Stockholm Healthcare Research Articles

Burden of systemic inflammation and associated health outcomes in adults with atherosclerotic cardiovascular disease managed in routine care

Abstract Background The burden and outcomes of inflammation in people with atherosclerotic cardiovascular disease (ASCVD) are poorly defined, particularly beyond the controlled settings of trials and research cohorts. Methods We conducted a longitudinal observational study of adults with ASCVD undergoing C-reactive-protein (CRP) testing in routine healthcare in Stockholm, Sweden. After excluding CRP tests associated with acute illness and patients with medications/conditions that bias CRP interpretation, the systemic inflammation of participants was defined over a 3-month ascertainment window. Baseline determinants of CRP≥2 mg/L were explored with logistic regression, and baseline CRP categories were compared via Poisson and Cox regression for subsequent healthcare resource utilization and occurrence of major adverse cardiovascular events (MACE), heart failure hospitalization, and all-cause death. Result After applying inclusion/exclusion criteria, we identified 84,399 adults with ASCVD with a mean age of 71 years and of which 54% were men. In total, 60% had CRP≥2 mg/L. At baseline, female sex, older age, lower kidney function, albuminuria, diabetes, hypertension, and recent anemia, were associated with CRP≥2 mg/L. Conversely, the use of RASi, antiplatelets, and lipid-lowering therapy were associated with lower odds. Over a median follow-up of 6.4 years and compared to people with CRP <2 mg/L, those with CRP≥2 mg/L had a higher rate of hospitalizations, days spent in hospital, outpatient consultations, and dispensed medications during follow-up (P<0.05 for all). They also had a higher rate of MACE [adjusted hazard ratio (HR), 1.30; 95% CI, 1.27–1.33], heart failure hospitalization [1.24; 1.20–1.39], and all-cause death [1.35; 1.20–1.30]. Results were consistent across subgroups and more granular CRP categories, and robust to the exclusion of extreme CRP values or early events. Conclusions Two in three adults with ASCVD have systemic inflammation. A CRP≥2 mg/L is associated with excess healthcare resource utilization as well as increased rates of MACE, heart failure, and death.

Systemic inflammation and health outcomes in patients receiving treatment for atherosclerotic cardiovascular disease.

The burden and outcomes of inflammation in patients with atherosclerotic cardiovascular disease (ASCVD) are not well defined beyond the controlled settings of trials and research cohorts. This was an observational study of ASCVD adults undergoing C-reactive protein testing in Stockholm's healthcare (2007-21). After excluding C-reactive protein tests associated with acute illness or medications/conditions that bias C-reactive protein interpretation, systemic inflammation was evaluated over a 3-month ascertainment window. Determinants of C-reactive protein ≥ 2 mg/L were explored with logistic regression. C-reactive protein categories were compared via negative-binomial/Cox regression for subsequent healthcare resource utilization and occurrence of major adverse cardiovascular events, heart failure hospitalization, and death. A total of 84 399 ASCVD adults were included (46% female, mean age 71 years, 59% with C-reactive protein ≥ 2 mg/L). Female sex, older age, lower kidney function, albuminuria, diabetes, hypertension, and recent anaemia were associated with higher odds of C-reactive protein ≥ 2 mg/L. The use of renin-angiotensin system inhibitors, antiplatelets, and lipid-lowering therapy was associated with lower odds. Over a median of 6.4 years, compared with C-reactive protein < 2 mg/L, patients with C-reactive protein ≥ 2 mg/L had higher rates of hospitalizations, days spent in hospital, outpatient consultations, and dispensed medications (P < .05 for all). They also had a higher rate of major adverse cardiovascular events [hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.27-1.33], heart failure (HR 1.24; 95% CI 1.20-1.30), and death (HR 1.35; 95% CI 1.31-1.39). Results were consistent across subgroups and granular C-reactive protein categories and robust to the exclusion of extreme C-reactive protein values or early events. Three in five adults with ASCVD have systemic inflammation, which is associated with excess healthcare resource utilization and increased rates of cardiovascular events and death.

Absolute and Relative Risks of Kidney and Urological Complications in Patients With Inflammatory Bowel Disease.

