Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF). OBJECTIVES: In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial. METHODS: STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n = 85), 50% to 59% (n = 215), and ≥60% (n = 229). RESULTS: At 52 weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95% CI: -2.7 to 12.8 points], EF 50%-59%: 9.8 points [95% CI: 5.0 to 14.6 points], and EF ≥60%: 7.4 points [95% CI: 2.8 to 12.0 points]; P interaction = 0.56) and body weight (EF: 45%-49%: -7.6 [95% CI: -10.7 to -4.4], EF 50%-59%: -10.6 [95% CI: -12.6 to -8.6] and EF ≥60%: -11.9 [95% CI: -13.8 to -9.9]; P interaction = 0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction = 0.19), hierarchal composite endpoint (P interaction = 0.43), and high-sensitivity C-reactive protein (P interaction = 0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (P interaction = 0.96). Semaglutide was well-tolerated across LVEF categories. CONCLUSIONS: In patients with HFpEF and obesity, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511).

Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity.

BACKGROUND: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction. METHODS: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).

Design and Baseline Characteristics of STEP-HFpEF Program Evaluating Semaglutide in Patients With Obesity HFpEF Phenotype.

BACKGROUND: The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF exist. OBJECTIVES: The aim of this study was to describe the design and baseline characteristics of 2 trials of semaglutide, a glucagon-like peptide-1 receptor agonist, in patients with the obesity HFpEF phenotype: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF; NCT04788511) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes; NCT04916470). METHODS: Both STEP-HFpEF and STEP-HFpEF DM are international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF and a body mass index ≥30 kg/m2 to once-weekly semaglutide at a dose of 2.4 mg or placebo. Participants were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%; NYHA functional class II to IV; a Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90 points; and ≥1 of the following: elevated filling pressures, elevated natriuretic peptides plus structural echocardiographic abnormalities, recent heart failure hospitalization plus ongoing diuretic use, and/or structural abnormalities. The dual primary endpoints are the 52-week change in the KCCQ-CSS and body weight. RESULTS: In STEP-HFpEF and STEP-HFpEF DM (N = 529 and N = 617, respectively), nearly half were women, and most had severe obesity (median body mass index of 37 kg/m2) with typical features of HFpEF (median LVEF of 57%, frequent comorbidities, and elevated natriuretic peptides). Most participants received diuretic agents and renin-angiotensin blockers at baseline, and approximately one-third were on mineralocorticoid receptor antagonists. Sodium-glucose cotransporter-2 inhibitor use was rare in STEP-HFpEF but not in STEP HFpEF DM (32%). Patients in both trials had marked symptomatic and functional impairments (KCCQ-CSS ∼59 points, 6-minute walking distance ∼300 m). CONCLUSIONS: In total, STEP-HFpEF program randomized 1,146 participants with the obesity phenotype of HFpEF and will determine whether semaglutide improves symptoms, physical limitations, and exercise function in addition to weight loss in this vulnerable group.

A State of Natriuretic Peptide Deficiency.

Measurement of natriuretic peptides (NPs) has proven its clinical value as biomarker, especially in the context of heart failure (HF). In contrast, a state of partial NP deficiency appears integral to several conditions in which lower NP concentrations in plasma presage overt cardiometabolic disease. Here, obesity and type 2 diabetes have attracted considerable attention. Other factors-including age, sex, race, genetics, and diurnal regulation-affect the NP "armory" and may leave some individuals more prone to development of cardiovascular disease. The molecular maturation of NPs has also proven complex, with highly variable O-glycosylation within the biosynthetic precursors. The relevance of this regulatory step in post-translational propeptide maturation has recently become recognized in biomarker measurement/interpretation and cardiovascular pathophysiology. An important proportion of people appear to have reduced effective net NP bioactivity in terms of receptor activation and physiological effects. The state of NP deficiency both entails a potential for further biomarker development and could also offer novel pharmacological possibilities. Alleviating the state of NP deficiency before development of overt cardiometabolic disease in selected patients could be a future path for improving precision medicine.

Cardiovascular risk prediction: Can Systematic Coronary Risk Evaluation (SCORE) be improved by adding simple risk markers? Results from the Copenhagen City Heart Study.

