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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 136-142

Prasugrel versus ticagrelor in Indian patients with acute coronary syndrome undergoing percutaneous coronary intervention: A prospective, randomized, comparative study


Department of Cardiology, Jehangir Hospital, Pune, Maharashtra, India

Date of Web Publication13-Dec-2018

Correspondence Address:
Dr. Ritu Bhatia
Row House 21, Hermes Heritage Phase 2, Shastri Nagar, Nagar Road, Pune, Maharashtra 411006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IHJI.IHJI_3_18

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  Abstract 


Objective: This prospective, open-label, randomized study compared the efficacy and safety of prasugrel and ticagrelor in the Indian patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Materials and methods: Patients were randomized to prasugrel (n = 50; 60mg loading dose, thereafter 10mg once daily [OD]) or ticagrelor (n = 50; 180mg loading dose, thereafter 90mg twice daily [BD]) for 12 months. Patients received aspirin 325mg loading and 150mg maintenance doses OD with prasugrel and 150mg bolus and 75mg OD with ticagrelor. Efficacy end points were reinfarction/repeat angina/repeat ischemia, death from cardiovascular causes, ischemic stroke, and stent thrombosis. Safety end points included bleeding, arrhythmias, and dyspnea. Results: At 12 months, the occurrence of composite efficacy end points was not significantly different between the groups (6.4% for both; P = 0.999). The incidence of stent thrombosis, reinfarction/recurrent angina/repeat ischemia was comparable between the groups. No significant difference was observed for major bleeding (0% for both groups) and minor bleeding (10.6% vs. 4.3%; P = 0.436) episodes between the groups. Similarly, bradycardia (6.5% vs. 0%; P = 0.242) and dyspnea (10.6% vs. 2.1%; P = 0.204) were not significantly different between the groups. No deaths were reported. Conclusion: Head-to-head comparison of prasugrel and ticagrelor in the Indian patients with ACS undergoing PCI showed that both are equally efficacious. Clinical safety and tolerance of the patients were comparable between prasugrel and ticagrelor groups at the end of 1 year.

Keywords: Acute coronary syndrome, percutaneous coronary intervention, prasugrel, stent thrombosis, ticagrelor


How to cite this article:
Bhatia R, Chaudhari N, Dugal JS, Mehta AC. Prasugrel versus ticagrelor in Indian patients with acute coronary syndrome undergoing percutaneous coronary intervention: A prospective, randomized, comparative study. Indian Heart J Interv 2018;1:136-42

How to cite this URL:
Bhatia R, Chaudhari N, Dugal JS, Mehta AC. Prasugrel versus ticagrelor in Indian patients with acute coronary syndrome undergoing percutaneous coronary intervention: A prospective, randomized, comparative study. Indian Heart J Interv [serial online] 2018 [cited 2019 Jul 21];1:136-42. Available from: http://www.ihji.org/text.asp?2018/1/2/136/247451




  Introduction Top


Acute coronary syndrome (ACS) has the highest burden in the Indian population with a high mortality rate (range, 2.1%–6.7%).[1],[2] Guidelines suggest use of dual antiplatelet therapy (DAPT), that is, a combination of aspirin + thienopyridine/non-thienopyridine for ACS.[3] Patients with ACS undergoing percutaneous coronary intervention (PCI) are commonly administered DAPT with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor).[4] Ticagrelor and prasugrel are the preferred antiplatelet agents over clopidogrel owing to better efficacy.[4]

The efficacy and safety of ticagrelor and prasugrel have been shown in patients with ACS undergoing PCI.[5] This study compared prasugrel and ticagrelor in the Indian patients with ACS undergoing PCI.


  Materials and Methods Top


Study population

Patients aged 18–70 years who had ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina undergoing PCI within 24h were included in the study. Patients who received clopidogrel or fibrinolytic therapy (either with non-fibrin-specific or fibrin-specific agent) were allowed. Patients were excluded if they were undergoing PCI for stable angina or in whom bioabsorbable vascular scaffold was used.

Study design

A prospective, analytical, randomized, open-label comparative study was conducted in patients of the cardiology department (outpatient and inpatient) from a hospital in Pune, India, from February 2014 to January 2015, and were followed up at 1, 6, and 12 months (till January 2016).

