Open access Original research Incidence and costs of cardiovascular events in Spanish patients with type 2 diabetes mellitus: a comparison with general population, 2015 Esteban Jodar,1 Sara Artola,2 Xavier Garcia-­Moll,3 Estefany Uría,4 Noemí López-­Martínez ‍ ‍,4 Rosa Palomino,4 Virginia Martín5 To cite: Jodar E, Artola S, ABSTRACT Garcia-­Moll X, et al. Incidence Introduction Cardiovascular (CV) disease affects a high Significance of this study and costs of cardiovascular percentage of patients with type 2 diabetes mellitus events in Spanish patients (T2DM), especially in the hospital setting, impacting on What is already known about this subject? with type 2 diabetes ►► Cardiovascular disease (CVD) affects a high percent- mortality, complications, quality of life and use of health mellitus: a comparison with age of patients with type 2 diabetes mellitus (T2DM), general population, 2015. resources. The aim of this study was to estimate the incidence, mean length of hospital stay (LOHS) and costs and this has major consequences on mortality, com- BMJ Open Diab Res Care attributable to hospital admissions due to CV events in plications, quality of life and use of health resources. 2020;8:e001130. doi:10.1136/ patients with T2DM versus patients without diabetes ►► In Spain, 7.8% of the adult population are diagnosed bmjdrc-2019-001130 mellitus (non-­DM) in Spain. with T2DM and about 29.8% of these have CVD. Research design and methods Retrospective What are the new findings? ►► Additional material is observational study based on the Spanish National Hospital published online only. To view, ►► T2DM population had a higher incidence in all the Discharge Database for 2015. Hospital admissions for cardiovascular (CV) complications studied compared please visit the journal online patients aged ≥35 years with a diagnosis of CV death, non-­ with the population without diabetes mellitus (non-­ (http://​dx.​doi.​org/​10.​1136/​ fatal acute myocardial infarction (AMI), non-­fatal stroke, bmjdrc-​2019-​001130). DM), with a relative risk exceeding 2 in all cases. unstable angina, heart failure and revascularization were ►► The mean length of hospital stay (LOHS) (days) was evaluated. The International Classification of Diseases, longer in the T2DM group compared with the non-­ Received 18 December 2019 Ninth Revision (250.x0 or 250.x2) coding was used to DM group for non-­fatal acute myocardial infarction Revised 2 June 2020 classify records of patients with T2DM. For each CV Accepted 8 June 2020 (AMI), unstable angina and revascularization. complication, the hospital discharges of the two groups, ►► The mean cost per hospital discharge was higher in T2DM and non-­DM, were precisely matched and the the T2DM versus the non-­DM cohort for non-­fatal number of hospital discharges, patients, LOHS and mean AMI and unstable angina. cost were quantified. Additional analyses assessed the robustness of the results. How might these results change the focus of Results Of the 276 925 hospital discharges analyzed, research or clinical practice? 34.71% corresponded to patients with T2DM. A higher ►► The results of this study will help in the under- incidence was observed in all the CV complications studied standing of incidence, LOHS and cost of the CV in the T2DM population, with a relative risk exceeding complications (classified considering major adverse 2 in all cases. The mean LOHS (days) was longer in the cardiovascular events variable) in the real-­world set- T2DM versus the non-­DM group for: non-­fatal AMI (7.63 vs ting comparing T2DM and non-­DM populations. 7.02, p<0.001), unstable angina (5.11 vs 4.78, p=0.009) ►► This study will provide complementary information on and revascularization (7.96 vs 7.57, p<0.001). The mean the most widely used intermediate variables in diabe- cost per hospital discharge was higher in the T2DM tes research, such as hemoglobin A1c and weight. versus the non-­DM group for non-­fatal AMI (€6891 vs ►► The findings of this study may support health €6876, p=0.029) and unstable angina (€3386 vs €3304, decision-­making by establishing the economic cost p<0.001). © Author(s) (or their of CV events avoided. Conclusions Patients with T2DM had a higher incidence employer(s)) 2020. Re-­use and number of hospital admissions per patient due to CV permitted under CC BY-­NC. No events versus the non-­DM population. This generates a commercial re-­use. See rights and permissions. Published significant clinical and economic burden given the longer (T2DM) affects around 9.3% of the adult by BMJ. admission stay and higher costs associated with some of population.1 Approximately 32.2% of these these complications. For numbered affiliations see patients suffer cardiovascular disease (CVD).2 end of article. In Spain, 7.8% of the adult population are Correspondence to BACKGROUND diagnosed with T2DM3 and about 23.2% of Mrs Noemí López-­Martínez; The International Diabetes Federation (IDF) these have CVD,4 with this figure reaching ​noemi.​lopez@​oblikue.