Clopidogrel vs. ticagrelor in ST-elevation myocardial infarction complicated by cardiogenic shock undergoing primary PCI

Abstract

Background

Although ticagrelor is recommended as opposed to clopidogrel in antiplatelet strategy for patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI), evidence is limited in patients with cardiogenic shock (CS).

Objective

This study aims to evaluate the comparative efficacy and safety profile of ticagrelor and clopidogrel in patients with STEMI-CS undergoing pPCI.

Methods

Using data from a nationwide, multicenter registry, eligible patients were stratified into clopidogrel or ticagrelor based on the choice of P2Y₁₂ inhibitors within 24 h of first medical contact. Multivariable-adjusted Cox regression analyses, along with Cox models adjusted for propensity score matching and inverse probability treatment weighting were conducted to compare outcomes between ticagrelor and clopidogrel. The efficacy and safety outcomes were in-hospital all-cause mortality and major bleeding.

Results

Among 729 STEMI-CS patients in our cohort, 403 received clopidogrel and 326 received ticagrelor. Multivariable-adjusted Cox regression analyses showed that ticagrelor was not associated with a significant difference in all-cause mortality (adjusted HR: 1.04; 95% CI: 0.69–1.56; p = 0.840) and major bleeding (adjusted HR: 1.30; 95% CI: 0.62–2.76; p = 0.489) compared to clopidogrel. Consistent results were found in the analyses adjusted by propensity score matching and inverse probability of treatment weighting.

Conclusions

Our findings suggest that the choice of either ticagrelor or clopidogrel was feasible as a P2Y₁₂ inhibitor for dual anti-platelet strategy in STEMI-CS patients undergoing pPCI, as no significant difference between these two agents was observed in all-cause mortality and major bleeding during hospitalization.

Trial registration

ClinicalTrials.gov, NCT02306616. Registered 29 November 2014.

Introduction

Cardiogenic shock (CS) is a clinical syndrome characterized as systemic hypoperfusion and tissue hypoxia caused by cardiac dysfunction, occurs in 5–10% of patients with ST-segment elevation myocardial infarction (STEMI), with 30-day mortality rates between 40–50% [1,2,3,4] primary percutaneous coronary intervention (pPCI) is the main reperfusion therapy to reduce mortality for patients with STEMI complicated by CS (STEMI-CS) [2, 3]. However, the strategy for dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y₁₂ inhibitor for STEMI-CS patients undergoing pPCI remains uncertain, as these patients were excluded from the large-scale randomized clinical trials (RCT) [5, 6]. Recommendations in the latest guidelines on the choice of P2Y₁₂ inhibitors in these patients were empirical and unspecified [1, 7, 8].

Small observational studies showed conflicting evidence regarding the effect of different P2Y₁₂ inhibitors in patients with STEMI-CS [9,10,11,12]. Pooled data of two large RCTs revealed no significant difference in the short-term and long-term mortality among patients treated with clopidogrel or ticagrelor [11]. In contrast, a single-center, retrospective cohort study showed newer P2Y₁₂ inhibitors including ticagrelor could reduce one-year mortality compared with clopidogrel in STEMI-CS patients [10]. The majority of studies assessing the effect of P2Y₁₂ inhibitors on outcomes for STEMI-CS patients were small-sample and retrospective.

By using prospective data from a national, multicenter cohort, this study aims to explore the comparative effect of DAPT with ticagrelor or clopidogrel in patients with STEMI-CS undergoing pPCI, and further optimize peri-PCI strategy for these patients.

Method

Study population

The Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome Project (CCC-ACS) (NCT02306616) is a collaborative initiative of the American Heart Association and the Chinese Society of Cardiology to enhance the quality of care for acute coronary syndrome (ACS) patients. Launched in 2014, the project involves 159 tertiary hospitals and 82 secondary hospitals in China, and details about the project design and methodology have been published previously [13]. The Institutional Review Board of Beijing Anzhen Hospital approved the CCC-ACS project with a waiver for informed consent. Patients with STEMI-CS treated with PCI were included in our study. Criteria for exclusion were as follows: (1) without information on DAPT or DAPT given within 24 h after first medical contact; (2) with crossover use or combination of P2Y₁₂ inhibitors during hospitalization; (3) with elective PCI.