AIM: European society of cardiology (ESC) guidelines recommend that cardiovascular disease (CVD) risk stratification in asymptomatic individuals is based on the Systematic Coronary Risk Evaluation (SCORE) algorithm, which estimates individual 10-year risk of death from CVD. We assessed the potential improvement in CVD risk stratification of 19 easily available risk markers by adding them to the SCORE algorithm. METHODS AND RESULTS: We followed 8476 individuals without prior CVD or diabetes from the Copenhagen City Heart study. The 19 risk markers were: major and minor electrocardiographic (ECG) abnormalities, heart rate, family history (of ischaemic heart disease), body mass index (BMI), waist-hip ratio, walking duration and pace, leisure time physical activity, forced expiratory volume (FEV)1%pred, household income, education, vital exhaustion, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), high-sensitive C-reactive protein (hsCRP) and fibrinogen. With the exception of family history, BMI, triglycerides and minor ECG changes, all risk markers remained significantly associated with CVD mortality after adjustment for SCORE variables. However, the addition of the remaining 15 risk markers resulted in only small changes in discrimination calculated by area under the curve (AUC) and integrated discrimination improvement (IDI) and no improvement in net reclassification improvement (NRI). HsCRP improved AUC by 0.006 (p = 0.015) and IDI by 0.012 (p = 0.002); FEV1%pred improved AUC by 0.006 (p = 0.032) and IDI by 0.006 (p = 0.029). In the intermediate risk group FEV1%pred, education, vital exhaustion and ApoA1 all improved NRI but FEV1%pred was the only risk marker to significantly improve both IDI, AUC and NRI. CONCLUSION: The SCORE algorithm predicted CVD mortality in a Danish cohort well. Despite strong association with CVD mortality, the individual addition of 19 easily available risk makers to the SCORE model resulted in small risk stratification improvements.

Heart Rate Variability Density Analysis (Dyx) and Prediction of Long-Term Mortality after Acute Myocardial Infarction.

AIMS: The density HRV parameter Dyx is a new heart rate variability (HRV) measure based on multipole analysis of the Poincaré plot obtained from RR interval time series, deriving information from both the time and frequency domain. Preliminary results have suggested that the parameter may provide new predictive information on mortality in survivors of acute myocardial infarction (MI). This study compares the prognostic significance of Dyx to that of traditional linear and nonlinear measures of HRV. METHODS AND RESULTS: In the Nordic ICD pilot study, patients with an acute MI were screened with 2D echocardiography and 24-hour Holter recordings. The study was designed to assess the power of several HRV measures to predict mortality. Dyx was tested in a subset of 206 consecutive Danish patients with analysable Holter recordings. After a median follow-up of 8.5 years 70 patients had died. Of all traditional and multipole HRV parameters, reduced Dyx was the most powerful predictor of all-cause mortality (HR 2.4; CI 1.5 to 3.8; P < 0.001). After adjustment for known risk markers, such as age, diabetes, ejection fraction, previous MI and hypertension, Dyx remained an independent predictor of mortality (P = 0.02). Reduced Dyx also predicted cardiovascular death (P < 0.01) and sudden cardiovascular death (P = 0.05). In Kaplan-Meier analysis, Dyx significantly predicted mortality in patients both with and without impaired left ventricular systolic function (P < 0.0001). CONCLUSION: The new nonlinear HRV measure Dyx is a promising independent predictor of mortality in a long-term follow-up study of patients surviving a MI, irrespectively of left ventricular systolic function.

Burden of hospital admission and repeat angiography in angina pectoris patients with and without coronary artery disease: a registry-based cohort study.