​com estimates that globally type 2 diabetes mellitus 40.8% in hospitalized patients with T2DM.5 BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 1 Epidemiology/Health Services Research The IDF estimates that diabetes has an 132% increased complications included in the MACE indicator in the risk of CVD death.1 In Spain, the probability of inpatient Spanish context. death from any cardiovascular (CV) event is higher in The aim of this study was to estimate the number of patients with T2DM compared with patients without this patients, hospital discharges, hospital stay and mean disease (OR 1.06; 95% CI 1.04 to 1.09).6 Furthermore, direct costs per hospitalization attributable to CV compli- patients with T2DM have a higher risk of CV events cations in Spain in 2015, based on whether the discharge compared with the population without T2DM.7–10 Both was related to T2DM or non-­diabetes mellitus (non-­DM). CVD and acute CV events have a major clinical impact and negatively affect patients’ quality of life.11 The Food and Drug Administration requires concrete METHODS evidence regarding CV safety when evaluating new treat- Study design and population ments for diabetes. This evidence includes an assessment A retrospective study of hospital discharges recorded of major adverse cardiovascular events (MACE), that between January 1, 2015 and December 31, 2015, in the is, non-­fatal stroke, non-­fatal acute myocardial infarc- SNHDD generated by the MoHCASW was carried out. tion (AMI) and CV death.12 Such evidence has had This data set compiles information on the characteris- consequences on the consensus report by the American tics of patients attended (age and sex), the hospitaliza- Diabetes Association and the European Association for tion (type of admission/discharge and length of hospital the Study of Diabetes.13 This report recommends antidi- stay (LOHS)) and the diagnoses coded according to the abetic therapy such as glucagon-­like peptide 1 receptor Spanish International Classification of Diseases, Ninth agonists or sodium-­ glucose cotransporter 2 inhibitors Revision, Clinical Modification (ICD-9-­CM). Completion due to their proven CV benefit for patients with CVD. of the SNHDD is mandatory and must include all hospital Also, reference T2DM clinical practice guidelines estab- discharges from acute hospitals belonging to the National lish CV risk reduction as one of the main treatment goals Healthcare System. In 2015, the SNHDD included 93% and recommend adjusting this treatment on an indi- of all hospital discharges in Spanish hospitals,30 of which vidual basis based on the patient’s CV risk profile.12 14–21 15% of all hospital discharges corresponded to private CV complications in T2DM also have significant hospitals.31 economic implications.22 23 Patients with T2DM and The study population included all hospital discharges macrovascular complications consume more health in which the main diagnosis or procedure was coded resources,22 24 being even possible to double the use of under any of the six CV complications included in the resources in emergency department admissions (OR expanded MACE indicator (CV death, non-­fatal myocar- 2.69; 95% CI 1.56 to 4.65) and hospitalizations (OR 2.58; dial infarction, non-­fatal stroke, heart failure, revascular- 95% CI 1.64 to 4.07) compared with patients with T2DM ization and unstable angina).32 Online supplementary without such complications.22 In Spain, the annual direct material table A1 displays the corresponding ICD-9-­CM cost per patient with T2DM and CVD was estimated at codes used to define each CV complication. Once the €4815.60, which is 82% higher than that in patients with hospital discharge records were selected, six cohorts were T2DM without CVD (€2648.80) and 46% higher than defined (one for each CV complication under study). that for patients without T2DM with CVD (€3306.80) Hospital discharge records of patients of both sexes, (EUR 2011).23 Results from the Spain estimated cost aged 35 years or older, were included and classified Ciberdem-­ Cabimer in Diabetes (SECCAID) study25 according to diabetes status: T2DM (ICD-9-­CM: 250.x0 showed that CVD generated 40% (€764 million) of the or 250.x2) recorded as the primary or secondary diag- total hospital costs (€1934 million) associated with DM nosis or non-­ DM. Hospital discharges coded as type (EUR 2012). 1 DM (T1DM) (ICD-9-­CM: 250.x1 or 250.x3), secondary Several studies have evaluated the clinical characteris- diabetes (ICD-9-­CM: 249) or abnormal glucose tolerance tics of patients with T2DM hospitalized due to CV events (ICD-9-­CM: 648.8) were excluded. using the Spanish National Hospital Discharge Database (SNHDD) of the Ministry of Health, Consumer Affairs Matching and Social Welfare (MoHCASW).5 6 8 9 26 The most prev- After grouping hospital discharges according to T2DM alent CV event in hospitalized patients with T2DM is (cases) or non-­DM (controls) for each CV complication, congestive heart failure (20.1%), followed by cerebro- cases and controls were exactly matched (1:1) by age, sex vascular disease (10.3%), coronary disease (9.4%) and and autonomous community (AC) in which the hospital peripheral arterial disease (9.1%).5 was located. As there was more than one control for each However, very few studies have evaluated the economic case, control selection was carried out