Publications by authors named "Per Winkel"

93 Publications

A screening method to spot biomarkers that may warn of serious events in a chronic disease - illustrated by cardiological CLARICOR trial data.

Clin Chem Lab Med 2021 Oct 12;59(11):1852-1860. Epub 2021 Aug 12.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker's clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable.

Methods: The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient's entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers.

Results: Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes.

Conclusions: For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.
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http://dx.doi.org/10.1515/cclm-2021-0333DOI Listing
October 2021

Prognostic value of 12 novel cardiological biomarkers in stable coronary artery disease. A 10-year follow-up of the placebo group of the Copenhagen CLARICOR trial.

BMJ Open 2020 08 20;10(8):e033720. Epub 2020 Aug 20.

The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objective: To assess if 12 novel circulating biomarkers, when added to 'standard predictors' available in general practice, could improve the 10-year prediction of cardiovascular events and mortality in patients with stable coronary heart disease.

Design: The patients participated as placebo receiving patients in the randomised clarithromycin for patients with stable coronary artery disease (CLARICOR) trial at a random time in their disease trajectory.

Setting: Five Copenhagen University cardiology departments and a coordinating centre.

Participants: 1998 participants with stable coronary artery disease.

Outcomes: Death and composite of myocardial infarction, unstable angina pectoris, cerebrovascular disease and death.

Results: When only 'standard predictors' were included, 83.4% of all-cause death predictions and 68.4% of composite outcome predictions were correct. Log(calprotectin) and log(cathepsin-S) were not associated (p≥0.01) with the outcomes, not even as single predictors. Adding the remaining 10 biomarkers (high-sensitive assay cardiac troponin T; neutrophil gelatinase-associated lipocalin; osteoprotegerin; N-terminal pro-B-type natriuretic peptide; tumour necrosis factor receptor 1 and 2; pregnancy-associated plasma protein A; endostatin; YKL40; cathepsin-B), which were all individually significantly associated with the prediction of the two outcomes, increased the figures to 84.7% and 69.7%.

Conclusion: When 'standard predictors' routinely available in general practices are used for risk assessment in consecutively sampled patients with stable coronary artery disease, the addition of 10 novel biomarkers to the prediction model improved the correct prediction of all-cause death and the composite outcome by <1.5%.

Trial Registration Number: NCT00121550.
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http://dx.doi.org/10.1136/bmjopen-2019-033720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443269PMC
August 2020

Internet-based therapy with FearFighter for anxiety disorders: a randomised clinical trial.

Nord J Psychiatry 2020 Oct 13;74(7):518-524. Epub 2020 May 13.

Stolpegaard Psychotherapy Centre, Mental Health Services, Capital Region of Denmark, Gentofte, Denmark.

Internet-based cognitive behavioural self-help psychotherapy (ICBT) can be an important alternative or supplement to ordinary face-to-face therapy. To assess effectiveness of ICBT for adults with an anxiety disorder. Sixty-four participants were randomised to 9 weeks with the FearFighter ICBT program ( = 32) or no intervention ( = 32). Outcomes included complete remission, severity of symptoms and occurrence of adverse events. No difference ( = 1.00) in remission between groups following 10 weeks of intervention nor at 37 weeks follow-up was found. There was significant reduction in the severity of symptoms ( < 0.05) at end of intervention of ICBT compared to the control group, while the reduction in symptoms at 37 weeks follow-up was equal for the two groups. Two participants in the ICBT group and none in the control group reported adverse events. We found no difference in remission, but a reduction of symptoms in the ICBT group compared with the control group at end of intervention. At six months follow-up the two groups showed the same level in the reduction of symptoms. Clinicaltrials.gov: NCT02499055. Registered 01 July 2015.
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http://dx.doi.org/10.1080/08039488.2020.1755363DOI Listing
October 2020

Serum osteoprotegerin as a long-term predictor for patients with stable coronary artery disease and its association with diabetes and statin treatment: A CLARICOR trial 10-year follow-up substudy.

Atherosclerosis 2020 05 4;301:8-14. Epub 2020 Apr 4.

The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background And Aims: Elevated circulating levels of osteoprotegerin (OPG) are known to add to the prediction of cardiovascular mortality. Our objective was to clarify the long-term risk associated with serum OPG and the possible influence of diabetes and statins on OPG levels in patients with stable coronary artery disease (CAD).

Methods: We assessed the placebo-treated group (n = 1998) from the CLARICOR trial (NCT00121550), a cohort with stable CAD. At entry, 15% of the participants had diabetes and 41% received statins. Serum OPG levels were measured in blood drawn at randomization. Participants were followed through public registers for 10 years.

Results: OPG levels correlated positively with diabetes status, age, CRP and female sex, but negatively with the use of statins. CAD participants with diabetes had significantly elevated serum OPG levels compared to participants without diabetes, p < 0.0001. The participants without diabetes treated with statins presented with significantly lower serum OPG levels than the corresponding non-statin-users (p < 0.0001). However, statin use showed no association with OPG levels in the participants with diabetes. High OPG levels at entry showed long-term associations with all-cause mortality and cardiovascular events (hazard ratio associated with factor 10 OPG increase 15.9 (95% CI 11.0-22.9) and 6.38 (4.60-8.90), p = 0.0001, even after adjustment for standard predictors (3.16 (1.90-5.25) and 2.29 (1.53-3.44), p < 0.0001).

Conclusions: Circulating OPG holds long-term independent predictive ability for all-cause mortality and cardiovascular events in CAD participants. OPG levels were associated with diabetes, age, and female sex and statin treatment was associated with lower OPG levels in the absence of diabetes.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.03.030DOI Listing
May 2020

Prognosis and Reclassification by YKL-40 in Stable Coronary Artery Disease.

J Am Heart Assoc 2020 03 2;9(5):e014634. Epub 2020 Mar 2.

Department of Cardiology Rigshospitalet University of Copenhagen København Denmark.

