Real-world Outcomes of Patients Loaded with Ticagrelor Following Fibrinolysis for ST-elevation MI

Timely reperfusion is crucial in the management of ST-elevation MI (STEMI) to prevent left ventricular dysfunction and cardiovascular mortality. In the contemporary era, primary percutaneous coronary intervention (pPCI) is the recommended reperfusion strategy for patients presenting with STEMI who have access to a pPCI centre within 2 hours of first medical contact.^1–3 In patients who cannot receive pPCI within this timeframe, the pharmacoinvasive strategy, defined as fibrinolysis followed by routine early percutaneous coronary intervention (PCI), is an acceptable alternative treatment option with comparable efficacy to pPCI but higher rates of bleeding complications.^1–7

When fibrinolysis is used, routine dual antiplatelet therapy with aspirin and the less potent P2Y₁₂ receptor inhibitor clopidogrel has been shown to improve infarct-related artery patency and reduce ischaemic complications.⁸ However, the utility of more potent P2Y₁₂ inhibitors, such as ticagrelor and prasugrel, following fibrinolysis remains unclear. Although the PLATO and TRITON-TIMI 38 trials showed benefits for the use of ticagrelor and prasugrel, respectively, in the treatment of patients with acute coronary syndrome, both pivotal trials excluded patients who had prior treatment with fibrinolysis.^9,10 Hence, current guidelines have recommended against the use of these more potent agents in patients receiving fibrinolysis due to a perceived increased risk of bleeding complications.¹

The recent MIRTOS and TREAT trials sought to address these concerns by randomising patients to ticagrelor or clopidogrel following fibrinolysis for STEMI with different durations of follow-up. In MIRTOS, the authors found no difference in major adverse cardiovascular events (MACE) or bleeding events at the 3-month follow-up.¹¹ This finding reaffirmed findings of the TREAT trial, a multicentre randomised trial similar to MIRTOS, but with a longer follow up duration of 1 year after PCI.¹¹ However, a limitation of TREAT was that 90% of patients randomised to ticagrelor had pretreatment with clopidogrel and transitioned to ticagrelor at a mean of 11.4 hours.^12–14 In addition, a small observational study of 44 patients reporting real-world outcomes following ticagrelor loading with fibrinolysis for STEMI found low rates of minor bleeding (three patients) despite four patients experiencing recurrent MI and cardiovascular death at 30 days.¹⁵

Therefore, the aim of this study was to investigate the safety and efficacy of upfront ticagrelor loading in a real-world cohort of patients undergoing fibrinolysis for STEMI.

Methods

Study Population

This was a single-tertiary-centre retrospective analysis of all patients aged >18 years who were treated with fibrinolysis for STEMI between 2010 and 2020, prior to transfer to a metropolitan PCI centre. Patients with a discharge diagnosis of STEMI were identified from the hospital’s electronic database, and individual patient records were reviewed to identify those who were treated with fibrinolysis. Patients were excluded from the study if they had an indication for long-term anticoagulation at time of presentation, did not receive antiplatelet loading or received prasugrel prior to index coronary angiography.

This study was reviewed and approved by the institution’s review board (Monash Health Research Support Services RES-20-0000-510Q-66267).

Data Collection

Demographic data, clinical factors, antiplatelet loading regimens, blood results and coronary angiography results were obtained from electronic medical records. The infarct-related artery (culprit vessel) for each patient was identified by an interventional cardiologist blinded to patient and the degree and length of stenosis were determined by quantitative coronary analysis. Thrombolysis in Myocardial Infarction (TIMI) flow before and after PCI was determined by an interventional cardiologist blinded to patient details. Decisions surrounding antiplatelet regimen, revascularisation, method of revascularisation and treatment with post-procedural antithrombotic agents were made by the treating interventional cardiologist at the time of the procedure.

