Hospitalization for Myocardial Infarction with Ticagrelor or Clopidogrel in Patients with Acute Coronary Syndrome: An On-Treatment Comparative Effectiveness Analysis

Acute coronary syndrome (ACS) is a significant cause of morbidity and mortality worldwide. There were more than 1 million unique hospitalizations for ACS in the United States (US) in 2016 [1]. Patients with a history of ACS have an increased long-term risk of recurrent major adverse cardiovascular events (MACE), including myocardial infarction (MI), and 1-year mortality [2, 3]. Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor for at least 12 months (6–12 months for patients with increased bleeding risk) has been shown to reduce the risk of recurrent cardiovascular events [4].

Ticagrelor is a direct-acting and reversible P2Y12 inhibitor with more potent antiplatelet activity than clopidogrel [5, 6]. DAPT with ticagrelor in preference to clopidogrel in combination with aspirin is recommended in current ACS guidelines from the American College of Cardiology/American Heart Association (class IIa) and the European Society of Cardiology, based on the results of the PLATO trial [4, 7, 8]. This randomized, double-blind trial in 18,624 patients with ACS, with or without ST-segment elevation, demonstrated a significant reduction in the risk of the composite end point of death due to vascular causes, MI, or stroke at 12 months with ticagrelor compared with clopidogrel (9.8 vs. 11.7%; hazard ratio [HR] 0.84, 95% CI 0.77–0.92; P < 0.001). There were also significant reductions with ticagrelor vs. clopidogrel in the rates of the prespecified secondary end points of death from any cause, MI, or stroke (10.2 vs. 12.3%; HR 0.84, 95% CI 0.77–0.92; P < 0.001), MI alone (5.8 vs. 6.9%; HR 0.84, 95% CI 0.75–0.95; P = 0.005), and death from vascular causes (4.0 vs. 5.1%; HR 0.79, 95% CI 0.69–0.91; P = 0.001) [9]. There was no significant difference in overall PLATO major bleeding; however, PLATO non-coronary artery bypass graft-related major bleeding was increased with ticagrelor compared with clopidogrel (P = 0.03) [9].

Ticagrelor and clopidogrel have also been compared in real-world studies in patients with ACS, although the results for these intention-to-treat (ITT) observational studies have been inconsistent. The benefit of ticagrelor compared with clopidogrel was demonstrated in a large real-world population of ACS patients treated over 24 months in the SWEDEHEART study [10]. In this ITT prospective cohort study, 45,073 patients were analyzed based on whether ticagrelor was prescribed on discharge [10]. The intended duration of DAPT with ticagrelor and aspirin at discharge was 12 months in 83.8% of patients and < 12 months in 7.1% [10]. Ticagrelor was associated with a lower adjusted risk of the composite end point of all-cause mortality or rehospitalization for MI or stroke compared with clopidogrel (HR 0.85, 95% CI 0.78–0.93) [10].

ITT methodologies in observational studies have inherent limitations, including that patient classification uses baseline treatment assignment, but outcome assessments occur later, at which point patients may have switched treatments [11, 12]. Bias may occur when treatment switching occurs more frequently in one group than others, treatment adherence varies among groups, confounders are not properly considered, or treatment duration varies depending on outcome [11, 12].

Differences in outcomes among ITT observational studies may reflect these methodological limitations. For example, a retrospective ITT analysis in 11,185 patients with ACS who underwent percutaneous coronary intervention (PCI) classified patients according to prescribed P2Y12 inhibitor treatment had findings that were discordant with those of SWEDEHEART as well as the PLATO trial, which included medically managed patients as well as those who underwent PCI [13]. In this study, a higher proportion of patients in the ticagrelor cohort than in the clopidogrel cohort switched treatments (14.0 and 2.3%, respectively) and most (91%) of the patients switching from ticagrelor to clopidogrel did so prior to a MACE, whereas only 57% of patients who switched from clopidogrel did so before a MACE [13]. The study did not find a reduced risk of the primary composite outcome of all-cause death, hospitalization for nonfatal ACS, coronary revascularization (excluding planned staged PCI) or stent thrombosis within 365 days after the index hospitalization, with ticagrelor compared with clopidogrel after multivariable adjustment (adjusted HR 0.97, 95% CI 0.85–1.10) [13].