Background The inflammatory biomarker YKL-40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum YKL-40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. We used Cox proportional hazards regression models adjusted for C-reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL-40 to the risk factors was calculated using the Cox-Breslow method and c-statistic. A total of 2200 patients were randomized to placebo, with a follow-up duration of 10 years. YKL-40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL-40) 1.13, 95% CI 1.03-1.24, =0.013) and all-cause mortality (hazard ratio 1.32, 95% CI 1.17-1.49, <0.0001). Considering whether a composite-outcome event was more likely to have, or not have, occurred to date, we found 68.4% of such predictions to be correct when based on the standard predictors, and 68.5% when serum YKL-40 was added as a predictor. Equivalent results were obtained with c-statistics. Conclusions Higher serum YKL-40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL-40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00121550.
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http://dx.doi.org/10.1161/JAHA.119.014634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335588PMC
March 2020

Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how.

BMJ Evid Based Med 2021 Jun 27;26(3):121-126. Epub 2020 Jan 27.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

When analysing and presenting results of randomised clinical trials, trialists rarely report if or how underlying statistical assumptions were validated. To avoid data-driven biased trial results, it should be common practice to prospectively describe the assessments of underlying assumptions. In existing literature, there is no consensus on how trialists should assess and report underlying assumptions for the analyses of randomised clinical trials. With this study, we developed suggestions on how to test and validate underlying assumptions behind logistic regression, linear regression, and Cox regression when analysing results of randomised clinical trials.Two investigators compiled an initial draftbased on a review of the literature. Experienced statisticians and trialists from eight different research centres and trial units then participated in a anonymised consensus process, where we reached agreement on the suggestions presented in this paper.This paper provides detailed suggestions on 1) which underlying statistical assumptions behind logistic regression, multiple linear regression and Cox regression each should be assessed; 2) how these underlying assumptions may be assessed; and 3) what to do if these assumptions are violated.We believe that the validity of randomised clinical trial results will increase if our recommendations for assessing and dealing with violations of the underlying statistical assumptions are followed.
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http://dx.doi.org/10.1136/bmjebm-2019-111268DOI Listing
June 2021

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial.

Eur Stroke J 2019 Sep 20;4(3):254-262. Epub 2019 Apr 20.

Department of Neurology, University Medical Centre Erlangen, Erlangen, Germany.

Introduction: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke.

Patients And Methods: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0-35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression.

Results: The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48-2.13;  = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65-1.94;  = 0.52).

Discussion: In this trial, cooling to a target of 34.0-35.0°C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes.

Conclusion: Before new trials are launched, the feasibility of cooling needs to be improved.
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http://dx.doi.org/10.1177/2396987319844690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960691PMC
September 2019

Pregnancy Associated Plasma Protein-A as a Cardiovascular Risk Marker in Patients with Stable Coronary Heart Disease During 10 Years Follow-Up-A CLARICOR Trial Sub-Study.

J Clin Med 2020 Jan 18;9(1). Epub 2020 Jan 18.

Division for Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 14183 Huddinge, Sweden.

Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR trial was a randomized controlled clinical trial including outpatients with stable CAD, randomized to clarithromycin versus placebo. The placebo group constituted our discovery cohort ( = 1.996) and the clarithromycin group the replication cohort ( = 1.975). The composite primary outcome was first occurrence of cardiovascular event or death. In the discovery cohort, incidence rates (IR) for the composite outcome were higher in those with elevated PAPP-A (IR 12.72, 95% Confidence Interval (CI) 11.0-14.7 events/100 years) compared to lower PAPP-A (IR 8.78, 8.25-9.34), with comparable results in the replication cohort. Elevated PAPP-A was associated with increased risk of the composite outcome in both cohorts (discovery Hazard Ratio (HR) 1.45, 95% CI 1.24-1.70; replication HR 1.29, 95% CI 1.10-1.52). In models adjusted for established risk factors, these trends were attenuated. Elevated PAPP-A was associated with higher all-cause mortality in both cohorts. We conclude that elevated PAPP-A levels are associated with increased long-term mortality in stable CAD, but do not improve long-term prediction of death or cardiovascular events when added to established predictors.
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http://dx.doi.org/10.3390/jcm9010265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019890PMC
January 2020

Storage time of red blood cells among ICU patients with septic shock.

Acta Anaesthesiol Scand 2019 11 25;63(10):1366-1377. Epub 2019 Jul 25.

Centre for Research in Intensive Care (CRIC), Copenhagen, Denmark.

Background: We aimed to describe the exposure to blood transfusions and mortality among patients with septic shock.

Methods: We did a retrospective cohort study of two cohorts-patients with septic shock registered in a Danish ICU database (2008-2010) and patients from the Transfusion Requirements in Septic Shock (TRISS) trial (2011-2013). We extracted information on blood transfusions issued to all patients. We investigated the number of patients receiving very fresh blood (less than 7 days), very old blood (more than 24 days) and blood with a mixture of storage time.

Results: In the Danish cohort, 1637 patients were included of whom 1394 (85%) received 20,239 blood units from 14 days prior the ICU admission to 90 days after; 33% were transfused before, 77% in the ICU and 36% after ICU. The exposure to exclusively very fresh or very old blood was 3% and 4%, respectively. In the TRISS cohort, 77% of the 937 patients received 5047 RBC units; 3% received exclusively very fresh and 13% very old blood. The point estimate of mortality was higher among patients receiving large amounts of exclusively very fresh and very old blood, but the number of patients were very small.

Conclusions: Patients with septic shock were transfused both before and after ICU. Exposure to blood of less than 7 days or more than 24 days old were limited. We were not able to detect higher mortality among the limited number of patients with septic shock transfused with very fresh or very old blood.
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http://dx.doi.org/10.1111/aas.13439DOI Listing
November 2019

Power estimations for non-primary outcomes in randomised clinical trials.

BMJ Open 2019 06 6;9(6):e027092. Epub 2019 Jun 6.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objective And Methods: It is rare that trialists report power estimations of non-primary outcomes. In the present article, we will describe how to define a valid hierarchy of outcomes in a randomised clinical trial, to limit problems with Type I and Type II errors, using considerations on the clinical relevance of the outcomes and power estimations.

Conclusion: Power estimations of non-primary outcomes may guide trialists in classifying non-primary outcomes as secondary or exploratory. The power estimations are simple and if they are used systematically, more appropriate outcome hierarchies can be defined, and trial results will become more interpretable.
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http://dx.doi.org/10.1136/bmjopen-2018-027092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588976PMC
June 2019

Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study.

