Diabetes association with self‐reported health, resource utilization, and prognosis post‐myocardial infarction

Abstract Background Diabetes mellitus (DM) is associated with increased cardiovascular (CV) risk. We compared health‐related quality of life (HRQoL), healthcare resource utilization (HRU), and clinical outcomes of stable post‐myocardial infarction (MI) patients with and without DM. Hypothesis In post‐MI patients, DM is associated with worse HRQoL, increased HRU, and worse clinical outcomes. Methods The prospective, observational long‐term risk, clinical management, and healthcare Resource utilization of stable coronary artery disease study obtained data from 8968 patients aged ≥50 years 1 to 3 years post‐MI (369 centers; 25 countries). Patients with ≥1 of the following risk factors were included: age ≥65 years, history of a second MI >1 year before enrollment, multivessel coronary artery disease, creatinine clearance ≥15 and <60 mL/min, and DM treated with medication. Self‐reported health status was assessed at baseline, 1 and 2 years and converted to EQ‐5D scores. The main outcome measures were baseline HRQoL and HRU during follow‐up. Results DM at enrollment was 33% (2959 patients, 869 insulin treated). Mean baseline EQ‐5D score (0.86 vs 0.82; P < .0001) was higher; mean number of hospitalizations (0.38 vs 0.50, P < .0001) and mean length of stay (LoS; 9.3 vs 11.5; P = .001) were lower in patients without vs with DM. All‐cause death and the composite of CV death, MI, and stroke were significantly higher in DM patients, with adjusted 2‐year rate ratios of 1.43 (P < .01) and 1.55 (P < .001), respectively. Conclusions Stable post‐MI patients with DM (especially insulin treated) had poorer EQ‐5D scores, higher hospitalization rates and LoS, and worse clinical outcomes vs those without DM. Strategies focusing specifically on this high‐risk population should be developed to improve outcomes. Trial registration ClinicalTrials.gov: NCT01866904 (https://clinicaltrials.gov).

health status was assessed at baseline, 1 and 2 years and converted to EQ-5D scores.
The main outcome measures were baseline HRQoL and HRU during follow-up.
Results: DM at enrollment was 33% (2959 patients, 869 insulin treated). Mean baseline EQ-5D score (0.86 vs 0.82; P < .0001) was higher; mean number of hospitalizations (0.38 vs 0.50, P < .0001) and mean length of stay (LoS; 9.3 vs 11.5; P = .001) were lower in patients without vs with DM. All-cause death and the composite of CV death, MI, and stroke were significantly higher in DM patients, with adjusted 2-year rate ratios of 1.43 (P < .01) and 1.55 (P < .001), respectively.
Conclusions: Stable post-MI patients with DM (especially insulin treated) had poorer EQ-5D scores, higher hospitalization rates and LoS, and worse clinical outcomes vs those without DM. Strategies focusing specifically on this high-risk population should be developed to improve outcomes.
Trial registration: ClinicalTrials.gov: NCT01866904 (https://clinicaltrials.gov).  1 Moreover, heart disease, including acute myocardial infarction (MI), is not only the leading cause of death but also the leading cause of lost disability-adjusted life years worldwide. DM is a major factor contributing to this burden of cardiovascular (CV) disease. 2 It is well established that DM is independently and strongly associated with CV risk. 3,4 In addition, patients with prior MI who also have DM comprise an important group at a heightened risk of major adverse CV events (MACE), including hospitalizations for heart failure (HF) and all-cause mortality. [5][6][7] These associations are even more important given the fact that, even with contemporary standard of care, patients with DM and prior MI have a reduced risk of MACE with prolonged dual antiplatelet therapy, 8 high-intensity lipid-lowering therapy, 9,10 and newer antihyperglycemic drugs with proven CV outcome benefits. 11 While the impact of DM in terms of "hard" clinical outcomes, such as recurrent MI, stroke, and CV mortality, is recognized, very little is known regarding its association with patient-reported outcomes, such as health-related quality of life (HRQoL) and healthcare resource utilization (HRU).
Several studies have demonstrated that DM may have a considerable negative impact on HRQoL in patients suffering from acute coronary syndrome (ACS), [12][13][14][15][16] with one report showing no association. 17 However, these studies had limitations such as small sample size, short-term follow-up, or being restricted to a single country.
Data regarding the potential impact of DM on HRU in the longterm after MI are even more scarce. Janzon et al demonstrated that patients deemed to be at high risk after MI contributed to a substantial burden on HRU. 18 Considering that DM is highly associated with recurrent hospitalizations due to recurrent ischemic MACE and HF, 5,6 its potential impact on HRU in a stable post-MI population is of major interest. Therefore, we sought to contribute to a better understanding of these issues in patients with DM in the TIGRIS (long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease) registry, which includes a unique international population with MI 1 to 3 years prior to enrollment. year prior to study enrollment, multivessel coronary artery disease, creatinine clearance ≥15 and <60 mL/min, and DM treated with medication. Main exclusion criteria were any condition or circumstance that could limit the complete follow-up of the patient (eg, end-stage disease with a life expectancy of <1 year, psychiatric disturbances, alcohol or drug abuse); current participation in a blinded, randomized controlled trial; and treatment with ticagrelor beyond 12 months after MI or off-label use of ticagrelor.
Data were collected during the initial visit and every 6 months thereafter for 24 months by telephone or in person. The EuroQol Research Foundation survey instrument for measuring self-reported health status in 5 dimensions (EQ-5D; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with three levels of severity (EQ-5D-3L; none, moderate, and severe) was completed by every individual at each visit. 21,22 A standardized electronic case report form was used for data collection, which included medical history, demographics, variables from routine examination (at baseline), medication use, HRU, and clinical events (ischemic and hemorrhagic), during follow-up.
In the present study, 8968 patients (97.2% of the total population) with complete data on DM status were analyzed. Data on selfreported health status were available in 7260 patients, and data on HRU were available in 7838 patients. The main focus of this study was HRQoL at baseline and HRU during follow-up.

