Prehospital Prasugrel Versus Ticagrelor in Real-World Patients With ST-Elevation Myocardial Infarction Referred for Primary PCI: Procedural and 30-Day Outcomes

Abstract: Objectives. Pretreatment with P2Y₁₂ inhibitors before primary percutaneous coronary intervention (PPCI) can reduce the incidence of major adverse cardiovascular event (MACE) rate in ST-segment elevation myocardial infarction (STEMI) patients. We investigated differences in coronary reperfusion and clinical outcomes between prehospital administration of prasugrel vs ticagrelor in a historical cohort analysis. Methods and Results. We conducted a retrospective analysis of prospectively collected data of 533 STEMI patients, directly referred by the ambulance for PPCI, and pretreated with either prasugrel (2013-2014) or ticagrelor (2015-2016). The primary outcome measurement was coronary and myocardial reperfusion prior to and after intervention. Secondary outcome measurements included MACE and stent thrombosis (ST) at 30 days. The median time from first medical contact to balloon was 82 minutes. There was no significant difference in preprocedural and postprocedural coronary reperfusion (TIMI flow grade 3) and postprocedural ST-segment elevation resolution between the prasugrel and ticagrelor groups. No significant differences in MACE and ST rates were found between the groups. No fatal or intracranial bleedings were reported up to 30-day follow-up. Conclusions. Prehospital administration of both prasugrel and ticagrelor in STEMI patients is safe, without differences in preprocedural and postprocedural reperfusion and short-term clinical outcomes.

J INVASIVE CARDIOL 2018;30(12):431-436. Epub 2018 October 15.

Key words: anticoagulation, P2Y₁₂ inhibitors, primary PCI, STEMI

In patients presenting with ST-segment elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (PPCI) is the recommended reperfusion strategy.¹ Timely reperfusion therapy is associated with improved outcomes in terms of infarct size and mortality.^2-4 

Prehospital STEMI triage not only allows a reduction in time to reperfusion, it also allows an effective pretreatment before PPCI.⁵ Prehospital administration of clopidogrel improved coronary patency before PPCI and clinical outcomes.⁶ Two newer oral P2Y₁₂ inhibitors – prasugrel and ticagrelor – have a more rapid onset of action, no issues with non-responsiveness, and evidence of clinical superiority vs clopidogrel in STEMI patients,^7,8 but no clear superiority of one vs the other.^9,10

The recently published PRAGUE-18 trial showed no significant differences between in-hospital pretreatment with prasugrel vs ticagrelor in STEMI patients undergoing PPCI.¹¹ To date, no comparison of prehospital administration of P2Y₁₂ inhibitors prior to PPCI has been performed. This study investigates whether in-ambulance administration of either ticagrelor or prasugrel in “real-world” STEMI patients directly referred for PPCI would result in better reperfusion and clinical outcomes. 

Methods

This is a retrospective analysis of prospectively collected data on STEMI patients pretreated with in-ambulance prasugrel or ticagrelor prior to PPCI. 

Study population. For the cohort of prasugrel patients, we performed a database search and longitudinal medical record review. Admissions for STEMI between July 2013 and December 2014 at OLVG Amsterdam were reviewed. 

Prospective data collection of ticagrelor patients started in January 2015 after implementation of in-ambulance ticagrelor, until December 2016. Written informed consent was obtained and the study protocol was approved by the local ethics committee. 

In the greater Amsterdam area, a system of prehospital triage for STEMI patients has been in effect since 2001. Ambulance personnel perform and transmit an electrocardiography (ECG) to the nearest PCI center when STEMI is suspected. Upon confirmation of the diagnosis, patients are pretreated in-ambulance with aspirin, unfractionated heparin, and (in absence of contraindications) a P2Y₁₂ inhibitor, and immediately dispatched to the cath lab.

Patients were included if presented by the ambulance service for PPCI and pretreated with prasugrel (60 mg orally) or ticagrelor (180 mg orally). Exclusion criteria were self-referral, time to first medical contact (FMC) >12 hours, resuscitation requiring intubation, and cardiogenic shock at presentation. Data were obtained up to 30 days following the index procedure, and included time intervals, baseline and procedural characteristics, in-hospital and 30-day clinical outcomes, and medicine use at discharge and at 30-day follow-up. 