The burden of kidney and urological complications in patients with inflammatory bowel disease (IBD) remains poorly characterized. We analyzed association between developing IBD (as a time-varying exposure) and relative risks of receiving diagnoses of chronic kidney disease (CKD), acute kidney injury (AKI), or kidney stones, and experiencing a clinically-relevant decline in estimated glomerular filtration rate (eGFR) (CKD progression; composite of kidney failure or an eGFR decline ≥30%) in 1,682,795 individuals seeking healthcare in Stockholm, Sweden, during 2006-2018. We quantified 5- and 10-year absolute risks of these complications in a parallel matched cohort of IBD cases and random controls matched (1:5) on sex, age, and eGFR. During median 9 years, 10,117 participants developed IBD. Incident IBD was associated with higher risks of kidney-related complications compared with non-IBD periods: hazard ratio (HR) (95% confidence interval) was 1.24 (1.10-1.40) for receiving a CKD diagnosis and 1.11 (1.00-1.24) for CKD progression. For absolute risks, 11.8% IBD cases had a CKD event within 10-year. Of these, 6.4% received a CKD diagnosis, and 7.9% reached CKD progression. The risks of AKI (HR 1.97 [1.70-2.29]; 10-year absolute risk 3.6%) and kidney stones (HR 1.69 [1.48-1.93]; 10-year absolute risk 5.6%) were also elevated. Risks were similar in Crohn's disease and ulcerative colitis. More than 10% of patients with IBD developed CKD within 10-year from diagnosis, with many not being identified through diagnostic codes. This, together with their elevated AKI and kidney stone risks, highlights the need of established protocols for kidney function monitoring and referral to nephrological/urological care for patients with IBD.

Implementing WGS-based rare inherited disease diagnostics in the Stockholm healthcare region

In healthcare clinical genetics is transitioning to clinical genomics and especially rare disease diagnostics is increasingly done through panel, exome and whole-genome sequencing. At Karolinska we have formed Genomic Medicine Center Karolinska Rare Diseases (GMCK-RD), a joint unit between healthcare and academia, enabling large-scale genome sequencing of patients. GMCK-RD brings together experts from various medical disciplines with clinical geneticists, bioinformaticians and researchers. Through GMCK-RD, over 10,000 individuals have been analysed by clinical genome sequencing (GS) with an overall yield of 33%, providing a genetic diagnosis to >2,543 individuals. By tight collaboration in 15 multidisciplinary expert teams thousands of patients with various rare diseases have been diagnosed. Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualisation of results for clinical interpretation is carried out in Scout- a custom-developed decision support system. To facilitate the discovery of new disease genes, GMCK-RD is reporting variants to ClinVar and has joined international data sharing initiatives, including UDNI, Beacon, and MatchMaker Exchange. Altogether, we at GMCK-RD have moved healthcare in our region towards precision diagnostics and precision medicine.

Impact of non-adherence to direct oral anticoagulants amongst Swedish patients with non-valvular atrial fibrillation: results from a real-world cost-utility analysis

Aims A third of non-valvular atrial fibrillation (NVAF) patients are non-adherent to direct oral anticoagulants (DOACs). Estimates of the economic value of full adherence and the cost of two types of adherence improving interventions are important to healthcare planners and decision-makers. Methods A cost-utility analysis estimated the impact of non-adherence over a 20-year horizon, for a patient cohort with a mean age of 77 years, based on data from the Stockholm Healthcare database of NVAF patients with incident stroke between 2011 and 2018. Adherence was defined using a medication possession ratio (MPR) cut-off of 90%; primary outcomes were the number of ischemic strokes and associated incremental cost–utility ratio. Results Hypothetical comparisons between cohorts of 1,000 patients with varying non-adherence levels and full adherence (MPR >90%) predicted an additional number of strokes ranging from 117 (MPR = 81–90%) to 866 (MPR <60%), and years of life lost ranging from 177 (MPR = 81– 90%) to 1,318 (MPR < 60%; discounted at 3%). Chronic disease co-management intervention occurring during each DOAC prescription renewal and patient education intervention at DOAC initiation will be cost-saving to the health system if its cost is below SEK 143 and SEK 4,655, and cost-effective if below SEK 858 and SEK 28,665, respectively. Conclusion Adherence improving interventions for NVAF patients on DOACs such as chronic disease co-management and patient education can be cost-saving and cost-effective, within a range of costs that appear reasonable to the Swedish healthcare system.