Atherosclerosis 2019 05 3;284:202-208. Epub 2019 Mar 3.

Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden. Electronic address:

Background And Aims: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain.

Methods: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979).

Results: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00-1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%).

Conclusions: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.02.031DOI Listing
May 2019

Assessing assumptions for statistical analyses in randomised clinical trials.

BMJ Evid Based Med 2019 Oct 4;24(5):185-189. Epub 2019 Apr 4.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Kobenhavn, Denmark.

In order to ensure the validity of results of randomised clinical trials and under some circumstances to optimise statistical power, most statistical methods require validation of underlying statistical assumptions. The present paper describes how trialists in major medical journals report tests of underlying statistical assumptions when analysing results of randomised clinical trials. We also consider possible solutions how to improve current practice by adequate reporting of tests of underlying statistical assumptions. We conclude that there is a need to reach consensus on which underlying assumptions should be assessed, how these underlying assumptions should be assessed and what should be done if the underlying assumptions are violated.
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http://dx.doi.org/10.1136/bmjebm-2019-111174DOI Listing
October 2019

Low vs high hemoglobin trigger for transfusion in vascular surgery: a randomized clinical feasibility trial.

Blood 2019 06 11;133(25):2639-2650. Epub 2019 Mar 11.

Department of General and Vascular Surgery, Slagelse Hospital, Slagelse, Denmark.

Current guidelines advocate to limit red blood cell (RBC) transfusion during surgery, but the feasibility and safety of such a strategy remain unclear, as the majority of evidence is based on postoperatively stable patients. We assessed the effects of a protocol aiming to restrict RBC transfusion throughout hospitalization for vascular surgery. Fifty-eight patients scheduled for lower limb bypass or open abdominal aortic aneurysm repair were randomly assigned, on hemoglobin drop below 9.7 g/dL, to either a low-trigger (hemoglobin < 8.0 g/dL) or a high-trigger (hemoglobin < 9.7 g/dL) group for RBC transfusion. Near-infrared spectroscopy assessed intraoperative oxygen desaturation in brain and muscle. Explorative outcomes included nationwide registry data on death and major vascular complications. The primary outcome, mean hemoglobin within 15 days of surgery, was significantly lower in the low-trigger group, at 9.46 vs 10.33 g/dL in the high-trigger group (mean difference, -0.87 g/dL; = .022), as were units of RBCs transfused (median [interquartile range (IQR)], 1 [0-2] vs 3 [2-6]; = .0015). Although the duration and magnitude of cerebral oxygen desaturation increased in the low-trigger group (median [IQR], 421 [42-888] vs 127 [11-331] minutes × %; = .0036), muscle oxygenation was unaffected. The low-trigger group associated to a higher rate of death or major vascular complications (19/29 vs 8/29; hazard ratio, 3.20; = .006) and fewer days alive outside the hospital within 90 days (median [IQR], 76 [67-82] vs 82 [76-84] days; = .049). In conclusion, a perioperative protocol restricting RBC transfusion successfully separated hemoglobin levels and RBC units transfused. Exploratory outcomes suggested potential harm with the low-trigger group and warrant further trials before such a strategy is universally adopted. This trial was registered at www.clinicaltrials.gov as #NCT02465125.
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http://dx.doi.org/10.1182/blood-2018-10-877530DOI Listing
June 2019

Early physical and psycho-educational rehabilitation in patients with coronary artery bypass grafting: A randomized controlled trial.

J Rehabil Med 2019 Feb;51(2):136-143

Department of Cardiothoracic Surgery/Department of Nursing, Faculty of Health and Technology, Rigshospitalet, University of Copenhagen/ Metropolitan University College, , 2100 Copenhagen , Denmark.

Objectives: Rehabilitation of patients following coronary artery bypass grafting (CABG) has been widely studied; however, research into early rehabilitation after CABG is sparse. The aim of this trial was to assess the impact of early rehabilitation, compared with usual care in patients following CABG.

Design: Randomized controlled trial.

Patients: A total of 326 patients treated with CABG.

Methods: Patients treated with CABG were randomized 1:1 to 4 weeks of comprehensive early rehabilitation or usual care. The primary outcome was the Six Minute Walk Test (6MWT). Secondary outcomes were mental health and physical activity (Medical Outcome Study Short Form; SF-12); anxiety and depression (Hospital Anxiety and Depression Scale; HADS); physical and emotional scores; sleep (Pittsburgh Sleep Quality Index; PSQI); pain (Örebro Musculoskeletal Screening Questionnaire; ÖMSQ) and muscle endurance (Sit-To-Stand test).

Results: Sixteen patients dropped out. No significant differences between groups in the primary outcome (6MWT) were found after 4 weeks (p = 0.27). For secondary outcomes the odds ratio of HADS-D ≥ 8 decreased in favour of the experimental intervention (p = 0.04). There was non-adherence to parts of the intervention. Per-protocol analysis showed differences between groups for the 6MWT (p = 0.02) and the Sit-To-Stand test (p = 0.046).

Conclusion: In general, the intervention had no effect on the 6MWT, or secondary outcomes, except for depressive symptoms. However, in adherent participants, the intervention had a positive effect for the primary and several secondary outcomes.
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http://dx.doi.org/10.2340/16501977-2499DOI Listing
February 2019

Sexual rehabilitation for cardiac patients with erectile dysfunction: a randomised clinical trial.

Heart 2019 05 31;105(10):775-782. Epub 2018 Oct 31.

Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Sexual dysfunction is common in patients with either ischaemic heart disease (IHD) or implantable cardioverter defibrillator (ICD) and has a negative impact on quality of life. Non-pharmacological treatment options are lacking. The purpose of this trial was to assess the effect of sexual rehabilitation versus usual care for males with erectile dysfunction and either IHD and/or ICD.

Methods: Participants with erectile dysfunction and IHD and/or ICD were randomised to 12 weeks of sexual rehabilitation consisting of physical exercise training, pelvic floor exercise and psychoeducation, or usual care.

Primary Outcome: sexual function by the International Index of Erectile Function (IIEF). Secondary outcome: sexual function by the Psychosocial Adjustment to Illness Scale. Exploratory outcomes: exercise capacity, pelvic floor strength/endurance, self-reported health and mental health.