Definition of time intervals. Time to FMC is defined as the time lapse between the insurgence of complaints and in-ambulance ECG. FMC to balloon time is defined as the time lapse between the in-ambulance ECG and coronary intervention. Total time to reperfusion is the sum of both. Time intervals were adjudicated by the investigators upon revision of different sources (electronic patient dossier, ambulance ride form, cath lab logbook).

Outcome measurements. The primary outcome measurement of the study is coronary and myocardial reperfusion, defined as Thrombolysis in Myocardial Infarction (TIMI) coronary flow grade 3 prior to and after the procedure, and ≥50% ST-segment elevation resolution (STR) at 90-120 minutes after the procedure.¹² Both were adjudicated by the investigators, who were blinded to the treatment.   

Main secondary outcome measurement of the study was major adverse cardiovascular event (MACE) at 30-day follow-up. MACE was defined as the composite of cardiac (or unknown cause) death, recurrent myocardial infarction (MI) in the target vessel (TV), and ischemia-driven target-lesion revascularization (TLR). Other secondary outcome measurements included individual MACE components at 30 days; major bleedings according to Bleeding Academic Research Consortium (BARC) criteria; definite stent thrombosis (ST) according to Academic Research Consortium (ARC) criteria; and medication compliance.

Statistical analysis. Ambulance protocols (except for the switch from prasugrel to ticagrelor), did not change across the study years: thus, we enrolled consecutive patients without a priori propensity-score matching. Results would be corrected for baseline and/or procedural characteristics in case significant differences were found. 

Continuous variables are presented as mean ± standard deviation in cases of normal distribution or as median (interquartile range) if not normally distributed. Categorical variables are presented as frequencies. The independent t-test was used for continuous variables with normal distributions and the Mann-Whitney U-test was used for non-normal distributions. Pearson’s Chi-square or Fisher’s exact test were used for categorical variables. Independent predictors for TIMI 3 flow prior to and after the procedure, STR ≥50%, and 30-day MACE were identified by binary logistic regression analysis. Baseline and procedural characteristics with a P-value <.10 and characteristics known to be clinically relevant were entered into both univariable and multivariable models. These results are expressed as odds ratio (OR) with 95% confidence interval (CI). Two-sided P-values of <.05 were considered to indicate statistical significance. Statistical analyses were performed using SPSS Statistics, version 22.0 (IBM).

Results

Baseline characteristics. Between July 2013 and December 2016, a total of 533 patients (210 prasugrel, 323 ticagrelor) were included in this study. Baseline characteristics are summarized in Table 1. In the overall study population, mean age was 61.7 years and 72% of the patients were men. The cardiovascular risk profile is compatible with other STEMI studies.¹³ There were no differences between the two studied groups except for hypercholesterolemia (11.9% prasugrel vs 21.0% ticagrelor; P<.01). 

Procedural characteristics. The procedural characteristics are shown in Table 2. Besides a P2Y₁₂ inhibitor, all patients were pretreated with aspirin (in-ambulance ≥160 mg or prior use). Transradial approach was predominant in both groups (>95%). Thrombus aspiration (70.0% vs 44.3%; P<.001) and periprocedural bivalirudin (81.9% vs 31.3%; P<.001) were more often used in the prasugrel group vs the ticagrelor group, respectively. Procedural success, defined as TIMI flow grade 3 post procedure or improvement in TIMI flow ≥2 grades, was achieved in 97% of all patients.

Coronary and myocardial reperfusion. Reperfusion data for both groups are shown in Table 2. In 55.0% of the patients, TIMI flow grade before PPCI was 0, while 92.7% had TIMI flow grade 3 post procedure. There were no significant differences in optimal TIMI flow either before the procedure (26.7% vs 27.0%; OR, 1.082; 95% CI, 0.716-1.635; P=.71) or post procedure (91.9% vs 93.2%; OR, 1.047; 95% CI, 0.463-2.369; P=.91) in prasugrel vs ticagrelor patients, respectively. No independent predictors of coronary reperfusion were identified.

