Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Influence of socioeconomic status on the referral process to cardiac rehabilitation following acute coronary syndrome: a cross-sectional study.

OBJECTIVE: To evaluate the association between socioeconomic status (SES) and referral to cardiac rehabilitation (CR) after incident acute coronary syndrome (ACS) by dividing the referral process into three phases: (1) informed about CR, (2) willingness to participate in CR, (3) and assigned CR setting. DESIGN: Cross-sectional study. SETTING: Department of Cardiology at a Danish University Hospital from 1 January 2011 to 31 December 2014. PARTICIPANTS: A total of 1229 patients assessed for CR during hospitalisation with ACS were prospectively registered in the Rehab-North Register from 2011 to 2014. SES was assessed using data from national registers, concerning: personal income, occupational status, educational level and civil status. Patients were excluded if one of the following criteria was fulfilled: (1) missing data on SES, or (2) acceptable reason for not informing patients about CR (treatment with coronary artery bypass grafting, transfer to another hospital, still under treatment or death). MAIN OUTCOME MEASURES: Outcomes were defined by dividing the referral process into three phases: (1) informed about CR, (2) willingness to participate, and (3) assigned CR setting (in-hospital/community centre) after ACS. RESULTS: A total of 854 (69.5 %) patients were referred to CR. After adjustment for age, gender, ACS diagnosis (ST-elevated myocardial infarction, non-ST-elevated myocardial infarction, unstable angina pectoris) and comorbidity, high income had the strongest association of referral to CR in all three phases (informed about CR: OR 2.17, 95% CI 1.01 to 4.64; willingness to participate in CR: OR 1.55, 95% CI 1.02 to 2.35; assigned in-hospital CR: OR 1.47, 95% CI 0.91 to 2.36). Educational level showed similar tendencies, however not statistically significant. The results did not vary according to gender. CONCLUSION: This is the first study to investigate the referral process to CR using a three-phase structure. It suggests income and education to influence all phases in the referral process to CR after ACS.

Arrhythmias in Patients on Maintenance Dialysis: A Cross-sectional Study.

RATIONALE & OBJECTIVE: Patients with kidney failure treated with maintenance dialysis experience a high rate of mortality, in part due to sudden cardiac death caused by arrhythmias. The prevalence of arrhythmias, including the subset that are clinically significant, is not well known. This study sought to estimate the prevalence of arrhythmias, characterize the pattern of arrhythmic events in relation to dialysis treatments, and identify associated clinical characteristics. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 152 patients with kidney failure treated with maintenance dialysis in Denmark. EXPOSURES: Dialysis treatment; clinical characteristics; cardiac output and preload defined using echocardiography. OUTCOMES: Prevalence and pattern of arrhythmias on 48-hour Holter monitoring; odds ratios for arrhythmias. ANALYTICAL APPROACH: Descriptive analysis of the prevalence of arrhythmias. Pattern of arrhythmias described using a repeated-measures negative binomial regression model. Associations between clinical characteristics and echocardiographic findings with arrhythmias were assessed using logistic regression. RESULTS: Among the 152 patients studied, 83.6% were treated with in-center dialysis; 10.5%, with home hemodialysis; and 5.9%, with peritoneal dialysis. Premature atrial and ventricular complexes were seen in nearly all patients and 41% had paroxysmal supraventricular tachycardia. Clinically significant arrhythmias included persistent atrial fibrillation observed among 8.6% of patients, paroxysmal atrial fibrillation among 3.9%, nonsustained ventricular tachycardia among 19.7%, bradycardia among 4.6%, advanced second-degree atrioventricular block among 1.3%, and third-degree atrioventricular block among 2.6%. Premature ventricular complexes were more common on dialysis days, while tachyarrhythmias were more often observed during dialysis and in the immediate postdialytic period. Older age (OR per 10 years older, 1.53; 95% CI, 1.15-2.03; P=0.003), elevated preload (OR, 4.02; 95% CI, 1.05-15.35; P=0.04), and lower cardiac output (OR per 1L/min greater, 0.66; 95% CI, 0.44-1.00; P=0.05) were independently associated with clinically significant arrhythmias. LIMITATIONS: Arrhythmia monitoring limited to 48 hours; small sample size; heterogeneous nature of the population, risk for residual confounding. CONCLUSIONS: Arrhythmias, including clinically significant abnormal rhythms, were common. Tachyarrhythmias were more frequent during dialysis and the immediate postdialytic period. The relevance of these findings to clinical outcomes requires additional study.