| Statistical analysis
Comparisons of patient characteristics by DM status were summarized by mean and SD for quantitative variables and by frequency/ percentage for categorical variables. P-values were based on a 2-sample t-test, χ 2 test, and test for trend for quantitative, binary, and ordinal variables, respectively.
For the EQ-5D-3L self-reported health questionnaire, the United Kingdom (UK)-weighted index has been used as the most widely accepted summary of overall health status. 23 This combines the five domains (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety) into a single score. A score of 1 indicates "no problems" on all five items, and a score of less than 1 indicates increasingly poor self-rated health status, down to a rare score of 0 indicating a state rated as "bad as being dead." Hospitalizations and other HRU items were based on 6-monthly patient recall during follow-up at 6, 12, 18, and 24 months after enrollment. These have been totaled to summarize each patient's HRU over 24 months of follow-up. The 2-year percentage incidence of clinical outcomes is reported by DM status, using Kaplan-Meier estimates to account for patients lost to follow-up. Poisson regression models were used to adjust for other baseline influences on risk of event. Variables included in the adjustment were those in the TIGRIS risk index model, 24 which were age ≥65 years, second prior MI, chronic kidney disease, HF, peripheral artery disease, CV event in the past 6 months, major bleeding, medical management of index MI, diuretic use, EQ-5D-weighted index score, region, and country (as random effects). All analyzes were performed using STATA version 15.1.