AIMS: To evaluate risk of hospitalization due to cardiovascular disease (CVD) and repeat coronary angiography (CAG) in stable angina pectoris (SAP) with no obstructive coronary artery disease (CAD) versus obstructive CAD, and asymptomatic reference individuals. METHODS AND RESULTS: We followed 11,223 patients with no prior CVD having a first-time CAG in 1998-2009 due to SAP symptoms and 5,695 asymptomatic reference individuals from the Copenhagen City Heart Study through registry linkage for 7.8 years (median). In recurrent event survival analysis, patients with SAP had 3-4-fold higher risk of hospitalization for CVD irrespective of CAG findings and cardiovascular comorbidity. Multivariable adjusted hazard ratios(95%CI) for patients with angiographically normal coronary arteries was 3.0(2.5-3.5), for angiographically diffuse non-obstructive CAD 3.9(3.3-4.6) and for 1-3-vessel disease 3.6-4.1(range)(all P<0.001). Mean accumulated hospitalization time was 3.5(3.0-4.0)(days/10 years follow-up) in reference individuals and 4.5(3.8-5.2)/7.0(5.4-8.6)/6.7(5.2-8.1)/6.1(5.2-7.4)/8.6(6.6-10.7) in patients with angiographically normal coronary arteries/angiographically diffuse non-obstructive CAD/1-, 2-, and 3-vessel disease, respectively (all P<0.05, age-adjusted). SAP symptoms predicted repeat CAG with multivariable adjusted hazard ratios for patients with angiographically normal coronary arteries being 2.3(1.9-2.9), for angiographically diffuse non-obstructive CAD 5.5(4.4-6.8) and for obstructive CAD 6.6-9.4(range)(all P<0.001). CONCLUSIONS: Patients with SAP symptoms and angiographically normal coronary arteries or angiographically diffuse non-obstructive CAD suffer from considerably greater CVD burdens in terms of hospitalization for CVD and repeat CAG compared with asymptomatic reference individuals even after adjustment for cardiac risk factors and exclusion of cardiovascular comorbidity as cause. Contrary to common perception, excluding obstructive CAD by CAG in such patients does not ensure a benign cardiovascular prognosis.

Predictive value of the corrected TIMI frame count in patients with suspected angina pectoris but no obstructive coronary artery disease at angiography.

AIMS: To evaluate whether the corrected thrombolysis in myocardial infarction frame count (CTFC), an index of resting coronary blood flow, is associated with the risk of major adverse cardiovascular events (MACE) in patients with suspected stable angina pectoris (SAP) but no obstructive coronary artery disease (CAD) at angiography. METHODS AND RESULTS: In this case-control study, CTFC at baseline in 127 patients (50 % women) who subsequently experienced a myocardial infarction, non-hemorrhagic stroke or cardiovascular death during 2001-2011 was compared with CTFC in 254 event-free matched controls. All patients had suspected SAP but no obstructive (≥50 % stenosis) CAD at baseline angiography. Mean CTFC in controls was 23.4 (95 % confidence interval 20.9-25.9) frames and mean CTFC in cases did not differ significantly with a difference of -1.0 (-3.1 to 1.1) frames (P = 0.35) and no sex-specific interaction (P = 0.18). In a conditional logistic regression model, we found no dose-response relationship between CTFC and the risk of MACE, i.e., compared to the risk in the lowest CTFC quintile, the odds ratios for MACE were 1.3 (0.7-2.6), 0.7 (0.3-1.3), 0.7 (0.4-1.5) and 1.0 (0.5-2.1) in the second, third, fourth and fifth CTFC quintiles, respectively. Adjustment for cardiac risk factors including diabetes, active smoking, body mass index, and use of lipid-lowering and antihypertensive medication did not significantly change the results. CONCLUSIONS: In patients with SAP symptoms without obstructive CAD at angiography, CTFC is not associated with the risk of MACE.

Symptoms of angina pectoris increase the probability of disability pension and premature exit from the workforce even in the absence of obstructive coronary artery disease.