Does socially differentiated cardiac rehabilitation affect the use of healthcare services after myocardial infarction? A 10-year follow-up study.

OBJECTIVE: To examine the long-term effect of a socially differentiated cardiac rehabilitation (CR) intervention tailored to reduce social inequalities in health regarding use of healthcare services in general practice and hospital among socially vulnerable patients admitted with first-episode myocardial infarction (MI). DESIGN: A prospective cohort study with 10 years' follow-up. SETTING: Department of cardiology at a university hospital in Denmark between 2000 and 2004. PARTICIPANTS: Patients <70 years admitted with first-episode MI categorised as socially vulnerable (n=208) or non-socially vulnerable (n=171) based on educational level and social network. INTERVENTION: A socially differentiated CR intervention. The intervention consisted of standard CR and expanded CR with focus on cross-sectional collaboration. MAIN OUTCOME MEASURES: Participation in annual chronic care consultations in general practice, contacts to general practice, all-cause hospitalisations and cardiovascular readmissions. RESULTS: At 2-year and 5-year follow-up, socially vulnerable patients receiving expanded CR participated significantly more in annual chronic care consultations (p=0.02 and p<0.01) but at 10-year follow-up, there were no significant differences in annual chronic care consultations (p=0.13). At 10-year follow-up, socially vulnerable patients receiving standard CR had significantly more contacts to general practice (p=0.03). At 10-year follow-up, there were no significant differences in the proportion of socially vulnerable patients receiving expanded CR in the mean number of all-cause hospitalisations and cardiovascular readmissions (p>0.05). CONCLUSIONS: The present study found no persistent association between the socially differentiated CR intervention and use of healthcare services in general practice and hospital in patients admitted with first-episode MI during a 10-year follow-up.

Dose-Response Association Between Level of Physical Activity and Mortality in Normal, Elevated, and High Blood Pressure.

It has been a challenge to verify the dose of exercise that will produce the maximum health benefits in hypertension. This study aimed to explore the association between level of daily physical activity, all-cause mortality and cardiovascular outcome at different blood pressure levels. A random sample of 18 974 white men and women aged 20 to 98 years were examined in a prospective cardiovascular population study. Self-reported activity level in leisure-time was drawn from the Physical Activity Questionnaire (level I: inactivity; II: light activity; and III: moderate/high-level activity). Blood pressure was defined as normal blood pressure: <120/<80 mm Hg; Prehypertension: 120-139/80-89 mm Hg; Stage I hypertension: 140-159/90-99 mm Hg; Stage II hypertension ≥160/≥100 mm Hg. The mean follow-up time was 23.4±11.7 years. At all levels of blood pressure, higher levels of physical activity were associated with lower all-cause mortality in a dose-response pattern. The pattern remained unchanged after adjustment for following confounders: sex, age, smoking status, education, diabetes mellitus, previous cardiovascular disease, body mass index, and calendar time. Compared with inactivity, following hazard ratios were found for stage I hypertension: light activity, hazard ratio 0.78 (0.72-0.84; P<0.001), moderate/high-level activity, hazard ratio 0.69 (0.63-0.75; P<0.001). At all levels of blood pressure, the risk of cardiovascular events was significantly reduced independent of the level of physical activity. In conclusion, the association between physical activity and all-cause mortality was present in an inverse dose-response pattern at all levels of blood pressure. Physical activity was associated with reduction in cardiovascular events independent of the level of physical activity.

Echocardiographic global longitudinal strain is associated with infarct size assessed by cardiac magnetic resonance in acute myocardial infarction.

