Dual antiplatelet therapy in patients with cirrhosis and acute myocardial infarction – A 13-year nationwide cohort study

Background Patients with cirrhosis and acute myocardial infarction (AMI) present dilemma whether dual antiplatelet therapy (DAPT) should be used. Methods Electronic medical records between 2001–2013 were retrieved from Taiwan National Health Insurance Research Database. Patients were excluded for missing information, age <20 years old, history of AMI, liver transplant, autoimmune disease, coagulopathy, taking DAPT 3 months before index date, follow-up <3 months, anticoagulation user, without DAPT, and events of myocardial infarction (MI), ischemic stroke, major bleeding, and heart failure within 3-month of enrollment. Primary outcomes were 1-year all-cause mortality, recurrent MI, major bleeding, and gastrointestinal bleeding. Results A total of 150,887 patients with AMI retrieved. After exclusion criteria and propensity score-matching, 914 cirrhotic and 3,656 non-cirrhotic patients with AMI on DAPT were studied. During 1-year follow-up, there was significantly increased mortality in cirrhotic patients compared to non-cirrhotic patients (HR = 1.49, 95% CI = 1.28–1.74). There was significantly decreased recurrent MI in cirrhotic patients compared to non-cirrhotic patients (subdistribution HR [SHR] = 0.71, 95% CI = 0.54–0.92). However, non-significantly increased major bleeding (SHR = 1.23, 95% CI = 0.87–1.73) and significantly increased gastrointestinal bleeding (SHR = 1.49, 95% CI = 1.31–1.70). Conclusions In cirrhotic patients with AMI, DAPT offers benefit with decreased recurrent MI at the expense of increased gastrointestinal bleeding.


Introduction
Coronary artery disease (CAD) burden is found in 20%-26% of all patients with end-stage liver disease, with increased mortality up to 40% even 1 year after liver transplant [1][2][3]. Since cirrhotic patients are at high risk of bleeding due to the inherent complications of thrombocytopenia, coagulopathy and variceal bleeding, those who have coexisting CAD are at management dilemma. In cirrhotic patients with acute myocardial infarction (AMI), the decision to use of dual antiplatelet therapy (DAPT) therefore can be a difficult one.
Percutaneous coronary intervention (PCI) has traditionally not been an option in patients with end-stage liver disease with many debating the risk and benefits of the requisite antiplatelet use. Initially, for patients with end-stage liver disease being candidate for liver transplant, there is the mandatory management of possible CAD by PCI prior to the transplant surgery. A study with a small group of liver transplant candidates of whom the majority had significant thrombocytopenia, PCI was demonstrated feasible and safe [4]. In another study where 423 patients with cirrhosis underwent liver transplant evaluation, coronary artery stenting with antiplatelet therapy was shown to be safe in cirrhotic patients without varices [5]. However, in recent study with 148 cirrhotic patients with CAD underwent stenting, there was a significantly increased risk of gastrointestinal bleeding without affecting survival and the it remained unclear whether cardiovascular benefits of stenting with DAPT outweigh the risk of bleeding [6].
Therefore in this study, we aimed to investigate whether DAPT is an appropriate therapy in cirrhotic patients with AMI.

Data source
Taiwan's National Health Institute (NHI) Program started in 1995 and provides 99.5% coverage for the 23 million residents in Taiwan. The NHI Research Database (NHIRD) provides all dates of inpatient and outpatient services, diagnosis, prescriptions, examinations, operations, and expenditures, and data are updated biannually. With over 95% of Taiwan's population consists of Han Chinese, our study is considered of uniform ethnic background. The NHI system offers detailed follow-up information on medication, intervention, admission, outpatient clinic, and emergency visit of patients. In addition, accurate records of health reimbursement is ensured by prescription of medications and arrangement of interventions be followed by appropriate examinations and indications, otherwise false reimbursement claims results in magnified penalty. Medications for chronic illnesses were refilled at outpatient clinic with a maximum length of 3 months per the Taiwan NHI reimbursement policy. The hospital identification number of each patient was encrypted and de-identified to protect their privacy, therefore informed consent was waived for this study. The study conformed to the principles of the Helsinki Declaration and the Institutional Review Board of Chang Gung Memorial Hospital Linkou Branch approved this study.

Study patients
By searching electronic medical records from the NHIRD between January 1, 2001 and December 31, 2013, we retrieved patients with a principal diagnosis of AMI admission. The first episode of AMI strike of each individual was selected as the index admission. We further identified patients with diagnosis of cirrhosis (two consecutive outpatient diagnoses or one inpatient diagnosis). Both the diagnostic codes of AMI and liver cirrhosis in the NHIRD have been validated against hospital electronic medical records in previous studies, with AMI and liver cirrhosis having positive predictive value of 88% and 100% respectively [7,8]. The date of discharge from the index admission was defined as the index date.
Patients who had missing information, age <20 years old, had history of AMI, liver transplant, autoimmune disease, and coagulopathy were excluded. We also excluded patients with conditions of taking DAPT 3 months before index date and follow-up days <3 months. In addition, we excluded patients with conditions of being warfarin or direct oral anticoagulant users, without DAPT, and patients with events of myocardial infarction, ischemic stroke, major bleeding, and heart failure within 3 months of the index date. The remaining were patients with new onset of AMI with DAPT. These patients were separated into cirrhotic patients and non-cirrhotic patients. (Fig 1). In addition, a separated analysis for cirrhotic patients who were prescribed DAPT group or single antiplatelet therapy (SAPT) after AMI. In our study, DAPT means prescribing aspirin plus clopidogrel while SAPT means prescribing aspirin alone or clopidogrel alone.