MO508: Estimated Glomerular Filtration Rate and the Risk of Inflammatory Bowel Disease in Adults: A Swedish Population-Based Study

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) and inflammatory bowel disease (IBD) share many risk factors. While kidney complications are seen in 4%–23% of patients with longstanding IBD, it is unknown whether low kidney function may predispose to developing IBD. METHOD We analyzed the association between estimated glomerular filtration rate (eGFR) and the risk of being diagnosed with IBD among 1 612 160 adults without prior IBD history who accessed healthcare in Stockholm during 2006–18. We categorized eGFR into five groups: &amp;lt;30, 30–59, 60–89, 90–104, 105 + mL/min/1.73m2 with 90–104 being the reference group. Flexible parametric survival models with stepwise adjustments and piecewise linear splines were used to investigate the association between eGFR, IBD and IBD-subtypes (Crohn's disease, ulcerative colitis and IBD unclassified). IBD cases were identified by two or more records with an IBD diagnosis. Subgroup analyses explored the consistency of the associations between age strata, sex, background education and the presence of selected comorbidities. To explore the possibility of detection bias and reverse causation, we estimated IBD risks from the first year after baseline eGFR. RESULTS We detected 9663 new cases of IBD (Crohn's disease: n = 3299 and ulcerative colitis: n = 5072), over a median follow-up of 9 years. Linear splines suggested the association between eGFR and IBD to be J-shaped, with higher IBD risk at both eGFR extremes. After multivariable adjustment and compared with eGFR 90–104 mL/min/1.73 m2 lower eGFR strata were associated with higher IBD risk {adjusted hazard ratio (HR), 1.14; [95% confidence interval (95% CI) 0.99–1.32] for eGFR = 30–59 mL/min and 1.63; 1.14–2.33 for eGFR &amp;lt;30 mL/min}. This association was stronger in magnitude for Crohn's disease, with an HR of 1.32 (1.03–1.71) for eGFR = 30–59 mL/min and 2.22 (1.24–3.97) for eGFR &amp;lt;30 mL/min. Subgroup analyses showed consistency across age, education categories, presence of diabetes and of CVD, but suggested that the association between low eGFR and IBD was stronger in women and in the absence of hypertension (P for interaction &amp;lt;.05). Associations were slightly attenuated after excluding IBD cases during the first year of follow-up, indicating the presence of detection bias and/or reverse causation. CONCLUSION We observed an association between decreased eGFR and the risk of developing IBD, which was stronger in magnitude for Crohn's disease, but that could be partly explained by bias.

Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients

BackgroundWe report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting.MethodsOur analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout—a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams.ResultsOverall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange.ConclusionsClinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.

COVID-19 healthcare demand and mortality in Sweden in response to non-pharmaceutical mitigation and suppression scenarios

BackgroundWhile the COVID-19 outbreak in China now appears suppressed, Europe and the USA have become the epicentres, both reporting many more deaths than China. Responding to the pandemic, Sweden has taken a different approach aiming to mitigate, not suppress, community transmission, by using physical distancing without lockdowns. Here we contrast the consequences of different responses to COVID-19 within Sweden, the resulting demand for care, intensive care, the death tolls and the associated direct healthcare related costs.MethodsWe used an age-stratified health-care demand extended SEIR (susceptible, exposed, infectious, recovered) compartmental model for all municipalities in Sweden, and a radiation model for describing inter-municipality mobility. The model was calibrated against data from municipalities in the Stockholm healthcare region.ResultsOur scenario with moderate to strong physical distancing describes well the observed health demand and deaths in Sweden up to the end of May 2020. In this scenario, the intensive care unit (ICU) demand reaches the pre-pandemic maximum capacity just above 500 beds. In the counterfactual scenario, the ICU demand is estimated to reach ∼20 times higher than the pre-pandemic ICU capacity. The different scenarios show quite different death tolls up to 1 September, ranging from 5000 to 41 000, excluding deaths potentially caused by ICU shortage. Additionally, our statistical analysis of all causes excess mortality indicates that the number of deaths attributable to COVID-19 could be increased by 40% (95% confidence interval: 0.24, 0.57).ConclusionThe results of this study highlight the impact of different combinations of non-pharmaceutical interventions, especially moderate physical distancing in combination with more effective isolation of infectious individuals, on reducing deaths, health demands and lowering healthcare costs. In less effective mitigation scenarios, the demand on ICU beds would rapidly exceed capacity, showing the tight interconnection between the healthcare demand and physical distancing in the society. These findings have relevance for Swedish policy and response to the COVID-19 pandemic and illustrate the importance of maintaining the level of physical distancing for a longer period beyond the study period to suppress or mitigate the impacts from the pandemic.