The aim of this study was to investigate if there was an association between infarct size (IS) measured by cardiac magnetic resonance (CMR) and echocardiographic global longitudinal strain (GLS) in the early stage of acute myocardial infarction in patients with preserved left ventricular ejection fraction (LVEF). Patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention were assessed with CMR and transthoracic echocardiogram within 1 week of hospital admission. Two-dimensional speckle tracking was performed using a semi-automatic algorithm (EchoPac, GE Healthcare). Longitudinal strain curves were generated in a 17-segment model covering the entire left ventricular myocardium. GLS was calculated automatically. LVEF was measured by auto-LVEF in EchoPac. IS was measured by late gadolinium enhancement CMR in short-axis views covering the left ventricle. The study population consisted of 49 patients (age 60.4 ± 9.7 years; 92% male). The study population had preserved echocardiographic LVEF with a mean of 45.8 ± 8.7%. For each percent increase of IS, we found an impairment in GLS by 1.59% (95% CI 0.57-2.61), P = 0.02, after adjustment for sex, age and LVEF. No significant association between IS and echocardiographic LVEF was found: -0.25 (95% CI: -0.61 to 0.11), P = 0.51. At the segmental level, the strongest association between IS and longitudinal strain was found in the apical part of the LV: impairment of 1.69% (95% CI: 1.14-2.23), P < 0.001, for each percent increase in IS. In conclusion, GLS was significantly associated with IS in the early stage of acute myocardial infarction in patients with preserved LVEF, and this association was strongest in the apical part of the LV. No association between IS and LVEF was found.

Medication adherence, biological and lifestyle risk factors in patients with myocardial infarction: a ten-year follow-up on socially differentiated cardiac rehabilitation.

Objective: There is strong evidence that medication adherence and lifestyle changes are essential in patients undergoing secondary cardiovascular disease prevention. Cardiac rehabilitation (CR) increases medication adherence and improves lifestyle changes. Patients with cardiac diseases and a low educational level and patients with little social support are less responsive to improve medication adherence and to adapt lifestyle changes. The aim of the present study was to investigate the long-term effects of a socially differentiated CR intervention on medication adherence as well as changes in biological and lifestyle risk factors at two- five- and ten-year follow-up. Design: A prospective cohort study. Setting: The cardiac ward at Aarhus University Hospital, Denmark. Intervention: A socially differentiated CR intervention in addition to the standard CR program. Subjects: Patients admitted with first-episode myocardial infarction between 2000 and 2004, N = 379. Patients were defined as socially vulnerable or non-socially vulnerable according to their educational level and extent of social network. Main outcome measures: Primary outcome was medication adherence to antithrombotics, beta-blockers, statins and angiotensin-converting enzyme inhibitors. Secondary outcomes were biological and lifestyle risk factors defined as; total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glycated hemoglobin, blood pressure and smoking status. Results: No significant long-term effect of the intervention was found. Conclusions: The results indicate a non-significant effect of the intervention. However, it was found that equality in health was improved in the study population except concerning smoking. General practitioners manage to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status. Key points The socially differentiated intervention did not significantly improve medication adherence or biological and lifestyle risk factors. Despite the non-significant effect of the intervention, equality in health was improved except concerning smoking. General practitioners managed to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status.

Coronary Artery Calcification and Mortality Risk in Patients With Severe Mental Illness.

Background Cardiovascular mortality is the leading contributor to the shortened life expectancy in patients with severe mental illness (SMI), but efforts to predict cardiovascular outcomes in these patients have been lacking. In this study, we aimed to determine the severity of coronary artery calcification (CAC), and its effect on mortality rates in patients with SMI, compared with the general population. Methods All individuals with a registered cardiac computed tomography for calcium scoring in the Western Denmark Heart Registry, from January 1, 2008 to December 31, 2016, were included. We identified patients diagnosed with SMI ( International Classification of Diseases, Tenth Revision: F20, F30, F31), whereas the remaining individuals were used as a comparison group. Results Among 48 757 individuals, including 564 patients with SMI (1.2%), we found no difference in CAC score between patients with SMI and the comparison group. SMI patients with CAC >100 had an increased mortality rate (hazard ratio, 3.16; 95% CI, 1.41-7.06), as well as SMI patients with CAC <100 (hazard ratio, 3.95; 95% CI, 2.36-6.62), compared with the comparison group with CAC <100 as reference, adjusted for age, sex, and calendar period. Conclusions Patients with SMI have increased cardiovascular risks, but show no difference in CAC score, compared with the comparison group. Mortality rates were increased in patients with SMI, independent of CAC severity; however, the relatively large number of noncardiovascular causes of death in this sample might indicate other contributing factors to death than coronary artery disease in this sample of SMI patients.