Results: 154 participants were included, mean age 61.6 years (SD 6.1). Sexual rehabilitation compared with usual care improved sexual function with a mean difference IIEF score of 6.7 (95% CI 3.1 to 10.4, p<0.0003) at 4 months between groups (unadjusted IIEF mean scores 36.4 vs 31.3) and a mean difference of 6.7, 95% CI 3.2 to 10.1 (p<0.0002) at 6 months between groups (unadjusted mean scores IIEF 37.1 vs 32.2). No effects were seen on the secondary outcome. Sexual rehabilitation improved exercise capacity on cycle ergometer measured by Watt max with a mean difference of 10.3, 95% CI 3.6 to 16.9 (p<0.003) and pelvic floor strength (p<0.01). No differences were seen on self-reported health and mental health.

Conclusion: Sexual rehabilitation compared with usual care improves sexual function and exercise capacity.

Trial Registration: NCT01796353; Results.
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http://dx.doi.org/10.1136/heartjnl-2018-313778DOI Listing
May 2019

Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years: a CLARICOR trial sub-study.

Atherosclerosis 2018 11 15;278:97-102. Epub 2018 Sep 15.

Division for Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden.

Background And Aims: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease.

Methods: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs.

Results: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events.

Conclusions: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.006DOI Listing
November 2018

Prognostic value of routinely available data in patients with stable coronary heart disease. A 10-year follow-up of patients sampled at random times during their disease course.

Open Heart 2018;5(2):e000808. Epub 2018 Sep 5.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital Blegdamsvej, Copenhagen, Denmark.

Objective: To characterise the long-term prognosis of patients with stable coronary artery heart disease by means of 'standard predictors' defined as demographic, clinical and biochemical quantities routinely available in general practices and ascertained at an interview not prompted by renewed cardiac complaints.

Methods: This is an observational study based on data from 2199 Copenhagen placebo patients from the 'clarithromycin for patients with stable coronary heart disease' trial of patients with stable coronary heart disease. In the trial, we compared the effects of 14 days of clarithromycin treatment versus placebo. The predictors were based on the interview forms and blood samples collected at entry, along with demographic information from hospital files.We studied 'standard predictors' of a composite outcome (myocardial infarction, unstable angina, cerebrovascular disease or all-cause death) and of all-cause death. Using Cox regression, we compared predictions of status at 3, 6 and 9 years without and with the use of 'standard predictors' and used receiver operating characteristic statistic.

Results: Few 'standard predictors' were associated (p<0.01) with the composite outcome or with all-cause death. When no 'standard predictors' were included, 63.2% of the model-based predictions of the composite outcome and 79.9% of death predictions were correct. Including all 'standard predictors' in the model increased the figures to 68.4% and 83.4%, respectively. indices were low, except when all-cause death was assessed as a single outcome where was 0.79.

Conclusion: 'Standard predictors' routinely available in general practices contribute only modestly to risk assessment in consecutively sampled patients with stable coronary heart disease as ascertained at a contact not prompted by renewed cardiac complaints. Novel biomarkers may improve the assessment.

Trial Registration Number: NCT00121550.
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http://dx.doi.org/10.1136/openhrt-2018-000808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135459PMC
February 2021

Simple, low-cost group-counselling programme vs treatment as usual for patients with newly notified occupational hand eczema-Exploratory analyses of effects on knowledge, behaviour and personal resources of the randomized PREVEX clinical trial.

Contact Dermatitis 2018 Sep 17;79(3):127-135. Epub 2018 May 17.

Department of Occupational and Environmental Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Sickness absence in hand eczema patients has been associated with stress rather than disease severity, indicating that personal aspects regarding hand eczema should be investigated further.

Objectives: To examine whether patient education vs treatment as usual can influence behaviour and knowledge regarding skin protection and care, as well as personal resources, in patients with occupational hand eczema.

Methods: PREVEX is an individually randomized clinical trial investigating the 1-year effects of a simple, low-cost group-counselling programme vs treatment as usual for patients with notified occupational hand eczema. Exploratory outcomes were behaviour, knowledge, self-efficacy, and self-evaluated skin care ability.

Results: In total, 1668 patients with notified occupational skin disease were invited to participate, of whom 769 were randomized and 756 were analysed: intervention group (n = 376) vs control group (n = 380). Behaviour was improved and the knowledge score increased in the intervention group as compared with the control group (respectively: estimate 0.08; 95%CI: 0.02-0.19; P = .01; and estimate 0.49; 95%CI: 0.28-0.70; P < .001). Self-efficacy was lower in the intervention group as compared with the control group (estimate -0.78; 95%CI: -1.25 to -0.30; P = .001). No difference was found regarding skin care abilities.

Conclusions: The intervention had a positive influence on 1-year behaviour and knowledge, but was insufficient to result in long-term positive changes in personal resources regarding dealing with hand eczema.
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http://dx.doi.org/10.1111/cod.13003DOI Listing
September 2018

10-Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy.

J Am Heart Assoc 2018 04 23;7(9). Epub 2018 Apr 23.

Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.

Background: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.

Methods And Results: CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; =0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; <0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).

Conclusions: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.
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http://dx.doi.org/10.1161/JAHA.117.008299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015281PMC
April 2018

Prevention of hand eczema: effect of an educational program versus treatment as usual - results of the randomized clinical PREVEX trial.

Scand J Work Environ Health 2018 03;44(2):212-218

Department of Occupational and Environmental Medicine, Bispebjerg Hospital, 2400 Copenhagen NV, Denmark.