Covariate and study outcomes
Disease was detected using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Covariates included gender, age, socioeconomic factor (monthly income and urbanization level), clinical medical history of hypertension, diabetes mellitus, hyperlipidemia, heart failure, peripheral arterial disease, atrial fibrillation, history of stroke, major bleeding, gastrointestinal bleeding, chronic kidney disease, end-stage renal disease, malignancy, and Charlson comorbidity score. The coronary intervention in prior admissions and at the index admission was also recorded. The information of post MI medications were also extracted. Most comorbidities were defined as having two outpatient diagnoses or one inpatient diagnosis in the previous year and also some cirrhosis-related or AMI-related complications were also defined according to previous study [9] or the diagnosis of ICD-9-CM. Some severe comorbidities were detected in inpatient diagnoses only, including heart failure, stroke, major bleeding, and gastrointestinal bleeding which can be tracked to Jan 1 1997. Usage of medication was retrieved based on claim data within 3 months of the index date.
Outcomes of primary interest included all-cause mortality, recurrent myocardial infarction (MI), major bleeding [10], and gastrointestinal bleeding. All-cause mortality was defined by a withdrawal from the national health insurance [11]. The recurrent MI was defined as a principal diagnosis in an admission setting and the diagnostic code was validated in a previous study [12]. Bleeding events were detected in an admission setting as well and the definition was widely reported in previous NHIRD studies [13,14]. Each patient was followed until the day of outcome occurrence, death or December 31, 2013, whichever came first.

Statistical analysis
To reach a comparability between the cirrhotic and non-cirrhotic groups, we conducted a propensity score matching. Each cirrhotic patient was matched with 4 non-cirrhotic patients. The propensity score was the predicted probability to be in the cirrhotic group derived from a multivariable logistic regression given value of covariates. The covariates were the aforementioned covariates in which the follow up year was replaced with the index date. Noticeably, the CCI score was not included in the calculation of propensity score because of liver disease was a component of CCI in which 1 point and 3 points were assigned to mild and severe liver diseases respectively. The matching was processed using a greedy nearest neighbor algorithm with a caliper of 0.2 times the standard deviation of the logit of propensity score and without replacement and with random matching order. The quality of matching was verified using the absolute value of standardized mean difference (SMD) which a value less than 0.1 was considered to have negligible difference between groups.
We compared the risk of all-cause mortality between groups using the Cox proportional hazard model. The risk of other time to event outcomes (recurrent MI and bleeding events) between groups was compared using the Fine and Gray subdistribution hazard model which considered death as a competing risk. Matching pairs were stratified in both Cox and Fine and Gray models. Unadjusted cumulative event rate of all-cause mortality was calculated and plotted. The cumulative incidence of recurrent MI and bleeding events was generated and plotted using subdistribution cumulative incidence function. The study group (cirrhosis vs. non-cirrhosis) was the only explanatory variable in the survival analyses.
We further performed a separate analysis to compare DAPT with SAPT in the cirrhotic patients. There were relatively small sample size in these two groups and substantially differences in the baseline characteristics (S1 Table) between groups, it would be infeasible to conduct propensity score matching. Therefore, we calculated a propensity score which was the predicted probability to be the DAPT group relative to be the SAPT group using the same covariates as the primary analysis. This propensity score was adjusted in the survival analyses when comparing the two groups [15]. A two-sided P value < 0.05 was considered to be statistically significant and no adjustment of multiple testing (multiplicity) was made in this study.
All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC), including procedure of 'psmatch' for propensity score matching, 'phreg' for survival analysis, and the macro of '%cif' for cumulative incidence function.

Study population
There were 150,887 patients admitted with a principal diagnosis of AMI during 2001 and 2013 in the NHIRD. After applying exclusion criteria, there remained 58,162 patients with new onset of AMI on DAPT and were separated into 914 (1.6%) cirrhotic patients and 57,248 (98.4%) non-cirrhotic patients. After conducting a 1:4 propensity score matching, there were 914 patients with cirrhosis and 3,656 patients without cirrhosis (Fig 1). The distribution of baseline characteristics, comorbidities, hospital level, coronary intervention, medications, and follow up duration were similar between the two groups (right panel in Table 1). Besides, the cirrhosis related clinical characteristics of these 914 cirrhotic patients were listed in Table 2.