| RESULTS
In this population of 8968 patients 1 to 3 years post-MI, 2959 (33%) had DM, of whom 869 (29%) were treated with insulin (see CON-SORT diagram; Figure S1). Baseline characteristics of the population by DM status are described in Table S2. Compared with patients without DM, patients with DM were younger (67.5 vs 65.8 years) and had a higher body mass index (BMI; 26.9 vs 28.3 kg/m 2 ). Patients with DM also had a higher prevalence of peripheral artery disease (5.2% vs 9.8%), HF (10.0% vs 14.6%), anemia (2.3% vs 4.1%), angina (8.9% vs 12.2%), and stroke (3.7% vs 5.9%). Moreover, patients with DM also had higher CV event-related hospitalization rates in the 6 months prior to enrollment (5.0% vs 6.4%). All these measures were more pronounced in patients with insulin-dependent DM, which comprised both patients with type 1 (N = 86) and type 2 (N = 783) DM (Table S3). Table S4 shows the prevalence of DM by region and country. The highest prevalence of DM was observed in Asia and Australia (37.0%), followed by Latin America (36.3%). The lowest prevalence was observed in Europe (29.2%). Table S5 shows the utilization of evidence-based treatments at enrollment by DM status. Of note, the use of dual antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and beta-blockers was higher in patients with DM. Conversely, patients without DM were treated more often with statins and/or other lipid-lowering drugs. Table 1 and Figure 1A show the association of DM with selfreported health status at baseline using the EQ-5D-3L questionnaire.
Patients with DM reported more problems in each domain of the EQ-5D questionnaire, which resulted in an overall significantly worse mean EQ-5D UK-weighted index score at enrollment. The mean EQ-5D visual analog score was also significantly worse in patients with DM. For all these aspects of EQ-5D, patients with insulin-treated DM fared worse than patients with noninsulin-treated DM. Table 2 documents how self-reported health status was poorer in patients with DM, especially those treated with insulin, and also deteriorated more over the 2-year follow-up. These associations persisted after adjustment for other patient characteristics and were driven by significantly poorer scores in each domain of the EQ-5D questionnaire, with the exception of anxiety/depression in which solely insulin-treated DM patients fared worse.
In terms of HRU, Table 3 and Figure 1B Table S6 shows the incidence of hospitalizations for CV events and bleeding events, emergency, and general practitioner visits for CV or bleeding events, cardiologist visits, and other specialist visits. The results are consistent with those shown in Table 1, with higher HRU in those with DM than in those without DM. All these aspects of HRU (except for cardiologist visits) were more pronounced in patients who were treated with insulin.
Regarding clinical outcomes, Table S7 shows that DM had significant associations with the risk of atherosclerotic events (MI, stroke, and unstable angina requiring urgent revascularization) and deaths (both all-cause and CV) but not with major bleeding events.  For the EQ-5D UK-weighted index, a score of 1 indicates no problems for mobility, self-care, usual activities, pain/discomfort, or depression/anxiety, whereas a score of 0 indicates a state as bad as death. b For the EQ-5D visual analog scale, a score of 100 indicates "best health you can imagine," while a score of 0 indicates "worst health you can imagine." between insulin-treated DM and non-DM ( pected finding could be ascribed to uncontrolled confounders rendering a spurious association or to the fact that subjects lost to follow-up in that cohort were more likely to have DM. 17 These previous reports enrolled patients from single countries. Considering reports including patients from different global regions, a subanalysis from the randomized MERLIN trial also found that DM was associated with lower HRQoL scores in serial measurements for 1 year after ACS. 14 In a subanalysis from the PLATO trial, DM was also independently associated with a worse HRQoL at 1 year after ACS, with parameter estimates comparable to those observed in patients having a prior MI. 16 In contrast to these two reports, in the TIGRIS registry, patients had experienced their last MI more than 1 year ago; therefore, the HRQoL could be assessed more remotely from the acute event. In addition, owing to less stringent inclusion criteria than those required for randomized clinical trials, TIGRIS enrolled a population more representative of Mean EQ-5D UK-weighted index score at baseline (N = 8919) Crude effect a (95% CI) P-value Adjusted effect a,b (95% CI) P-value definitive causal relationship, since the results could be related to unmeasured confounders.

| CONCLUSIONS
In stable outpatients' post-MI, the presence of DM is associated with decreased long-term survival and an increased risk for ischemic events. In addition, DM is associated with a higher HRU and worse HRQoL. These results could help inform healthcare system planning internationally in view of the global DM pandemic.

ACKNOWLEDGMENTS
Editorial support was provided by Cactus Life Sciences (part of Cactus Communications) and funded by AstraZeneca. The long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease (TIGRIS) study is sponsored by AstraZeneca