Comparison of the patient-derived modified Japanese Orthopaedic Association scale and the European myelopathy score.

PURPOSE: To compare the patient-derived modified Japanese Orthopaedic Association (P-mJOA) scale with the European myelopathy score (EMS) for the assessment of patients with degenerative cervical myelopathy (DCM). METHODS: In this register-based cohort study with prospectively collected data, included patients were surgically treated for DCM and had reported both P-mJOA and EMS scores at baseline, 1-year follow-up, and/or 2-year follow-up to the Swedish Spine Register. P-mJOA and EMS scores were defined as severe (P-mJOA 0-11 and EMS 5-8), moderate (P-mJOA 12-14 and EMS 9-12), or mild (P-mJOA 15-18 and EMS 13-18). P-mJOA and EMS mean scores were compared, and agreement was evaluated with Spearman's rank correlation coefficient (ρ), the intraclass correlation coefficient (ICC), and kappa (κ) statistics. RESULTS: Included patients (n = 714, mean age 63.2 years, 42.2% female) completed 937 pairs of the P-mJOA and the EMS. The mean P-mJOA and EMS scores were 13.9 ± 3.0 and 14.5 ± 2.7, respectively (mean difference -0.61 [95% CI -0.72 to -0.51; p < 0.001]). Spearman's ρ was 0.84 (p < 0.001), and intra-rater agreement measured with ICC was 0.83 (p < 0.001). Agreement of severity level measured with unweighted and weighted κ was fair (κ = 0.22 [p < 0.001]; κ = 0.34 [p < 0.001], respectively). Severity levels were significantly higher using the P-mJOA (p < 0.001). CONCLUSION: The P-mJOA and the EMS had similar mean scores, and intra-rater agreement was high, whereas severity levels only demonstrated fair agreement. The EMS has a lower sensitivity for detecting severe myelopathy but shows an increasing agreement with the P-mJOA for milder disease severity. A larger interval to define severe myelopathy with the EMS is recommended.

MRI-based measurements of spondylolisthesis and kyphosis in degenerative cervical myelopathy.

BACKGROUND: To provide normative data and to determine accuracy and reliability of preoperative measurements of spondylolisthesis and kyphosis on supine static magnetic resonance imaging (MRI) of patients with degenerative cervical myelopathy. METHODS: T2-weighted midsagittal images of the cervical spine were in 100 cases reviewed twice by one junior observer, with an interval of 3 months, and once by a senior observer. The spondylolisthesis slip (SSlip, mm) and the modified K-line interval (mK-line INT, mm) were assessed for accuracy with the standard error of measurement (SEm) and the minimum detectable change (MDC). Intraobserver and interobserver reliability levels were determined using the intraclass correlation coefficient (ICC). RESULTS: The SEm was 0.5 mm (95% CI 0.4-0.6) for spondylolisthesis and 0.6 mm (95% CI 0.5-0.7) for kyphosis. The MDC, i.e., the smallest difference between two examinations that can be detected with statistical certainty, was 1.5 mm (95% CI 1.2-1.8) for spondylolisthesis and 1.6 mm (95% CI 1.3-1.8) for kyphosis. The highest reliability levels were seen between the second observation of the junior examiner and the senior observer (ICC = 0.80 [95% CI 0.70-0.87] and ICC = 0.96 [95% CI 0.94-0.98] for SSlip and mK-line INT, respectively). CONCLUSIONS: This study provides normative values of alignment measurements of spondylolisthesis and kyphosis in DCM patients. It further shows the importance of taking measurement errors into account when defining cut-off values for cervical deformity parameters and their potential clinical application in surgical decision-making.

Laminectomy alone versus laminectomy with fusion for degenerative cervical myelopathy: a long-term study of a national cohort.

PURPOSE: To compare patient-reported 5-year clinical outcomes between laminectomy alone versus laminectomy with instrumented fusion in patients with degenerative cervical myelopathy in a population-based cohort. METHODS: All patients in the national Swedish Spine Register (Swespine) from January 2006 until March 2019, with degenerative cervical myelopathy, were assessed. Multiple imputation and propensity score matching based on clinicodemographic and radiographic parameters were used to compare patients treated with laminectomy alone with patients treated with laminectomy plus posterior-lateral instrumented fusion. The primary outcome measure was the European Myelopathy Score, a validated patient-reported outcome measure. The scale ranges from 5 to 18, with lower scores reflecting more severe myelopathy. RESULTS: Among 967 eligible patients, 717 (74%) patients were included. Laminectomy alone was performed on 412 patients (mean age 68 years; 149 women [36%]), whereas instrumented fusion was added for 305 patients (mean age 68 years; 119 women [39%]). After imputation, the propensity for smoking, worse myelopathy scores, spondylolisthesis, and kyphosis was slightly higher in the fusion group. After imputation and propensity score matching, there were on average 212 pairs patients with a 5-year follow-up in each group. There were no important differences in patient-reported clinical outcomes between the methods after 5 years. Due to longer hospitalization times and implant-related costs, the mean cost increase per instrumented patient was approximately $4700 US. CONCLUSIONS: Instrumented fusions generated higher costs and were not associated with superior long-term clinical outcomes. These findings are based on a national cohort and can thus be regarded as generalizable.