Definitions and study variables

Patient demographics, medical history, presenting characteristics, acute treatments, and in-hospital outcomes were prespecified and collected by participating centers according to standardized definitions in the operating manual. A Web-based platform (Oracle Clinical Remote Data Capture, Oracle Corporation) was used for data collection, where patients’ data, including clinical outcomes, were entered directly from medical charts by trained abstractors. Data reliability was further enhanced through on-site quality checks by third-party clinical research associates, alongside monthly monitoring and reporting to hospitals to ensure completeness and quality. STEMI was defined by the Chinese Society of Cardiology guidelines for the diagnosis and management of patients with STEMI [14]. The criteria for CS were a systolic blood pressure of ≤ 90 mmHg for ≥ 30 min or requiring supportive management to maintain systolic blood pressure > 90 mmHg, clinical features and/or laboratory evidence of tissue hypoperfusion, such as cold extremities, oliguria, altered mental status, hyperlactatemia [15]. pPCI was defined as the emergency PCI performed on the infarct-related artery in STEMI-CS patients using a balloon, stent, or other approved devices.

Participants were divided into two groups: the clopidogrel group and the ticagrelor group, according to the administration of P2Y₁₂ inhibitors within 24 h of first medical contact. The selection of P2Y₁₂ is at the discretion of the physician. The loading dose of a P2Y₁₂ inhibitor was defined as ≥ 300 mg of clopidogrel or ≥ 180 mg of ticagrelor, followed by a maintenance dose of 75 mg daily or 90 mg twice daily respectively. If antiplatelet drugs have been used before, the corresponding maintenance dose would be given within 24 h after first medical contact.

Clinical outcome

The primary outcome was in-hospital all-cause mortality and major bleeding. Major bleeding was defined as type 3 or 5 of Bleeding Academic Research Consortium (BARC) bleeding [16]. Other outcomes were major adverse cardiovascular events (MACE), and net adverse cardiovascular events (NACE). MACE was defined as composite outcomes of all-cause mortality, cardiac arrest, reinfarction, stroke, or in-stent thrombosis. NACE was defined as composite outcomes of all-cause mortality, cardiac arrest, reinfarction, stroke, in-stent thrombosis, or major bleeding. In-stent thrombosis was defined angiographically as an acute or subacute occlusion in a stented vessel with the presence of a thrombus.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation or median with the 25th percentile and 75th percentile, and categorical variables were presented as frequencies and percentages. The comparisons in continuous and categorical variables between the clopidogrel group and the ticagrelor group were performed by unpaired Student’s t-test or rank-sum test and Pearson’s chi-square test, respectively. Kaplan-Meier methods were plotted to compare the 15-day event rates for each endpoint between the two groups. In addition to univariate Cox regression analysis, the following three models were applied to explore the relationships between the selection of P2Y₁₂ inhibitors and study outcomes. (1) multivariable-adjusted Cox regression model with covariates including age > 65 years, sex, body mass index (BMI) ≥ 24 kg/m², systolic blood pressure > 90 mmHg, previous disease history (diabetes, hypertension, myocardial infarction, heart failure), prior PCI, thrombolytic, intra-aortic balloon pump (IABP), use of glycoprotein IIb/IIIa inhibitors (GPI), culprit artery, multivessel coronary artery disease, and time for PCI after onset of symptom; (2) propensity-score matched (PSM) analyses using the nearest-neighbor algorithm with a caliper of 0.05. A logistic regression was performed to estimate propensity score, adjusting for the following variables: age, BMI, systolic blood pressure, thrombolytic, culprit artery, multivessel coronary artery disease, IABP, use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, vascular access site for PCI, time for PCI after onset of symptom, and use of GPI. Univariate Cox analysis was used for the evaluation of treatment effects; (3) Univariate Cox analysis, adjusted through inverse probability of treatment weighting (IPTW) based on the previously mentioned propensity score was also used. Sensitivity analysis was performed by subgroup analyses. A 2-sided P < 0.05 was considered statistically significant.

