Diabetes mellitus and its impact on mortality rate and outcome in pulmonary embolism

Abstract Aims/Introduction In patients with pulmonary embolism (PE), the impact of diabetes mellitus on patient profile and outcome is not well investigated. Material and Methods The German nationwide inpatient sample of the years 2005–2018 was analyzed. Hospitalized PE patients were stratified for diabetes, and the impact of diabetes on in‐hospital events was investigated. Results Overall, 1,174,196 PE patients (53.8% aged ≥70 years, 53.5% women) and, among these, 219,550 (18.7%) diabetes patients were included. In‐hospital mortality rate amounted to 15.8%, and was higher in diabetes patients than in non‐diabetes patients (19.8% vs 14.8%, P < 0.001). PE patients with diabetes had a higher prevalence of cardiovascular risk factors, comorbidities, right ventricular dysfunction (31.8% vs 27.7%, P < 0.001), prolonged in‐hospital stay (11.0 vs 9.0 days, P < 0.001) and higher rates of adverse in‐hospital events. Remarkably, diabetes was independently associated with increased in‐hospital mortality (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.20–1.23, P < 0.001) when adjusted for age, sex and comorbidities. Within the observation period of 2005–2018, a relevant decrease of in‐hospital mortality in PE patients with diabetes was observed (25.5% to 16.8%). Systemic thrombolysis was more often administered to diabetes patients (OR 1.18, 95% CI 1.01–3.49, P < 0.001), and diabetes was associated with intracerebral (OR 1.19, 95% CI 1.12–1.26, P < 0.001), as well as gastrointestinal bleeding (OR 1.11, 95% CI 1.07–1.15, P < 0.001). Type 1 diabetes mellitus was shown to be a strong risk factor in PE patients for shock, right ventricular dysfunction, cardiopulmonary resuscitation and in‐hospital death (OR 1.75, 95% CI 1.61–1.90, P < 0.001). Conclusions Despite the progress in diabetes treatments, diabetes is still associated with an unfavorable clinical patient profile and higher risk for adverse events, including substantially increased in‐hospital mortality in acute PE.


INTRODUCTION
Pulmonary embolism (PE) represents a leading cause of cardiovascular death worldwide 1,2 , with an improvement of mortality over the past years 2,3 , but increasing annual incidence rates 3,4 . The mortality risk of PE patients is associated with the patient's clinical condition in the setting of acute PE, including hemodynamic status and acute cardiac adaptations (for example, right ventricular dysfunction [RVD]), pre-existing comorbidities, method of treatment and adverse events 5,6 . Diabetes is known as a relevant cardiovascular risk factor 7,8 that has a tremendous impact on various organ systems, including the heart 9 and the coagulation system, inducing a shift from normal hemostasis to a hypercoagulable state with prothrombotic characteristics [10][11][12] . Various mechanisms have been proposed to explain the prothrombotic state in impaired glucose metabolism, including transcription of coagulation factors caused by hyperglycemiainduced oxidative stress, loss of the endothelial glycocalyx layer that harbors coagulation factors, direct activation of coagulation factors and decreased fibrinolysis [13][14][15][16][17] . In consequence, individuals with diabetes experience an elevated risk for arterial, as well as venous, thrombosis 18 , including the risk for PE 19 . Until today, data on the impact of diabetes on clinical outcome including mortality of PE patients is scarce, and the findings of available studies are controversial [20][21][22] .
In a previously published analysis of our research group on patients with PE in the German nationwide inpatient sample, more diabetes patients were observed to be present in the non-survivor group compared with PE patients who were discharged alive. Consequently, in this previously published study, diabetes was identified as an independent predictor of in-hospital mortality in patients with PE 3 . Due to this relevant finding and the well-known vast impact of diabetes on the cardiovascular system, the present in-depth study was carried out with the aim to investigate the impact of diabetes on patient profile and clinical outcome of individuals hospitalized with PE, as well as thereon the impact of special diabetes subtypes, such as type 1 diabetes, on the outcomes in this patient group.