Improvement rates, adverse events and predictors of clinical outcome following surgery for degenerative cervical myelopathy.

PURPOSE: To investigate improvement rates, adverse events and predictors of clinical outcome after laminectomy alone (LAM) or laminectomy with instrumented fusion (LAM + F) for degenerative cervical myelopathy (DCM). METHODS: This is a post hoc analysis of a previously published DCM cohort. Improvement rates for European myelopathy score (EMS) and Neck Disability Index (NDI) at 2- and 5-year follow-ups and adverse events are presented descriptively for available cases. Predictor endpoints were EMS and NDI scores at follow-ups, surgeon- and patient-reported complications, and reoperation-free interval. For predictors, univariate and multivariable models were fitted to imputed data. RESULTS: Mean age of patients (LAM n = 412; LAM + F n = 305) was 68 years, and 37.4% were women. LAM + F patients had more severe spondylolisthesis and less severe kyphosis at baseline, more surgeon-reported complications, more patient-reported complications, and more reoperations (p ≤ 0.05). After imputation, the overall EMS improvement rate was 43.8% at 2 years and 36.3% at 5 years. At follow-ups, worse EMS scores were independent predictors of worse EMS outcomes and older age and worse NDI scores were independent predictors of worse NDI outcomes. LAM + F was associated with more surgeon-reported complications (ratio 1.81; 95% CI 1.17-2.80; p = 0.008). More operated levels were associated with more patient-reported complications (ratio 1.12; 95% CI 1.02-1.22; p = 0.012) and a shorter reoperation-free interval (hazard ratio 1.30; 95% CI 1.08-1.58; p = 0.046). CONCLUSIONS: These findings suggest that surgical intervention at an earlier myelopathy stage might be beneficial and that less invasive procedures are preferable in this patient population.

Screening of biomarkers for prediction of multisite artery disease in patients with recent myocardial infarction.

A few studies have examined biomarkers in patients with myocardial infarction (MI) and peripheral artery disease (PAD), i.e. multisite artery disease (MSAD). The aim of the study was firstly, to associate biomarkers with the occurrence of PAD/MSAD and secondly, if those can, in addition to clinical characteristics, identify MI patients with MSAD.In two prospectively observational studies including unselected patients with recent MI, PAD was defined as an abnormal ankle-brachial index (ABI) score (<0.9 or >1.4). The proximity extension assay (PEA) technique was used, simultaneously analyzing 92 biomarkers with association to cardiovascular disease. Biomarkers were tested for univariate associations with PAD. Random forest was used to identify biomarkers with a higher association to PAD. The additional discriminatory accuracy of adding biomarkers to clinical characteristics was analyzed by the c-statistics. Nine biomarkers were identified as significantly associated with MSAD/PAD in the primary patient cohort, analyzed early after the MI. In the prediction analysis, six biomarkers were identified associated with PAD. Three of these; Tumor necrosis factor receptor (TNFR-1), Tumor necrosis factor receptor 2 (TNFR-2) and Growth Differentiation Factor 15 (GDF-15) improved c-statistics when added to clinical characteristics from 0.683 (95% CI 0.610-0.756) to 0.715 (95% CI 0.645-0.784) in the primary patient cohort with a similar result, 0.729 (95% CI 0.687-0.770) to 0.752 (95% CI 0.771-0.792) in the secondary patient cohort. Biomarkers associated with inflammatory pathways are associated with MSAD in MI patients. Three biomarkers of 92; TNFR-1, TNFR-2 and GDF-15, in this exploratory added information in the prediction of MSAD and emphasis the importance of further studies.

Temporal trends in bleeding events in acute myocardial infarction: insights from the SWEDEHEART registry.

