Impact of immune thrombocytopenic purpura on clinical outcomes in patients with acute myocardial infarction

Abstract Background Patients with immune thrombocytopenic purpura (ITP) admitted with acute myocardial infarction (AMI) may be challenging to manage given their increased risk of bleeding complications. There is limited evidence in the literature guiding appropriate interventions in this population. The objective of this study is to determine the difference in clinical outcomes in AMI patients with and without ITP. Methods Using the United States national inpatient sample database, adults aged ≥18 years, who were hospitalized between 2007 and 2014 for AMI, were identified. Among those, patients with ITP were selected. A propensity‐matched cohort analysis was performed. The primary outcome was in‐hospital mortality. Secondary outcomes were coronary revascularization procedures, bleeding and cardiovascular complications, and length of stay (LOS). Results The propensity‐matched cohort included 851 ITP and 851 non‐ITP hospitalizations for AMI. There was no difference in mortality between ITP and non‐ITP patients with AMI (6% vs7.3%, OR:0.81; 95% CI:0.55‐1.19; P = .3). When compared to non‐ITP patients, ITP patients with AMI underwent fewer revascularization procedures (40.9% vs 45.9%, OR:0.81; 95% CI:0.67‐0.98; P = .03), but had a higher use of bare metal stents (15.4% vs 11.3%, OR:1.43; 95% CI:1.08‐1.90; P = .01), increased risk of bleeding complications (OR:1.80; CI:1.36‐2.38; P < .0001) and increased length of hospital stay (6.14 vs 5.4 days; mean ratio: 1.14; CI:1.05‐1.23; P = .002). More cardiovascular complications were observed in patients requiring transfusions. Conclusions Patients with ITP admitted for AMI had a similar in‐hospital mortality risk, but a significantly higher risk of bleeding complications and a longer LOS compared to those without ITP. Further studies are needed to assess optimal management strategies of AMI that minimize complications while improving outcomes in this population.


| INTRODUCTION
Immune thrombocytopenic purpura (ITP) is an autoimmune hematological disorder where antibodies directed against platelets lead to premature platelet destruction, resulting in low platelet count and increased tendency for mucocutaneous bleeding. It is a relatively rare disease with an incidence of about 10-125 cases per million per year. 1 Despite thrombocytopenia, there is an increased risk of thrombotic complications due to the presence of abnormally enlarged immature platelets and increased antibody-mediated damage to the endothelium. 2 Additionally, the thrombotic risk is amplified by therapies targeting ITP such as steroids, intravenous immune globulins and rituximab. 3 Patients with ITP are at increased risk of bleeding complications and as such, those presenting with acute myocardial infarction (AMI) requiring revascularization or antiplatelet therapy may be challenging to manage. 4,5 The exact incidence of AMI in ITP is not reported in the literature and the topic appears to be mostly addressed in brief reports. [6][7][8][9] Moreover, guidelines on the management of AMI in ITP patients are ambiguous as ITP patients were excluded from the majority of trials addressing therapy of AMI. 6,10 Given the low incidence of ITP in the general population, there are no large center studies focusing on the impact of ITP on the outcomes of myocardial ischemia. Herein, we resort to the US-based national level inpatient data to study the impact of ITP in patients admitted with AMI on mortality, coronary revascularization therapy, in-hospital complications and length of stay.

| Study design
The study data was retrieved from the national inpatient sample (NIS), the largest all-payer inpatient care database in the United States. The NIS contains discharge-level data on more than seven million hospitalizations and approximates a sample of 20% of all US community hospitals. The sampling methodology adopted by the NIS allows the approximation of national estimates by applying weighting variables to the discharges. 11 Hospitalizations within the database provide basic demographic information such as age, gender, and race as well as the international classification of diseases, ninth revision, clinical modification (ICD-9-CM) coded diagnoses, outcomes, total costs and lengths of hospital stay. 11 Since we used a public database with no reports of patient personal identifying information, this study was deemed exempt by the Institutional Review Board.