Kidney function and the risk of heart failure in patients with new-onset atrial fibrillation

AimsHeart failure (HF) is the most common complication of patients with atrial fibrillation (AF), but possible risk factors or health consequences are not well described. Low kidney function is a risk factor for both AF and HF. We evaluated estimated glomerular filtration rate (eGFR) as a predictor of HF in patients with AF, and then quantified the adverse health outcomes associated to incident HF. Methods and resultsThis is an observational analysis of 19,662 adults without a previous history of HF who had new-onset AF in Stockholm healthcare (Sweden) during 2007–2011.During a median of 713 (IQR 281–1253) days of follow up, 3342 (16.4%) patients developed HF, with incidence rate of 7.4 per 100-person-years (95% CI 7.2–7.7). In Cox regression, eGFR was linearly associated with subsequent HF risk. Compared to eGFR≥60 ml/min/1.73 m2, patients with eGFR 30–59 and eGFR<30 ml/min/1.73 m2 had 13% (HR 1.13; 95% CI 1.04–1.23) and 53% (HR 1.53; 1.25–1.88) higher risk of HF. Results were consistent across various pre-specified subgroups and after excluding early events. Compared to non-HF, developing HF (as a time-varying exposure) was associated with a 5-fold (HR 5.05; 4.07–6.28) higher risk of subsequent kidney function decline, a 1.5 times higher risk of stroke (HR 1.54; 1.35–1.76), and a doubling in the risk of myocardial infarction (HR 2.21; 1.87–2.62) and death (HR 2.17; 2.01–2.33). ConclusionIn patients with AF, low kidney function associates with the risk of HF. Developing HF heightened the subsequent risk of kidney function decline, cardiovascular event and death.

Navigating the policy stream: Contested solutions and organizational strategies of policy entrepreneurship

In the Multiple Streams Framework (MSF), policy entrepreneurs are primarily defined by their ability to promote and seek support for policy solutions. Recent research, however, points to the importance of policy entrepreneurs as “arena shapers” who attempt to create favorable conditions for their solutions in conflictual policy settings. In this paper, we seek to incorporate such strategies into the MSF by drawing on the organizational foundations of the original garbage can model. The main question is what role do policy entrepreneurs play in “organizing out” opposition from pre-decision processes, as a way of advancing contested policy solutions. We answer this question in a case study of a controversial hospital “mega-project” in Stockholm healthcare that shows how a small but influential team of entrepreneurs used the project as an opportunity for policy change. The study helps to identify three different organizational strategies: 1) regulating participation in order to neutralize opponents: 2) specializing attention to limit the “searchlight” and 3) sequential attention in order to reduce complexity and build commitment. While effective for advancing solutions in the face of conflict and entrenched positions, organizational strategies also have important democratic implications for the legitimacy of pre-decision processes and the prospects for broad deliberation.

Long-term persistence and adherence with non-vitamin K oral anticoagulants in patients with atrial fibrillation and their associations with stroke risk.

Aims Studies on adherence and persistence with non-vitamin K oral anticoagulant (NOAC) treatment have relied on data from the early years of NOAC availability. We aimed to study long-term adherence and persistence with NOACs and their association with stroke risk.Methods and results From the Stockholm Healthcare database, we included 21 028 atrial fibrillation patients claiming a first NOAC prescription from July 2011 until October 2018, with more than 1000 patients having more than 5 years of follow-up (median: 2.0, interquartile range: 1.0–3.2). Persistence rates, defined as continuing to claim NOAC prescriptions within a 90-day gap, decreased to 70% at the end of follow-up. However, 85% of the patients were treated at the end of the study due to reinitiations. Adherence, calculated as medication possession rate (MPR) in 3 and 6-month intervals among persistent users, remained stable at 90%, with 75% of patients having an MPR >95% throughout the study period. Using a case–control design, we calculated associations of persistence and adherence with stroke risk, adjusting for potential confounders. The outcome was a composite of ischaemic or unspecified stroke and transient ischaemic attack. Non-persistence and poor adherence were both associated with increased stroke risk [non-persistence adjusted odds ratio (aOR): 2.05; 95% confidence interval (CI): 1.49–2.82, 1% reduction MPR aOR: 1.03; CI: 1.01–1.05]. There was no association between non-persistence or poor adherence and the falsification endpoints; fractions and respiratory infections, indicating no ‘healthy-adherer’ effect.Conclusion Persistence rates decreased slowly over time, but persistent patients had high adherence rates. Both non-persistence and poor adherence were associated with an increased stroke risk.