AIMS: To describe the time trends of in-hospital and out-of-hospital bleeding parallel to the development of new treatments and ischaemic outcomes over the last 20 years in a nationwide myocardial infarction (MI) population. METHODS AND RESULTS: Patients with acute MI (n = 371 431) enrolled in the SWEDEHEART registry from 1995 until May 2018 were selected and evaluated for in-hospital bleeding and out-of-hospital bleeding events at 1 year. In-hospital bleeding increased from 0.5% to a peak at 2% 2005/2006 and thereafter slightly decreased to a new plateau around 1.3% by the end of the study period. Out-of-hospital bleeding increased in a stepwise fashion from 2.5% to 3.5 % in the middle of the study period and to 4.8% at the end of the study period. The increase in both in-hospital and out-of-hospital bleeding was parallel to increasing use of invasive strategy and adjunctive antithrombotic treatment, dual antiplatelet therapy (DAPT), and potent DAPT, while the decrease in in-hospital bleeding from 2007 to 2010 was parallel to implementation of bleeding avoidance strategies. In-hospital re-infarction decreased from 2.8% to 0.6% and out-of-hospital MI decreased from 12.6% to 7.1%. The composite out-of-hospital MI, cardiovascular death, and stroke decreased in a similar fashion from 18.4% to 9.1%. CONCLUSION: During the last 20 years, the introduction of invasive and more intense antithrombotic treatment has been associated with an increase in bleeding events but concomitant there has been a substantial greater reduction of ischaemic events including improved survival.

Haemorrhagic stroke and major bleeding after intervention with biological aortic valve prosthesis: risk factors and antithrombotic treatment.

The majority of patients with severe aortic stenosis are recommended intervention with a surgical biological prosthesis (bioSAVR) or a transcatheter aortic valve intervention (TAVI). The antithrombotic strategies after aortic valve intervention vary and include drugs targeting both platelets and the coagulation cascade. Long-term exposure and changes of antithrombotic treatment influence the risk of both bleeding and thromboembolic events.The aim was to describe an unselected sample of patients who have experienced haemorrhagic stroke and other major bleeding events after biological aortic prosthesis, their antithrombotic treatment and changes of treatments in relation to the bleeding event.All patients performing an bioSAVR or a TAVI 2008-2014 were identified in the SWEDEHEART registry and included in the study (n = 10 711). The outcome events were haemorrhagic stroke and other major bleeding event. Information of drug exposure was collected from the dispensed drug registry.The incidence rate of any bleeding event was 2.85/100 patient-years the first year after aortic valve intervention. Heart failure and atrial fibrillation were present more often in patients with a first haemorrhagic stroke or other major bleeding event compared to without. The proportion of exposure to warfarin was 28.7% vs. 21.3% in patients with and without a haemorrhagic stroke. Comparable figures were 31.2% vs. 19.0% in patients with and without other major bleeding event. During 1 month prior a haemorrhagic stroke or other major bleeding event 39.4% and 38.0%, respectively, of the patients not previously exposed to antithrombotic treatment started warfarin or single antiplatelet therapy.Major bleeding events are not uncommon after aortic valve intervention with a biological prosthesis. Evaluation of comorbidities and previous bleeding might improve risk stratification for bleeding in these elderly patients. The pattern of change of antithrombotic treatment was similar in the groups with and without a bleeding event and in most patients the antithrombotic regime was unchanged the month before an event.

A la mayoría de los pacientes con estenosis de la válvula aórtica grave se les recomienda someterse a una valvuloplastia con prótesis biológica (bioSAVR) o a una valvuloplastia aórtica transcateteral (TAVI). Las estrategias antitrombóticas tras una valvuloplastia aórtica son distintas y, entre ellas, se incluyen fármacos dirigidos tanto a las plaquetas como a la cascada de la coagulación. La exposición prolongada y los cambios en el tratamiento antitrombótico influyen en el riesgo de sufrir complicaciones hemorrágicas y tromboembólicas.El objetivo es describir una muestra de pacientes sin seleccionar que han padecido ictus hemorrágicos u otros episodios hemorrágicos importantes tras una valvuloplastia aórtica con prótesis biológica, así como el tratamiento antitrombótico y los cambios de tratamientos en relación con la hemorragia.Todos los pacientes sometidos a bioSAVR o TAVI en 2008-2014 se encontraban en el registro SWEDEHEART y se incluyeron en el estudio (n = 10 711). Los criterios de valoración fueron ictus hemorrágico y otras hemorragias importantes. La información de la exposición al fármaco se recogió del registro de dispensación de fármacos.En el primer año tras la valvuloplastia aórtica, la tasa de incidencia de cualquier episodio hemorrágico fue de 2,85 por 100 pacientes. La insuficiencia cardíaca y la fibrilación auricular fueron más frecuentes en pacientes con presencia de un primer ictus hemorrágico u otras hemorragias importantes en comparación con el grupo de control. La proporción de exposición a warfarina fue del 28,7% frente al 21,3% en pacientes con presencia y ausencia de un ictus hemorrágico, respectivamente. Cifras comparables fueron el 31,2% frente al 19,0% en pacientes con presencia y ausencia de otros episodios hemorrágicos importantes, respectivamente. Un mes antes de que se produjera el ictus hemorrágico u otras hemorragias importantes, el 39,4% y el 38,0%, respectivamente, de los pacientes que no estaban previamente expuestos a un tratamiento antitrombótico comenzaron un tratamiento con warfarina o antiagregante plaquetario simple.La presencia de episodios hemorrágicos importantes es frecuente tras una valvuloplastia aórtica con prótesis biológica. La evaluación de comorbilidades y hemorragias anteriores puede mejorar la estratificación de riesgos de sufrir hemorragias en pacientes de avanzada edad. El tipo de cambio del tratamiento antitrombótico fue similar en el grupo de control y en el grupo con presencia de un episodio hemorrágico y, en la mayoría de los pacientes, no se modificó la pauta de administración del antitrombótico en el mes previo al episodio hemorrágico.

Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries.

BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD). METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age- and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses. RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-κ-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls. CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts.

A Nationwide, Population Based Analysis of Patients with Organ Confined, Muscle Invasive Bladder Cancer Not Receiving Curative Intent Therapy in Sweden from 1997 to 2014.

PURPOSE: While radical cystectomy remains the standard treatment of muscle invasive bladder cancer, the natural history of patients unable or unwilling to receive therapy with curative intent is not well understood. The study objective was to identify these patients in a population based cohort, investigate the clinical profile and describe time to mortality. MATERIALS AND METHODS: We analyzed the Bladder Cancer Data Base Sweden, a database collected from 1997 to 2014, and identified 9,811 patients with stage T2-T4 disease. Median overall and cancer specific survival was estimated by the Kaplan-Meier method. Relative risks due to prognostic factors were estimated using Cox proportional hazards models. RESULTS: Of the 5,592 patients who did not receive therapy with curative intent 68% were male and 32% were female with a median age of 79 and 81 years, respectively. After 1 year patients had been hospitalized an average of 2.1 times for an average of 18.8 days. Major and minor urological surgeries were the most commonly registered procedures during these hospitalizations. Median overall survival was worse in women than in men (7 vs 8 months). Risk factors for death from bladder cancer were higher tumor stage, age greater than 80 years, later year of diagnosis and female gender. Organ confined disease (T2-T3 M0) was diagnosed in 1,352 patients (24%). These patients had a median of 2.4 hospitalizations per patient during the first 12 months after diagnosis. Half of these hospitalizations were due to cancer or genitourinary symptoms. Median overall survival in the organ confined subgroup was 11 months. Most of these patients had stage N0 disease. They had 2-month longer median overall survival but otherwise similar outcomes. CONCLUSIONS: These patients experience substantial disease specific morbidity. They are hospitalized frequently during the final year of life and primarily die of bladder cancer progression.

How to measure temporal changes in care pathways for chronic diseases using health care registry data.

BACKGROUND: Disease trajectories for chronic diseases can span over several decades, with several time-dependent factors affecting treatment decisions. Thus, there is a need for long-term predictions of disease trajectories to inform patients and healthcare professionals on the long-term outcomes and provide information on the need of future health care. Here, we propose a state transition model to describe and predict disease trajectories up to 25 years after diagnosis in men with prostate cancer (PCa), as a proof of principle. METHODS: States, state transitions, and transition probabilities were identified and estimated in Prostate Cancer data Base of Sweden (PCBaSeTraject), using nationwide population-based data from 118,743 men diagnosed with PCa. A state transition model in discrete time steps (i.e., 4 weeks) was developed and applied to capture all possible transitions (PCBaSeSim). Transition probabilities were estimated for changes in both treatment and comorbidity. These models combined yielded parameter estimates to run an individual-level simulation based on the state-transition model to obtain prediction estimates. Predicted estimates were then compared to real world data in PCBaSeTraject. RESULTS: PCBaSeSim estimates for the cumulative incidence of first and second transitions, death from PCa and death from other causes were compared to observed transitions in PCBaSeTraject. A good agreement was found between simulated and observed estimates. CONCLUSIONS: We developed a reliable and accurate simulation tool, PCBaSeSim that provides information on disease trajectories for subjects with a chronic disease on an individual and population-based level.

Relations between implementation of new treatments and improved outcomes in patients with non-ST-elevation myocardial infarction during the last 20 years: experiences from SWEDEHEART registry 1995 to 2014.