MATERIAL AND METHODS
We analyzed all in-patient cases with PE in Germany between the years 2005 and 2018 (source: Research Data Center of the Federal Statistical Office and the Statistical Offices of the federal states, Diagnosis Related Groups Statistics 2005-2018, and our own calculations) including PE as the main reason for admission, as well as PE not being the main reason for admission or PE developed during hospitalization. As described previously 3,23 , in Germany, diagnoses are coded according to the coding guidelines, International Classification of Diseases, 10th Revision with German Modification (ICD-10-GM), and diagnostical, surgical and interventional procedures with OPS codes (surgery, diagnostic and procedures codes [Operationen-und Prozedurenschl€ ussel]). The data from all inpatient cases in Germany, which are processed according to the diagnosis related groups system, are collected by the Federal Statistical Office of Germany (Statistisches Bundesamt, Wiesbaden, Germany).
In the present study, we included all hospitalizations of patients with a PE event, who were identified by the ICD-code I26 between the years 2005 and 2018 in Germany. Included hospitalizations of PE patients were further stratified for the presence of diabetes (ICD-codes E10-E14). PE patients coded with diabetes had diabetes as a chronic disease at admission or a new onset of diabetes was diagnosed during hospitalization (main or secondary diagnosis). We compared PE patients with and without diabetes regarding patient characteristics, venous thromboembolism (VTE) risk factors, risk stratification markers for PE, comorbidities, use of revascularization treatments and adverse in-hospital events. In addition, temporal trends were investigated.

Study end-points and in-hospital adverse events
The primary study outcome was defined as death of allcauses (in-hospital death). Furthermore, the prevalence of adverse events during in-hospital stay, such as pneumonia (ICD-codes J12-J18), high-risk PE (defined as PE patients in shock and/or PE patients, who had to undergo cardiopulmonary resuscitation), acute kidney injury (AKI, ICD-code N17), stroke (ischemic and hemorrhagic stroke, ICD-codes I61-64), intracerebral bleeding events (ICD-code I61), gastrointestinal bleeding (ICD-codes K920-K922) and transfusion of blood components (OPS code 8-800), were assessed. These adverse events were defined according to the relevant current guidelines [24][25][26][27][28][29] , and occurred during or shortly before the hospitalization and were treated during hospitalization.

Ethical aspects
In accordance with German law, approval by an ethics committee and informed consent were not required, as the present study did not involve direct access of the investigators to data of individual patients. The present analysis was carried out on our behalf by the Research Data Center of the Federal Statistical Office and the Statistical Offices of the federal states. Aggregated statistic results were provided on the basis of SPSS â codes (IBM SPSS â Statistics for Windows, version 20.0; IBM Corp. Armonk, NY, USA), which were supplied to the Research Data Center 3 .

Statistical analysis
Regarding baseline comparisons, comparison of treatments, and adverse outcomes of PE patients with and without diabetes, descriptive statistics are shown as the median and interquartile range (IQR) or absolute numbers and corresponding percentages. Continuous variables were assessed with the Mann-Whitney U-test, and categorical variables using the Fisher's exact or the v 2 -test, as appropriate.
The hospitalization rate of PE patients with and without diabetes as well as mortality rate (case-fatality rate), revascularization treatments carried out (systemic thrombolysis [OPS code 8-020.8] and/or surgical embolectomy [OPS code 5-380.42]) and the rate of adverse in-hospital events, were calculated on an annual basis. Linear regressions were used to assess trends over time, and the results are given as beta (b) with the corresponding 95% confidence intervals (CI).
The investigation of the impact of diabetes, including type 1 diabetes mellitus and type 2 diabetes, on in-hospital events and in-hospital death among PE patients was carried out using univariate and multivariate logistic regression models given as odds ratio (OR) and 95% CI. Logistic regression analysis is widely used in epidemiological studies concerned with quantifying an association between a study factor (i.e., an exposure variable) and a health outcome (i.e., disease status, binary data) 30 .