Result

Baseline characteristics

From November 1, 2014, to December 31, 2019, of 113,650 patients enrolled in the CCC-ACS registry, 870 patients were identified with STEMI-CS on admission undergoing pPCI, and 729 patients were included in the final analysis with 403 patients received clopidogrel and 326 received ticagrelor as shown in Fig. 1. Compared to the clopidogrel group, patients in the ticagrelor group had a higher prevalence of multivessel disease and a higher chance of receiving pPCI within 12 h. There were 24 (3.3%) patients who received rescue PCI after thrombolytic therapy, with 17 (4.2%) in the clopidogrel group and 7 (2.1%) in the ticagrelor group (Table 1). After adjustment using the PSM and IPTW methods, baseline characteristics were well balanced in Table 1.

Fig. 1

Flow chart of our research. Abbreviation: STEMI: ST-segment elevation myocardial infarction; CS: cardiogenic shock; pPCI: primary percutaneous coronary intervention; DAPT: dual antiplatelet therapy.

Table 1 Baseline characteristics of the cohort study

Primary outcome and other outcomes

The in-hospital all-cause mortality in the clopidogrel group was 14.64% and 13.50% in the ticagrelor group. The Kaplan-Meier curve of in-hospital mortality is shown in Fig. 2. A non-significant difference in in-hospital mortality was observed between the two groups assessed by multivariable-adjusted Cox regression analysis (adjusted HR: 1.04; 95% CI: 0.69–1.56; p = 0.840), PSM (adjusted HR: 1.07; 95% CI: 0.68–1.69; p = 0.768), and IPTW (adjusted HR: 1.00; 95% CI: 0.67–1.50; p = 0.997) in STEMI-CS patients (Table 2).

Fig. 2

Kaplan-Meier curve of outcomes during the 15-day in-hospital period in the whole study population: (A) mortality, (B) major bleeding, (C) major adverse cardiovascular event (MACE), and (D) net adverse cardiovascular event (NACE). Abbreviation: clo: clopidogrel; tica: ticagrelor; HR: hazard ratio; CI: confidence interval.

Table 2 Outcomes in the clopidogrel group and Ticagrelor group

The incidence of in-hospital major bleeding, MACE, and NACE of the two groups are listed in Table 2. The Kaplan-Meier curves of 15-day event rates are shown in Fig. 2. Assessed by multivariate Cox regression analysis, ticagrelor was not associated with an increasing risk of major bleeding (adjusted HR: 1.30; 95% CI: 0.62–2.76; p = 0.489), MACE (adjusted HR: 1.03; 95% CI: 0.70–1.51; p = 0.887) and NACE (adjusted HR: 1.05; 95% CI: 0.74–1.50; p = 0.766) compared to clopidogrel. Analyses using PSM and IPTW also indicated that there was no significant difference in major bleeding, MACE, and NACE between the two groups as shown in Table 2.

Subgroups analysis

The risk of in-hospital mortality was assessed across subgroups grouped by age, sex, BMI, history of hypertension or diabetes, IABP, culprit artery, multivessel coronary artery disease, time to PCI after symptom onset, and use of GPI. The results were consistent across all subgroups, with no significant interactions between the variables in patients treated with clopidogrel and ticagrelor (Fig. 3).

Fig. 3

Subgroup analysis for in-hospital all-cause mortality. Abbreviation: BMI: Body Mass Index; LM: left main coronary artery; LAD: left anterior descending coronary artery; RCA: right coronary artery; LCX: left circumflex coronary artery; MVD: multivessel coronary artery disease; GPI: glycoprotein IIb/IIIa inhibitors; PCI: Percutaneous Coronary Intervention; MI: myocardial infarction; HR: hazard ratio; CI: confidence interval.

Discussion

This is, to our knowledge, the largest study using data from a nationwide, multicenter, prospective registry comparing the relative efficacy and safety of ticagrelor and clopidogrel in STEMI-CS patients undergoing pPCI. The main findings showed ticagrelor was not associated with a lower risk of in-hospital all-cause mortality compared to clopidogrel in STEMI-CS patients undergoing pPCI. No significant difference in major bleeding was observed between the two groups. Our findings indicate that either ticagrelor or clopidogrel is a viable option as a P2Y₁₂ inhibitor for a DAPT strategy in STEMI patients with CS undergoing pPCI.