Abstract MP34: Acceleration of Kidney Function Decline After Incident Hospitalization With Cardiovascular Disease: The Stockholm Creatinine Measurements (scream) Project

Background: The cardiorenal syndrome suggests a bidirectional relationship between worsening kidney function and cardiac dysfunction. However, to our knowledge, no studies have quantified changes in slopes of kidney function decline before and after the incidence of major cardiovascular disease (CVD) subtypes. Methods: We compared the individual slopes of estimated glomerular filtration rate (eGFR) decline in the 2 years before vs. after the incident hospitalization with heart failure (HF) (n=20,420), coronary heart disease (CHD) (n=18,152), and stroke (n=1,808) using data from the complete laboratory data collection of Stockholm healthcare (Sweden) between 2006 and 2011. Using mixed effect models with unstructured residual correlation matrix, we examined changes in individual slopes of eGFR decline before and after incident CVD in the overall population, and by index eGFR strata (≥60, 30-59, &lt;30 ml/min/1.73m 2 ). Results: Incident hospitalization with HF and CHD, but not stroke, was significantly associated with a subsequent acceleration of eGFR decline, with a faster eGFR decline and greater slope change after HF than CHD. The pre-event vs. post-event eGFR slope (ml/min/1.73m 2 per year) were -1.67 (-1.77 to -1.57) vs. -2.76 (-2.82 to -2.71), with Δslope of -1.09 (-1.16 to -1.02) for HF; -1.09 (-1.20 to -0.98) vs. -1.87 (-1.92 to -1.81), with Δslope of -0.78 (-0.85 to -0.70) for CHD; and -1.00 (-1.37 to -0.63) vs. -0.99 (-1.19 to -0.78), with , Δslope of 0.02 (-0.24 to 0.27) for stroke ( Figure ). The accelerated eGFR declines after HF and CHD were consistently observed across eGFR strata, with pre-event eGFR slopes steeper in lower eGFR (e.g., pre-event eGFR slope for HF -0.64 (-0.76 to -0.53) for eGFR ≥60, -1.43 (-1.57 to -1.30) for eGFR 30-59, and -2.42 (-2.71 to -2.12) for eGFR &lt;30 ml/min/1.73m 2 ). Conclusions: Incident hospitalization with cardiac diseases (ie, HF and CHD) was significantly associated with a subsequent acceleration of eGFR decline.

Abstract P3-08-07: Expression of the novel tumor suppressor gene SAMHD1 correlates with favourable clinical outcome in basal-like (BL) early breast cancer

Abstract Introduction: The SAM domain and HD domain 1 (SAMHD1) protein is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase initially described to restrict human immunodeficiency virus type 1 (HIV-1) in the immune cells through depletion of intracellular dNTP substrates required for HIV-1 replication. Because of its ability to deplete the dNTP pool, SAMHD1 may operate as a tumor suppressor in cancer. Mutations of SAMHD1 gene have been associated with Aicardi-Goutières syndrome and have been detected in certain hematologic malignancies. However, the potential role of SAMHD1 in breast oncogenesis as well as its expression patterns and clinical significance are not yet known. Methods: SAMHD1 expression was investigated at the mRNA and protein levels in a large cohort consisting of 562 patients diagnosed with primary breast cancer between 1997-2005 in Stockholm health care region. Gene expression profiling was performed using DNA microarrays (GSE48091). SAMHD1 protein expression was assessed by a previously validated double immunostaining method (SAMHD1/CD68) using tissue microarrays (TMA) that included duplicate cores from each tumor and specific antibody (SAMHD1, Bethyl laboratories; #A303-691A). CD68+ macrophages known to be strongly positive for SAMHD1 served as positive controls in each tumor core. Any nuclear staining for SAMHD1 was considered positive with either weak (1), intermediate (2), or strong (3) staining intensity. At least 500 neoplastic cells were counted in order to determine the percentage of SAMHD1+ tumor cells. The latter was combined with the staining intensity into the quickscore method, and a positive cutoff of greater or equal to 3 was used to dichotomize SAMHD1 protein expression. Survival analyses were performed using the Kaplan-Meier method (SAMHD1 mRNA level cutoff: median) and Cox proportional hazards models (univariate and multivariable analysis; SAMHD1 mRNA level was evaluated as continuous variable). Distant metastasis-free survival (DMFS) was used as the clinical endpoint. Results: Evaluable immunohistochemical (IHC) data for SAMHD1 were available for 439 of 562 (78%) patients. In the entire study group, SAMHD1 mRNA and protein levels were significantly correlated (Mann-Whitney p=5.2e-5). SAMHD1 mRNA level was higher in HER2-enriched (PAM50) tumors compared to the other subtypes (Kruskal-Wallis p=2.5e-12). By IHC, SAMHD1 was positive in 33/192 (17%) Luminal A, 17/85 (20%) Luminal B, 10/49 (20%) HER2-enriched, and 26/99 (26%) basal-like (BL). In the entire cohort, SAMHD1 expression was not associated with DMFS. However, in the group of BL subtype (n=122), high SAMHD1 mRNA level (logrank p=0.026) or SAMHD1 protein expression (logrank p=0.025) were associated with favourable DMFS. Using the Cox proportional hazards model, high SAMHD1 mRNA level (HR=0.68; 95% CI=0.48-0.96; p=0.029) and high SAMHD1 protein expression (HR=0.22; 95% CI=0.05-0.95; p=0.042; reference: SAMHD1 negative) were associated with improved survival in patients with BL subtype of breast cancer. In the multivariable analysis, SAMHD1 mRNA level was independently associated with survival (HR=0.66; 95% CI=0.47-0.94; p=0.021), after adjustment for lymph node status and tumor size, along with lymph node status (HR: 3.29; 95% CI=1.58-6.83; p=0.001; reference: lymph node negative) in the BL subgroup. At the meeting we will also present data on prognosis in relation to given adjuvant therapies.Conclusions: SAMHD1 gene is differentially expressed at the mRNA and protein levels among the breast cancer subtypes. SAMHD1 expression is significantly and independently associated with favourable clinical outcomes in breast cancer of BL subtype. Citation Format: Maria Kouvaraki, Emmanuil G Sifakis, Ioannis Zerdes, Nikolas Herold, Jonas Bergh, George Z. Rassidakis, Theodoros Foukakis. Expression of the novel tumor suppressor gene SAMHD1 correlates with favourable clinical outcome in basal-like (BL) early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-07.