The multivariate regression models were adjusted for.
• Adjustment I: age, sex, cancer, heart failure, coronary artery disease, peripheral artery disease, chronic obstructive pulmonary disease, essential arterial hypertension, acute and chronic kidney disease, atrial fibrillation/flutter, and hyperlipidemia.
• Adjustment II: age, sex, cancer, heart failure, coronary artery disease, peripheral artery disease, chronic obstructive pulmonary disease, essential arterial hypertension, acute and chronic kidney disease, atrial fibrillation/flutter, hyperlipidemia, and anemia.
This epidemiological approach regarding the adjustment was chosen to prove the widespread independence of these outstanding predictors of case fatality rate during hospitalization. Statistical significance was assumed in case of P-value <0.05 (two-sided). Statistical analyses were carried out with the software SPSS â (IBM SPSS â Statistics for Windows, version 20.0; : IBM Corp. Armonk, NY, USA).

RESULTS
The present study comprised 1,174,196 Figure S1).
Clinical profile of PE patients with and without diabetes PE patients with diabetes were older (75.0 vs 71.0 years, P < 0.001), more often women (54.6 vs 53.2%, P < 0.001) and required a prolonged in-hospital stay (11.0 vs 9.0 days, P < 0.001) compared with those without diabetes. Diabetes patients showed an aggravated cardiovascular risk profile with an approximately doubled prevalence of obesity and hyperlipidemia, as well as a 1.5-fold higher occurrence of arterial hypertension. Also, comorbidities were considerably more prevalent in diabetes patients with approximately doubled prevalence of coronary artery disease, tripled occurrence of peripheral artery disease and 1.5-2-fold more heart failure, chronic obstructive pulmonary disease and atrial fibrillation/flutter. Anemia was 1.4-fold more prevalent in PE patients with diabetes compared with those without (Table 1). Regarding risk factors for VTE, more often surgery had been carried out in diabetes patients (55.4 vs 49.8%, P < 0.001), whereas more patients without diabetes were affected by cancer (19.8 vs 20.2%, P < 0.001) and thrombophilia (0.7 vs 1.2%, P < 0.001). The Charlson Comorbidity Index was substantially higher in PE patients with diabetes than those without diabetes (6.0 [5.0-8.0] vs 4.0 [2.0-6.0], P < 0.001; Table 1).
In   Table S1). With higher age, a rise of in-hospital mortality was observed, whereas the rates of pneumonia, CPR, stroke and AKI declined (Figure 1d). The portion of women increased during the observational period in parallel with cardiac risk factors, comorbidities (Figures S1 and S3) and the prevalence of deep venous thrombosis or thrombophlebitis of the leg veins  Table S1). With rising age, the rate of deep venous thrombosis or thrombophlebitis of the leg veins and shock decreased from the third to the greater than ninth decade, whereas regarding the prevalence of RVD, as well as syncope, a small increase could be detected ( Figure S4, Table S1). Within the investigated time period, the rates of pneumonia (b 0.45, 95% CI 0.41-0.49, P < 0.001), stroke and AKI increased, whereas the need for CPR (b -0.27, 95% CI -0.33 to -0.21, P < 0.001) decreased (Figures 1b, 2a; Table S1).