Study Definitions

The antiplatelet regimen in this study was determined by the initial antiplatelet loading following fibrinolysis prior to index coronary angiography, rather than discharge antiplatelet regimen. Antiplatelet loading in this study was either administered by ambulance staff at the time of fibrinolysis in the community or hospital staff on arrival at the PCI centre. The heart rate and blood pressure measurements used in the study analysis were the first results recorded at the time of first medical contact. Killip class was determined at the time of patient presentation to hospital. Total ischaemic time was defined as the time from symptom onset to fibrinolysis in patients who had successful fibrinolysis or as the time from symptom onset to pPCI in patients who had failed fibrinolysis. Successful fibrinolysis was defined as at least a 50% reduction in ST elevation on 12-lead ECG accompanied by complete resolution of symptoms. Therapeutic anticoagulation prior to arrival at the PCI centre was defined as treatment with heparin or enoxaparin following fibrinolysis prior to coronary angiography. Severe infarct-related artery stenosis was defined as stenosis ≥70% on quantitative coronary analysis, as analysed by a cardiologist who was blinded to the patient’s demographic and clinical history details (Figure 1 ).

Study Endpoints

The primary endpoint of the study was in-hospital major bleeding, which was defined as Bleeding Academic Research Consortium (BARC) types 3–5 bleeding events during index admission following fibrinolysis for STEMI. The secondary study endpoint was 30-day MACE, which was a composite of cardiac death, MI and cardiac arrest. Each individual outcome was also analysed as part of the secondary outcomes.

Statistical Analysis

Categorical variables were analysed using Chi-squared analysis and are reported as counts or percentages. The distribution of continuous variables was assessed for normality using the Shapiro–Wilk test. Continuous variables with a normal distribution were compared using t-tests and are reported as the mean ± SD. Non-parametric variables were compared with the Wilcoxon rank-sum test and are reported as median values with an interquartile range. Multivariate logistic regression models were used to adjust for baseline differences between the two groups as predictors of in-hospital BARC type 3–5 major bleeding and 30-day MACE. ORs were calculated for both the primary and secondary outcomes and are reported with 95% CIs. Two-tailed p<0.05 was considered statistically significant. Data were analysed using Stata (Stata Corp LP).

Results

Demographics

In all, 495 consecutive patients with STEMI treated with fibrinolysis were identified from the hospital’s database over the 10-year period (Figure 2). Of these patients, 41 were excluded because their complete medical records were unavailable for review. A further 53 patients were excluded because they did not receive antiplatelet loading prior to coronary angiography following fibrinolysis, and another two patients were excluded because they received prasugrel. The final patient population available for analysis was 399 patients, 234 of whom were loaded with clopidogrel and 165 of whom were loaded with ticagrelor. All patients received fibrinolysis with tenecteplase and underwent coronary angiography following fibrinolysis.

Baseline characteristics and clinical features on presentation for both patient groups are presented in Table 1. The clopidogrel group had higher rates of male patients (p=0.03), diabetes (p=0.02) and smoking (p=0.01), as well as a higher Killip score on presentation (p=0.01). Compared with the ticagrelor group, the clopidogrel group had higher rates of successful fibrinolysis (p=0.02), but a longer median total ischaemic time (p=0.01) due to the longer time from symptom onset to fibrinolysis (p<0.01). There were no differences between the two groups with regard to rates of therapeutic anticoagulation following fibrinolysis and location of STEMI on 12-lead ECG.

Coronary angiography findings and treatment outcomes for both groups are presented in Table 2. Patients who were loaded with ticagrelor were more likely to undergo coronary angiography earlier than patients receiving clopidogrel, regardless of the success of fibrinolysis (p<0.01 for both successful and failed fibrinolysis). There were higher rates of culprit lesions in the left anterior descending artery (LAD) in the clopidogrel group (p=0.04), but higher rates of culprit lesions in previous bypass grafts in the ticagrelor group (p=0.04). Patients who received ticagrelor were more likely to undergo PCI (p=0.03), including rescue PCI (p<0.01), whereas patients receiving clopidogrel were more likely to undergo coronary artery bypass graft surgery (p=0.04). There were no differences in further antithrombotic treatment following coronary angiography between the groups.