| Study population
Our study population includes patients ≥18 years of age, admitted with a primary discharge diagnosis of AMI using the ICD-9-CM code 410 between 2007 and 2014, with or without ITP. A systematic review of the discharge diagnosis codes for AMI found that the ICD-9-CM code 410 had a 94% sensitivity and 99% specificity. 12 ITP was identified using the ICD-9 code 287.31 as a secondary diagnosis. Specific details of the study population are highlighted in Figure 1. Those who were discharged on the same day, transferred between facilities, or with an elective admission, were excluded from the analysis. Those hospitalized with possible secondary causes of ITP such as coagulation disorders and other causes of thrombocytopenia, such as systemic lupus erythematosus, human immunodeficiency virus (HIV), sepsis, malignancies, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and pregnancy were excluded, as highlighted in the study by Danese et al. 13 The ICD-9 codes used to identify these conditions are listed in the supplementary file.

| Outcomes
The primary outcome of interest was in-hospital mortality. Secondary outcomes were revascularization therapies (percutaneous coronary intervention, bare metal stents, and drug eluting stents coronary bypass), bleeding (epistaxis, hematoma, gastrointestinal, genitourinary and intracranial bleeds), cardiovascular complications (cardiogenic shock, complete heart block, hemopericardium and cardiac tamponade, and iatrogenic cardiac complications), blood product transfusions and length of hospital stay. We further examined the outcomes in ITP and non-ITP hospitalization in the following prespecified subgroups: patients with ST-elevation myocardial infarction (STEMI) and patients with non-ST-elevation myocardial infarction (NSTEMI). Data pertaining to the outcomes were extracted from the NIS database using their corresponding ICD-9 codes illustrated in the supplementary index.

| Statistical analysis
A propensity score matching model was developed to derive two matched groups for comparative outcome analysis, to account for potential confounding factors and reduce the effect of selection bias. We used a multivariable logistic regression model with AMI with ITP as the outcome variable, and all co-morbidities in Table 1 and patientlevel NIS weights as covariates. We used a one-to-one greedy matching protocol and a caliper width of 0.1 multiplied by the SD of the logit of the propensity score to create a matched cohort that includes matched demographics, comorbidities, and year of admission, between ITP and non-ITP hospitalization with AMI. 14, 15 We first conducted bivariate analyses to compare demographic, clinical and hospital characteristics in AMI admissions with and without ITP. Chi-square tests were used for categorical variables and the t-test for continuous variables with normal distribution. For matched variables, the mean and SD were reported for continuous variables, and percentages were reported for categorical variables. Binary outcomes were modeled with binomial logistic regressions, while discrete numeric variables were modeled with generalized linear model regressions. Subsequently, a stratified analysis was done on those hospitalized with ITP who received transfusions to identify the effect of transfusion on major outcomes in ITP hospitalization. Multivariable logistic regression was performed to identify the predictors of these major outcomes.
Variables included in the model were age and sex, in addition to statistically and clinically significant variables derived from univariate analysis. Cumulative in-hospital mortality among AMI hospitalization with and without ITP was characterized using a Kaplan-Meier plot, with the log-rank (Mantel-Cox) test used for comparison between the two groups.
Data extraction and analyses were performed with IBM SPSS statistics (Version 25.0 Armonk, NY). All statistical tests were two-sided and a P value of <.05 was considered statistically significant.

| In-patient short-term mortality
There was no significant difference between patient with AMI and ITP when compared to those without ITP (6% vs 7.3%, OR:0.81; 95% CI: 0.55-1.19; P = .3). This is further illustrated in Kaplan-Meier curves ( Figure S1) showing no difference in cumulative survival between hospitalizations for AMI of patients with and without ITP at different time intervals since admission (P = .5 using log-rank test). When stratified based on the type of AMI (STEMI or NSTEMI), it was found that there was no difference in short-term inpatient mortality between hospitalizations of ITP and non-ITP patients for both STEMI (8.6% vs 14.9%, OR:0.54; 95%CI: 0.28-1.00; P = .05) and NSTEMI (5.3% vs 4.6%, OR:1.15; 95%CI: 0.70-1.91; P = .6) ( Table 2). and NSTEMI, those who were admitted with ITP and STEMI had similar rates of revascularization with either PCI or CABG compared to non-ITP (Table 2). However, those admitted with NSTEMI and ITP were less likely to undergo PCI (23.2% vs 31.3%, OR: 0.66; 95%CI: 0.52-0.85; P = .001) compared to those hospitalized with no ITP, but no difference was noted using CABG as a method of revascularization.