Objective Occupational hand eczema has adverse health and socioeconomic impacts for the afflicted individuals and society. Prevention and treatment strategies are needed. This study aimed to assess the effectiveness of an educational intervention on sickness absence, quality of life and severity of hand eczema. Methods PREVEX (PreVention of EXema) is an individually randomized, parallel-group superiority trial investigating the pros and cons of one-time, 2-hour, group-based education in skin-protective behavior versus treatment as usual among patients with newly notified occupational hand eczema, with follow-up after one year. Co-primary outcomes were total sickness absence, health-related quality of life (HR-QoL), and self-reported severity of hand eczema. Results Patients (N=1668) with notified occupational skin diseases from July 2012 to November 2014 were invited to participate in the trial. Of these, 756 were randomized to the intervention (N= 376) versus control (N=380) group. The intervention group had 21% fewer sickness absence days compared with the control group [95% confidence interval (CI) -55-40%, P=0.43]. We found no significant difference in the change of HR-QoL for the intervention compared with the control group (4% lower in the intervention group, 95% CI -18-13%, P=0.67). The ordinal odds of scoring worse on self-reported hand eczema severity was 15% lower in the intervention compared with the control group (95% CI -39-18%, P=0.34). Post-hoc sub-group analyses indicated that the effect of the intervention on severity differed between occupations, being detrimental to healthcare workers and beneficial in all other occupations. Conclusion The educational skincare program had no marked effect on the primary outcomes sickness absence, HR-QoL, and severity of hand eczema when compared with treatment as usual.
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http://dx.doi.org/10.5271/sjweh.3687DOI Listing
March 2018

When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts.

BMC Med Res Methodol 2017 Dec 6;17(1):162. Epub 2017 Dec 6.

The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Missing data may seriously compromise inferences from randomised clinical trials, especially if missing data are not handled appropriately. The potential bias due to missing data depends on the mechanism causing the data to be missing, and the analytical methods applied to amend the missingness. Therefore, the analysis of trial data with missing values requires careful planning and attention.

Methods: The authors had several meetings and discussions considering optimal ways of handling missing data to minimise the bias potential. We also searched PubMed (key words: missing data; randomi*; statistical analysis) and reference lists of known studies for papers (theoretical papers; empirical studies; simulation studies; etc.) on how to deal with missing data when analysing randomised clinical trials.

Results: Handling missing data is an important, yet difficult and complex task when analysing results of randomised clinical trials. We consider how to optimise the handling of missing data during the planning stage of a randomised clinical trial and recommend analytical approaches which may prevent bias caused by unavoidable missing data. We consider the strengths and limitations of using of best-worst and worst-best sensitivity analyses, multiple imputation, and full information maximum likelihood. We also present practical flowcharts on how to deal with missing data and an overview of the steps that always need to be considered during the analysis stage of a trial.

Conclusions: We present a practical guide and flowcharts describing when and how multiple imputation should be used to handle missing data in randomised clinical.
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http://dx.doi.org/10.1186/s12874-017-0442-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717805PMC
December 2017

Statistical analysis plan for the EuroHYP-1 trial: European multicentre, randomised, phase III clinical trial of the therapeutic hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke.

Trials 2017 Nov 29;18(1):573. Epub 2017 Nov 29.

Neurologische Klinik, Universitætsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.

Background: Cooling may reduce infarct size and improve neurological outcomes in patients with ischaemic stroke. In phase II trials, cooling awake patients with ischaemic stroke has been shown to be feasible and safe, but the effects in functional outcomes has not yet been investigated in an adequately sized randomised clinical trial.

Methods/design: The EuroHYP-1 trial is a multinational, randomised, superiority phase III clinical trial with masked outcome assessment testing the benefits and harms of therapeutic cooling in awake adult patients with acute ischaemic stroke. The outcomes dealt with here include the primary outcome the Rankin score (mRS) at day 91 +/-14 days after randomisation. The secondary and exploratory outcomes at day 91 +/-14 days unless otherwise stated encompassing: (1) death or dependency, defined as mRS score > 2; (2) death; (3) National Institutes of Health Stroke Score; (4) brain infarct size at 48 +/-24 hours; (5) EQ-5D-5 L score, and (6) WHODAS 2.0 score. Other outcomes are: the primary safety outcome serious adverse events; and the incremental cost-effectiveness, and cost utility ratios. The analysis sets include (1) the intention-to-treat population, and (2) the per protocol population. The sample size is estimated to 800 patients (5% type 1 and 20% type 2 errors). All analyses are adjusted for the protocol-specified stratification variables (nationality of centre), and the minimisation variables. In the analysis, we use ordinal regression (the primary outcome), logistic regression (binary outcomes), general linear model (continuous outcomes), and the Poisson or negative binomial model (rate outcomes).

Discussion: Major adjustments compared with the original statistical analysis plan encompass: (1) adjustment of analyses by nationality; (2) power calculations for the secondary outcomes; (3) to address the multiplicity problem using of a fixed-sequence testing procedure starting with the primary outcome followed by the secondary outcomes ordered according to falling power; (4) assignment of worst possible score to patients who are not alive at the planned date of measurement of the continuous scores; (5) improved imputations; (6) outline of a supplementary exploratory analysis of the temperature measurements and time to death; and (7) substantial reduction of sample size.

Trial Registration: Clinicaltrials.gov, identifier: NCT01833312 . 4 April 2013.
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http://dx.doi.org/10.1186/s13063-017-2302-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706304PMC
November 2017

Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial.

Lancet Psychiatry 2017 08 7;4(8):605-618. Epub 2017 Jun 7.

Psychiatric Centre Copenhagen, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark & Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

Background: Head-to-head trials to guide antipsychotic treatment choices for paediatric psychosis are urgently needed because extrapolations from adult studies might not be implementable. In this superiority trial with two-sided significance testing, we aimed to compare the efficacy and safety of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other.

Methods: In this multicentre, double-blind, randomised trial in seven Danish university clinics, we recruited children and adolescents aged 12-17 years with a diagnosis of ICD-10 schizophrenia-spectrum disorder, delusional disorder, or affective-spectrum psychotic disorder, and psychotic symptoms scoring at least 4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution), and G9 (unusual thought content), and a total PANSS score greater than 60. Patients were randomly assigned (1:1) to 12 weeks of treatment with target doses of 600 mg/day of quetiapine-ER (starting from 50 mg/day) or 20 mg/day of aripiprazole (starting from 2·5 mg/day). The assigned drug was titrated over five levels, with 2 days at each dose, and the final dose achieved on day 9. Randomisation was done using a computer-generated concealed sequence with a block size of 8, and stratified by baseline PANSS positive score (≤20 points or >20 points) and age (12-14 years or 15-17 years). Study drugs were administered in identical capsules, and interventions, assessments, and data analysis were done masked. The primary outcome was PANSS positive score. Key adverse outcomes were bodyweight, homoeostatic model of insulin resistance (HOMA-IR), akathisia, and sedation. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01119014.