The use of revascularization of PE patients with diabetes increased from 2005 to 2018 (Figure 2a), whereby only an increase of systemic thrombolysis (b 0.26, 95% CI 0.19-0.34, P < 0.001) was present with unchanged rates of surgical embolectomy (Table S1). In line with these findings, an increase of intracerebral (b 0.30, 95% CI 0.10-0.49, P = 0.003) and gastrointestinal (b 0.48, 95% CI 0.36-0.60, P < 0.001) bleeding was present (Figure 2b, Table S1). Revascularization was predominantly carried out in younger patients (peak decade 20-29 years with a revascularization rate of 12.3%), and declined with increasing age (Figure 2c). Concomitant to revascularization, the need for transfusion of blood constituents was highest in patients aged 20-29 years, but intracerebral bleeding occurred most frequently in patients aged between 30 and 59 years. In contrast, the portion of gastrointestinal bleeding events was 1.5% in patients aged 20-29 years, with rising prevalence in older age groups (Figure 2d).

Impact of diabetes subtypes on adverse in-hospital events in patients with PE
Among the PE patients with diabetes, 3,540 (1.6%) were coded with type 1 diabetes , 208,996 (94.9%) with type 2 diabetes, and in 7,014 (3.2%) patients, the subtype was unknown or not coded ( Table 1). The proportion of PE patients with type 1 diabetes subtype decreased over time (b -0.99, 95% CI -1.12 to -0.86, P < 0.001) and with increasing age (b -1.10, 95% CI -1.14 to -1.06, P < 0.001; Figure 3; Table S1). The proportion of PE patients aged ≥70 years was substantially higher in patients with type 2 diabetes than PE patients without diabetes and compared with those with type 1 diabetes (Table S2). Traditional cardiovascular risk factors, as well as atherosclerotic diseases, such as coronary artery disease and peripheral arterial disease, but also heart failure, were all more prevalent in PE patients with both diabetes subtypes. PE patients with type 1 diabetes (15.7 vs 8.3%, P < 0.001), as well as PE patients with type 2 diabetes (11.4 vs 8.3%, P < 0.001) presented more often with a high-risk PE compared with PE patients without diabetes (Table S2). Consequently, patients with type 1 diabetes, as well as patients with type 2 diabetes were more frequently treated with systemic thrombolysis. The Charlson Comorbidity Index was higher in both subgroups of diabetes patients. PE patients with a type 1 diabetes died more often in hospital (22.1 vs 14.8%, P < 0.001), and showed a higher number of strokes, bleeding and acute kidney injury. Similarly, PE patients with type 2 diabetes showed a higher mortality rate compared with PE patients without diabetes (19.6 vs 14.8%, P < 0.001).
Remarkably, the in-hospital mortality of PE patients with type 1 diabetes was significantly higher than in the type 2 diabetes subgroup (P < 0.001; Table S2).
The vast clinical impact of type 1 diabetes mellitus in PE patients was emphasized by multivariate regression analyses:   (Table S3). The impact of type 2 diabetes on the in-hospital outcomes was less strong: PE patients with type 2 diabetes were independently associated with increased mortality risk (adjustment I: OR 1.19, 95% CI 1.18-1.21, P < 0.001), high-risk PE (adjustment I: OR 1.19, 95% CI 1.17-1.21, P < 0.001) and all investigated bleeding complications compared with PE patients without diabetes (Table S4).

DISCUSSION
In the present study assessing >1.1 million hospitalizations of patients with PE, vast differences regarding cardiovascular profile and adverse in-hospital mortality between PE patients with and without diabetes were identified.