AIMS: To evaluate probabilities of disability pension (DP) and premature exit from the workforce (PEW) in patients with stable angina symptoms and no obstructive coronary artery disease (CAD) at angiography compared with obstructive CAD and asymptomatic reference individuals. METHODS AND RESULTS: We followed 4303 patients with no prior cardiovascular disease having a first-time coronary angiography (CAG) in 1998-2009 due to stable angina symptoms and 2772 reference individuals from the Copenhagen City Heart Study, all aged <65 years, through registry linkage until 2009 for DP and PEW. Five-year age-adjusted DP-free survival probabilities for reference individuals, patients with angiographically normal coronary arteries, angiographically diffuse non-obstructive CAD, 1 stenotic coronary vessel (1VD), 2VD, and 3VD, respectively, were 0.96, 0.88, 0.84, 0.82, 0.85, and 0.78 in women and 0.98, 0.90, 0.89, 0.89, 0.88, and 0.87 in men. Significant predictors of DP were higher age, angina symptoms, higher body mass index, diabetes, smoking, job status, non-marital status in men, lower income, lower educational level, and co-morbidity. Compared with the reference population, probabilities of DP and PEW were significantly increased in all patients with no gender difference (P > 0.2 for interaction). Thus, in pooled multivariable-adjusted analysis, patients referred to CAG for angina had a three-fold higher probability of DP and ~50% higher probability of PEW, with little difference between patients with angiographically normal coronary arteries, angiographically diffuse non-obstructive CAD, 1VD, 2VD, 3VD, the hazard ratios for DP being 2.7, 3.0, 3.3, 3.1, and 3.2 (all P < 0.001) and for PEW being 1.3, 1.4, 1.5, 1.6, and 1.6 (all P < 0.05). CONCLUSION: Patients with angina symptoms and angiographically normal coronary arteries, diffuse non-obstructive CAD, or obstructive CAD at angiography have a three-fold increased probability of DP regardless of angiographic findings.

Persistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris.

AIMS: To evaluate persistent angina in stable angina pectoris with no obstructive coronary artery disease (CAD) compared to obstructive CAD and its relation to long-term anxiety, depression, quality of life (QOL), and physical functioning. METHODS AND RESULTS: We invited 357 patients (men = 191; women = 166; response rate 83 %) with no prior cardiovascular disease who had a first-time coronary angiography (CAG) in 2008-2009 due to suspected stable angina to participate in a questionnaire survey in 2011 with the Seattle Angina Questionnaire and the Hospital Anxiety and Depression Scale as key elements. Long-term persistent angina (i.e., symptoms at least once a month) was present in 64 % of patients with diffuse non-obstructive CAD (1-49 % stenosis), 49 % of patients with normal coronary arteries (0 % stenosis), and 41 % of patients with obstructive CAD (≥ 50 % stenosis) (P = 0.01). Depression and anxiety were more common in patients with persistent angina: 24 versus 7 % (P < 0.001) reported HADS-Depression-scores >7 and 42 versus 21 % (P < 0.001) reported HADS-Anxiety-scores >7. In multivariate regression models, persistent angina was associated with depression (OR 4.3, 95 % confidence interval (CI) 1.9-9.6, P < 0.001), anxiety (OR 2.9, 95 % CI 1.6-5.1, P < 0.001), the severity of persistent angina with impaired physical functioning (P < 0.001), and QOL (P < 0.001); whereas outcomes were not related to age, gender, or degree of CAD. CONCLUSIONS: The study indicates higher prevalence of persistent angina in patients with diffuse non-obstructive CAD or normal coronary arteries than in patients with obstructive CAD. Persistent angina symptoms were associated with long-term anxiety, depression, impaired physical functioning, and QOL irrespective of the degree of CAD. Contrary to common perception, excluding obstructive CAD in stable angina does not ensure a favorable disease course, and further risk stratification and treatment strategies are warranted.

Use of nonsteroidal anti-inflammatory drugs prior to chronic renal replacement therapy initiation: a nationwide study.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with severe renal complications, including acute renal failure, reduced glomerular filtration rate and interstitial nephritis. Caution against NSAIDs is therefore recommended in advanced chronic kidney disease. In this study, we examined NSAID use, aetiology and comorbidity among a national cohort of patients before the initiation of chronic renal replacement therapy (RRT). METHODS: Patients initiated on chronic RRT in the period 1997-2006 were identified in the Danish National Registry on Regular Dialysis and Transplantation, including etiological diagnosis. The use of NSAID before the start of RRT was studied by linkage to the National Prescription Register and comorbidity by linkage to the National Patient Registry. RESULTS: A total of 6663 patients were included in the study, and 2407 patients (36.1%) were prescribed NSAID in the 3 years before the start of RRT. These patients were older (mean age = 63.0 vs 61.4 years) and had a significantly higher degree of comorbidity (Charlson score = 2.85 vs 2.61, p < 0.05) compared with patients not treated with NSAIDs. In the 3 years leading up to RRT, the number of patients treated with NSAID each year and the cumulated median length of treatment including all NSAIDs were stable at approximately 20% and 40 days, respectively. CONCLUSIONS: In this study of a nationwide group of patients, we observed a widespread use of NSAID with an unaffected high annual incidence in the 3 years leading up to the initiation of RRT.