Aims: We assessed the changes in short- and long-term outcomes and their relation to implementation of new evidence-based treatments in all patients with non-ST-elevation myocardial infarction (NSTEMI) in Sweden over 20 years. Methods and results: Cases with NSTEMI (n = 205 693) between 1995 and 2014 were included from the nationwide Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry. During 20 years in-hospital invasive procedures increased from 1.9% to 73.2%, percutaneous coronary intervention or coronary artery bypass grafting 6.5% to 58.1%, dual antiplatelet medication 0% to 72.7%, statins 13.3% to 85.6%, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker 36.8% to 75.5%. The standardized 1-year mortality ratio compared with a control population decreased from 5.53 [95% confidence interval (CI) 5.30-5.75] to 3.03 (95% CI 2.89-3.19). If patients admitted the first 2 years were modelled to receive the same invasive treatments as the last 2 years the expected mortality/myocardial infarction (MI) rate would be reduced from 33.0% to 25.0%. After adjusting for differences in baseline characteristics, the change of 1-year cardiovascular death/MI corresponded to a linearly decreasing odds ratio trend of 0.930 (95% CI 0.926-0.935) per 2-year period. This trend was substantially attenuated [0.970 (95% CI 0.964-0.975)] after adjusting for changes in coronary interventions, and almost eliminated [0.988 (95% CI 0.982-0.994)] after also adjusting for changes in discharge medications. Conclusion: In NSTEMI patients during the last 20 years, there has been a substantial improvement in long-term survival and reduction in the risk of new cardiovascular events. These improvements seem mainly explained by the gradual uptake and widespread use of in-hospital coronary interventions and evidence-based long-term medications.

Improved outcomes in patients with ST-elevation myocardial infarction during the last 20 years are related to implementation of evidence-based treatments: experiences from the SWEDEHEART registry 1995-2014.

AIMS: Impact of changes of treatments on outcomes in ST-elevation myocardial infarction (STEMI) patients in real-life health care has not been documented. METHODS AND RESULTS: All STEMI cases (n = 105.674) registered in the nation-wide SWEDEHEART registry between 1995 and 2014 were included and followed for fatal and non-fatal outcomes for up to 20 years. Most changes in treatment and outcomes occurred from 1994 to 2008. Evidence-based treatments increased: reperfusion from 66.2 to 81.7%; primary percutaneous coronary intervention: 4.5 to 78.0%; dual antiplatelet therapy from 0 to 89.6%; statin: 14.1 to 93.6%; beta-blocker: 78.2 to 91.0%, and angiotensin-converting-enzyme/angiotensin-2-receptor inhibitors: 40.8 to 85.2% (P-value for-trend <0.001 for all). One-year mortality decreased from 22.1 to 14.1%. Standardized incidence ratio compared with the general population decreased from 5.54 to 3.74 (P < 0.001). Cardiovascular (CV) death decreased from 20.1 to 11.1%, myocardial infarction (MI) from 11.5 to 5.8%; stroke from 2.9 to 2.1%; heart failure from 7.1 to 6.2%. After standardization for differences in demography and baseline characteristics, the change of 1-year CV-death or MI corresponded to a linear trend of 0.915 (95% confidence interval: 0.906-0.923) per 2-year period which no longer was significant, 0.997 (0.984-1.009), after adjustment for changes in treatment. The changes in treatment and outcomes were most pronounced from 1994 to 2008. CONCLUSION: Gradual implementation of new and established evidence-based treatments in STEMI patients during the last 20 years has been associated with prolonged survival and lower risk of recurrent ischaemic events, although a plateauing is seen since around 2008.

Early invasive versus non-invasive treatment in patients with non-ST-elevation acute coronary syndrome (FRISC-II): 15 year follow-up of a prospective, randomised, multicentre study.

BACKGROUND: The FRISC-II trial was the first randomised trial to show a reduction in death or myocardial infarction with an early invasive versus a non-invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome. Here we provide a remaining lifetime perspective on the effects on all cardiovascular events during 15 years' follow-up. METHODS: The FRISC-II prospective, randomised, multicentre trial was done at 58 Scandinavian centres in Sweden, Denmark, and Norway. Between June 17, 1996, and Aug 28, 1998, we randomly assigned (1:1) 2457 patients with non-ST-elevation acute coronary syndrome to an early invasive treatment strategy, aiming for revascularisation within 7 days, or a non-invasive strategy, with invasive procedures at recurrent symptoms or severe exercise-induced ischaemia. Plasma for biomarker analyses was obtained at randomisation. For long-term outcomes, we linked data with national health-care registers. The primary endpoint was a composite of death or myocardial infarction. Outcomes were compared as the average postponement of the next event, including recurrent events, calculated as the area between mean cumulative count-of-events curves. Analyses were done by intention to treat. FINDINGS: At a minimum of 15 years' follow-up on Dec 31, 2014, data for survival status and death were available for 2421 (99%) of the initially recruited 2457 patients, and for other events after 2 years for 2182 (89%) patients. During follow-up, the invasive strategy postponed death or next myocardial infarction by a mean of 549 days (95% CI 204-888; p=0·0020) compared with the non-invasive strategy. This effect was larger in non-smokers (mean gain 809 days, 95% CI 402-1175; pinteraction=0·0182), patients with elevated troponin T (778 days, 357-1165; pinteraction=0·0241), and patients with high concentrations of growth differentiation factor-15 (1356 days, 507-1650; pinteraction=0·0210). The difference was mainly driven by postponement of new myocardial infarction, whereas the early difference in mortality alone was not sustained over time. The invasive strategy led to a mean of 1128 days (95% CI 830-1366) postponement of death or next readmission to hospital for ischaemic heart disease, which was consistent in all subgroups (p<0·0001). INTERPRETATION: During 15 years of follow-up, an early invasive treatment strategy postponed the occurrence of death or next myocardial infarction by an average of 18 months, and the next readmission to hospital for ischaemic heart disease by 37 months, compared with a non-invasive strategy in patients with non-ST-elevation acute coronary syndrome. This remaining lifetime perspective supports that an early invasive treatment strategy should be the preferred option in most patients with non-ST-elevation acute coronary syndrome. FUNDING: Swedish Heart-Lung Foundation, Swedish Foundation for Strategic Research, and Uppsala Clinical Research Center.