Study treatments

Patients were randomized (1:1) to prasugrel (60mg loading dose thereafter 10mg once daily [OD]) or ticagrelor (180mg loading dose thereafter 90mg twice daily [BD]) for 12 months. Patients received once daily aspirin 325mg or 150mg loading dose, and 150mg maintenance dose with prasugrel and 75mg with ticagrelor.

The study protocol was reviewed and approved by the institutional ethics committee of the hospital. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and in accordance with the International Conference on Harmonization’s Good Clinical Practice guidelines, applicable regulatory requirements, and in compliance with the protocol.

Study assessment

The efficacy end points were defined as reinfarction/repeat angina/repeat ischemia, death from cardiovascular causes, ischemic stroke, transient ischemic attack (TIA), and stent thrombosis. Death from vascular causes was defined as death from cardiovascular causes or cerebrovascular causes and any death without other known causes. Stroke was defined as focal loss of neurologic function caused by an ischemic or hemorrhagic event with residual symptoms lasting at least 24h or leading to death. Academic Research Consortium (ARC) criteria were used to define stent thrombosis.[6] The definitions were early-stent thrombosis: (i) acute, during PCI and (ii) subacute, within 30 days from PCI; late-stent thrombosis: 1–12 months after stent implantation; and very late–stent thrombosis: after 1 year of stent implantation. All reinfarctions were defined from third universal definition of myocardial ischemia (MI) and classified as: type 1, spontaneous; type 2, secondary to supply and demand imbalance; type 3, sudden death; type 4a, related to PCI, and type 4b, related to stent.[7] Repeat angina was defined as constricting, suffocating, crushing heavy, and squeezing type of angina chest pain occurring after PCI when initial symptoms of ACS are completely relieved.[8] Repeat ischemia was defined as the decreased blood flow and oxygen to the heart muscles after successful PCI with or without angina and onset changes on electrocardiography (ECG)/ecocardiography/noninvasive stress testing. TIA was defined as a brief episode of neurological dysfunction resulting from an interruption in the blood supply to the brain or the eye, sometimes as a precursor of a stroke. Safety end points were defined as major and minor bleeding (as per the study of platelet inhibition and patient outcomes [PLATO] criteria[9]), arrhythmias (bradycardia/tachycardia), and dyspnea.

Sample size calculation

Power and sample size calculation software was used, which can determine the sample size needed to detect a specified alternative hypothesis with the required power, the power with which a specific alternative hypothesis can be detected with a given sample size, or the specific alternative hypotheses that can be detected with a given power and sample size. Sample size calculation based on the effect sizes from the published literature[10],[11],[12],[13] showed that 26 patients in each group (total 52 patients) were sufficient to show statistical power of 80% (β error = 0.20) and 5% α error (17 units) between two study groups with a two-tailed alternative hypothesis. On the basis of results of similar TRITON TIMI 38[14] and PLATO[9] trials, event rate in our study for composite efficacy end points would be 8%–10% for both ticagrelor and prasugrel. The anticipated event rate in prasugrel group for MI is 7%–8%, stroke is 1%–2%, stent thrombosis is 1%–1.5%, and non-coronary artery bypass graft (CABG)-related bleeding is 2%–3%. The anticipated event rate in ticagrelor group for MI is 5%–6%, stroke is 1%–2%, stent thrombosis is 2%–3%, and non-CABG-related bleeding would be 4–5%.

Statistical analysis

Descriptive statistical analysis was carried out to explore the distributions of several characteristics of the cases studied. The results on categorical data were shown as n (% of cases) and the results on quantitative variables were shown as “mean ± standard deviation” across the two study groups. The statistical significance of difference of various qualitative responses between two study groups was tested using χ2 test for independence of attributes or Fisher’s exact probability test for 2×2 contingency tables. For comparing quantitative variables across two study groups, independent sample t-test was used after confirming the underlying normality assumption. P values <0.05 was considered to be statistically significant. Statistical Package for Social Sciences (SPSS; version 11.5, Chicago, IL) was used for statistical analysis.


