. After matching, the study population consisted of 2953 cases and 5857 controls, mean age 70 years, and 65% men. At 1‐year follow‐up the primary outcome occurred in 1154 (39%) cases and 1826 (31%) matched controls, yielding an adjusted hazard ratio (HR) of 1.30 (95% CI 1.21–1.40). This increased risk was observed for both HF hospitalization (30% vs. 23%, HR 1.35 [1.24–1.47]) and all‐cause death (19% vs. 15%, HR 1.21 [1.08–1.34]). Conclusions: In this nested case–control study derived from a nationwide cohort of amiodarone‐treated HF patients, new‐onset thyroid dysfunction was associated with a 30% higher risk of a composite of HF hospitalization and death within 1 year.

BACKGROUND: Sparse information regarding the long-term risk of acute myocardial infarction (MI) following a transient ischemic attack (TIA) emphasizes further research to guide preventive strategies and risk stratification in patients with a TIA. METHODS: We conducted a nationwide cohort study to investigate the 5-year risk of MI and all-cause mortality in patients with a first-time TIA. Patients with a first-time TIA were identified in the Danish Stroke Registry (2013–2020), matched on age, sex, and calendar year (1:4) with the general population and (1:1) with patients with first-time ischemic stroke. The 5-year risks of MI and all-cause mortality were estimated by the Aalen-Johansen and Kaplan-Meier estimators. The groups were compared using Cox regression, while adjusting for cardiovascular comorbidities. RESULTS: We identified 21 743 patients with TIA, 86 972 matched individuals from the general population, and 21 743 matched control patients with ischemic stroke. Median age was 70 (25th to 75th percentile, 60–78) years; 52% were male. Comorbidity burden was the lowest in general population controls, intermediate in patients with TIA, and the highest in patients with ischemic stroke. The 5-year risk of MI was 2.0% in patients with TIA, 1.5% in the general population ( P P P P <0.001). The differences in mortality persisted following adjustments for patients with TIA versus general population (hazard ratio, 1.25 [95% CI, 1.19–1.31]) and for patients with TIA versus ischemic stroke (hazard ratio, 0.43 [95% CI, 0.41–0.46]). CONCLUSIONS: Patients with first-time TIA had a low 5-year incidence of MI, which was not significantly different from that of the general population and patients with first-time ischemic stroke after adjustments for comorbidities. However, patients with TIA had a 25% higher all-cause mortality rate than the general population, which was not readily explained by MI risk. Hence, the findings do not endorse the need to raise further awareness regarding MI in patients with TIA.

BACKGROUND: Pleural effusion is present in 50% to 80% of patients with acute heart failure, depending on image modality. We aim to describe the association between the presence and size of pleural effusion and central hemodynamics, including pulmonary capillary wedge pressure (PCWP) in an advanced heart failure population. METHODS: An observational, cross-sectional study in a cohort of patients with advanced heart failure (left ventricular ejection fraction ≤45%) who underwent right heart catheterization at The Department of Cardiology at Copenhagen University Hospital, Rigshospitalet, Denmark, between January 1, 2002 and October 31, 2020. The presence and size of pleural effusion were determined by a semiquantitative score of chest x -rays or computed tomography scans performed within 2 days of right heart catheterization. RESULTS: In 346 patients (50±13 years; 78% males) with median left ventricular ejection fraction of 20% (15–25), we identified 162 (47%) with pleural effusion. The pleural effusion size was medium in 38 (24%) and large in 30 (19%). Patients with pleural effusion had a 4.3 mm Hg (2.5–6.1) higher PCWP and 2.4 mm Hg (1.2–3.6) higher central venous pressure ( P P P =0.032), central venous pressure (OR, 1.14 [1.06–1.23]; P P <0.001) were independently associated with the presence of a medium/large-sized pleural effusion. CONCLUSIONS: In patients with left ventricular ejection fraction ≤45% undergoing right heart catheterization as part of advanced heart failure work-up, pleural effusion was associated with higher PCWP and central venous pressure and lower serum albumin.