Findings: Between June 10, 2010, and Jan 29, 2014, 231 participants were assessed for elegibility, of whom 113 were randomly assigned to quetiapine-ER (n=55) or aripiprazole (n=58). PANSS positive score did not differ between groups after 12 weeks (adjusted mean change -5·05 [5·46] for quetiapine-ER, -6·21 [5·42] for aripiprazole; p=0·98), but decreased over time in both groups (p<0·0001). Weight gain was more rapid with quetiapine-ER (p=0·0008), with an adjusted mean weight group difference at week 12 of 3·33 kg (SD 7·23; effect size 0·64; p<0·0001). The HOMA-IR group difference at week 12 favoured aripiprazole (adjusted mean log-transformed group difference 0·259 [SD 0·906]; effect size 0·35; p=0·0060). Akathisia was more common with aripiprazole at week 2 (observed in 34 [60%] of 57 patients; estimated 63·5%) than with quetiapine-ER (15 [30%] of 50; estimated 31·3%; p=0·0021), but not at other timepoints. Sedation proportions did not change significantly over time with either intervention (observed at weeks 2, 4, and 12, respectively, for quetiapine-ER in 43 [83%] of 52, 40 [83%] of 48, and 34 [72%] of 47 patients and for aripiprazole in 49 [89%] of 55, 52 [96%] of 54, and 44 [92%] of 48 patients), and the overall estimated probability combining all timepoints was significantly higher for aripiprazole (97·1%) than for quetiapine-ER (89·2%; p=0·012). In addition to sedation and akathisia, the most common adverse events were tremor (42 [79%] patients in the quetiapine-ER group vs 52 [91%] patients in the aripiprazole group), increased duration of sleep (47 [92%] vs 39 [71%]), orthostatic dizziness (42 [78%] vs 46 [81%]), depression (43 [80%] vs 44 [77%]), tension/inner unrest (37 [69%] vs 50 [88%]), failing memory (41 [76%] vs 44 [77%]), and weight gain (46 [87%] vs 38 [68%]).

Interpretation: This first head-to-head comparison of quetiapine-ER versus aripiprazole in early-onset psychosis showed no significant group differences in severity of psychopathology after 12 weeks of treatment. Quetiapine-ER was associated with more metabolic adverse events and aripiprazole with more initial akathisia and, unexpectedly, more sedation. The limited antipsychotic efficacy and high level of adverse events were noticeable. This trial provides novel information for the treatment of early-onset psychosis and highlights the importance of adverse event profiles when choosing among antipsychotics for children and adolescents who often require chronic treatment.

Funding: The National Research Council for Health and Disease Foundation for Health Promotion, AP Møller Foundation, Rosalie Petersens Foundation, Stevn and Rindom Foundation, Foundation for the Promotion of Medical Science, The Capital Region Psychiatric Research Foundation, Tryg Foundation, Region of Southern Denmark Research Foundation, Danish Psychiatric Research Educational Fund, Psychiatry Foundation, Foundation of 17-12-1981, Psychiatric Research Foundation Region Zealand, Capital Region Strategic Research Foundation, Knud og Dagny Andresens Foundation, Psychiatric Research Foundation of 1967, The Capital Region Research Foundation, Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship, Tømrerhandler Johannes Fogs Foundation, Brdr Hartmanns Foundation DKK, Aase and Ejnar Danielsens Foundation, Jacob Madsen and wife Olga Madsens Foundation, CC Klestrup and wife Scholarship, Lundbeck Foundation Scholarship, and Tømrermester Jørgen Holm and wife Elisas Scholarship.
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http://dx.doi.org/10.1016/S2215-0366(17)30166-9DOI Listing
August 2017

Antenatal small-class education versus auditorium-based lectures to promote positive transitioning to parenthood - A randomised trial.

PLoS One 2017 2;12(5):e0176819. Epub 2017 May 2.

The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

Prospective parents widely use education to gain information about, e.g., labour and parenting skills. It is unknown if antenatal education in small classes is more beneficial for parenting stress and parenting alliance compared with other types of antenatal education. In the present randomised trial, we examined the effect of antenatal education in small classes versus auditorium-based lectures on perceived stress, parenting stress, and parenting alliance. A total of 1,766 pregnant women were randomised to receive: antenatal education in small classes three times in pregnancy and one time after delivery, each session lasted 2.5 hours, versus standard care consisting of two times two hours auditorium-based lectures. Previous analysis of the primary outcome showed no difference between intervention and control group. Here we conduct an exploratory analysis of three secondary outcomes. Effects of the interventions on parents' global feelings of stress at 37 weeks gestation and nine weeks and six months postpartum and parenting stress nine weeks and six months postpartum were examined using linear regression analyses and mixed models with repeated measurements. The effect on parenting alliance six months postpartum was examined using the non-parametric Wilcoxon rank-sum test. Antenatal education in small classes had a small beneficial main effect on global feelings of stress six months postpartum and a statistically significant interaction between time and group favoring antenatal education in small classes. The P values of intervention effects on parenting stress and parenting alliance were all larger than the threshold value (0.05).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413036PMC
September 2017

Predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC): statistical analysis plan for data originating from the CLARICOR (clarithromycin for patients with stable coronary heart disease) trial.

Diagn Progn Res 2017 29;1:10. Epub 2017 Mar 29.

1Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Blegdamsvej 9, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: The purpose of the predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC) study is exploratory and hypothesis generating. We want to identify biochemical quantities which-conditionally on the values of available standard demographic, anamnestic, and biochemical data-may improve the prediction of cardiovascular outcomes and/or death in patients suffering from stable ischaemic heart disease. The candidate biochemical quantities include N-terminal pro-B-type natriuretic peptide, YKL-40, osteoprotegerin, high-sensitive assay cardiac troponin T (hs-cTnT), pregnancy-associated plasma protein-A (PAPP-A), cathepsin B, cathepsin S, soluble TNF receptor 1 and 2, neutrophil gelatinase-associated lipocalin, endostatin, and calprotectin. As an extra objective, we also want to assess if skewness in these predictors may explain why the clarithromycin for patients with stable coronary heart disease (CLARICOR) trial found increased all-cause and cardiovascular (CV) mortality on a brief clarithromycin regimen compared with placebo.