Since the publication of a series of large RCTs and meta-analyses, DAPT with aspirin and a potent P2Y₁₂ inhibitor has been recommended as the default strategy for ACS patients [1]. The results of the phase III PLATelet Inhibition and Patient Outcomes (PLATO) trial demonstrated the superiority of ticagrelor over clopidogrel in patients with ACS. However, patients with CS were excluded from this trial [6]. The current choice of oral P2Y₁₂ inhibitors for STEMI-CS patients in real-world practice is mostly empirical or consensus-based. Specific recommendations on DAPT strategies for these patients were not provided in the latest guidelines from the European Society of Cardiology or the American College of Cardiology/American Heart Association [1, 8]. Although lacking direct evidence, a 2021 joint position paper by the Acute Cardiovascular Care Association and the European Association of Percutaneous Cardiovascular Interventions suggested that ticagrelor or prasugrel should be preferred over clopidogrel as part of the DAPT strategy in STEMI-CS patients with low bleeding risk [7].

Our study showed that, in contrast to the recommendations from the joint position paper, ticagrelor does not demonstrate superior performance compared to clopidogrel in STEMI-CS patients, which aligns with previous observational study results. A post hoc analysis of two large RCTs showed no significant difference in 30-day mortality between ticagrelor and clopidogrel, and ticagrelor was associated with a lower bleeding risk [11]. However, the pooled RCTs had different designs, patient populations, and excluded a substantial number of patients, potentially introducing heterogeneity and selection bias. Similarly, a retrospective study by Kanic et al. drew comparable conclusions with the post hoc analysis, but its results were limited by single-center design and small size [12]. In our study, the incidence of major bleeding in the ticagrelor group was higher than in the clopidogrel group, consistent with the higher level of platelet inhibition by ticagrelor, but the difference was not statistically significant. The only meta-analysis showed that newer P2Y₁₂ inhibitors were associated with lower rates of short-term mortality without increasing the risk of major bleeding compared to clopidogrel in acute myocardial infarction with CS or cardiac arrest [17]. However, the meta-analysis included studies with significant heterogeneity, as it involved patients with both CS and cardiac arrest, as well as those undergoing therapeutic hypothermia or receiving varying revascularization strategies. Additionally, the meta-analysis only compared newer P2Y₁₂ inhibitors with clopidogrel, without assessing the relative safety and efficacy between ticagrelor and clopidogrel. Further studies, particularly large RCTs, are needed to verify these findings and optimize DAPT strategies in these patients.

Shock states may diminish the effectiveness of oral P2Y₁₂ inhibitors due to delayed administration, reduced gastrointestinal blood flow and motility, and impaired gastric emptying and absorption. In patients with STEMI-CS, the absorption and metabolism of P2Y₁₂ inhibitors might be impaired, leading to insufficient antithrombotic effects [7]. The enhanced potency and quicker activation of certain P2Y₁₂ inhibitors are particularly important in the setting of STEMI-CS, where rapid and effective platelet inhibition could reduce the risk of recurrent ischemic events and improve survival during the critical early period following PCI [18]. Compared with ticagrelor, one of the major limitations of clopidogrel is that it is a prodrug requiring biotransformation into its active form, which shows significant inter-individual variability. The metabolic activation of clopidogrel involves multiple enzymatic steps, and genetic variations in enzymes such as CYP2C19 can lead to substantial differences in how patients metabolize and respond to the drug [19]. This variability results in a low clopidogrel response in a significant number of patients, reducing the drug’s efficacy and increasing the risk of adverse cardiovascular events. However, the advantages of ticagrelor seem to be diminished in patients with STEMI-CS. The following are the possible reasons. Compared with the irreversible binding of clopidogrel to the P2Y₁₂ receptor, ticagrelor binds reversibly, which may result in less consistent platelet inhibition, especially in patients with STEMI-CS, characterized by altered tissue perfusion and organ dysfunction, leading to unpredictable pharmacokinetic and pharmacodynamic alterations of antithrombotic drugs [19, 20]. Better adherence to antiplatelet therapy is crucial in the early post-PCI period to prevent stent thrombosis and other ischemic complications. Unlike ticagrelor, which requires twice-daily dosing, clopidogrel is administered once daily. This simpler regimen may result in better adherence, especially in critically ill patients in whom maintaining consistent medication schedules can be challenging. Based on the results of our study and previous research, different P2Y₁₂ inhibitors have a limited impact on the early prognosis of CS patients, which is primarily influenced by hemodynamics and early revascularization.