randomly. implications of CV events in patients with T2DM treated in the Spanish hospital setting.27 We have only identified Covariates internationally based studies that specifically examine Records were stratified by comorbidity based on the the economic impact associated with clinical outcomes Charlson Comorbidity Index (CCI),33 adapted for use based on the MACE variable.28 29 Therefore, it is diffi- with administrative databases.34 To calculate the CCI, cult to quantify the economic impact associated with the 15 disease categories were used, excluding diabetes and 2 BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 Epidemiology/Health Services Research the corresponding CV complication, as described by All analyses were performed using the statistical Thomsen et al.35 package R V.3.5.1. The presence of risk factors such as smoking, obesity, hypertension and lipid metabolism disorder was also analyzed based on the ICD-9-­CM code (online supple- mentary material table A1). RESULTS Of the total 503 651 hospital discharges registered in Incidence estimation Spain in 2015 that met the selection criteria defined for A unique patient identifier was generated from the the analysis, 226 726 records were excluded after data registry variables: recoded medical record number, cleansing (figure 1). Therefore, the cohort to be analyzed recoded hospital, date of birth, sex and AC of residence. before matching was 276 925 hospital discharges. CV The specific incidence rate of the CV complications in complications were not considered mutually exclusive, in T2DM and non-­DM adjusted by sex and age groups was other words, the same record could be included in the estimated by dividing the number of patients by the corre- analysis of more than one complication. sponding number of people for that population group. For the estimation, the prevalence data of the Di@betes Descriptive analysis of the unmatched study population study3 and census data in 2015 from the Spanish Office Of the total unmatched hospital discharges analyzed, for National Statistics36 were used. 34.71% were patients with T2DM with a mean age of 75 years (SD: 10.91 years) and 56.93% were men. In Direct costs estimation the non-­ DM group, the mean age was 74 years (SD: All Patients Refined-­ Diagnosis Related Groups direct 13.68 years) and 57.18% were men. There was a higher costs estimated by the MoHCASW were used.37 All costs frequency of risk factors in the T2DM cohort compared were expressed in Euros of 2019. with the non-­ DM cohort: obesity (17.25% vs 9.46%), hypertension (55.88% vs 45.44%) and lipid metabo- Stratification by patient age and sex lism disorder (42.37% vs 27.54%), as well as of patients The number of hospital discharges, LOHS and mean with high CCI (33.18% vs 25.90%). A higher mean (SD) direct cost attributable to the CV complications were LOHS was observed in the T2DM cohort (8.19 (7.98)) described according to whether the hospitalization was than in the non-­DM cohort (8.02 (9.30)), whereas the related to T2DM or non-­DM and stratified according to non-­DM cohort had a higher cost per hospitalization age groups (35–60 years; 61–70 years; 71–80 years; ≥81 (5908 (4952) vs 6194 (6622), T2DM vs non-­DM, respec- years) and sex. tively) (online supplementary material table A2). On analyzing patients’ sociodemographic and epide- Additional analysis miological characteristics for each of the six CV compli- To validate the results obtained in our analysis, we cations evaluated, the proportion of patients with risk compared them against the database of the Spanish factors (obesity, hypertension and lipid metabolism Network of Hospital Costs (Red Española de Costes Hospita- disorder) was higher in the T2DM population compared larios (RECH))38 made up of 16 Spanish hospitals whose with the non-­DM group (table 1). cost system is based on activity (full-­costing).37 The non-­DM population had a higher percentage of The procedure was the same for this analysis; hospital smokers in four of the complications (non-­fatal AMI, discharges between 2013 and 2015 whose main diagnosis non-­fatal stroke, unstable angina and revascularization). was any of the six CV complications under study and that Also, statistically significant differences were found in the met the defined study criteria. Cases (hospital discharges sociodemographic characteristics (age and sex) between with T2DM) and controls (hospitalizations without DM) both groups in all CV complications except for the sex were matched according to sex, age and AC of hospital. variable in death due to CV event and unstable angina. The LOHS and mean direct costs attributable to the CV In general, a greater proportion of patients under 60 complications were described according to whether the years was observed in the non-­DM group, both aggre- hospital discharge was related to T2DM or non-­DM. gately (online supplementary material table A2) and for each individual CV complication (table 1). A higher percentage of women was observed in the T2DM group in Statistical analysis three CV complications: non-­fatal AMI, unstable angina The quantitative variables were described using the and revascularization. For all CV