Prognostic significance of electrocardiographic Q-waves in a low-risk population.

AIMS: In individuals without known heart disease, electrocardiographic Q-waves predict a poor prognosis. We aimed to examine whether prognostic information can be derived from the size and location of Q-waves in persons from the general population without known ischaemic heart disease (IHD) or heart failure (HF). METHODS AND RESULTS: Electrocardiograms (ECGs) of 5381 persons without known IHD or HF from the 4th Copenhagen City Heart Study were reviewed and Q-waves were classified according to their size and location. Multivariate Cox proportional hazards regression models were used to examine the associations of Q-waves adjusted for age, hypertension, diabetes, and estimated glomerular filtration rate with the risk of the combined endpoint of death and hospitalization for IHD. During a median of 7.8 years of follow-up, 1003 persons reached the combined endpoint. One hundred and fourteen (2.1%) had pathological Q-waves, of whom 44% suffered from an event compared with 18% from the control group, P< 0.001. Persons with hypertension, diabetes, and impaired renal function were more likely to have Q-waves. Even small Q-waves (i.e. Minnesota code 1.2.x-1.3.x) were associated with a poor prognosis, hazard ratio (HR) 1.4 [95% confidence interval (CI): 1.0-2.0; P< 0.05], though not as grave as large Q-waves (i.e. Minnesota code 1.1.x) HR 2.8 (95%CI: 1.6-5.0; P< 0.001). Conversely, there was no difference in the outcome of patients with anteriorly HR 1.6 (95%CI: 1.1-2.4) vs. posteriorly HR 1.5 (95%CI: 0.9-2.4) located Q-waves (P= 0.85). CONCLUSION: In the general population without known IHD or HF, even small Q-waves in the ECG are associated with a poor prognosis.

Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.

AIMS: Patients with chest pain and no obstructive coronary artery disease (CAD) are considered at low risk for cardiovascular events but evidence supporting this is scarce. We investigated the prognostic implications of stable angina pectoris in relation to the presence and degree of CAD with no obstructive CAD in focus. METHODS AND RESULTS: We identified 11 223 patients referred for coronary angiography (CAG) in 1998-2009 with stable angina pectoris as indication and 5705 participants from the Copenhagen City Heart Study for comparison. Main outcome measures were major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, stroke or heart failure, and all-cause mortality. Significantly more women (65%) than men (32%) had no obstructive CAD (P< 0.001). In Cox's models adjusted for age, body mass index, diabetes, smoking, and use of lipid-lowering or antihypertensive medication, hazard ratios (HRs) associated with no obstructive CAD were similar in men and women. In the pooled analysis, the risk of MACE increased with increasing degrees of CAD with multivariable-adjusted HRs of 1.52 (95% confidence interval, 1.27-1.83) for patients with normal coronary arteries and 1.85 (1.51-2.28) for patients with diffuse non-obstructive CAD compared with the reference population. For all-cause mortality, normal coronary arteries and diffuse non-obstructive CAD were associated with HRs of 1.29 (1.07-1.56) and 1.52 (1.24-1.88), respectively. CONCLUSION: Patients with stable angina and normal coronary arteries or diffuse non-obstructive CAD have elevated risks of MACE and all-cause mortality compared with a reference population without ischaemic heart disease.

Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality.