BACKGROUND: Oral anticoagulation is suggested in patients with atrial fibrillation and a CHA ₂ DS ₂ -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 CHA ₂ DS ₂ -VASc 1, the incidence of arterial thromboembolism according to CHA ₂ DS ₂ -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 CHA ₂ DS ₂ -VASc score: CHA ₂ DS ₂ -VASc 0 (male and female subjects); CHA ₂ DS ₂ -VASc 1 (hypertension, heart failure, diabetes, vascular disease, and age 65–74 years); or CHA ₂ DS ₂ -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 CHA ₂ DS ₂ -VASc 0 score; 22 915 with CHA ₂ DS ₂ -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 CHA ₂ DS ₂ -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 CHA ₂ DS ₂ -VASc 0, heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years (CHA ₂ DS ₂ -VASc 1), and age ≥75 years (CHA ₂ DS ₂ -VASc 2), respectively. No statistically significant difference was identified among subgroups of CHA ₂ DS ₂ -VASc 1 ( P =0.15 for difference). CONCLUSIONS: For patients with atrial fibrillation, all subgroups of CHA ₂ DS ₂ -VASc 1 were associated with lower incidence of arterial thromboembolism compared with age ≥75 years without other risk factors (ie, CHA ₂ DS ₂ -VASc 2) and a higher incidence compared with CHA ₂ DS ₂ -VASc 0. No statistically significant difference was identified between the subgroups of CHA ₂ DS ₂ -VASc 1. These findings support current recommendations that patients within this intermediate risk group could be identified with a similar risk of arterial thromboembolism.

Sodium-glucose cotransoporter-2 inhibitors (SGLT-2Is) improve prognosis in heart failure (HF) patients both with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, these drugs can have some side effects. To estimate the relative risk of side effects in HF patients treated with SGLT-2Is irrespective from left ventricular EF and setting (chronic and non-chronic HF). Five randomized controlled trials (RCTs) enrolling patients with HFrEF, 4 RCTs enrolling non-chronic HF, and 3 RCTs enrolling HFpEF were included. Among side effects, urinary infection, genital infection, acute kidney injury, diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations were considered in the analysis. Overall, 24,055 patients were included in the analysis: 9020 (38%) patients with HFrEF, 12,562 (52%) with HFpEF, and 2473 (10%) with non-chronic HF. There were no differences between SGLT-2Is and placebo in the risk to develop diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations. HFrEF patients treated with SGLT-2Is had a significant reduction of acute kidney injury (RR = 0.54 (95% CI 0.33–0.87), p = 0.011), whereas no differences have been reported in the HFpEF group (RR = 0.94 (95% CI 0.83–1.07), p = 0.348) and non-chronic HF setting (RR = 0.79 (95% CI 0.55–1.15), p = 0.214). A higher risk to develop genital infection (overall 2.57 (95% CI 1.82–3.63), p < 0.001) was found among patients treated with SGLT-2Is irrespective from EF (HFrEF: RR = 1.96 (95% CI 1.17–3.29), p = 0.011; HFpEF: RR = 3.04 (95% CI 1.88–4.90), p < 0.001). The risk to develop urinary infections was increased among SGLT-2I users in the overall population (RR = 1.13 (95% CI 1.00–1.28), p = 0.046) and in the HFpEF setting (RR = 1.19 (95% CI 1.02–1.38), p = 0.029), whereas no differences have been reported in HFrEF (RR = 1.05 (95% CI 0.81–1.36), p = 0.725) and in non-chronic HF setting (RR = 1.04 (95% CI 0.75–1.46), p = 0.806). SGLT-2Is increase the risk of urinary and genital infections in HF patients. In HFpEF patients, the treatment increases the risk of urinary infections compared to placebo, whereas SGLT-2Is reduce the risk of acute kidney disease in patients with HFrEF.

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 P P 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.