complications, a higher mean, SD, median and IQR. Qualitative variables were number of hospital discharges per patient was observed analyzed according to absolute and relative frequencies. in the T2DM group, especially in heart failure (table 1). For the comparisons, the Mann-­Whitney U test was used Online supplementary material table A3 describes the for continuous variables and the χ2 test for categorical sociodemographic and epidemiological characteristics of variables. A significance of 5% was assumed in all the tests hospitalized patients with matched cohorts for each of performed. the complications studied. BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 3 Epidemiology/Health Services Research Figure 1 Episodes valuable for analysis. *Mutually non-­exclusive CV complications. AMI, acute myocardial infarction; CV, cardiovascular; DM, diabetes mellitus; N, hospital discharge; SNHDD, Spanish National Hospital Discharge Database; TIDM, type 1 diabetes mellitus. Incidence rate and unstable angina (€3386 (1468) vs €3304 (1854)) The incidence of T2DM in CV complications ranged (figure 3B). In death from CV cause, a lower cost was between 0.42 hospital discharges/1000 inhabitants in observed in the T2DM group compared with non-­DM unstable angina and 6.11 hospital discharges/1000 group (€7281 (7742) vs €8617 (12 374)). In the other inhabitants in heart failure. The T2DM population had complications, the non-­DM cohort presented a slightly a higher incidence for all CV complications versus the higher cost per hospitalization (percentage differ- non-­DM population, observing an incidence rate at ence <5%). All differences were statistically significant least two times higher in T2DM. CV complications with (figure 3B). the greatest difference were heart failure (rate ratio (RR)=3.80), death due to CV event (RR=3.05), unstable angina (RR=3.04) and revascularization (RR=3.04) LOHS and costs according to age group (figure 2). Online supplementary material table A4 shows the mean direct cost and LOHS stratified by age group. Both the Hospital stay mean LOHS and mean cost continued to be higher in the In three CV complications, a higher mean (SD) LOHS T2DM group in non-­fatal AMI (except for the cost in the was observed in T2DM: 7.63 (6.76) vs 7.02 (7.31) in non-­ 71–80 and ≥81 age groups) and unstable angina (except fatal AMI; 5.11 (4.54) vs 4.78 (4.33) in unstable angina for cost in the ≥81 age group). Likewise, the mean LOHS and 7.96 (8.64) vs 7.57 (10.20) in revascularization, in and cost continued to be higher in the non-­DM group T2DM versus non-­DM, respectively, all statistically signif- in death due to CV event, non-­fatal stroke (except for icant (figure 3A). Conversely, a lower mean (SD) LOHS LOHS in the ≥81 age group) and heart failure. was observed in the T2DM versus the non-­DM group in death due to CV event: 8.77 (10.42) vs 9.39 (12.81); non-­ LOHS and costs according to sex fatal stroke: 8.70 (9.15) vs 8.76 (10.28) and heart failure: Online supplementary material table A5 shows the strati- 8.26 (7.00) vs 8.64 (8.53). fication of LOHS and direct cost by sex. The mean LOHS Direct costs continued to be higher in the T2DM group for non-­fatal A slightly higher mean (SD) cost was observed for the AMI, unstable angina and revascularization. For non-­fatal cohort with T2DM compared with the non-­DM cohort stroke, the mean LOHS in the T2DM group was higher for non-­ fatal AMI (€6891 (4685) vs €6876 (5058)) in women (8.85 T2DM vs 8.73 non-­DM). The mean direct 4 BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 Table 1 Sociodemographic and epidemiological characteristics of hospitalized patients according to CV complications and presence of T2DM: unmatched T2DM and non-­DM groups Death from CV cause Non-­fatal AMI Non-­fatal stroke T2DM Non-­DM P value T2DM Non-­DM P value T2DM Non-­DM P value Hospital 8644 (32.80%) 17 717 (67.20%) NA 14 714 (30.60%) 33 448 (69.40%) NA 20 326 (30.80%) 45 576 (69.20%) NA discharges— N (%) Patients—n 8644 17 717 14 049 32 347 19 578 44 216 Hospital 1.00 1.00 1.05 1.03 1.04 1.03 discharges/patient Gender—n (%)* 0.550     <0.001     <0.001  Men 4114 (47.59%) 8362 (47.20%) 10 082 (68.52%) 24 637 (73.66%) 11 548 (56.81%) 24 521 (53.80%)  Women 4528 (52.38%) 9354 (52.80%) 4632 (31.48%) 8810 (26.34%) 8778 (43.19%) 21 053 (46.20%) Age (years) <0.001     <0.001     <0.001 BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130  Mean (SD) 81.13 (15.42) 82.31 (10.73) 70.73 (12.91) 65.75 (14.02) 74.98 (13.57) 73.68 (13.25)  Median (Q1; Q3) 83.00 (77.00; 85.00 (78.00; 89.00) 72.00 (62.00; 65.00 (55.00; 77.00 (68.00; 77.00 (65.00; 87.00) 80.00) 78.00) 83.00) 84.00) Age (years)—n (%) <0.001     <0.001     <0.001  35–60 292 (3.38%) 975 (5.50%) 3186 (21.65%) 13 170 (39.37%) 2207 (10.86%) 8250 (18.10%)  61–70 790 (9.14%) 1289 (7.28%) 3614 (24.56%) 7356 (21.99%) 4029 (19.82%) 7918 (17.37%)  71–80 2339 (32.39%) 3486 (19.68%) 4382 (29.78%) 6680 (19.97%) 7012 (34.50%) 12 522 (27.47%)  ≥81 5223 (60.42%) 11 967 (67.55%) 3532 (24.00%) 6242 (18.66%) 7078 (34.82%) 16 886 (37.05%) Smoker—n (%) 1076 (12.45%) 2191 (12.37%) 0.860 5546 (37.69%) 17 244 (51.55%) <0.001 4538 (22.33%) 11 274 (24.74%) <0.001 Obesity—n (%) 