Abstract Background Given the many advances in treating heart failure (HF) and atrial fibrillation (AF) separately over the past decades, it remains unclear how the prognosis of patients diagnosed with both conditions has changed over time. Purpose We aimed to investigate the temporal trends in all-cause mortality, HF hospitalisation, and stroke from 1997 to 2018 in patients diagnosed with both HF and AF. Methods From Danish nationwide registries, we identified 152,059 patients with a first-time HF-diagnosis from 1997 to 2018. Patients were categorised into groups based on their AF status: prevalent AF (n=34,734), new-onset AF (n=12,691), and absence of AF (n=104,634). Patients were further subdivided into four year groups (1997-2001, 2002-2006, 2007-2012, 2013-2018), based on the year of HF onset. The primary outcome of interest was the absolute five-year risk of all-cause mortality, and key secondary outcomes were HF hospitalisation and stroke, investigated using the Aalen-Johansen estimator, accounting for competing risk of death. Results Between 1997 and 2018 the proportion of patients with new-onset HF and prevalent AF increased from 17.0% (n = 6,372) to 27.7% (n = 11,569), while those with concurrent new-onset AF increased from 7.7% (n = 2,884) to 8.1% (n = 3401). Contrary, the proportion of patients decreased among those with no AF from 75.3% (n = 28,235) to 64.2% (n = 26,850). The five-year risk of all-cause mortality decreased from 69.1% (95% CI): 67.9%-70.2%) to 51.3% (49.9%-52.7%), 62.3% (60.5%-64.4%) to 43.0% (40.5%-45.5%), and 61.9% (61.3%-62.4%) to 36.7% (35.9%-37.6%) for the prevalent AF, new-onset AF, and no AF group, respectively (Figure 1). The five-year risk of HF hospitalisation went from 33.3% (32.1%-34.4%) to 30.3% (29.2%-31.4%) in the prevalent AF group, from 25.8% (24.2%-27.4%) to 29.6% (27.7%-31.5%) in the new-onset AF group, and from 28.4% (27.8%-28.9%) to 28.0% (27.2%-28.6%) in the no AF group. The five-year risk of stroke decreased from 8.5% (7.8%-9.1%) to 5.0% (4.4%-5.5%) in the prevalent AF group, 8.2% (7.2%-9.2%) to 4.6% (3.7%-5.5%) in the new-onset AF group, and 6.3% (6.1%-6.6%) to 4.9% (4.6%-5.3%) in the no AF group (Figure 2). Simultaneously, the proportion of patients prescribed anticoagulant therapy within 90 days after HF onset increased from 42.7% to 93.1% in patients with prevalent AF and 41.9% to 92.5% in patients with new-onset AF. Conclusion From 1997 to 2018, we observed an increase in patients with HF and coexisting AF. The five-year risk of mortality and stroke decreased across all patient groups regardless of AF-status. Additionally, prescriptions of anticoagulation therapy increased, and stroke risk in patients with HF and AF was reduced to similar levels as patients with HF without AF at the end of the study period.Figure 1 - Mortality in HF patientsFigure 2 - Stroke risk in HF patients

Abstract Background Hyponatremia is common in patients with heart failure and in patients with type 2 diabetes (T2D), and is a risk marker for increased morbidity and mortality. However, it is unclear whether hyponatremia in patients with T2D is associated with an increased risk of new-onset heart failure. Purpose To investigate whether hyponatremia is associated with an increased risk of new-onset heart failure in patients with T2D. Methods From Danish nationwide registers, all patients with T2D with no history of heart failure were identified from 2013-2021. Patients with at least two samples of plasma sodium measured (at least one month apart), during the first six months following their T2D diagnosis, were included with follow-up start six months after T2D diagnosis as well. Patients were categorized in two groups according to the mean plasma sodium concentration at baseline: 1) sodium >137 mmol/L; and 2) sodium <137mmol/L. Cumulative incidence curves and Cox proportional hazards models (crude and adjusted for age, sex, comorbidities, and potential hyponatremia-inducing medications including diuretics, anticonvulsants, and antidepressants) were used to investigate the association of sodium concentration with the incidence of heart failure during follow-up. Incidence rates of heart failure per 1000 person-years were calculated across the spectrum of the measured sodium levels. Results We included 69,750 patients where 57% were male and the median age was 63 (interquartile range: 54-71). At index, 57,723 (83%) patients had a mean sodium concentration of >137 mmol/L and 12,027 (17%) patients had a mean sodium concentration <137 mmol/L (hyponatremia). Patients with a sodium level <137 mmol/L were associated with a significantly higher hazard rate of heart failure compared to patients with sodium concentrations >137 mmol: adjusted hazard ratio (HR) 1.27 (95% confidence interval 1.15-1.41, p-value <0.001). In analyses where sodium concentration was considered a continuous variable, increasing concentration of 1 mmol/L was associated with a decreasing hazard rate of heart failure: adjusted HR 0.96 (0.94-0.97, p-value <0.001). Conclusions Hyponatremia was common and associated with a significantly higher risk of new-onset heart failure in patients newly diagnosed with T2D. Whether hyponatremia could be a new treatment target to prevent heart failure in T2D remains to be determined.Cumulative incidence of heart failureIncident heart failure