Geographical variations in the incidence of oesophageal cancer in Sweden

Background: Geographical variations in the incidence and tumour stage distribution of oesophageal cancer in Sweden are not well characterised.Methods: Using data from the Swedish Cancer Registry over 45 years (1972–2016), we compared the age-standardised incidence rates of oesophageal cancer by histological type across all seven national areas (in five-year periods) and 21 counties (in 15-year periods) in Sweden, and assessed the geographical distribution of tumour stage at diagnosis since 2004.Results: The incidence rate of oesophageal adenocarcinoma increased in all national areas and counties and in both sexes over time, while the rate of oesophageal squamous cell carcinoma decreased from the 1980s onwards. In the latest period (2012– 2016), the incidence rate of adenocarcinoma in men ranged from 3.5/100,000 person-years in West Sweden to 6.2/100,000 person-years in North Middle Sweden. At the county level, the rate of adenocarcinoma in men was lowest in Jämtland (2.7/100,000 person-years) and highest in Gotland (6.2/100 000 person-years) in 2002–2016. The incidence rates of both adenocarcinoma and squamous cell carcinoma in women were below 2/100,000 person-years in all national areas and counties in the latest calendar periods, i.e., 2012–2016 and 2002–2016, respectively. The proportion of patents with tumour stage IV ranged from 22% in Stockholm area to 31% in Middle Norrland, while at the healthcare region level it was lowest in Stockholm healthcare region (23%) and highest in North (30%) and Uppsala-Örebro (29%) healthcare regions.Conclusion: There are considerable geographical variations in the incidence and tumour stage distribution of oesophageal cancer in Sweden.

Implementation researchers can improve the responses of services to the COVID-19 pandemic.

This article describes a rapid implementation research project with the Stockholm health care system to assist the system to respond to the COVID-19 pandemic. It uses this example to illustrate some ways in which implementation research and knowledge can contribute to improving service responses to the pandemic and its consequences as these evolve over the coming months. A sub-specialty of rapid implementation science is proposed to provide practical assistance and as one way to develop implementation research.Plain language abstractThis article describes a rapid implementation research project with the Stockholm health care system to assist the system to respond to the COVID-19 pandemic. It uses this example to illustrate some ways in which implementation research and knowledge can contribute to improving service responses to the pandemic and its consequences as these evolve over the coming months. A sub-specialty of rapid implementation science is proposed to provide practical assistance and as one way to develop implementation research.

Association of preceding antithrombotic therapy in atrial fibrillation patients with ischaemic stroke, intracranial haemorrhage, or gastrointestinal bleed and mortality.