1022 (11.82%) 994 (5.61%) <0.001 2729 (18.55%) 3831 (11.45%) <0.001 2356 (11.59%) 2852 (6.26%) <0.001 Hypertension—n 4152 (48.03%) 6683 (37.72%) <0.001 8641 (58.73%) 14 643 (43.78%) <0.001 13 539 (66.61%) 23 939 (52.53%) <0.001 (%) Disorders of lipid 2821 (32.64%) 2930 (16.54%) <0.001 7132 (48.47%) 11 554 (34.54%) <0.001 8664 (42.63%) 12 569 (27.58%) <0.001 metabolism—n (%) Charlson Comorbidity Index† <0.001     <0.001     <0.001  Low 3577 (41.38%) 8298 (46.84%) 8206 (55.77%) 23 670 (70.77%) 10 464 (51.48%) 25 394 (55.72%)  Medium 3726 (43.11%) 6846 (38.64%) 4492 (30.53%) 7446 (22.26%) 7486 (36.83%) 15 569 (34.16%)  High 1341 (15.51%) 2573 (14.52%) 2016 (13.70%) 2332 (6.97%) 2376 (11.69%) 4613 (10.12%) Continued Epidemiology/Health Services Research 5 6 Table 1 Continued Unstable angina Heart failure Revascularization T2DM Non-­DM P value T2DM Non-­DM P value T2DM Non-­DM P value Hospital discharges— 2488 (32.00%) 5058 (67.00%) NA 42 738 (38.70%) 67 828 (61.30%) NA 20 544 (32.90%) 41 836 (67.10%) NA N (%) Patients—n 2392 4907 34 844 57 268 19 682 40 465 Hospital discharges/ 1.04 1.03 1.23 1.18 1.04 1.03 patient Gender—n (%)* 0.220     <0.001     <0.001  Men 1473 (59.20%) 3070 (60.70%) 20 955 (49.03%) 31 407 (46.30%) 15 199 (73.98%) 32 678 (78.11%)  Women 1015 (40.80%) 1988 (39.30%) 21 783 (50.97%) 36 421 (53.70%) 5344 (26.01%) 9155 (21.88%) Age (years) <0.001     <0.001     <0.001 Epidemiology/Health Services Research  Mean (SD) 71.96 (13.29) 69.18 (12.92) 78.53 (15.07) 80.72 (10.66) 68.59 (11.84) 65.15 (12.38)  Median (Q1; Q3) 73.00 (65.00; 80.00) 70.00 (59.00; 80.00) 80.00 (73.00; 85.00) 83.00 (76.00; 88.00) 69.00 (61.00; 77.00) 65.00 (56.00; 75.00) Age (years)—n (%) <0.001     <0.001     <0.001  35–60 402 (16.16%) 1355 (26.79%) 2281 (5.34%) 4003 (5.90%) 4818 (23.45%) 15 737 (37.62%)  61–70 665 (26.73%) 1225 (24.22%) 5936 (13.89%) 6357 (9.37%) 6361 (30.96%) 10 925 (26.11%)  71–80 807 (32.43%) 1335 (26.40%) 13 651 (31.94%) 15 795 (23.29%) 6542 (31.84%) 10 002 (23.91%)  ≥81 614 (24.68%) 1143 (22.60%) 20 870 (48.83%) 41 673 (61.44%) 2823 (13.74%) 5172 (12.36%) Smoker—n (%) 700 (28.14%) 1770 (34.99%) <0.001 7088 (16.58%) 10 922 (16.10%) 0.040 8465 (41.20%) 21 187 (50.64%) <0.001 Obesity—n (%) 467 (18.77%) 558 (11.03%) <0.001 8503 (19.90%) 7352 (10.84%) <0.001 3886 (18.92%) 4727 (11.30%) <0.001 Hypertension—n (%) 1544 (62.06%) 2486 (49.15%) <0.001 20 201 (47.27%) 27 385 (40.37%) <0.001 12 813 (62.37%) 19 411 (46.40%) <0.001 Disorders of lipid 1290 (51.85%) 1917 (37.90%) <0.001 15 903 (37.21%) 14 314 (21.10%) <0.001 10 913 (53.12%) 15 828 (37.83%) <0.001 metabolism—n (%) Charlson Comorbidity Index† <0.001     <0.001     <0.001  Low 1252 (50.32%) 3098 (61.25%) 15 168 (35.49%) 28 872 (42.57%) 3890 (18.93%) 7243 (17.31%)  Medium 928 (37.30%) 1560 (30.84%) 20 096 (47.02%) 28 687 (42.29%) 13 334 (64.90%) 30 656 (73.28%)  High 308 (12.38%) 400 (7.91%) 7474 (17.49%) 10 269 (15.14%) 3320 (16.16%) 3937 (9.41%) *No data on eight hospital discharges. †Low: no disease; medium: one to two diseases; high: three or more diseases. AMI, acute myocardial infarction; CV, cardiovascular; DM, diabetes mellitus; NA, not applicable; Q1, first quartile; Q3, third quartile; T2DM, type 2 diabetes mellitus. BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 Epidemiology/Health Services Research Figure 2 Incidence rate of patients hospitalized due to CV complications per 1000 inhabitants and RR: unmatched T2DM and non-­DM groups. AMI, acute myocardial infarction; CV, cardiovascular; DM, diabetes mellitus; RRAMI, non-­fatal myocaridal infarction rate ratio; RRD, death from CV cause rate ratio; RRHI, heart failure rate ratio; RRR, revascularization ratio; RRUA, unstable angina rate ratio; T2DM, type 2 diabetes mellitus. cost continued to be higher in T2DM group for non-­fatal women in both study cohorts, which could be related to a AMI (only in men) and unstable angina. poorer prognosis compared with men. In a Spanish study in women hospitalized for ischemic stroke, an increased Additional analyses risk of mortality was observed in women with T2DM RECH database versus non-­DM (OR 1.07; 95% CI 1.05 to 1.11).9 In line with the results presented, a higher mean LOHS Regarding costs, the results of our analysis show a was observed in the T2DM group versus the non-­DM slightly higher cost for the population with T2DM in group for non-­ fatal AMI (8.01 vs 7.51, respectively), unstable angina and non-­fatal AMI. A Spanish study that unstable angina (6.62 vs 6.42, respectively) and revascu- evaluated hospitalized patients with a primary diagnosis larization (8.11 vs 7.98, respectively) (figure 4A). While of AMI found a slightly lower cost in patients with DM the mean direct cost was higher in the non-­DM group for versus non-­DM, €6228 and €6283, respectively (Euro the six CV complications evaluated (figure 4B). 