| Implantation of bare metal vs drug eluting stent
Among patients admitted with AMI who had PCI, bare metal stents were used more in patients with ITP (15.4% vs11.3%, OR:1.43;95% CI:1.08-1.90; P = .01) whereas drug eluting stents were used more in patient with non-ITP (12.7% vs 24.6%, OR = 0.45; 95% CI:0.35-0.58; P < .0001). The proportion of ITP vs non-ITP patients among those who obtained a bare metal stent and those who obtained a drug eluting stent were 55% vs 45% and 32.3% vs 67.7%, respectively (P < .0001). Similar findings were noted in those admitted with STEMI T A B L E 1 Baseline characteristics of acute myocardial infarction hospitalizations with and without immune thrombocytopenic purpura (ITP)

| Length of hospital stay
Overall, hospitalizations with ITP had a longer hospital stay compared to non-ITP (6.14 vs 5.4 days; mean ratio: 1.14; CI: 1.05-1.23; P = .002) with AMI. When stratified by STEMI and NSTEMI, those with ITP and NSTEMI had a significantly longer mean hospital stay compared to non-ITP admissions (6.44 vs 5.54 days, P = .001), but no difference was noted among STEMI hospitalizations (5.09 vs 5.02 days, P = .9).

| Transfusion of blood products
We also explored whether transfusion of blood products (including both platelets and packed red blood cells) were predictors of major adverse events in those admitted with ITP (  Khera et al. (2015), revascularization rates were similar such that PCI was performed in 68.4% of women and 76.7% of men who experienced STEMI. This latter study primarily looked into patients ranging from 18 to 59 years old. 21 Thus, our data reflects a real-world situation and the population which is much more heterogeneous compared to myocardial infarction-research populations.
Moreover, our study found that there is greater tendency to place bare metal stents and lesser tendency to place drug eluting stents in ITP patients with AMI compared to the non-ITP patients. These findings were consistent with Ayoub et al, in which they found that patients with a history of chronic thrombocytopenia are more likely to undergo bare metal stentings and less likely to undergo drug eluting stents compared to patients with normal platelet levels. 22 It is likely that physicians prefer the use of bare metal stents in patients with lower platelet levels to avoid longer treatment with dual anti-platelet therapy as highlighted in a review by McCarthy et al. 23 43 Since the study is cross sectional in the nature, establishment of causality was not possible.
Reverse causality is however less likely as the studied outcomes are not known to cause ITP. Finally, since the database relies heavily on reported diagnoses, our study is at high risk for misclassification bias. Misclassification in this case is more likely to be nondifferential, drawing the study results toward the null hypothesis. These limitations were compounded by a large sample size of an underrepresented population along with the use of propensity-matched cohorts which significantly reduced the risk of both selection and confounding bias.

| CONCLUSION
Despite no difference in in-hospital mortality between ITP and non-ITP patients admitted for AMI, those with ITP were more likely to have bleeding complications and require a longer hospital stay. Bare metal stents were more likely to be utilized in ITP patients than drug eluting stents. Moreover, ITP patients who required transfusions were found to have a higher frequency of cardiovascular complications.
This reflects the need for evidence-based guidelines to standardize the management of patients with ITP and other thrombocytopenic disorders presenting with AMI, assess the best revascularization strategy, platelet cutoff for interventions, antiplatelet choice and duration, and perioperative strategies to minimize complications and improve outcomes in this under-represented population.
infarction: a meta-analysis and diversity-adjusted study sequential analysis.