In patients with ACS, ticagrelor has been shown to be a clinically superior and cost-effective option for the prevention of thrombotic events when compared to clopidogrel [21, 22]. In China, however, the widespread use of ticagrelor in ACS patients is hampered by both economic and accessibility considerations. The affordability of clopidogrel makes it a more pragmatic option for many healthcare providers and patients, particularly in regions with limited healthcare resources. Additionally, the lack of robust healthcare reimbursement systems for newer, more expensive drugs like ticagrelor further limits its utilization. Our study demonstrated no significant difference in outcomes between ticagrelor and clopidogrel in patients with STEMI undergoing pPCI. Given the unique hemodynamic challenges and multi-organ involvement in CS, this finding suggests that both P2Y₁₂ inhibitors can be considered feasible options in this specific patient population. And the choice between ticagrelor and clopidogrel may be based on other factors, such as patient tolerance, drug cost, and availability, making the use of either P2Y₁₂ inhibitor a viable strategy. Further studies may be needed to explore potential patient subsets who could benefit more from one drug over the other in the context of CS.

Limitation

Our study was limited by its observational nature, which may be subject to selection bias and confounding. Additionally, the high utilization rate of GPI may mask potential differences between the two groups. To address these issues, multivariable-adjusted Cox regression, PSM, IPTW, and subgroup sensitivity analysis were conducted, suggesting that the results were consistent. Furthermore, variations in treatment strategies, differences in PCI expertise across centers, and antithrombotic approaches may have influenced outcomes. Patient distribution by hospital levels was analyzed to account for these factors (Supplementary Table S1) and was included as a covariate in a multivariate Cox regression analysis of all-cause mortality and major bleeding (Supplementary Table S2). The results remained consistent with our initial findings. Additionally, subgroup analysis stratified by hospital levels confirmed these findings (Fig. 3). Moreover, there is significant heterogeneity in CS severity, yet the effects of different P2Y₁₂ inhibitors in risk-stratified populations remain unexplored. However, the Society for Cardiovascular Angiography and Interventions shock stage was not available during the enrollment of our registry for the differentiation of CS patients with different stages [23]. In our study, more than 60% of the patients achieved an improvement in blood pressure after initial therapy, and were considered in stage C (classic shock stage) by SCAI classification. This indicated a relatively low severity of CS in this population. The overall in-hospital mortality of CS patients in our study was 14.64%, which is consistent with rates in low to moderate risk CS patients published previously [24]. To assess the impact of CS severity on outcomes, we performed a subgroup analysis based on IABP usage. The results showed that ticagrelor was not associated with a lower all-cause mortality rate compared to clopidogrel, regardless of IABP use (Fig. 3). Further studies are warranted to investigate the comparative impact of DAPT in more severe AMI-CS patients. Moreover, the absence of platelet function assessment in this study precludes the evaluation of the bioactivity of various P2Y₁₂ inhibitors in STEMI-CS patients. Additionally, as prasugrel has not been introduced to the market in China, relevant data are lacking, and thus a comparison of the efficacy and safety of the three P2Y₁₂ inhibitors cannot be performed.

Conclusion

In this study, we conducted a comprehensive analysis by integrating data from a large cohort to evaluate the impact of ticagrelor and clopidogrel on outcomes in patients with STEMI-CS undergoing pPCI. Our findings suggest that, compared to clopidogrel, ticagrelor was not associated with a reduction in in-hospital mortality, MACE, or NACE events, and it did not demonstrate an increased risk of bleeding.