2006).27 In line with our study, the differences between the two cohorts were minimal. A study in the USA40 DISCUSSION found that the total average cost was 2.2 times higher in The results of this study highlight the clinical and patients with T2DM versus non-­DM. However, although economic burden of hospital admissions due to CV the incidence of vascular complications was higher in events in patients with T2DM. In the group of patients the T2DM group, the average cost per CV event was with T2DM, a higher incidence was observed for all CV similar between groups. Another study that included complications evaluated compared with the non-­ DM 4657 Australian patients, although the association with group, with a RR over 3 for heart failure (RR=3.80), death CVD was not described,41 found that the presence of DM due to CV event (RR=3.05), unstable angina (RR=3.04) comorbidity increased both the cost of hospitalization and revascularization (RR=3.04). Also, for three of the (1.22-­fold; 95% CI 1.12 to 1.33, p<0.001) and LOHS (OR six CV complications evaluated (non-­fatal AMI, unstable 1.19; 95% CI 1.06 to 1.33, p=0.002). angina and revascularization), the mean LOHS increased Our results showed a lower hospital cost in the popula- between 5% and 9% in the group with T2DM. This, tion with T2DM for three complications: non-­fatal stroke, consequently, has economic implications given the fact heart failure and revascularization. Other Spanish studies that a reduction in LOHS may result in a decrease in the when evaluating hospitalized patients for transcatheter hospital costs and also provide free hospital-­bed-­days to aortic valve implantation or surgical aortic valve replace- be used for other patients.39 ment also found this same trend: lower costs in the T2DM Among the main results, a shorter LOHS was observed population versus the non-­DM, which they attributed to in patients with T2DM in the complication death due to shorter LOHS for patients with T2DM.42 However, the CV event (reduction of 6.60%; p=0.161). Patients with increase of hospitalization due heart failure in Spain T2DM have more comorbidities and CV risk factors.6 in the last years43 and the large difference in incidence Moreover, they present greater severity and worse clinical means that the overall cost remains clearly higher in characteristics, which would be associated with higher people with diabetes. inpatient mortality after a CV event. Furthermore, the Regarding heart failure, no statistically significant LOHS was shorter for death due to CV complication in differences were observed in this study in the LOHS BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 7 Epidemiology/Health Services Research Figure 3 (A) LOHS and (B) direct hospital costs (mean [SD]) attributable to CV complications by presence of T2DM: matched T2DM and non-­DM groups. Euros 2019. AMI, acute myocardial infarction; CV, cardiovascular; DM, diabetes mellitus; LOHS, length of hospital stay; T2DM, type 2 diabetes mellitus; Q1, first quartile; Q3, third quartile. between the two groups and the cost per hospitaliza- associated with some extent to the higher inpatient tion was slightly lower in the cohort with T2DM at mortality in patients with T2DM for this complication, €179 (reduction of 3.74%, p<0.001). These results Muñoz-­Rivas, et al44 found that inpatient mortality was corroborate those from Muñoz-­Rivas et al44 who, for the lower in the T2DM (8.15%) group compared with the 2013–2015 period, found both a shorter mean LOHS non-­DM group (10.54%). In fact, diabetes was associ- due to heart failure for the T2DM versus non-­DM popu- ated with a lower inpatient mortality (OR 0.84; 95% CI lation (8.43 vs 8.48, respectively) and a slightly lower mean cost per hospitalization in the T2DM versus the 0.83 to 0.86). Possible underdiagnosis of T2DM in non-­DM group (€4184 (€2575) and €4209 (€2822), patients hospitalized for heart failure could also affect respectively). Although these results could be a priori these results.45 8 BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 Epidemiology/Health Services Research Figure 4 (A) LOHS and (B) direct hospital costs attributable to CV complications by presence of T2DM (mean (SD)) (Red Española de Costes Hospitalarios database): matched T2DM and non-­DM groups. Euros 2019. AMI, acute myocardial infarction; CV, cardiovascular; DM, diabetes mellitus; LOHS, length of hospital stay; T2DM, type 2 diabetes mellitus. Moreover, the burden of the heart failure complication the presence of T2DM was statistically significantly asso- must be placed in context bearing in mind that in our ciated with all-­cause mortality (HR 1.54; 95% CI 1.20 to study it is the complication that shows the largest differ- 1.97, p=0.001) and with a higher probability of readmis- ences in the incidence between the T2DM and non-­DM sions (HR 1.46; 95% CI 1.18 to 1.80, p<0.001). cohorts (RR=3.80). Muñoz-­Rivas et al44 estimated a five- Among the main strengths of this study is that it is the fold higher risk (IRR 4.93; 95% CI 4.91 to 4.95) in patients first time that LOHS and cost of the CV complications, with T2DM. Finally, in another Spanish study based on classified considering MACE variable, are evaluated in data from the National Heart Failure Registry (Registro the Spanish setting. The study also provides data on the Nacional de Insuficiencia Cardiaca)46 in which patients incidence, hospital stays and costs comparing T2DM and hospitalized for heart failure were followed up for 1 year, non-­DM populations stratified