Abstract Introduction During the past decades, the incidence, management, and outcomes of myocardial infarction (MI) have improved considerably.(1-4) However, the characteristics and outcomes of patients who experience a recurrent MI are sparsely described. Purpose This study aimed to analyse the epidemiology and temporal trends of recurrent MI during the reperfusion era. Methods A nationwide registry-based cohort study was conducted, including all hospital admissions for recurrent MI in Denmark during 2000 to 2020. Descriptive statistics were used to analyse changes in patient characteristics and management. Survival analyses, taking competing risks into account when relevant, and multivariable Cox proportional hazards models adjusted for sex, age, comorbidities, and pre-recurrent MI pharmaceutical treatment were used to analyse the outcomes of interest: all-cause mortality, hospitalisation for heart failure (HHF), and additional recurrent MI. Results A total of n=55,722 admissions for recurrent MI between 2000 and 2020 were included. Median age at admission was 73 years, 68.0% were male, and 32.9% were patients with a 3rd or more recurrent MI. Between 2000-02 (n=9,490) and 2018-20 (n=5,520), patients admitted with a recurrent MI had an increased prevalence of comorbidities such as diabetes, chronic kidney disease, and cancer (Condensed Table 1). Likewise, the use of guideline directed management at the time of recurrent MI increased during the study period: percutaneous coronary intervention (PCI) from 12.8% to 47.2%, coronary angiography (CAG) from 21.8% to 68.0%, statins from 30.5% to 74.2%, and adenosine diphosphate (ADP) receptor inhibitors from 8.2% to 41.8%. Statistically significant linear calendar time trends were observed for all three outcomes (Figure 1). Between 2000-02 and 2018-20 (Figure 2), the absolute 1-year risk of mortality declined from 31.6% to 16.0% (adjusted hazard ratio [aHR]: 0.46 [95% CI: 0.43-0.50]). The absolute 1-year risk of an additional recurrent MI declined from 13.9% to 6.2% (aHR: 0.38 [0.34-0.43]). The absolute 1-year risk of HHF increased from 8.8% in 2000-02 to 10.5% in 2009-11 (aHR: 1.09 [0.99-1.21]), before declining to 7.4% in the final calendar year period (aHR: 0.75 [0.66-0.84]). Interpretation and conclusion Despite remarkable advances in the management and outcomes of patients experiencing recurrent MI during the reperfusion era, this remains a vulnerable, high-risk population. Special attention is warranted regarding the optimization of guideline directed care and prevention of heart failure following a recurrent MI.Figure 1Figure 2 & Condensed Table 1

Abstract Background Guidelines on type 2 diabetes (T2D) recommend targeting patients at greater risk of heart failure with sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and patients at greater risk of cardiovascular ischemic events with glucagon-like peptide-1 receptor agonists (GLP1-RA) or SGLT2-i. It is currently unclear whether distinct biochemical profiles are more or less associated with the occurrence of heart failure or a cardiovascular ischemic event. Purpose To investigate the risk of the first occurring event of either heart failure or a cardiovascular ischemic event associated with different biochemical profiles in newly diagnosed T2D patients without cardiovascular disease. Methods From Danish nationwide registers, we identified all patients newly diagnosed with T2D who were free of cardiovascular disease (heart failure, ischemic heart disease, peripheral artery disease, and previous stroke), from 2013-2021. Patients <40 years, and patients without a registered blood test within three months prior to the T2D diagnosis, were excluded. The absolute 5-year risk of the first occurring event of either heart failure or a cardiovascular ischemic event, was calculated for patients with different levels of three biochemical markers that are known to be associated with cardiovascular disease: 1) HbA1c 2) low-density lipoprotein (LDL); and 3) estimated glomerular filtration rate (eGFR) calculated from serum creatinine. Results Of the 81,095 patients included in the study, 53% were male and the median age was 60 years [interquartile range 52-69]. For all pre-defined biochemical profiles—HbA1c below or above 8%, LDL below or above 4 mmol/L, and eGFR below or above 60ml/min/1.73m2—the absolute 5-year risk of a cardiovascular ischemic event was greater than the risk of heart failure (risk ratio ranging from 2.3–4.2), as the first occurring event following the diagnosis of T2D. The highest risk of heart failure was observed in those with moderately to severely reduced eGFR (<60 ml/min/1.73m2). Conclusions Among patients newly diagnosed with T2D and free of cardiovascular disease, different biochemical profiles of HbA1c, LDL, and eGFR, were all associated with a higher risk of an ischemic cardiovascular event as the first occurring event following T2D diagnosis, as opposed to heart failure.Flowchart of patient selectionCumulative incidence of CIE Vs. HF