Methods: Baseline data were obtained from the hospital files at five cardiology clinics covering the Copenhagen area. The CLARICOR trial included data from 4372 stable coronary artery disease patients recruited among such patients alive and diagnosed with acute myocardial infarction or unstable angina pectoris during 1993 to 1999 in Copenhagen and randomised during October 1999 to April 2000 to the CLARICOR trial of 14 days clarithromycin versus placebo.Initial follow-up lasted for 2.6 years, during which outcomes were collected through hospital and death registries and assessed by an adjudication committee. Corresponding register data later showed to produce similar results. The adjudicated outcomes were therefore replaced and augmented by register data on outcomes to cover 10 years of follow-up. Biochemical marker data were obtained from analysis of serum from the CLARICOR bio-bank collected at randomisation and stored at -80° C.Using Cox proportional hazard method, we will identify among the candidate biochemical quantities those which are significant predictors when used alone and in combination with the standard predictors as defined in the present study.

Discussion: Patients who became stable during the period 1993 to 1999 and died before October 1999 are missing. The data from the placebo patients are nevertheless useful to identify new prognostic biomarkers in patients with stable coronary artery disease, and data from both trial groups are useful to assess important potential skewness between randomised groups. However, due to the potential selection bias, we do not feel that it is advisable to try to rank identified biochemical predictors relative to each other nor to use the results for predictive purposes.

Trial Registration: ClinicalTrials.gov, NCT00121550 Date of registration 13 July 2005Date of enrolment of first participant 12 October 1999.
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http://dx.doi.org/10.1186/s41512-017-0009-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460814PMC
March 2017

Feedback in group psychotherapy for eating disorders: A randomized clinical trial.

J Consult Clin Psychol 2017 05 23;85(5):484-494. Epub 2017 Mar 23.

Mental Health Services, Stolpegaard Psychotherapy Centre, Capital Region of Denmark.

Objective: To investigate the effect of client feedback in group psychotherapy on attendance and treatment outcome for patients with eating disorders.

Method: We conducted a randomized clinical trial with central randomization stratified for diagnosis and treatment type according to a computer-generated allocation sequence concealed to the investigators. One-hundred and 59 adult participants, diagnosed with bulimia nervosa, binge eating disorder, or eating disorder not otherwise specified according to DSM-IV, were included. Eighty participants were allocated to the experimental group, and 79 participants to the control group. Both groups received 20-25 weekly group psychotherapy sessions. In the experimental group, participants gave and received feedback about therapy progress and alliance, measured before and after each session using the Outcome Rating Scale and the Group Session Rating Scale. The primary outcome was rate of attendance to treatment sessions; the secondary outcome was severity of eating disorder symptoms measured with the Eating Disorder Examination interview. Exploratory outcomes were psychological distress measured with the Symptom Checklist-90-R and the Outcome Rating Scale, social functioning measured with the Sheehan Disability Scale, and episodes of self-harm and suicide measured with a modified version of the Self-Harm Inventory.

Results: Feedback compared with control did not affect the rate of attendance (0.59 vs. 0.58; p = .96), the severity of symptoms (2.03 vs. 2.02; p = .46), or any of the exploratory outcomes (p values from 0.06 to 0.67).

Conclusions: Feedback neither increased attendance nor improved outcomes for outpatients in group psychotherapy for eating disorders. The results are discussed from different perspectives. (PsycINFO Database Record
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http://dx.doi.org/10.1037/ccp0000173DOI Listing
May 2017

Early biomarkers of brain injury and cerebral hypo- and hyperoxia in the SafeBoosC II trial.

PLoS One 2017 22;12(3):e0173440. Epub 2017 Mar 22.

Department of Neonatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: The randomized clinical trial, SafeBoosC II, examined the effect of monitoring of cerebral oxygenation by near-infrared spectroscopy combined with a guideline on treatment when cerebral oxygenation was out of the target range. Data on cerebral oxygenation was collected in both the intervention and the control group. The primary outcome was the reduction in the burden of cerebral hypo- and hyperoxia between the two groups. In this study we describe the associations between the burden of cerebral hypo- and hyperoxia, regardless of allocation to intervention or control group, and the biomarkers of brain injury from birth till term equivalent age that was collected as secondary and explorative outcomes in the SafeBoosC II trial.

Methods: Cerebral oxygenation was continuously monitored during the first 72h of life in 166 extremely preterm infants. Cranial ultrasound was performed at day 1,4,7,14, and 35 and at term. Electroencephalogram (EEG) was recorded at 64h. Blood-samples taken at 6 and 64 hours were analysed for the brain injury biomarkers; S100beta, brain-fatty-acid-binding-protein, and neuroketal. All analyses were conducted post hoc.

Results: Significantly more infants with a cerebral burden of hypoxia within the 4th quartile versus infants within quartile 1-3 were diagnosed with severe intracranial haemorrhage (11/39 versus 11/117, p = 0.003), had low burst rate on EEG (12/28 versus 21/103, p = 0.015), or died (14/41 versus 18/123, p = 0.006), whereas none of these events were significantly associated with cerebral hyperoxia. The blood biomarkers were not significantly associated with the burden of cerebral hypo- or hyperoxia.

Conclusions: The explorative analysis showed that early burden of cerebral hypoxia, but not hyperoxia was significantly associated with low brain electrical activity and severe intracranial haemorrhage while none of the three blood biomarkers were associated with the burden of either cerebral hypo- or hyperoxia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173440PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362210PMC
August 2017

SheppHeartCABG trial-comprehensive early rehabilitation after coronary artery bypass grafting: a protocol for a randomised clinical trial.

BMJ Open 2017 01 17;7(1):e013038. Epub 2017 Jan 17.

Department of Cardiothoracic Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Introduction: Patients undergoing coronary artery bypass graft surgery often experience a range of symptoms. Studies indicate that non-pharmacological interventions such as exercise training and psychoeducation have a positive physiological and psychological effect in early outpatient rehabilitation. The SheppHeartCABG trial will investigate the effect of early comprehensive rehabilitation in early phase rehabilitation versus usual care. The aim of this paper is to present the protocol for the SheppHeartCABG trial.