  Results Top


Patients’ disposition and demographics

A total of 100 patients were randomized to ticagrelor (n = 50) or prasugrel (n = 50) as a second antiplatelet agent along with aspirin. Majority of the patients were men (76.0% in ticagrelor group and 86.0% in prasugrel group). Majority of the patients had diabetes + hypertension (30.0% in both groups), ST elevation (ticagrelor group, 46.0% and prasugrel group, 44.0%), single-vessel disease (ticagrelor group, 74.0% and prasugrel group, 72.0%), and one drug-eluting stent (DES) deployed (ticagrelor group, 74.0% and prasugrel group, 68.0%). Majority of the patients had received ticagrelor + aspirin + statin treatment (80.0%) in ticagrelor group and prasugrel + aspirin + statin (78.0%) in prasugrel group. The two treatment groups were well balanced with regard to all baseline characteristics for left ventricular function, body mass index, angiographic severity, thrombolysis, lytic agent, ECG, markers (troponin T and creatinine phosphokinase-MB), non-thrombotic medications, and number of stents [Table 1]. Three patients from each group (6%) were lost to follow-up during the study period.
Table 1: Patient disposition and baseline characteristics

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Thrombolytic therapy

Overall, thrombolysis was carried out in 46.6% (21/45) patients in the study; 43.5% (10/23) patients in the ticagrelor group and 50% (11/22) in the prasugrel group received thrombolysis. In the ticagrelor group, five (50%) patients were given ticagrelor loading along with thrombolysis, whereas remaining five (50%) patients received loading at least 2h before PCI and within 24h of thrombolysis. Similarly, in prasugrel group, four patients (36.4%) received prasugrel loading along with thrombolysis, whereas seven (63.6%) received prasugrel loading at least 2h before PCI and within 24h of thrombolysis. Streptokinase (28.9%, 13/45) and tenecteplase (17.8%, 8/45) were the commonly used agents. Streptokinase and tenecteplase, respectively, were given in 60% (6/10) and 40% (4/10) patients in the ticagrelor group and 63.7% (7/11) and 36.4% (4/11) patients in the prasugrel group. The distribution of thrombolysis and distribution of different lytic agents did not differ significantly (P > 0.05) between the treatment groups.

Efficacy

The efficacy end points did not differ significantly between the two groups (P > 0.05 for all end points) at 1-month and 12-month follow-up.

At 1-month follow-up, stent thrombosis developed in 2% (n = 1, early-stent thrombosis) of patients in the ticagrelor group. No patient had other efficacy end points including reinfarction/recurrent angina/repeat ischemia, stroke, or death from cardiovascular or other cause in any of the treatment groups. Overall, the rate of composite efficacy end points was 2% in ticagrelor group versus 0% in prasugrel group (P > 0.05).

At 12-month follow-up, stent thrombosis had developed in 4.3% (2/47) patients (early- and late-stent thrombosis each in 2.1% [n = 1] patients) in ticagrelor group, and in 2.1% (1/47) patients (late type) in the prasugrel group. Other efficacy end point, that is, reinfarction/recurrent angina/repeat ischemia was observed in 2.1% patients (n = 1) in ticagrelor group and in 4.3% patients (n = 2) in the prasugrel group. No death from cardiovascular or other cause was reported in any of the treatment groups. Overall, the rate of composite efficacy end points was not significantly different between the groups (6.4% in both the groups, P > 0.05) [Table 2].
Table 2: Intergroup comparison of efficacy end points

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Safety

At 1- and 12-month follow-up, minor bleeding was reported in 4% and 10.6% patients, respectively, in the ticagrelor group, and 2% and 4.3% patients, respectively, in the prasugrel group. Bradycardia and dyspnea each were reported in 4% patients at 1-month follow-up and 6.4% and 10.6% patients, respectively, at 12-month follow-up. In prasugrel group, dyspnea was reported in 2% patients at 1 month and 2.1% patients at 12 months. Safety end points did not differ significantly between the two intervention groups (P > 0.05) at 1-month and 12-months follow-up [Table 3].
Table 3: Intergroup comparison of safety end points

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  Discussion Top


Atherothrombosis is the major cause of ACS and cardiovascular death. Disruption of atherosclerotic lesion with overlaid thrombus is the characteristic presentation.[15] Atherothrombosis plays a central role in complications occurring around PCI including recurrent ACS, procedure-related MI, or stent thrombosis. Platelet adhesion, activation, and aggregation are the essential mechanisms in atherothrombosis formation, and inhibition of platelet aggregation may decrease thrombus formation and thus, beneficial in the prevention of ACS.[16],[17],[18],[19]