Outcomes

There was no significant difference between the two groups when analysed for the primary outcome of in-hospital BARC type 3–5 major bleeding (OR 1.68 [favouring clopidogrel]; 95% CI [0.56–5.10]; p=0.35; Table 3). There was also no statistically significant difference in 30-day MACE between the two groups (OR 0.70 [favouring ticagrelor]; 95% CI [0.27–1.76]; p=0.45). This result was consistent when individual efficacy endpoints of death (p=0.91), recurrent MI (p=0.09) and cardiac arrest (p=0.33) were analysed. There was no significant difference between the two groups for both in-hospital BARC type 3–5 major bleeding and 30-day MACE outcomes after adjusting for baseline differences between the two groups (Supplementary Tables 1 and 2).

Discussion

In this retrospective analysis of 399 patients treated with fibrinolysis for STEMI, we have reported real-world outcomes of patients who were loaded upfront with ticagrelor, a more potent P2Y₁₂ inhibitor, following fibrinolysis. This is the largest single-centre analysis to date evaluating the efficacy and safety of ticagrelor loading with fibrinolysis. The major findings of this analysis are that ticagrelor loading with fibrinolysis was not associated with statistically significant in-hospital major bleeding (BARC type 3–5) and that rates of MACE at 30 days were similar for ticagrelor and clopidogrel following fibrinolysis for STEMI.

This study is complementary to the results of the recent MIRTOS and TREAT trials, which showed similar major bleeding outcomes between the clopidogrel and ticagrelor groups following fibrinolysis.^11,14 However, the majority of patients (90%) in the ticagrelor arm of the TREAT trial were originally loaded with clopidogrel at the time of fibrinolysis and only changed over to ticagrelor at a mean of 11.4 hours.¹⁴ This is in contrast with the ticagrelor population in the present study, where patients received upfront ticagrelor loading with fibrinolysis. Furthermore, there was an extended time window of up to 72 hours for antithrombotic therapy in MIRTOS due to the study’s participating centres’ geographical constraints. Compared with the other trials, the present study is also unique given its use of a single fibrinolytic agent (i.e. tenecteplase), and tenecteplase has been established to offer a more favourable safety profile compared with other fibrin-specific agents.¹⁶ Thus, the findings of this study add to the current literature and strengthen the hypothesis that ticagrelor may be safely administered at the time of fibrinolysis for STEMI.

Similar to the MIRTOS and TREAT trials, the present study did not find significant differences between the clopidogrel and ticagrelor groups with regard to reductions in MACE.^11,13 This is in contrast to the results of the pivotal PLATO trial, including the PLATO-STEMI subgroup analysis, in which there was a reduction in cardiovascular outcomes as early as 30 days after randomisation.⁹ Despite the retrospective study design, short follow-up time and small patient population, the results of the present study mirror those of MIRTOS, which was a prospective study, and are in concordance with what is already known from previous studies.^11,13,15

Limitations

This study has some potential limitations. First, this was a retrospective and non-randomised study, which may have resulted in selection bias. Because there were too few patients in the cohort for propensity score matching, the statistical analysis instead used multivariate regression analysis to adjust for baseline difference between the two groups.

Another limitation is the lack of data surrounding the timing of antiplatelet loading following fibrinolysis. The groups in this study were determined by the first antiplatelet loading following fibrinolysis prior to coronary angiography, but there was a lack of documentation of the timing of antiplatelet administration following fibrinolysis, which could introduce confounding into the results. Finally, this study could not analyse longer-term efficacy and safety outcomes from this population due to a high rate of patients lost to follow-up. Most patients included in this study were transferred to the PCI centre from distant rural locations up to 700 km away, with long-term follow-up undertaken by local medical practitioners because of geographical reasons.

Conclusion

Although guidelines recommend clopidogrel as the mainstay P2Y₁₂ inhibitor of choice in the setting of fibrinolysis, the findings of this study suggest that upfront loading with ticagrelor may be a safe alternative.^1–3 This finding is exploratory and further robust prospective studies would be required to investigate the long-term efficacy and safety of ticagrelor in patients treated with fibrinolysis.

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