Disparities in the regional, hospital and individual levels of antibiotic use in gallstone surgery in Sweden.

BACKGROUND: Antimicrobial resistance may be promoted by divergent routines and lack of conformity in antibiotic treatment, especially regarding the practice of antibiotic prophylaxis. The aim of the present study was to assess differences in gallstone surgery regarding antibiotic use in Sweden. METHODS: The study was based on data from the Swedish Register for Gallstone Surgery and ERCP (GallRiks) 2005-2015. Funnel plots were used to test impact of grouping factors, including, hospital and surgeon and to identify units that deviated from the rest of the population. RESULTS: After adjusting for cofounders including age, gender, ASA classification, indication for surgery, operation time, gallbladder perforation and emergency status, there were 0/21 (0%) at the regional level, 18/76 (24%) at the hospital level and 128/1038 (12%) at the surgeon level outside the 99.9% confidence interval (CI). The estimated median odds ratios were 1.13 (95% CI 1.00-1.31) at the regional level, 1.93 (95% CI 1.70-2.19) at the hospital level and 2.38 (95% CI 2.26-2.50) at the surgeon level. CONCLUSION: There are significant differences between hospitals and surgeons, but little or no differences between regions. These deviations confirm the lack of standardization in regards to prescription of antibiotic prophylaxis and the need more uniform routines regarding antibiotic usage. Randomized controlled trials and large population-based studies are necessary to assess assessing the effectiveness and safety of antibiotic prophylaxis in gallstone surgery.

How to model temporal changes in comorbidity for cancer patients using prospective cohort data.

BACKGROUND: The presence of comorbid conditions is strongly related to survival and also affects treatment choices in cancer patients. This comorbidity is often quantified by the Charlson Comorbidity Index (CCI) using specific weights (1, 2, 3, or 6) for different comorbidities. It has been shown that the CCI increases at different times and with different sizes, so that traditional time to event analysis is not adequate to assess these temporal changes. Here, we present a method to model temporal changes in CCI in cancer patients using data from PCBaSe Sweden, a nation-wide population-based prospective cohort of men diagnosed with prostate cancer. Our proposed model is based on the assumption that a change in comorbidity, as quantified by the CCI, is an irreversible one-way process, i.e., CCI accumulates over time and cannot decrease. METHODS: CCI was calculated based on 17 disease categories, which were defined using ICD-codes for discharge diagnoses in the National Patient Register. A state transition model in discrete time steps (i.e., four weeks) was applied to capture all changes in CCI. The transition probabilities were estimated from three modelling steps: 1) Logistic regression model for vital status, 2) Logistic regression model to define any changes in CCI, and 3) Poisson regression model to determine the size of CCI change, with an additional logistic regression model for CCI changes ≥ 6. The four models combined yielded parameter estimates to calculate changes in CCI with their confidence intervals. RESULTS: These methods were applied to men with low-risk prostate cancer who received active surveillance (AS), radical prostatectomy (RP), or curative radiotherapy (RT) as primary treatment. There were large differences in CCI changes according to treatment. CONCLUSIONS: Our method to model temporal changes in CCI efficiently captures changes in comorbidity over time with a small number of regression analyses to perform - which would be impossible with tradition time to event analyses. However, our approach involves a simulation step that is not yet included in standard statistical software packages. In our prostate cancer example we showed that there are large differences in development of comorbidities among men receiving different treatments for prostate cancer.

Association between the use of fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients with non-ST-segment elevation myocardial infarction.