Various medical agents targeting thromboxane A2, adenosine diphosphate (ADP), glycoprotein (GP)IIb/IIIa, thrombin, collagen, and von Willebrand factor pathways are developed/in development for use as antiplatelet agents.[19] Currently, the antiplatelet agents include thromboxane inhibitors (aspirin, NCX-4016, S18886), ADP receptor antagonists (or P2Y12 inhibitors [Gi/adenylyl cyclase pathway]) such as the thienopyridines (ticlopidine, clopidogrel, prasugrel, and AZD6140) and the non-thienopyridines (elinogrel, ticagrelor, and cangrelor); the GPIIb/IIIa inhibitors (abciximab and eptifibatide); and medication working through other pathways including dipyridamole, cilostazol, protease-activated receptor antagonists, and the platelet adhesion antagonists.[19]

Prasugrel is a third-generation thienopyridine, and its intermediary metabolite irreversibly binds to the P2Y12 receptor on the platelet for lifetime, causing the inhibition of activation and aggregation of the platelets.[20] Ticagrelor directly and reversibly binds to and inhibits the P2Y12 receptor and shows rapid onset of effects.[21] Ticagrelor and prasugrel are preferred over clopidogrel as antiplatelet agent as they show better efficacy.[4] The efficacy and safety comparison of ticagrelor and prasugrel in patients with ACS undergoing PCI has been shown in a clinical study. However, head-to-head comparison of these agents in the Indian population is not established. Hence, this prospective, analytical, randomized, open-label study was conducted to compare the efficacy and safety of prasugrel and ticagrelor in the Indian patients with ACS undergoing PCI.

This prospective, randomized study compared the efficacy and safety of two P2Y12 inhibitors, ticagrelor and prasugrel, in the Indian patients with ACS undergoing PCI. The study compared the two agents for efficacy end points of occurrence of MI events (reinfarction or repeat angina or repeat ischemia), death from cardiovascular causes, ischemic stroke, TIA, and stent thrombosis; and safety end point of occurrence of minor/major bleeding, dyspnea, and arrhythmias.

Ticagrelor and prasugrel provide stronger platelet inhibition compared with clopidogrel.[4] In a prospective, single-center, single-blind study (n = 44) conducted in Greece by Alexopoulos et al.,[10] ticagrelor (90mg, BD) showed a significantly higher platelet inhibition compared with prasugrel (10mg, OD) 24h post-PCI in patients with ACS exhibiting high on-treatment platelet reactivity while on clopidogrel.

PRAGUE-18 study (n = 1230) first described the head-to-head comparison of ticagrelor and prasugrel in patients with AMI treated with primary or immediate PCI at cardiology centers in the Czech Republic.[5] To the best of our knowledge, our study is the first such study to compare ticagrelor and prasugrel in the Indian patients with ACS undergoing PCI. This study reported that prasugrel and ticagrelor did not differ significantly for their clinical efficacy. The results are in line with the PRAGUE-18 study, which demonstrated no significant difference between ticagrelor and prasugrel groups. Clinical safety and tolerance were comparable between prasugrel and ticagrelor in patients with ACS undergoing PCI at the end of 1 year.

In this study, stent thrombosis was comparable between both the groups, with two patients (4.3%) in ticagrelor group and one patient (2.1%) in the prasugrel group. The rate of late-stent thrombosis was more than early-stent thrombosis. The PLATO trial (n = 18,624) showed that ticagrelor reduces the incidence of stent thrombosis in patients with ACS, with consistent benefits across a broad range of patients, stents, and treatment characteristics compared with clopidogrel.[22] However, in the PLATO trial among those who had thrombosis, 43% in the clopidogrel arm and 31% in the ticagrelor arm were not on their medications. This makes definitive conclusions harder to obtain. Also, stent thrombosis was identified from adjudication forms for events identified as death, myocardial infarction, severe recurrent ischemia, and recurrent ischemia. However, the ARC definition of stent thrombosis takes into account not only myocardial infarction and death but also angiographic-stent thrombosis, but this information was not available for a large number of participants in the PLATO trial.[23] In our study, all patients of suspected stent thrombosis had undergone coronary angiography for confirmation, which represents the true rate of stent thrombosis as compared to PLATO trial.

In a real-world setting study, ticagrelor significantly reduced the risk of definite-stent thrombosis than clopidogrel in patients with ACS undergoing PCI (1-year risk rate in ticagrelor group [n = 1134], n = 5 [0.5%] vs. clopidogrel group [n = 1201], n = 17 [1.4%]; hazards ratio, 0.31; 95% confidence interval, 0.11–0.84),[24] whereas a retrospective observational analysis showed no significant difference in the stent thrombosis rates in ticagrelor and prasugrel groups in patients with ACS with successful PCI.[25] Overall, the rate of stent thrombosis in patients receiving ticagrelor (4.3%) and prasugrel (2.1%) in our study is consistent with the findings from earlier studies, ranging from 0.5%[24] to 4.95%[25] for ticagrelor, and 1.1%[14] to 3.96%[25] for prasugrel.