Methods/analysis: SheppHeartCABG is an investigator-initiated randomised clinical superiority trial with blinded outcome assessment, employing 1:1 central randomisation to rehabilitation plus usual care versus usual care alone. On the basis of a sample size calculation, 326 patients undergoing coronary artery bypass grafting will be included from two clinical sites. All patients receive usual care and patients allocated to the experimental intervention follow 4 weeks rehabilitation consisting of an exercise programme, psycho-educative consultations and a compact mindfulness programme. The primary outcome is physical function measured by the 6-min walk test. The secondary outcomes are mental health and physical activity measured by the Medical Outcome Study Short Form (SF-12), anxiety and depression measured by the Hospital Anxiety and Depression Scale questionnaire, physical, emotional and global scores by the HeartQoL questionnaire, sleep measured by the Pittsburgh Sleep Quality Index, pain measured by the Örebro Musculoskeletal Screening Questionnaire and muscle endurance measured by the sit-to-stand test. A number of explorative analyses will also be conducted.

Ethics And Dissemination: SheppHeartCABG is approved by the regional ethics committee (no. H-4-2014-109) and the Danish Data Protection Agency (no. 30-1309) and is performed in accordance with good clinical practice and the Declaration of Helsinki in its latest form. Positive, neutral and negative results of the trial will be submitted to international peer-reviewed journals. Furthermore, results will be presented at national and international conferences relevant to the subject fields.

Trial Registration Number: NCT02290262; pre-results.
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http://dx.doi.org/10.1136/bmjopen-2016-013038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253598PMC
January 2017

Cardiac rehabilitation versus usual care for patients treated with catheter ablation for atrial fibrillation: Results of the randomized CopenHeart trial.

Am Heart J 2016 Nov 31;181:120-129. Epub 2016 Aug 31.

Rigshospitalet, The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

Background: To assess the effects of comprehensive cardiac rehabilitation compared with usual care on physical activity and mental health for patients treated with catheter ablation for atrial fibrillation.

Methods: The patients were randomized 1:1 stratified by paroxysmal or persistent atrial fibrillation and sex to cardiac rehabilitation consisting of 12 weeks physical exercise and four psycho-educational consultations plus usual care (cardiac rehabilitation group) versus usual care. The primary outcome was Vo peak. The secondary outcome was self-rated mental health measured by the Short Form-36 questionnaire. Exploratory outcomes were collected.

Results: 210 patients were included (mean age: 59 years, 74% men), 72% had paroxysmal atrial fibrillation prior to ablation. Compared with usual care, the cardiac rehabilitation group had a beneficial effect on Vo peak at four months (24.3mL kg min versus 20.7mL kg min, p of main effect=0.003, p of interaction between time and intervention=0.020). No significant difference between groups on Short Form-36 was found (53.8 versus 51.9 points, P=.20). Two serious adverse events (atrial fibrillation in relation to physical exercise and death unrelated to rehabilitation) occurred in the cardiac rehabilitation group versus one in the usual care group (death unrelated to intervention) (P=.56). In the cardiac rehabilitation group 16 patients versus 7 in the usual care group reported non-serious adverse events (P=.047).

Conclusion: Comprehensive cardiac rehabilitation had a positive effect on physical capacity compared with usual care, but not on mental health. Cardiac rehabilitation caused more non-serious adverse events.
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http://dx.doi.org/10.1016/j.ahj.2016.08.013DOI Listing
November 2016

Internet-based self-help therapy with FearFighter™ versus no intervention for anxiety disorders in adults: study protocol for a randomised controlled trial.

Trials 2016 10 28;17(1):525. Epub 2016 Oct 28.

Stolpegaard Psychotherapy Centre, Mental Health Services, Capital Region of Denmark, Stolpegaardsvej 20, 2820, Gentofte, Denmark.

Background: Internet-based self-help psychotherapy (IBT) could be an important alternative or supplement to ordinary face-to-face therapy. The findings of randomised controlled trials indicate that the effects of various IBT programmes for anxiety disorders seem better than no intervention and in some instances are equivalent to usual therapy. In Denmark, IBT is part of future treatment plans in mental health care services, but the verification level of the current clinical scientific knowledge is insufficient. The objective of this trial is feasibility assessment of benefits and harms of the Internet-based cognitive behavioural therapy (ICBT) programme FearFighter™ versus no intervention for anxiety disorders in adults.

Methods And Design: We will conduct an investigator-initiated, feasibility randomised controlled trial. Sixty-four participants are expected to be recruited via an advertisement posted on the homepage of the Student Counselling Service in Denmark. The inclusion criterion for participation in the trial will be the presence of anxiety disorder as assessed with the Mini International Neuropsychiatric Interview. The exclusion criteria will be suicidal risk, an ongoing episode of bipolar disorder or psychosis, concurrent psychological treatment for the anxiety disorder, considered unable to attend the intervention as planned (due to vacation, work/study placement, sickness, or similar occurrences), or lack of informed consent. The intervention group will be offered nine sessions with the ICBT programme FearFighter™ and a weekly telephone contact to support compliance. The control group will receive no intervention. We define the feasibility outcomes as follows: the fraction of randomised participants out of the eligible people (the lower 95 % confidence interval (CI) ≥ 50 %); and the fraction of compliant participants (those receiving at least six out of nine sessions) in the intervention group (the lower 95 % CI ≥ 60 %). The exploratory clinical outcomes are the number of participants no longer meeting the diagnostic criteria for an anxiety disorder at the end of the trial and level of distress (Beck Anxiety Inventory, Symptom Checklist-90-R, WHO Well-Being Index, Sheehan Disability Scale); the number of severe adverse events; and the occurrence of any psychological treatment outside the trial. To prevent bias in design, and in the gathering and analysis of data throughout the trial, we will follow the SPIRIT 2013 statement which defines standard protocol items for clinical trials.

Discussion: Based on our findings, we will discuss the feasibility of a future randomised controlled trial examining the benefits and harms of FearFighter™ versus no intervention for anxiety disorders in adults.

Trial Registration: ClinicalTrials.gov Identifier: NCT02499055 , registered on 1 July 2015.
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http://dx.doi.org/10.1186/s13063-016-1619-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084324PMC
October 2016
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