Postprocedural myocardial reperfusion (STR ≥50%) was achieved in 88.5% of prasugrel patients and 87.7% of ticagrelor patients (OR, 1.106; 95% CI, 0.520-2.356; P=.79). Time to reperfusion and postprocedural TIMI flow grade were independent predictors of STR.

Time intervals. Total time to reperfusion was slightly shorter in the prasugrel group (145 minutes [IQR, 112-195 minutes] vs 158 minutes [IQR, 122-219 minutes]; P<.01). This was due both to a shorter time to FMC, and a shorter FMC to balloon time (Table 2).

Clinical outcomes. In-hospital follow-up data were available for all patients. Thirty-day follow-up data were available for 88.6% of prasugrel patients and 87.3% of ticagrelor patients. Those lost to follow-up were due either to withdrawn consent or inability to reach patients living abroad. MACE, bleeding, and ST rates at 30 days are presented in Table 3. No periprocedural death or major bleeding was reported. A total of 12 MACEs (3 in-hospital cardiac deaths and 9 MACEs during follow-up [2.6%]) were reported at 30-day follow-up. This MACE rate is the composite of 6 deaths (1.3%) (5 confirmed cardiac, 1 unknown), 5 TLRs (1.1%) due to recurrent MI caused by (very) early ST, and 1 TLR (0.2%) due to iatrogenic dissection of the infarct-related artery during staged procedure of a non-target vessel related intervention. The MACE rate did not differ significantly between the treatment groups (1.6% in prasugrel and 3.2% in ticagrelor group; OR, 0.723; 95% CI, 0.127-4.108; P=.71). No independent predictors for MACE were identified. No differences were seen regarding major bleeding or definite ST rates. Out of 5 definite ST cases, 1 was related to premature discontinuation of dual-antiplatelet therapy, 1 was due to severe stent malapposition (as assessed by optical coherence tomography during reintervention), and 1 was due to suspected clopidogrel non-responsiveness in a patient in whom ticagrelor was replaced.

Medication compliance. The use of medication at discharge and at 30-day follow-up is shown in Table 4. At discharge, all patients received a P2Y₁₂ inhibitor in combination with either aspirin or oral anticoagulation therapy. At 30-day follow-up, 98.8% of the prasugrel group and 98.5% of the ticagrelor group (P>.05) maintained this therapy. Beta-blockers were more often used at discharge in the prasugrel group (93.2%) vs the ticagrelor group (88.0%; P=.05), mainly due to documented bradycardia. 

Discussion

This observational cohort study is the first to compare the outcomes of “real-world” STEMI patients undergoing PPCI, treated with either prasugrel or ticagrelor in a prehospital setting. No significant differences in coronary reperfusion, MACE, or ST rates were found between the two treatments. No fatal or intracranial bleeding was reported up to 30-day follow-up.

The primary goal of antiplatelet therapy in the setting of PPCI is to reduce the risk of thrombotic complications, such as suboptimal reperfusion, reinfarction, and ST. Aggressive platelet inhibition by aspirin improved outcomes in STEMI patients.¹⁴ Further improvements were achieved by adding clopidogrel and, to a greater extent, by the newer P2Y₁₂ inhibitors.^6-8,15 In acute coronary syndrome (ACS) cases, prasugrel and ticagrelor did not significantly differ in terms of MACE.⁹ This was confirmed by the PRAGUE-18 trial.¹¹ On the other hand, in a cohort of 89,000 United Kingdom STEMI patients undergoing PPCI, prasugrel was associated with lower 30-day and 1-year mortality rates than ticagrelor or clopidogrel.¹⁰

An open vessel before PPCI has a prognostic advantage in STEMI patients.¹⁶ The rapid onset of action of both prasugrel (within 30 minutes) and ticagrelor (within 90 minutes) justifies pretreatment in-ambulance, as some recanalization is expected before mechanical intervention.^17,18 Unfortunately, the ATLANTIC study failed to show any advantage in terms of preprocedural recanalization when ticagrelor was administered in-ambulance vs in the cath lab.¹⁹ This could be due to delayed platelet inhibition in the subset of STEMI patients.²⁰ The FMC to balloon time in our study was short (median, 82 minutes [IQR, 70-97 minutes]). These time intervals confirm, on one hand, that European Society of Cardiology (ESC) recommendations for appropriateness of treatment in STEMI can also be achieved in real-life settings. On the other hand, the drug would have insufficient time to reperfuse.^4,20 