IMPORTANCE: Fondaparinux was associated with reduced major bleeding events and improved survival compared with low-molecular-weight heparin (LMWH) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI). Large-scale experience of the use of fondaparinux vs LMWH in a nontrial setting is lacking. OBJECTIVE: To study the association between the use of fondaparinux vs LMWH and outcomes in patients with NSTEMI in Sweden. DESIGN, SETTING, AND PATIENTS: Prospective multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry involving 40,616 consecutive patients with NSTEMI who received fondaparinux or LMWH between September 1, 2006, through June 30, 2010, with the last follow-up on December 31, 2010. EXPOSURES: In-hospital treatment with fondaparinux or LMWH during the hospital stay. MAIN OUTCOMES AND MEASURES: In-hospital severe bleeding events and death and 30- and 180-day death, MI, stroke, and major bleeding events. Logistic regression models adjusted for calendar time, admitting hospital, baseline characteristics, and in-hospital revascularization. RESULTS: In total, 14,791 patients (36.4%) were treated with fondaparinux and 25,825 (63.6%) with LMWH. One hundred sixty-five patients (1.1%) in the fondaparinux group vs 461 patients (1.8%) in the LMWH group experienced in-hospital bleeding events (adjusted odds ratio [OR], 0.54; 95% CI, 0.42-0.70). A total of 394 patients (2.7%) in the fondaparinux group died while in the hospital vs 1022 (4.0%) in the LMWH group (adjusted OR, 0.75; 95% CI, 0.63-0.89). The differences in major bleeding events and mortality between the 2 treatments were similar at 30 and 180 days. There were no significant differences in the number of recurrent MI and stroke events at 30 or 180 days among the 2 treatment groups. CONCLUSIONS AND RELEVANCE: In routine clinical care of patients with NSTEMI, fondaparinux was associated with lower odds than LMWH of major bleeding events and death both in-hospital and up to 180 days afterward.

C3 and C4 are strongly related to adipose tissue variables and cardiovascular risk factors.

BACKGROUND: In several reports, C3 and C4 have been linked to diabetes and cardiovascular disease (CVD). Here, we investigate this link and the degree of C3 activation in elderly individuals. METHODS: In this study, C3 and C4 and the activation fragment C3a-desArg were analysed in 1016 subjects aged 70, in which blood pressure, lipid variables and fasting blood glucose were assessed. RESULTS: C3 levels were related to all the investigated classical cardiovascular risk factors and the metabolic syndrome (BMI, waist circumference, fat distribution, blood pressure, blood glucose levels, TG) except total cholesterol and LDL cholesterol in a highly significant fashion (Spearman up to 0,5; P < 0·0001). C4 and C3a-desArg were associated in the same fashion but less significantly, while the ratios C4/C3 or C3a-desArg/C3 were not, indicating that the association was not directly related to complement activation. The levels C3 and to a lesser degree C4 and C3a-desArg were associated particularly with CRP, but also with E-selectin and ICAM-1. In addition, C3 and C4 levels were shown to decline significantly in 15 female subjects enrolled in a weight-reduction programme over 4 months. CONCLUSION: A strong relation between C3, C4 and C3a-desArg levels, adipose tissue and risk factors of CVD was established. The data support that the adipose tissue produces complement components and generates initiators of inflammation, such as C3a and C5a, able to trigger a cyto/chemokine response, in proportion to the amount of adipose tissue. This corroborates the concept that complement contributes to the low-grade inflammation associated with obesity.

Level-adjusted funnel plots based on predicted marginal expectations: an application to prophylactic antibiotics in gallstone surgery.

Funnel plots are widely used to visualize grouped data, for example, in institutional comparison. This paper extends the concept to a multi-level setting, displaying one level at a time, adjusted for the other levels, as well as for covariates at all levels. These level-adjusted funnel plots are based on a Markov chain Monte Carlo fit of a random effects model, translating the estimated model parameters to predicted marginal expectations. Working within the estimation framework, we accommodate outlying institutions using heavy-tailed random effects distributions. We also develop computer-efficient methods to compute predicted probabilities in the case of dichotomous outcome data and various random effect distributions. We apply the method to a data set on prophylactic antibiotics in gallstone surgery.

Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation.