AimsTo analyse 90-day mortality in atrial fibrillation (AF) patients after a stroke or a severe bleed and assess associations with the type of antithrombotic treatment at the event.Methods and resultsFrom the Stockholm Healthcare database, we selected 6017 patients with a known history of AF who were diagnosed with ischaemic stroke, 3006 with intracranial haemorrhage, and 4291 with a severe gastrointestinal bleed (GIB). The 90-day mortality rates were 25.1% after ischaemic stroke, 31.6% after intracranial haemorrhage, and 16.2% after severe GIB. We used Cox regression and propensity score-matched analyses to test the association between antithrombotic treatment at the event and 90-day mortality. After intracranial haemorrhage, there was a significantly higher mortality rate in warfarin compared to non-vitamin K oral anticoagulant (NOAC)-treated patients [adjusted hazard ratio (aHR) 1.36, 95% confidence interval (CI) 1.04–1.78]. After an ischaemic stroke and a severe GIB, patients receiving antiplatelets or no antithrombotic treatment had significantly higher mortality rates compared to patients on NOACs, but there was no difference comparing warfarin to NOACs (aHR 0.84, CI 0.63–1.12 after ischaemic stroke, aHR 0.91, CI 0.66–1.25 after severe GIB). Propensity score-matched analysis yielded similar results.ConclusionMortality rates were high in AF patients suffering from an ischaemic stroke, an intracranial haemorrhage, or a severe GIB. NOAC treatment was associated with a lower 90-day mortality after intracranial haemorrhage than warfarin.

P4745Concomitant oral anticoagulant and antidepressant therapy in patients with atrial fibrillation and risk of stroke and bleeding: a population based cohort study

Abstract Background Anticoagulation treatment reduces the risk of stroke but increases the risk of bleeding in atrial fibrillation (AF) patients. Antidepressants use is associated with increased risk for stroke and bleeds. Objective To assess the association between antidepressant use in AF patients with oral anticoagulants and bleeding and stroke risk. Methods All AF patients newly prescribed with an oral anticoagulant in the Stockholm Healthcare database (n=2.3 million inhabitants) from July 2011 until 2016 were included and followed for one year or shorter if they stopped claiming oral anticoagulant treatment or had an outcome of interest. Outcomes were severe bleeds and strokes, requiring acute hospital care. During follow-up, patients were considered exposed to antidepressant after claiming a prescription for the duration of the prescription. With a time-varying Cox regression, we assessed the association between antidepressant use and strokes and bleeds, adjusting for confounders (i.e., age, sex, comorbidities, comedication, and year of inclusion). In addition, we performed a propensity score matched analysis to test the robustness of our findings. Results Of the 30,595 patients included after claiming a prescription for a NOAC (n=13,506) or warfarin (n=17,089), 4 303 claimed a prescription for an antidepressant during follow-up. A total of 712 severe bleeds and 551 strokes were recorded in the cohort. Concomitant oral anticoagulant and antidepressant use was associated with increased rates of severe bleeds (4.7 vs 2.7 per 100 person-years) compared to oral anticoagulant treatment without antidepressant use (aHR 1.42, 95% CI: 1.12–1.80), but not significantly associated with increased stroke rates (3.5 vs 2.1 per 100 person-years, aHR 1.23, 95% CI: 0.93–1.62). No significant differences were observed between different oral anticoagulant classes (i.e., warfarin or NOAC) or different antidepressant classes (i.e., SSRI, TCA, or other antidepressant). Additional propensity-score matched analyses yielded similar results but showed a significantly increased risk for stroke (HR: 1.47, 95% CI: 1.08–2.02). Incidence rates of strokes and bleeds Conclusion Concomitant use of an oral anticoagulant and an antidepressant, irrespective of type, is associated with an increased bleeding risk. Increased awareness and a critical consideration for the need of an antidepressant is recommended in this population. Acknowledgement/Funding Swedish Heart Lung Foundation

3053High mortality in atrial fibrillation patients suffering ischemic stroke, intracranial hemorrhage or a gastrointestinal bleed and associations with the preceding antithrombotic treatment