Given the limitations of ITT analyses in observational studies, the aim of this study was to compare the incidence of hospitalization for MI in an on-treatment population of patients with ACS receiving post-discharge treatment with either ticagrelor or clopidogrel in real-world clinical practice.

This was a retrospective, observational cohort study using real-world data from patients treated with ticagrelor or clopidogrel following hospitalization for an ACS event. Data were obtained from the Optum™ Clinformatics™ Data Mart (Optum CDM) database, a closed system of de-identified health claims data for patients with commercial or Medicare Advantage coverage from a large national US health insurer. The database includes summary information on inpatient hospital stays and information on services performed in an inpatient setting, which were used to identify hospitalizations for MI. This analysis used patient-level data on diagnoses, prescriptions, place of service (inpatient hospitalizations), and procedures from January 1, 2011 to September 30, 2019.

Institutional Review Board approval and written informed consent from patients were not required because this study used only de-identified claims data. The data source for this study was the Optum™ Clinformatics™ database, which can be accessed by license from Optum (https://​www.​optum.​com/​business/​solutions/​life-sciences.​html).

There were 339,387 patients with Medicare/commercial claims for hospitalization for ACS between January 1, 2012 and September 30, 2019. Of these, 71,592 patients met the inclusion criteria: 14,110 and 57,482 in the ticagrelor and clopidogrel cohorts, respectively (Fig. 1), providing 5219 and 26,457 patient-years of data for the primary end point, respectively; corresponding values for the secondary end point were 5489 and 27,560 patient-years, respectively. After PSM, the ticagrelor and clopidogrel cohorts included 13,373 and 29,656 patients, respectively, corresponding to 94.8 and 51.6% of the pre-PSM cohorts. There were 4945 and 13,895 patient-years of data for the primary end point and 5202 and 14,464 patient-years of data for the secondary end point for the ticagrelor and clopidogrel cohorts, respectively.

The majority of patients were male and the mean age in the ticagrelor and clopidogrel cohorts was 66 and 70 years (66 and 68 years post-PSM), respectively; most patients had no prior history of MI or hospitalization for major bleeding (Table 1). The proportion of patients using anticoagulants during the follow-up period was lower in the ticagrelor cohort than in the clopidogrel cohort. Before PSM, 851 patients (6.0%) in the ticagrelor cohort and 6779 patients (11.8%) in the clopidogrel cohort were taking anticoagulants; post-PSM values were 830 (6.2%) and 3510 (11.8%), respectively. The mean (standard deviation) duration of anticoagulant use in the post-PSM population was 91 (84) days in the ticagrelor cohort and 120 (100) days in the clopidogrel cohort.

Before PSM, the ticagrelor and clopidogrel cohorts were unbalanced with respect to age, some index years (2012, 2013, 2014, 2017, 2018, and 2019), male gender, Charlson’s Comorbidity Index score, some baseline comorbidities (heart failure, dyslipidemia, peripheral artery disease, CKD, T2D, atrial fibrillation, hypertension, and anemia), and some index ACS types (NSTEMI, UA, STEMI) (see Figure S1i and Table S5 in the electronic supplementary material). These covariates were balanced after PSM, as indicated by SMD or raw difference values below the < 0.05 threshold (see Table S5 in the electronic supplementary material), and similar propensity score distributions for both cohorts (see Figure S1ii in the electronic supplementary material). PSM also produced balanced cohorts for the subgroups analyzed (data not shown).