Ticagrelor group reported less MI events (reinfarction/recurrent angina/repeat ischemia) compared to prasugrel group (2.1% vs. 4.3%) in this study. No death was reported from cardiovascular causes/any other cause/stroke–ischemic/TIA in both the groups. Overall, the rate of composite efficacy end points did not differ significantly between ticagrelor and prasugrel groups (6.4% in each). The results are in line with the previous findings, which showed the incidence of composite end point of reinfarction/recurrent ischemia/death from cardiovascular or any cause/stroke/TIA ranging from 4.3%[26] to 12%[27] with ticagrelor, and from 9.9% to 14.6% with prasugrel.[14]

A systemic review of randomized controlled trials that compared new (reteplase, tenecteplase) versus older (alteplase, streptokinase) thrombolytic agents in the treatment of acute MI showed a similar efficacy in reducing mortality of all thrombolytic agents.[28] In this study, 46.6% of the patients received fibrinolytic therapy with a greater number (62%, 13/21) of patients receiving streptokinase (first-generation lytic agent) compared to tenecteplase (third-generation lytic agent, 38%, 8/21). No patients in either prasugrel or ticagrelor groups had bleeding manifestations within 24–48h after the thrombolysis or during procedure. Patients who underwent pre-thrombolysis in prasugrel group did not show increased bleeding tendencies up to 1 year after the procedure, whereas in the ticagrelor group, one patient had minor hematuria at 4 months after the procedure. Since only a small group of patients received thrombolytic therapy, the results comparing the efficacy between the groups were not analyzed.

Overall, minor bleeding, bradycardia, and dyspnea did not differ significantly between prasugrel and ticagrelor at 12-month follow-up. The results are consistent with the previously reported studies.[9],[14] Bradycardia developed in three patients receiving ticagrelor, whereas it was not seen in patients who received prasugrel. Of these patients, one patient developed symptomatic bradycardia within 24h and two patients developed bradycardia after 7 days following PCI. The patients were not receiving any treatment that may have affected the patients’ heart rate. Dyspnea is not frequently reported with prasugrel. Incidence of dyspnea is reported as higher with reversible P2Y12 antagonists (such as ticagrelor) than with irreversible P2Y12 inhibitors (such as prasugrel).[29] In this study, one patient (NSTEMI) developed dyspnea on exertion in the prasugrel group and five in the ticagrelor group, in line with the above information. Furthermore, no patient reported major bleeding episodes in this study.

An adjusted indirect meta-analysis reported that prasugrel and ticagrelor are superior to clopidogrel for the treatment of ACS. The efficacy and safety of prasugrel and ticagrelor have been shown to be similar in head-to-head comparisons, with prasugrel offering more protection from stent thrombosis, while showing more bleeding episodes.[30] Similarly in our study, head-to-head comparison of ticagrelor with prasugrel showed that the risk of composite efficacy end points was similar between the two groups, whereas the rate of stent thrombosis was similar. The overall incidence of adverse events (combined bleeding events, dyspnea, and bradycardia) was numerically higher with ticagrelor group as compared with prasugrel.

Limitations of our study include a small sample size (for statistical significance) and study being conducted at a single center (racial or regional variations). Comparing clinical efficacy and safety with platelet function tests would have been better to validate the results of the study and to draw the conclusions more accurately, which was not done because of cost constraints.


  Conclusion Top


Head-to-head comparison of prasugrel and ticagrelor in patients with ACS undergoing PCI showed that both are equally efficacious. Clinical safety and tolerance were comparable between prasugrel and ticagrelor at the end of 1 year.

Acknowledgements

We would like to thank Mr. Shreekant Sharma (Lambda Therapeutic Research) for providing writing assistance and Dr. Venugopal Madhusudhana (Lambda Therapeutic Research) for additional editorial assistance for the development of this manuscript. We would also like to thank the study participants of the study, without whom the study would never have been accomplished.

Financial support and sponsorship

This research study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Medical writing services were procured from Lambda Therapeutic Research and supported by Terumo India.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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