Abstract Background Anticoagulation treatment reduces the risk of stroke but increases the risk of bleeding in atrial fibrillation (AF) patients. There is little data on survival after a stroke or a severe bleed. Objective To analyze 90-day mortality in AF patients after an ischemic stroke, an intracranial hemorrhage (ICH) or a gastrointestinal bleed (GIB) and assess associations with the type of antithrombotic treatment preceding the event. Methods From the Stockholm Healthcare database (n=2.3 million inhabitants) we selected all AF patients suffering from an ischemic stroke, an intracranial bleed, or a severe GIB requiring acute hospital care between July 2011 and August 2018 and assessed 90-day mortality rates. We assessed current use of warfarin, non-vitamin K oral anticoagulants (NOAC), or antiplatelet agents at the time of the event. We used a Cox regression to calculate adjusted hazard ratios (aHRs), adjusting for components of the Charlson Comorbidity Index, the CHADsVASc score, the HAS-BLED score, comedication, and year of inclusion, for the association between treatment preceding the event and mortality. In addition, we performed log-rank tests in propensity score matched cohorts. Results Of 105 313 patients with AF, 6 017 were included after an ischemic stroke, 3 006 after an ICH, and 4 291 after a GIB. 90-day mortality rates were 25.1%, 31.6% and 16.2%, respectively. Patients suffering from an ischemic stroke were the oldest at 81.6±9.8 (S.D:) years of age followed by patients suffering from an ICH (80.2±9.8 years) or a GIB (78.7±10.5 years). A large proportion of patients suffering ischemic stroke (72%) had no anticoagulant treatment preceding the event. After ICH, there was a significantly increased risk of mortality in warfarin compared to NOAC treated patients after adjusting for confounders (aHR: 1.36 CI: 1.04–1.78). Patients receiving antiplatelets or no treatment had significantly higher mortality rates than patients on NOAC treatment, both after an ischemic stroke and a GIB, but there was no significant difference between warfarin and NOACs (aHR 0.84 CI: 0.63–1.12 after ischemic stroke, aHR 0.91 CI: 0.66–1.25 after GIB). Propensity score matched analyses yielded similar results. Survival curves after event Conclusion Mortality rates are high in AF patients suffering from an ischemic stroke, an ICH, or a GIB. NOAC treatment was associated with a lower 90-day mortality after ICH than warfarin, but no such difference was found after ischemic stroke or GIB. After ischemic stroke and GIB, mortality rates were higher in antiplatelet treated and untreated patients compared to NOAC treated patients. Acknowledgement/Funding Swedish Heart Lung Foundation

Concomitant Anticoagulant and Antidepressant Therapy in Atrial Fibrillation Patients and Risk of Stroke and Bleeding.

We aimed to quantify the effects of antidepressant (AD) use in oral anticoagulant (OAC)-treated patients with atrial fibrillation (AF). Using the Stockholm Healthcare database, we analyzed AF patients initiated with an OAC. Outcomes were severe bleeds and strokes and were analyzed using Cox models. We included 17,210 patients claiming warfarin and 13,385 claiming a non-vitamin K OAC. The number of patients that claimed an AD during follow-up was 4,303. Concomitant OAC and AD use was associated with increased rates of severe bleeds (4.7 vs. 2.7 per 100 person-years) compared with OAC treatment alone (adjusted hazard ratio (aHR) 1.42, confidence interval (CI): 1.12-1.80), but not significantly associated with increased stroke rates (3.5 vs. 2.1 per 100 person-years, aHR 1.23, CI: 0.93-1.62). No significant differences in risks were observed between different OAC classes or different AD classes. In conclusion, concomitant use of an OAC and an AD is associated with an increased bleeding risk.

High-sensitivity C-reactive protein and the risk of chronic kidney disease progression or acute kidney injury in post–myocardial infarction patients

BackgroundPersistent, low-grade inflammation likely participates in the pathophysiology of both atherosclerosis and kidney disease. Although high-sensitivity C-reactive protein (hsCRP) predicts future cardiovascular risk in patients with chronic kidney disease (CKD), it is unknown whether hsCRP levels predict adverse renal outcomes in patients with cardiovascular disease. MethodsWe studied all myocardial infarction (MI) survivors undergoing hsCRP testing >30 days after their MI during routine health care in Stockholm, Sweden (2006-2011), with available information on estimated glomerular filtration rate (eGFR). HsCRP tests measured during hospitalization/emergency room visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window. Study outcomes were CKD progression (composite of doubling plasma creatinine, renal replacement therapy, or renal death) and acute kidney injury (AKI, acute creatinine peaks according to Kidney Disease: Improving Global Outcomes criteria). Multivariable Cox regression was used to adjust for age, sex, eGFR, hemoglobin, time since MI, comorbidities, undertaken procedures, and medications. ResultsA total of 12,905 patients (62% men, mean age 73 years and 3 years since MI) were included, of whom 35% had an eGFR<60 mL/min/1.73 m2. The mean (SD) hsCRP was 3.0 (4.4) mg/L. Baseline hsCRP levels were increasingly higher across lower eGFR categories. During a median follow-up of 3.2 years, 1,019 CKD progressions and 1,481 AKI events were recorded. Patients with hsCRP ≥2 mg/L were at higher risk of both CKD progression (adjusted hazard ratio 1.42; 95% CI 1.21-1.66) and AKI (1.29; 1.13-1.47) compared to those with hsCRP <2 mg/L. This association persisted across single CKD severity stages and after further hsCRP categorization into 4 groups (≤1, 1-3, 3-10, >10 mg/L). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6-12 months. ConclusionsIn post-MI patients undergoing routine health care, elevated hsCRP was associated with subsequent risk of AKI and progression of CKD, irrespective of baseline kidney function.