This is the first on-treatment analysis with the primary objective of comparing hospitalization for MI after an ACS event with ticagrelor and clopidogrel in a US population in a real-world setting. After an ACS event, a significant proportion of patients experience recurrent MACE, including MI [2, 3], with consequent clinical and economic impacts. Non-adherence to therapy is a major predictor of developing subsequent cardiovascular events leading to rehospitalization in patients with ACS [14]. This analysis underscores the importance of adherence to the appropriate guideline-recommended therapy, in this case ticagrelor in preference to clopidogrel for at least 12 months (6–12 months for patients with increased bleeding risk) post-ACS [4]. This study supports the efficacy findings of the PLATO trial [9], and confirms the effectiveness of ticagrelor in a real-world setting.

In this population of patients who were on-treatment with their discharged P2Y12 inhibitor, hospitalization for MI was significantly lower in the overall ticagrelor cohort compared with the clopidogrel cohort. Reductions in hospitalization for MI were also seen with ticagrelor vs. clopidogrel in subgroups of patients aged ≥ 65 years, without T2D at baseline, without CKD at baseline, and with PCI for the index ACS event.

The reduction in hospitalizations for MI seen with ticagrelor vs. clopidogrel in the overall study population was also not at the expense of an increase in hospitalizations due to major bleeding. There was no significant difference between ticagrelor and clopidogrel in the risk of hospitalization for major bleeding in most of the subgroups studied. The exception was the subgroup of patients who did not undergo PCI for the index ACS event, in which ticagrelor was associated with a higher risk for hospitalization due to major bleeding compared with clopidogrel. However, this should be interpreted with caution due to the small size of this subgroup (549 and 1936 patient-years of follow-up for bleeding for ticagrelor and clopidogrel, respectively).

In the US, prescribing patterns and treatment persistence have presented methodological challenges for real-world head-to-head comparisons. The methods used in this analysis to ensure patients were on-treatment with their discharged index P2Y12 inhibitor throughout the follow-up period, combined with balancing of the cohorts by PSM, overcome some of the potential limitations of real-world observational studies.

Results of this study vary from the findings of earlier real-world studies comparing ticagrelor and clopidogrel, which had the inherent limitations of the ITT analysis methods used. An ITT observational analysis in approximately 11,000 patients with ACS with planned PCI found no significant reduction in hospitalization for ACS with ticagrelor vs. clopidogrel (adjusted HR 0.93; 95% CI 0.79–1.09) 365 days after the index ACS hospitalization [13]. However, major bleeding was increased with ticagrelor vs. clopidogrel [13]. Similarly, the SWEDEHEART study reported readmission for MI at 24 months was lower with ticagrelor vs. clopidogrel, although the difference was not statistically significant after adjustment for confounders (adjusted HR 0.89; 95% CI 0.78–1.01) [10]. The study also reported that bleeding requiring admission occurred more frequently with ticagrelor vs. clopidogrel over 24 months [10].

The findings of this study highlight the importance of adherence and persistence with guideline-recommended antiplatelet therapy for the reduction of hospitalization for MI post-ACS. However, despite guideline recommendations for DAPT for at least 12 months (6–12 months for patients with increased bleeding risk) post-ACS with ticagrelor in preference to clopidogrel [4], a significant proportion of patients discontinue P2Y12 inhibitor therapy within 1 year [15‐18]. Furthermore, de-escalation of P2Y12 inhibitor therapy, from ticagrelor or prasugrel to clopidogrel, occurs relatively frequently [19, 20]. Early discontinuation of DAPT has been found to be associated with an increased risk of MACE [17, 18]; therefore, efforts to improve adherence (including addressing affordability for patients) [16, 21], and maintaining patients on more potent P2Y12 inhibitors have the potential to improve outcomes in patients with ACS without the expense of hospitalization due to major bleeding.

This real-world on-treatment analysis showed that among patients with ACS that persisted with treatment, hospitalization for MI was significantly reduced with ticagrelor compared with clopidogrel, with no significant difference in hospitalization for bleeding. These findings in a real-world contemporary US ACS population highlight the importance of adherence to guideline-recommended antiplatelet therapy post-ACS.