The results can be summarized as follows. First, diabetes patients were 4 years older (in median), and showed an unbeneficial clinical profile with a higher prevalence of cardiovascular risk factors and atherosclerotic comorbidities compared with non-diabetes patients. Second, regarding typical VTE risk factors, diabetes patients were more often operated on, whereas cancer and thrombophilia were more prevalent in non-diabetes patients. Third, patients with diabetes were more often afflicted with risk stratification markers, such as RVD, tachycardia and syncope, and were more often hemodynamically unstable. Consequently, treatment with systemic thrombolysis was more often administered in patients with diabetes, and higher rates of intracerebral and gastrointestinal bleeding complications were detected. Fourth, in-hospital mortality was substantially elevated by approximately 30% compared with non-diabetes patients, but declined from 25.5 to 16.8% within the investigated time period. Fifth, remarkably, in the present study, type 1 diabetes was identified as a strong risk factor independently associated with a higher occurrence of shock, stroke, RVD, CPR and inhospital death in hospitalized PE patients, despite the younger   age of this patient group in comparison with the other PE patients with diabetes. The annual incidence of VTE in patients with diabetes was estimated as 0.12% 19,31 . Nevertheless, data on the impact of diabetes on the occurrence of PE remain controversial in the literature. In several investigations, diabetes was associated with an increased risk for PE 19,22,[32][33][34][35][36] , whereas in other studies, no correlation was present 37,38 . The Atherosclerosis Risk in Communities (ARIC) study on four communities of the USA showed a more than doubled incidence of VTE (including deep vein thrombosis and PE) in people with diabetes 32 , and an investigation of US Veteran Health Administration Hospitals reported that diabetes was identified as an independent risk factor for the development of PE 35 , which was in line with study results from Sweden 33 , Taiwan 19,36 , Italy 22 and previously published studies from the USA 32 . A meta-analysis of this topic confirmed an elevated VTE risk in participants with diabetes 34 . In contrast, a large USA epidemiological study with a 25-year observational period found no correlation between diabetes and the occurrence of VTE 37 , and another large population-based case-control study from the Netherlands including approximately 5,000 VTE patients was also unable to confirm an association between diabetes and the occurrence of VTE 38 . In addition, a study of the US National Hospital Discharge Survey including >92 million patients investigating a follow-up observational period of 26 years showed an increased agedependent VTE risk only in patients aged <59 years (with a peak in the age decade of 20-29 years) 39 . In line with these findings, in a large nationwide population-based cohort study in Taiwan, people with diabetes were associated with an elevated prevalence for PE, with the highest risk in patients aged ≤49 years 19 . These data stand in contrast to the results of the present study, where the peak co-prevalence of PE and diabetes was found in the eighth decade of life. Interestingly, the aforementioned large USA study further detected a similar risk for VTE in patients with type 1 diabetes and type 2 diabetes 39 . These findings are contradictory to a recent British study of >1.5 million participants with special focus on this issue in which an elevated risk for VTE was especially found in patients with type 1 diabetes, but not in patients with type 2 diabetes 40 . In addition, the impact of type 1 diabetes on the occurrence of VTE was recently confirmed by a National Health Insurance Research Database study from Taiwan 36 . Importantly, antidiabetes treatments are also associated with VTE occurrence 31 . In particular, dipeptidyl peptidase-4 inhibitors were found to be associated with an elevated occurrence of VTE (OR 2.0, 95% CI 1.7-2.3) compared with other non-insulin glucose-lowering drugs 31 .
Besides the association of diabetes with the development of VTE, diabetes is a well-recognized important driver for  cardiovascular morbidity and mortality 7,[41][42][43][44][45] . Nevertheless, data on the impact of diabetes on mortality and other adverse outcomes of PE patients are sparse and contradictory [20][21][22] . Although, in accordance with the present results, the majority of studies showed an increased risk of adverse outcomes and especially mortality among PE patients with diabetes, other studies were not able to confirm this finding. Diabetes is associated with higher prevalences of other cardiovascular risk factors, such as arterial hypertension and dyslipidemia, often leading to the metabolic syndrome. Furthermore, diabetes promotes various morbidities, such as coronary artery disease, atrial fibrillation, kidney disease and peripheral artery disease 46 . Also, in the present study, patients with diabetes showed a crucially unbeneficial clinical profile, but additionally, diabetes affected mortality substantially (25.5 vs 16.8%) in PE patients, and was identified as an independent risk factor for increased in-hospital mortality with an OR of 1.21 (95% CI 1.20-1.23).