BACKGROUND: Subcutaneous allergen-specific immunotherapy (SCIT) is a well-documented treatment of IgE-mediated allergic disease. Little is known about potential effects of SCIT on the risk of other chronic immune-related diseases. Over the years, a few casuistic reports have caused concern that SCIT might act as a trigger of autoimmune disease. OBJECTIVE: We aimed to investigate the association of SCIT with the incidence of autoimmune disease and ischemic heart disease (IHD), as well as all-cause mortality. METHODS: All Danish citizens without other known diseases were linked and followed through central registries on medications and hospital admissions. Persons receiving SCIT and persons receiving conventional allergy treatment (CAT; nasal steroids or oral antihistamines) were compared with regard to mortality and development of autoimmune diseases, acute myocardial infarction (AMI), and IHD. Cox regression (survival analysis) with age as the underlying time scale was used to estimate relative risks (hazard ratios [HRs] with 95% CIs) associated with SCIT compared with CAT adjusted for age, sex, vocational status, and income. RESULTS: During the 10-year study period (1997-2006), a total of 18,841 and 428,484 persons were followed in the SCIT and CAT groups, respectively. Receiving SCIT was associated with lower mortality (HR, 0.71; 95% CI, 0.62-0.81) and lower incidence of AMI (HR, 0.70; 95% CI, 0.52-0.93), IHD (HR, 0.88; 95% CI, 0.73-1.05), and autoimmune disease (HR, 0.86; 95% CI, 0.74-0.99). CONCLUSION: In this registry-based observational study, receiving SCIT compared with CAT was associated with lower risk of autoimmune disease and AMI, as well as decreased all-cause mortality.

Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study.

AIMS: Psoriasis is a chronic inflammatory disease and inflammation contributes to the pathogenesis of atrial fibrillation (AF) and ischaemic stroke. We therefore investigated the risk of these endpoints in patients with psoriasis. METHODS AND RESULTS: Cohort study of the entire Danish population followed from 1997 to 2006 by individual-level-linkage of nationwide prospectively recorded registers. Multivariable Poisson's regression and sensitivity analyses were used to assess the psoriasis-related risk of AF and ischaemic stroke. A total of 36 765 patients with mild psoriasis and 2793 with severe psoriasis were compared with 4 478 926 individuals, i.e., the reference population. In patients with mild psoriasis, the adjusted rate ratios (RRs) for AF were 1.50 (1.21-1.86) and 1.16 (1.08-1.24) in patients aged <50 and ≥50 years, respectively. Patients with severe psoriasis had a higher risk of AF with RRs 2.98 (1.80-4.92) in patients aged <50 years and 1.29 (1.01-1.65) in patients aged ≥50 years. Patients with psoriasis also demonstrated a disease severity-dependent increased risk of ischaemic stroke, i.e. RRs 1.97 (1.66-2.34) and 2.80 (1.81-4.34) in patients aged <50 years with mild and severe psoriasis, and RRs 1.13 (1.04-1.21) and 1.34 (1.04-1.71) in patients aged ≥50 years with mild and severe psoriasis, respectively. A range of sensitivity analyses yielded comparable results. CONCLUSION: Psoriasis is associated with increased risk of AF and ischaemic stroke. These novel results add to a growing body of evidence, suggesting that patients with psoriasis could be considered at increased cardiovascular risk.

Long-term clinical outcome in STEMI patients treated with primary PCI and drug-eluting or bare-metal stents: insights from a high-volume single-center registry.

OBJECTIVE: Use of drug-eluting stents (DES) in patients with ST-elevation myocardial infarction (STEMI) during routine primary percutaneous coronary intervention (pPCI) is controversial. METHODS: From January 2004 to July 2008, a total of 2,155 STEMI patients were treated with pPCI [DES or bare-metal stent (BMS)] at a single high-volume invasive center. We present 4-year outcomes in this observational registry study. RESULTS: A total of 1,725 were treated with DES and 430 with BMS. Patients treated with DES were younger and had more complex angiographic characteristics compared to BMS patients. Patients treated with DES had lower adjusted risk of target lesion revascularization (TLR) [hazard ratio (HR) = 0.68; 95% confidence interval (CI): 0.40-0.98; p = 0.04], but had a trend toward increased risk of definite stent thrombosis (HR = 1.96; 95% CI: 0.83-4.61; p = 0.12). No difference was found when evaluating all-cause mortality and non-fatal myocardial infarction. CONCLUSIONS: In this study, we set out to evaluate the independent impact of DES or BMS treatment on long-term clinical outcomes in STEMI patients treated with pPCI in a real-life setting. DES use was associated with a reduced risk of TLR, but a trend toward increased risk of stent thrombosis was found. However, this safety issue did not translate into an increased risk of death or overall non-fatal myocardial infarction for DES patients.