IMPORTANCE: Conflicting evidence exists regarding the association between warfarin treatment, death, and ischemic stroke incidence in patients with advanced chronic kidney disease (CKD) and atrial fibrillation. OBJECTIVE: To study outcomes associated with warfarin treatment in relation to kidney function among patients with established cardiovascular disease and atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS: Observational, prospective, multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry (2003-2010), which includes all Swedish hospitals that provide care for acute cardiac diseases. Participants included consecutive survivors of an acute myocardial infarction (MI) with atrial fibrillation and known serum creatinine (N = 24,317), including 21.8% who were prescribed warfarin at discharge. Chronic kidney disease stages were classified according to estimated glomerular filtration rate (eGFR). MAIN OUTCOMES AND MEASURES: (1) Composite end point analysis of death, readmission due to MI, or ischemic stroke; (2) bleeding (composite of readmission due to hemorrhagic stroke, gastrointestinal bleeding, bleeding causing anemia, and others); or (3) the aggregate of these 2 outcomes within 1 year from discharge date. RESULTS: A total of 5292 patients (21.8%) were treated with warfarin at discharge, and 51.7% had manifest CKD (eGFR <60 mL/min/1.73 m2 [eGFR<60]). Compared with no warfarin use, warfarin was associated with a lower risk of the first composite outcome (n = 9002 events) in each CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 28.0 for warfarin vs 36.1 for no warfarin; adjusted hazard ratio (HR), 0.73 (95% CI, 0.65 to 0.81); eGFR>30-60: event rate, 48.5 for warfarin vs 63.8 for no warfarin; HR, 0.73 (95% CI, 0.66 to 0.80); eGFR>15-30: event rate, 84.3 for warfarin vs 110.1 for no warfarin; HR, 0.84 (95% CI, 0.70-1.02); eGFR≤15: event rate, 83.2 for warfarin vs 128.3 for no warfarin; HR, 0.57 (95% CI, 0.37-0.86). The risk of bleeding (n = 1202 events) was not significantly higher in patients treated with warfarin in any CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 5.0 for warfarin vs 4.8 for no warfarin; HR, 1.10 (95% CI, 0.86-1.41); eGFR>30-60 event rate, 6.8 for warfarin vs 6.3 for no warfarin; HR, 1.04 (95% CI, 0.81-1.33); eGFR>15-30 event rate, 9.3 for warfarin vs 10.4 for no warfarin; HR, 0.82 (95% CI, 0.48-1.39); eGFR≤15 event rate, 9.1 for warfarin vs 13.5 for no warfarin; HR, 0.52 (95% CI, 0.16-1.65). Warfarin use in each CKD stratum was associated with lower hazards of the aggregate outcome (n = 9592 events) for event rates per 100 person-years: eGFR>60 event rate, 32.1 for warfarin vs 40.0 for no warfarin; HR, 0.76 (95% CI, 0.69-0.84); eGFR>30-60 event rate, 53.6 for warfarin vs 69.0 for no warfarin; HR, 0.75 (95% CI, 0.68-0.82); eGFR>15-30 event rate, 90.2 for warfarin vs 117.7 for no warfarin; HR, 0.82 (95% CI, 0.68-0.99); eGFR≤15 event rate, 86.2 for warfarin vs 138.2 for no warfarin; HR, 0.55 (95% CI, 0.37-0.83). CONCLUSIONS AND RELEVANCE: Warfarin treatment was associated with a lower 1-year risk for the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding in consecutive acute MI patients with atrial fibrillation. This association was not related to the severity of concurrent CKD.

Cardiovascular medications, high-sensitivity cardiac troponin T concentrations, and long-term outcome in non-ST segment elevation acute coronary syndrome.

AIMS: Cardiac troponin plays an essential role in the management of non-ST segment elevation acute coronary syndrome (NSTE-ACS). However, it is not clear whether troponin concentrations provide guidance regarding the initiation of prognostically beneficial cardiovascular medications [i.e. betablockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and statins] in NSTE-ACS. METHODS AND RESULTS: Registry-based study investigating three NSTE-ACS cohorts (n = 43 075, 40 162, and 46 698) with elevated high-sensitivity cardiac troponin concentrations >14 ng/L. Cox proportional regression models with the addition of interaction terms were used to analyse the interrelations of high-sensitivity cardiac troponin T (hs-cTnT) concentrations, new initiated medications with the respective three drug classes, and long-term risk of all-cause mortality and major adverse events (MAE). Betablockers were associated with risk reductions of 8 and 5% regarding all-cause mortality and MAE, respectively. There was no evidence of an interaction with hs-cTnT concentrations. RAAS inhibitors were associated with 13 and 8% risk reductions, respectively, with a weak interaction between hs-cTnT and MAE (Pinteraction = 0.016). However, no increasing prognostic benefit was noted at hs-cTnT concentrations >100 ng/L. Statins were associated with 38 and 32% risk reductions, respectively, with prognostic benefit across the entire range of hs-cTnT concentrations, and with a weak interaction regarding MAE (Pinteraction = 0.011). CONCLUSION: Cardiovascular medications provide different prognostic benefit in patients with NSTE-ACS with elevated hs-cTnT, and there was some evidence of greater treatment effects regarding MAE along with higher hs-cTnT concentrations. However, hs-cTnT appears only to have limited value overall for customizing such treatments.