In accordance with the present results, a recently published analysis of the Spanish National Health System Hospital Discharge Database in the timescale 2016-2018 comprising 47,190 patients aged ≥40 years who were hospitalized due to PE showed that diabetes was also associated with increased inhospital mortality (OR 1.15, 95% CI 1.05-1.26) 21 . These results from Spain (2016-2018) confirmed a former analysis comprising data of >120,000 PE patients in which diabetes was also related to higher in-hospital mortality (men OR 1.22, 95% CI 1.12-1.32; women OR 1.24, 95% CI 1.15-1.33) 47 . Interestingly, a study of 577 PE patients aiming to investigate sex differences in outcome also showed an elevated mortality of PE patients with diabetes, but after sex-specific assessment, the association between diabetes and increased mortality among PE patients was attenuated in women who were associated with a doubled risk of death compared with patients without diabetes 48 . In contrast to the aforementioned studies, in a matched retrospective cohort study (RIETI registry) comprising 2,010 diabetes patients with PE who were compared with two age-and sexmatched controls, diabetes was not independently associated with mortality 20 .
The association between diabetes and deep vein thrombosis is controversially discussed in the literature, varying from diabetes as a high-risk factor to minor associated risk to no independent risk factor for deep vein thrombosis 49 . In line, a nationwide cohort study from Taiwan, for instance, found an elevated risk for patients with diabetes for developing deep vein thrombosis 19 , whereas in a German nationwide study congruent with the present results, diabetes was not associated with a higher risk for deep vein thrombosis 46 . A possible reason for this difference might lie in the differing cohort characteristics, as the Taiwan study focused on adults aged ≤49 years, whereas in the present study, the median patient age was >70 years. By all means, as proposed by Nielsen 50 , the controversy on this issue, including the present results, shows that PE and deep vein thrombosis should rather be regarded as separate clinical entities than as one consequence of the other, with differing risk factorsprobably including diabetesas suggested by the results of the present investigation and further data 46 .
Regarding the safety outcomes of the anticoagulant therapy, the present study showed higher bleeding rates in PE patients with diabetes in comparison with those without, that could only in part be explained by higher use of revascularization treatments. Diabetes was independently associated with an increased risk of intracerebral (OR 1.19, 95% CI 1.12-1.26), as well as gastrointestinal bleeding (OR 1.11, 95% CI 1.07-1.15). This finding is in line with a study from Piazza et al. 51 , who reported that patients with diabetes more likely suffer from a complicated clinical course with a higher frequency of recurrent deep vein thrombosis and major bleeding complications. Similarly, the study of Zhang et al. 52 confirmed that diabetes was an independent risk factor for major bleeding (OR 2.11, 95% CI 1.10-4.12) and clinically relevant non-major bleeding (OR 2.11, 95% CI 1. 10-4.12) in PE patients under anticoagulation therapy in a 3-month follow-up period.
Remarkably, although data from large studies about the impact of type 1 diabetes on adverse outcome and mortality in PE patients were missing up to now, the present study gives new insights for relevant clinical associations between both diseases. The results of the present study suggest that type 1 diabetes mellitus is a strong risk factor for adverse outcomes in PE patients. Type 1 diabetes was shown to be a substantial risk factor in the setting of PE, with higher risk for shock, stroke, RVD, CPR and in-hospital death. In this context, studies reported that diabetes affected cardiac structure and function, and this might contribute to higher RVD rate in PE patients with diabetes 9 .