The Danish Heart Register.

INTRODUCTION: The Danish Heart Register (DHR) is a clinical database of invasive procedures within cardiology. CONTENT: All providers of these procedures have been obliged to report to DHR since 2000. DHR is used to monitor the activity and quality of the procedures and serves as a data source for research. VALIDITY AND COVERAGE: The coverage is high (>95%) but some variables have many missing. CONCLUSION: The combination of both cardiological and surgical data in this register is internationally unique and makes it possible to follow the patient from the invasive examination to treatment and by linkage to other registers to follow the prognosis.

Register-based studies of cardiovascular disease.

INTRODUCTION: The use of the unique personal identification number in the Nordic database systems enables the researchers to link the registers at the individual level. The registers can be used for both defining specific patient populations and to identify later events during follow-up. This review gives three examples within cardiovascular epidemiology to illustrate the use of the national administrative registers available to all researchers upon request. RESEARCH TOPICS: The hospitalisation rate of acute myocardial infarction (AMI) was expected to be increased and case-fatality rate to decrease when the diagnostic criteria were changed in 2000. Linkage of national registers found a relative increase in hospitalisation rate of 14% while the case-fatality rate was unaffected. The pharmacological treatment of AMI patients was evaluated by linkage of administrative data. The use of evidence-based treatment increased significantly over time and adherence to treatment was high. Finally, use of specific nonsteroidal antiinflammatory drugs by healthy subjects was associated with a dose-dependent increase in cardiovascular risk. CONCLUSION: The nationwide registers have proven very useful in monitoring the hospitalisation rate and treatment of cardiovascular disease. The risk of unmeasured factors affecting the results calls for cautious interpretation of the results.

Incidence of atrial fibrillation in patients with either heart failure or acute myocardial infarction and left ventricular dysfunction: a cohort study.

BACKGROUND: We examined the incidence of new-onset atrial fibrillation in patients with left ventricular dysfunction. Patients either had a recent myocardial infarction (with or without clinical heart failure) or symptomatic heart failure (without a recent MI). Patients were with and without treatment with the class III antiarrhythmic drug dofetilide over 36 months. METHODS: The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies included 2627 patients without atrial fibrillation at baseline, who were randomised to treatment with either dofetilide or placebo. RESULTS: The competing risk analyses estimated the cumulative incidences of atrial fibrillation during the 42 months of follow-up to be 9.6% in the placebo-treated heart failure-group, and 2.9% in the placebo-treated myocardial infarction-group. Cox proportional hazard regression found a 42% significant reduction in the incidence of new-onset AF when assigned to dofetilide compared to placebo (hazard ratio 0.58, 95% confidence interval 0.40-0.82) and there was no interaction with study (p = 0.89). In the heart failure-group, the incidence of atrial fibrillation was significantly reduced to 5.6% in the dofetilide-treated patients (hazard ratio 0.57, 95% confidence interval 0.38-0.86). In the myocardial infarction-group the incidence of atrial fibrillation was reduced to 1.7% with the administration of dofetilide. This reduction was however not significant (hazard ratio 0.61, 95% confidence interval 0.30-1.24). CONCLUSION: In patients with left ventricular dysfunction the incidence of AF in 42 months was 9.6% in patients with heart failure and 2.9% in patients with a recent MI. Dofetilide significantly reduced the risk of developing atrial fibrillation compared to placebo in the entire study group and in the subgroup of patients with heart failure. The reduction in the subgroup with recent MI was not statistically significant, but the hazard ratio was similar to the hazard ratio for the heart failure patients, and there was no difference between the effect in the two studies (p = 0.89 for interaction).