The degree of reperfusion post procedure correlates with short-term and long-term cardiovascular survival.^21-23 Our study showed high rates of optimal TIMI flow grade post procedure, without significant differences between prasugrel and ticagrelor. Contrary to former studies, our study did not confirm that a longer total time to reperfusion nor a preprocedural TIMI flow grade ≤1 would predict a suboptimal TIMI flow post procedure.^21,24 In both groups, we achieved high rates of ≥50% STR. TIMI flow post procedure and total time to reperfusion were confirmed as independent predictors of STR. Neither postprocedural TIMI flow grade nor STR were influenced by the use of thrombus aspiration or bivalirudin.

The 30-day MACE rate in our study was low (1.6% prasugrel vs 3.2% ticagrelor; P>.05). In the ATLANTIC study, the incidence of 30-day MACE in the pretreated subset was somewhat higher (4.4%). On the other hand, early ST is usually lower in prehospital-treated patients.¹⁴ In our study, the incidence of definite ST at 30 days was very low, without significant differences between treatments (0.5% prasugrel vs 1.4% ticagrelor; P=.65). 

Major bleeding is a powerful independent predictor of mortality in ACS, and STEMI patients undergoing PPCI are those at the highest bleeding risk.^25,26 Several studies showed higher incidences of (major) bleeding with prasugrel when compared to either clopidogrel or ticagrelor.^14,27 These findings were not confirmed in our study, as we found very low bleeding rates, without fatal or intracranial bleedings, for both treatments. As expected, the routine use of transradial access contributed to a consistent reduction in access-related bleedings.²⁸ A shift toward concomitant use of bivalirudin (81.9% for prasugrel vs 31.3% for ticagrelor) due to changed guidelines was irrelevant for ST and major bleeding rates.²⁹ Results were not influenced by compliance to antithrombotic therapy, which was very high in both treatment groups (>98.5%).

Recent ESC guidelines express no preference for either prasugrel or ticagrelor in STEMI patients undergoing PPCI.⁴ While the faster onset of action could favor prasugrel, ticagrelor has fewer contraindications.³⁰ Our study is not able to answer the question whether prehospital treatment with P2Y₁₂ inhibitors is effective and desirable. A large, randomized controlled trial would also be needed to investigate which of the two, if any, should be preferred for pretreating STEMI patients in the prehospital setting prior to PPCI.

Study limitations. First, this was not a randomized study. Although the in-ambulance treatment protocol was standardized, strict inclusion and exclusion criteria were chosen, and baseline characteristics did not differ, unreported bias may have influenced our results. Unfortunately, specific data on stent/device were not collected. Interventional practice in STEMI changed significantly during recruitment; while we do not expect this to influence short-term results, this might not be true for TLR and ST rates during longer-term follow-up. Second, not only was the study under-powered for MACE, but the incidence of MACE was lower than expected. Third, the peculiar logistics in Amsterdam (direct patient transfer, high-volume PPCI center, systematic transradial approach) may not be representative for PPCI settings in other centers and countries.

Conclusion

In this observational cohort study of STEMI patients undergoing PPCI, there were no significant differences between prasugrel and ticagrelor in terms of reperfusion, early clinical outcomes, bleeding rate, or ST rate when either drug was administered in a prehospital in-ambulance setting. 

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From the ¹OLVG Hospital, Amsterdam, The Netherlands; ²Spaarne Gasthuis, Hoofddorp, The Netherlands; and ³Academic Medical Centre, Amsterdam, The Netherlands.

Funding: This work was supported by an unrestricted grant from AstraZeneca.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 6, 2018, final version accepted August 19, 2018.

Address for correspondence: Giovanni Amoroso, MD, PhD, Department of Interventional Cardiology, OLVG Hospital, Oosterpark 9, 1091 AC, Amsterdam, The Netherlands. Email: g.amoroso@olvg.nl