Discussion
Our study has the following findings. (1) This is the largest study to date to directly compare the clinical outcomes of DAPT in cirrhotic patients with AMI and non-cirrhotic patients with AMI, which showed DAPT had significant benefit in preventing recurrent MI in cirrhotic patients with AMI compared to non-cirrhotic patient with AMI (2) This is the first study to compare the clinical outcomes DAPT and SAPT in cirrhotic patients with AMI, which showed similar protection of DAPT and SAPT in recurrent MI, major bleeding, and gastrointestinal bleeding in physician directed treatment. In patients with liver cirrhosis, bleeding diathesis is an important consideration when antiplatelet is a necessary therapy whether it is CAD, cerebrovascular disease, or peripheral vascular disease. In these patients who have CAD undergoing PCI requiring DAPT, the situation becomes a treatment dilemma. There is currently no guideline recommendation, and only limited evidences exist regarding the effectiveness and safety on the use of antiplatelet in cirrhotic patients from previously published studies [4][5][6].
In this study, we enrolled patients with AMI and separated into cirrhotic and non-cirrhotic patients with propensity score matching performed between groups. During the one year follow up, we showed that the cirrhotic patients with AMI had decreased recurrent AMI using DAPT compared to non-cirrhotic patients using DAPT. Our finding is important because in this situation, we are confirmed the benefits of DAPT even more prominent in cirrhotic patients. Although use of DAPT was encountered with more bleeding events, mainly gastrointestinal bleeding, there was a non-significant increase of major bleeding, suggesting it may related to old gastrointestinal bleeding (33.7%) but not variceal bleeding due to its small percentage (2.8%) ( Table 2). The all-cause mortality was still higher in cirrhotic patients with AMI, although if not DAPT prescribed, the overall mortality rate may be still higher. To investigate whether DAPT or SAPT should be recommended in cirrhotic patients with AMI, we did secondary analysis of primary outcomes in this special population. As seen in S1 Table, the baseline characteristics showed patients who were prescribed with SAPT had higher percentage of heart failure, old gastrointestinal bleeding suggest poorer underlying diseases. Hence, patients who were prescribed with SAPT also had lower percentage of ACEi/ARB, beta blockers, nitrates, and statin, and a higher percentage of digoxin and proton pump inhibitor given, which in turn reflected the poorer underlying comorbidities. Under these conditions, use of DAPT showed no difference in terms of recurrent MI, major bleeding, and gastrointestinal bleeding compared to use of SAPT in these cirrhotic patients that may be seen with different coexisting diseases. Under better coexisting conditions, cirrhotic patients with AMI could be prescribed with the standard DAPT as in non-cirrhotic patients with AMI. Together the results however, suggested that in patients with cirrhosis, whether DAPT or SAPT should be used is justified by the physician's discretion.
In summary, this is the largest study to directly compare selective DAPT in cirrhotic and non-cirrhotic patients for the clinical outcomes. DAPT offers benefits in recurrent MI while suffers from increased risks of gastrointestinal bleeding. SAPT may be judged appropriately and prescribed according to clinical situations in patients with cirrhosis.

Limitations
There are several limitations in epidemiologic data from NHIRD. First, using ICD-9-CM codes for patient screening may miss some cases for conditions not coded correctly. However, ICD-9-CM codes against hospital electronic medical records (EMR) have been performed in the validation studies for NHIRD, the ICD codes have as sensitivity up to 99% for positive predictive value against the gold standard EMR. Second, due to the limitation of NHIRD where laboratory results and clinical evaluation were unavailable, the traditional risk stratification using Child-Pugh criteria in patients with liver cirrhosis could not be performed. However, we substituted Child-Pugh score with surrogate markers for cirrhosis severity such as the requirement for fresh frozen plasma and albumin transfusion to indicate the patients' coagulopathy and hypoalbuminemia, and application of which have been used in our previous works [16,17]. Thus the results of our statistical analysis may have partially ruled out the confounding due to the lack of Child-Pugh score when comparing outcomes between the SAPT and DAPT patients groups. Third, we did not analyze whether major bleeding contributed to increased all-cause mortality during DAPT use in cirrhotic patients. Forth, hospital data suffer from selection bias. Since the data we can analyze are derived from those patients who required the services from the hospitals and clinics, and those who adhere to physicians' orders, therefore this is a limitation of the study. On the other hand, Taiwan's National Health Institute (NHI) Program started in 1995 and provides 99.5% coverage for the 23 million residents in Taiwan. Therefore, this is the most comprehensive real-world data that the researchers can access. Fifth, the adherence cannot be assessed in this study However, we assumed "good adherence" wound be in our study base on patients who had severe disease such as acute myocardial infarction would not easily change their medication uses and would adhere to physicians' order. In addition, we included patients who had been taking antiplatelets for at least 3 months, and the treatment of antiplatelet up to 9 months is reimbursed by the NHI. Sixth, we did not compare clopidogrel versus ticagrelor in our study and further studies maybe required for risk and benefit of these antiplatelet agents. Last, since the current study derived from the Han Chinese in Taiwan, applications of our results to other population require further studies.

Conclusions
In cirrhotic patients with AMI, DAPT offers benefit with decreased recurrent MI at the expense of increased gastrointestinal bleeding. In cirrhotic patients with worse comorbidities, SAPT may be considered. In addition, further randomized controlled trials were needed to further evaluate the benefit of DAPT (short term vs long term) therapy in cirrhotic patients.