by age and sex. The data BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 9 Epidemiology/Health Services Research used are representative of the entire Spanish context, as LOHS or required more procedures while admitted.27 the SNHDD from the MoHCASW pools data from all the To overcome this, the results based on the SNHDD were Spanish AC. checked against the RECH38 database which provides The results of this study could serve to support health more detailed information on hospitalization costs, decision-­making by establishing the economic cost of CV making it possible to differentiate the cost based on the events avoided in Spain, and providing complementary actual resource used during hospitalization. information on the most widely used intermediate vari- Only direct hospital costs were considered in this anal- ables, such as hemoglobin A1c (HbA1c) and weight.29 ysis, which represent one of the main direct cost item The main limitation of this study is related with the use associated with CV events,49 reaching up to 48.6% of the of the administrative SNHDD, as the results are condi- mean direct health cost in the case of stroke.50 Other tioned by the quality of the data record in the discharge relevant cost categories would be non-­healthcare direct reports. While this database is an extremely useful tool costs, for example, informal care that represents 60% of in hospital management, it lacks relevant information the total average cost.50 Other studies have also estimated to assess the impact on the results obtained, such as left the cost associated with MACE events including only the ventricular ejection fraction, medication, like statins or cost of the event the first time it occurs or the year of the aspirin, taken by patients prior to or during hospitaliza- event.28 However, it is far to notice that CV complications tion or other variables of interest in the patient’s medical can have clinical and economic repercussions in both the history.39 Other limitations include possible undercoding medium-­term and long-­term. of T2DM in the hospital setting as HbA1c is not deter- mined during hospitalization or that recording of T2DM Conclusion diagnoses in the SNHDD is low.5 27 44 Additionally, there CV complications associated with T2DM represent a is often some difficulty in correctly coding the type of major burden for the Spanish healthcare system as diabetes as T1DM being sometimes reported if the patient LOHS are longer or equivalent in patients with T2DM uses multiple doses of insulin and T2DM if being treated compared with the non-­DM population. Both the inci- with antidiabetics and/or basal insulin. Nonetheless, the dence and number of hospital discharges per patient for SNHDD is widely used in the study of hospital discharges all the CV complications are higher in the T2DM popu- in patients with T2DM,5 6 8 9 25–27 39 42 44 and the diagnosis lation. Finally, in terms of the unstable angina and revas- of diabetes in SHNDD was validated in a previous study, cularization complications, the cost per hospitalization is where a sensitivity of 55% was observed and a specificity higher in patients with T2DM than in the non-­DM group. of close to 97%, which would indicate that may be some This is the first study evaluating the clinical and patients with T2DM who are not encoded in the discharge economic impact of CV complications (defined as report, but that most patients not diagnosed with T2DM MACE) comparing T2DM and non-­DM populations and do not have T2DM, as suggested by the high specificity.47 including representative data from the national Spanish Another limitation is due to the methodology used for setting. matching. After a thorough review of the literature and evaluation by the clinical coordinators of the study, the Author affiliations 1 exact matching between T2DM and non-­DM according Department of Endocrinology and Nutrition, Quirón Salud Madrid and Ruber Juan Bravo University Hospitals, Universidad Europea de Madrid, Madrid, Spain to sex, age and AC of the hospital seemed correct. While 2 José Marvá Health Centre, RedGDPS Foundation, Madrid, Spain it is true that other covariates in the matching such as 3 Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, IIB-­Sant smoking, obesity, hypertension and lipid metabolism Pau Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain 4 could have been considered, it was decided not to Oblikue Consulting, S.L, Barcelona, Spain 5 include them, given the nature of the database used, Novo Nordisk Pharma SA, Madrid, Spain which was designed for administrative purposes rather Acknowledgements The authors would like to thank Elisenda Pomares who than research. Thus, these conditions may not have been helped in the data analysis and interpretation. adequately recorded in the database.47 Previous studies Contributors All authors contributed to the study conception and design, data in Spain and other countries found that smoking, obesity interpretation and the drafting of the manuscript. EU and RP contributed to are frequently not coded in administrative database.9 47 48 the analysis of the study. All authors gave final approval for this version to be Additionally, we