Pathophysiologically, diabetes causes endothelial dysfunction, inflammation and hypercoagulability, resulting in vascular complications and a shift to a prothrombotic state 13 . Hyperglycemia induces insulin-independent passive glucose diffusion into endothelial cells, leading to consecutive activation of secondary metabolic pathways, which, besides other consequences, imitates the effects of hypoxia by converting nicotinamide adenine dinucleotide phosphate to oxidized nicotinamide adenine dinucleotide phosphate, causing endothelial cytotoxicity and decreased nitric oxide availability with the result of endothelial dysfunction 13,53,54 . These alterations promote both a procoagulatory and pro-inflammatory condition by endothelial cell release of thrombogenic factors, such as tromboxan A2, plasminogen activator inhibitor-1 and von-Willebrand factor, as well as expression of inflammatory adhesion molecules, such as P-selectin, E-selectin, vascular adhesion molecular-1 and intercellular adhesion molecule-1 13,55 . Oxidative stress and endothelial activation are further induced by advanced glycation endproducts, which irreversibly result from protein glycation 13,56,57 . In addition, the diabetic state promotes alterations on the fibrin network structure and causes affects fibrinolysis 15,58 . These hyperglycemia-induced mechanisms orchestrate the induction of both a pro-coagulatory and pro-inflammatory condition, potentially leading to a pro-thrombotic state in people with diabetes 11,13,58 .
Diabetes patients who suffer from VTE are at elevated risk for adverse events and a complicated clinical course 51 , which was also confirmed in the present study. Due to the important impact of diabetes on the risk for VTE and outcome of PE patients, including mortality and bleeding, risk stratification and identification of vulnerable patient groups are essential to optimize patient treatment in the setting of PE. For this, the development and continuous improvement of risk assessment strategies represent a vital tool aiming to identify the best individual treatment option in consideration of relevant comorbidities, such as diabetes, for each of these PE patient 6,59,60 . Beyond this, in view of the contradictory data on this issue, further investigations are required to elucidate the underlying mechanisms and impact of disturbed glucose metabolism on the generation and clinical outcome of PE. Improved understanding of the influence of diabetes on the coagulation system might help to prevent VTE events and enhance treatment modalities, as well as health consequences for affected patients. Although the adjustments of the multivariate regression models were very widely chosen, aiming to address most of the cofounders in light of the differences in PE patients' characteristics between patients with and without diabetes, we could not be completely sure that we purposefully addressed all of these differences by these adjustments.
In summary, the present study involves by far the largest cohort, investigating the impact of diabetes on mortality within hospitalized PE patients. Diabetes was found to be independently associated with an increase of in-hospital mortality in patients with PE. This stands in line with other findings on the influence of glucose metabolism on outcome of PE patients. In this context, a large study investigating the association between mortality and serum glucose level at admission in PE patients showed increased elevated admission glucose levels to be independently associated with increased mortality, even in patients without diabetes 61 . Furthermore, elevated admission glucose levels were shown to be associated with increased mortality in the treatment of PE patients within thrombolytic therapy 62 .
There were certain limitations of the present study, which need to be mentioned. First, the study was based on ICD and OPS discharge codes of hospitalized patients, which might lead to an under-reporting/under-coding. Nevertheless, the coding carried out by hospitals to receive their remuneration (in Germany, primarily carried out by physicians or administrative specialists) has to follow high-quality standards, in order not to compromise and lower the remuneration payments. Second, detailed baseline data, such as concomitant medications, cardiac troponin plasma concentrations and echocardiographic parameters, and outcome data, such as major bleeding, were not available. Third, due to the data structure including only the inhospital stay, follow-up evaluation after discharge was not possible.
Diabetes is common in patients with PE in Germany. PE patients with diabetes showed an unfavorable clinical profile, including higher prevalence of cardiovascular risk factors and atherosclerotic comorbidities, but also typical risk stratification markers, such as RVD, were found to be elevated in this patient group. In PE patients, diabetes was associated with hemodynamic instability and higher rates of adverse in-hospital events, such as bleeding events and, in particular, increased inhospital mortality. Diabetes was identified as an independent and important risk factor for short-term mortality, as well as bleeding events in PE patients. Additionally, type 1 diabetes was shown to be a strong independent risk factor in the setting of PE, with higher risk for shock, stroke, RVD, CPR and inhospital death. The present findings might help to identify patients with PE at higher risk for in-hospital mortality and should draw more attention to the concomitant presence of diabetes.

SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of the article.