Educational level and living arrangements are associated with dietary intake of red meat and fruit/vegetables: A Danish cross-sectional study.

Aims: To evaluate the association between education and living arrangements and the intake of fish, red meat and fruit and vegetables.Methods: The study design was cross-sectional and conducted in Denmark in 2013. Participants filled in questionnaires about their educational level and living arrangements (living alone or with others) and dietary intake including fish, red meat, fruit and vegetables. Regression analyses were performed to assess the associations within 85,456 randomly sampled healthy men and women who were at least 25 years old.Results: Length of education was statistically significant and positively associated with the intake of fruit and vegetables and negatively associated with the intake of red meat for both men and women. Men with a high level of education had a 187g/week (95% confidence interval: 199-175g/week) lower intake of red meat and a 109g/day (95% confidence interval: 102-117g/day) higher intake of fruit and vegetables than men with a low level of education. Women with a high level of education had a 175g/week (95% confidence interval: 186-164g/week) lower intake of red meat and a 106g/day (95% confidence interval: 97-114g/day) higher intake of fruit and vegetables than women with a low level of education. Living with others was statistically significant and positively associated with the intake of red meat, and fruit and vegetables. There were no clear associations between education, living arrangements and intake of fish.Conclusions: Men and women with a high educational level ate more fruit and vegetables but less red meat than men and women with a low educational level. Men and women living with others ate more red meat, fruit and vegetables than men and women living alone.

Positive predictive value of first-time rheumatoid arthritis diagnoses and their serological subtypes in the Danish National Patient Registry.

PURPOSES: To assess whether the positive predictive value (PPV) of first-time rheumatoid arthritis (RA) diagnosis registration in the Danish National Patient Registry increases when data are linked to the RA treatment codes and to assess the PPV of first-time RA diagnoses according to RA serological subtypes. METHODS: Participants from the Danish Diet, Cancer, and Health cohort with at least one RA diagnosis, registered at one of the Central Denmark Region hospitals in the Danish National Patient Registry during the period 1977-2016, were identified. Register-based RA diagnoses were verified by scrutinizing medical records against RA classification criteria or clinical case RA. PPVs for overall RA, seropositive RA, and other RA were calculated for two models: first-time RA diagnosis registration ever in the Danish National Patient Registry and first-time RA diagnosis registration ever where subsequently a prescription had been redeemed for a synthetic disease-modifying antirheumatic drug. RESULTS: Overall, 205 of 311 first-time register-based RA diagnoses were verified (PPV: 61.9%; 95% CI: 56.9-67.0). Regarding RA serological subtypes, 93 of 150 register-based seropositive RA (PPV: 62.0; 95% CI: 53.9-69.5) and 36 of 144 other RA (PPV: 25.0; 95% CI: 18.5-32.8) were confirmed. When register-based RA diagnosis codes were linked to RA treatment codes, the PPVs increased substantially: the PPV for overall RA was 87.7% (95% CI: 82.5-91.5), the PPV for seropositive RA was 80.2% (95% CI: 71.6-86.7), and the PPV for other RA was 41.1% (95% CI: 30.2-52.9). CONCLUSION: The first-time RA diagnoses in the Danish National Patient Registry should be used with caution in epidemiology research. However, linking registry-based RA diagnoses to the subsequent RA treatment codes increases the probability of identifying true RA diagnoses, especially overall RA and seropositive RA.