Abstract Background Thiazide diuretics and calcium channel blockers (CCB's) are two important and widely used antihypertensive drugs classes among patients with type 2 diabetes (T2D). The risk of developing heart failure (HF) is increased in patients with T2D but whether use of these two drugs are associated with changes in HF risk is unknown. Purpose To examine and compare the association of two different classes of antihypertensive drugs, thiazide diuretics and CCB's, with the development of new onset HF in patients with T2D. Methods The study cohort comprised T2D patients >40 years on metformin and renin-angiotensin system inhibitor (RAS-i) without a history of HF or use of loop diuretics identified in Danish health care registers (period 1995 to 2015). A nested case-control study was conducted by matching all HF cases on sex, age and duration of T2D with 10 controls from the T2D population. Exposure was defined as three redeemed prescriptions of either a thiazide diuretic or a CCB up to 365 days before index, which corresponds to one year of antihypertensive therapy. Conditional logistic regression adjusted for comorbidities (atrial fibrillation, chronic obstructive pulmonary disease and anemia) was used to estimate and compare the treatment effect of thiazide diuretics and CCB's, with patients receiving neither of the two drugs as reference. Results The study population consisted of 170,514 T2D patients using metformin and RAS-i, comprising 13,814 HF cases each matched on sex, age and duration of T2D with 10 controls. The median age was 62 years and 55% were men. T2D patients, who had received antihypertensive treatment with only thiazide diuretics one year prior to index had a significantly lower risk of HF compared to the reference group who did not receive treatment with neither thiazide diuretics or CCB's: Hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.74–0.85]. Patients who had received treatment with only CCB's had a comparable risk of HF: HR 0.98 [95% CI 0.94–1.02]. Patients who had received treatment with both thiazide diuretics and CCB's were not associated with a lower risk of HF: HR 1.01 [95% CI 0.96–1.08]. Conclusion Patients with T2D who received antihypertensive therapy with thiazide diuretics for at least one year had a significantly lower risk of HF compared to those who were not treated with either thiazide diuretics or CCB's. No association between use of CCB's and HF was observed. Use of thiazide diuretics may prevent development of HF in T2D and a randomized clinical trial evaluating diuretics is patients with T2D is warranted. Risk of new onset heart failure Funding Acknowledgement Type of funding source: None

Abstract Background Reflecting recent clinical trial findings, updated type 2 diabetes (T2D) guidelines recommend targeting SGLT2 inhibitors at patients at risk of heart failure (HF)-related events and GLP-1 receptor agonists at those at greater risk of atherosclerotic events. However, which cardiovascular disease phenotype in patients with T2D is more predictive of one or other type of these events is unclear. Purpose To estimate the risk of HF-related events and atherosclerotic events, according to background cardiovascular phenotype, in patients with T2D. Methods Patients with T2D and new-onset cardiovascular disease were identified using Danish health care registers (period 1995 to 2015). Patients were divided in four groups based on the primary type of cardiovascular disease: 1) HF, 2) ischemic heart disease (IHD), 3) ischemic stroke, and 4) peripheral artery disease (PAD). The absolute 5-year risks of the subsequent event, either a HF-related event or an atherosclerotic event (IHD, ischemic stroke and PAD), and the associated risk of death, were compared across the four groups. The Aalen-Johansen estimator was used to account for censoring, the competing risk of HF and atherosclerotic events, respectively, and death. Results We included 37,850 patients with T2D and new-onset cardiovascular disease. Median age was 70 years and 40% were female. Patients with HF were at higher risk of readmission for HF (18.1%; 95% confidence interval (CI): 17.2–19.0) than of an atherosclerotic event (14.2%; 13.4–15.0) (Figure). Patients with IHD were at higher risk of a new atherosclerotic event (23.5%; 22.8.-24.2) than of developing HF (9.3%; 8.9–9.8), although the risk of HF was still substantial. Conversely, patients with ischemic stroke were at low risk of HF (3.3%; 2.9–3.8) and higher risk of an atherosclerotic event (16.9%; 95% CI: 16.0–17.7). Patients with PAD had the lowest risk of HF (3.1%; 95% CI: 2.8–3.4) and the highest risk of an atherosclerotic event (35.0%; 95% CI: 33.4–36.7). Compared to a new atherosclerotic event, developing HF was associated with a higher 1-year risk of death (16.0%; 95% CI: 14.7–17.3 versus 33.0%; 95% CI: 31.8–34.2) amongst all patients. Cumulative incidence of first new event Conclusions In T2D, a patient's history of cardiovascular disease was predictive of type of subsequent cardiovascular event. While history of ischemic stroke and PAD were associated with a high risk of future atherosclerotic events, and low risk of HF, patients with IHD were at substantial risk of both types of event. Conversely, while history of HF was most predictive of future HF events, the risk of atherosclerotic events in patients with HF was also high. Our findings may help determine which type of therapy T2D patients with a particular cardiovascular disease history might benefit from – SGLT2 inhibitors, GLP-1 receptor agonists or potentially both. Acknowledgement/Funding Mariam Elmegaard Malik was funded by a research grant from Department of Cardiology, Herlev and Gentofte Hospital.