could also have evaluated trends in the published. cost and prevalence of CV complications in recent years. Funding This study was funded by Novo Nordisk Pharma SA. Oblikue Consulting However, the objective was not to evaluate temporal received funding from Novo Nordisk Pharma SA for the development and analysis of this study. Oblikue Consulting performed the analysis independently. trends but rather to carry out a cross-­ sectional study to estimate the cost of these complications in the most Competing interests EU, NL-­M and RP are employees of Oblikue Consulting. EJ, SA and XG-­M received an honorarium from the sponsor and participated as recent year available in Spain at the time of the study. independent consultants. VM is a Novo Nordisk Pharma SA employee. A further limitation would be that the costs obtained Patient consent for publication Not required. from the SNHDD correspond to the cost per DRG which Ethics approval This study does not contain any studies with human participants or implies a series of limitations as it represents an equal animals performed by any of the authors. It is exclusively based on the exploitation of cost for each DRG code. It is not possible to differentiate information from the Spanish National Hospital Discharge Database (SNHDD), which the cost depending on whether the patient had a longer is hosted by the Ministry of Health, Consumer Affairs and Social Welfare (MoHCASW). 10 BMJ Open Diab Res Care 2020;8:e001130. doi:10.1136/bmjdrc-2019-001130 Epidemiology/Health Services Research The SNHDD is regulated by the Spanish law and both dissociation and anonymization 14 Diabetes Canada Clinical Practice Guidelines Expert Committee. of all the records enclosed in it are guaranteed. The data were requested to the Diabetes Canada 2018 clinical practice guidelines for the MoHCASW, which evaluated our study and concluded that it complied with all ethical prevention and management of diabetes in Canada. Can J Diabetes aspects in accordance with the Spanish legislation. 2018;42:S1–326. 15 Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement Provenance and peer review Not commissioned; externally peer reviewed. by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 Data availability statement Data may be obtained from a third party and are not diabetes management algorithm - 2019 executive summary. Endocr publicly available. According to the agreement signed with the Spanish Ministry Pract 2019;25:69–100. of Health, Consumer Affairs and Social Welfare, which provided access to the 16 Reyes-­García R, Moreno-­Pérez Óscar, Tejera-­Pérez C, et al. databases from the Spanish National Hospital Discharge Database (Conjunto Document on a comprehensive approach to type 2 diabetes Mínimo Basico de Datos; CMBD), the authors cannot share the databases with any mellitus. Endocrinol Diabetes Nutr 2019;66:443–58. 17 Gomez-­Peralta F, Escalada San Martín FJ, Menéndez Torre E, other investigator, and the databases have to be destroyed once the investigation et al. Spanish diabetes Society (SED) recommendations for the has concluded. Consequently, the authors cannot upload the databases to pharmacologic treatment of hyperglycemia in type 2 diabetes: 2018 any public repository. However, any investigator can apply for access to the update. Endocrinol Diabetes Nutr 2018;65:611–24. databases by filling out the questionnaire available at: https://www.​mscbs.​gob.​es/​ 18 Artola Menéndez S, Práctica D. Actualización del algoritmo de estadEstudios/​estadisticas/​estadisticas/​estMinisterio/​SolicitudCMBDdocs/​2018_​ hiperglucemia 2017. Diabetes Práctica 2017;08:57. Formulario_​Peticion_​Datos_​RAE_​CMBD.​pdf. All other relevant data are included in 19 American Diabetes Association. Standards of medical care in diabetes - 2019. Diabetes Care 2019;42:1–187. the paper. 20 Arrieta F, Iglesias P, Pedro-­Botet J, et al. Diabetes mellitus and Open access This is an open access article distributed in accordance with the cardiovascular risk: update of the recommendations of the diabetes Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which and cardiovascular disease Working group of the Spanish diabetes permits others to distribute, remix, adapt, build upon this work non-­commercially, Society (SED, 2018). Clin Investig Arterioscler 2018;30:137–53. 21 Ruiz-­García A, Arranz-­Martínez E, Morón-­Merchante I, et al. and license their derivative works on different terms, provided the original work is Consensus document of the Spanish Society of arteriosclerosis (sea) properly cited, appropriate credit is given, any changes made indicated, and the for the prevention and treatment of cardiovascular disease in type 2 use is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. diabetes mellitus. Clin Investig Arterioscler 2018;30:1–19. 22 Fu AZ, Qiu Y, Radican L, et al. Impact of concurrent macrovascular ORCID iD co-­morbidities on healthcare utilization in patients with type Noemí López-­Martínez http://​orcid.​org/​0000-​0001-​9339-​3883 2 diabetes in Europe: a matched study. Diabetes Obes Metab 2010;12:631–7. 23 Mata-­Cases M, Casajuana M, Franch-­Nadal J, et al. 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