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 Table of Contents  
JOURNAL CLUB
Year : 2019  |  Volume : 5  |  Issue : 3  |  Page : 154-156

Platelet Blockage: Prasugrel versus Ticagrelor: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5


Department of Cardiology, AIIMS, New Delhi, India

Date of Submission20-Nov-2019
Date of Acceptance20-Nov-2019
Date of Web Publication20-Dec-2019

Correspondence Address:
Dr. Venkatakrishnan Ramakumar
Department of Cardiology, AIIMS, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_72_19

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  Abstract 


The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 trial randomized patients with acute coronary syndrome for whom invasive treatment was planned to ticagrelor versus prasugrel. At 1-year, prasugrel was associated with a 2.4% absolute reduction in the primary outcome. The trial suggests that prasugrel may be superior to ticagrelor in reducing the thrombotic outcomes. It could be that once daily dosing with prasugrel and higher rate of drug discontinuation in the ticagrelor group may be the mechanism.

Keywords: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5, journal club, prasugrel, ticagrelor


How to cite this article:
Ramakumar V. Platelet Blockage: Prasugrel versus Ticagrelor: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5. J Pract Cardiovasc Sci 2019;5:154-6

How to cite this URL:
Ramakumar V. Platelet Blockage: Prasugrel versus Ticagrelor: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5. J Pract Cardiovasc Sci [serial online] 2019 [cited 2020 Feb 18];5:154-6. Available from: http://www.j-pcs.org/text.asp?2019/5/3/154/273751




  Introduction Top


Large double-blind randomized control trials have established prasugrel and ticagrelor as high-efficacy P2Y12 inhibitors which are superior to clopidogrel.[1],[2] Prasugrel has shown efficacy in reducing the ischemic events[1] in post-PCI patients but not those managed conservatively[3] and without preloading,[4] whereas ticagrelor was shown to be beneficial in both.[2] Currently, prasugrel has a Class I indication in CS patients in whom the coronary anatomy is known, with PCI being planned without pretreatment, whereas ticagrelor can be given in acute coronary syndrome (ACS) patients regardless of invasive strategy with pretreatment. Till date, no major head-to-head trial existed comparing the efficacy and safety of the two agents in all ACS patients.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14]


  Methods Top


The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 (ISAR REACT 5) [Figure 1] was a phase IV multicenter randomized open-label control trial, testing the efficacy and safety of ticagrelor versus prasugrel in patients with ACS in whom an invasive strategy was planned. Patients were randomized 1:1 to ticagrelor versus prasugrel, with randomization being done through sealed envelopes containing a computer-generated sequence number assigned randomly to either arm. Patients in the ticagrelor were given a loading dose of 180 mg soon after randomization regardless of type pf ACS, whereas patients in the prasugrel arm received a loading dose of 60 mg either immediately in case of ST-elevation myocardial infarction (STEMI) or after coronary anatomy was known and before guidewire crossing in NSTEACS patients. A 5 mg/day dose was followed in patients >75 years of age or under 60 kg weight in 5.4% of the prasugrel patients. Follow-up was planned for 1-month, 6 months, and 12 months. The primary endpoints assessed were all-cause mortality, myocardial infarction (MI), and stroke at 1-year. The secondary endpoints studied were the individual components of the primary composite endpoint, and in addition, major BARC bleeding with three or more and definite stent thrombosis at 1-year. All events were adjudicated by two independent observers from the event adjudication committee. The sample size was calculated based on expected 10.0% primary events in 1-year in the ticagrelor arm, which was based on the PLATO trial and 12.9% in the prasugrel arm. This trial had 80% power to detect a relative risk reduction of 22.5% in the ticagrelor arm with respect to the prasugrel arm, and all endpoints were analyzed according to the intention to treat principle except the bleeding endpoint which was analyzed on a modified intention to treat principle.
Figure 1: Trial Design

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Patient characteristics

A total of 4018 patients were randomized. At baseline, both arms were well matched. The presentation of ACS was NSTEMI in 46% of patients, 41% in STEMI, and the rest were unstable angina. Approximately 81% of the patients were discharged with their respective antiplatelet agents. About 15% in the ticagrelor arm and 12% in the prasugrel arm had discontinued the drug in the 1 year study.


  Results Top


The primary composite endpoint of all-cause mortality, MI, and stroke was seen in 9.1% in the ticagrelor arm versus 6.8% in the prasugrel arm at the end of 1-year, with a statistically significant (P = 0.006) relative reduction of 36% in the prasugrel arm. The composite endpoint of cardiovascular (CV) death, MI, and stroke at 1 year occurred 8.3% in the ticagrelor arm and 6.3% in the prasugrel arm representing a 32% relative risk reduction in the prasugrel arm. Among the individual components, the rate of MI was increased in the ticagrelor arm (4.8% vs. 3.0% with a hazard ratio of 1.63). The bleeding endpoint was similar in both arms (5.4% with ticagrelor vs. 4.8% in prasugrel).


  Discussion Top


This study represents the first major randomized control trial comparing the efficacy and safety of ticagrelor versus prasugrel in all ACS where PCI is planned. To note, in addition, it essentially also compares the two different regimens that were followed in each respective arm. This is in accordance with the evidence we have gathered with the benefits and risks of prasugrel through previous trials.[1],[4] This trial addresses an important unanswered question in today's era, which newer anti-platelet agents should one chose and is well designed keeping in mind the prior evidence of benefit and harm with these agents. Prasugrel was associated with a statistically significant 36% reduction in three-point MACE at the end of 1 year without an increase in BARC major bleeding.

However, does this necessarily mean the end of the road for ticagrelor in patients with ACS in whom an invasive strategy is planned? In previous trials, the addition of a second antiplatelet agent, clopidogrel to aspirin, for NSTEACS patients had led to a 20% relative risk reduction of CV death, stroke, and MI at 9 months.[5] This trial showed a much higher relative risk reduction of 32% over 3 years. In addition, in previous trials with much larger patient populations, prasugrel showed a 19% and 16% relative risk reduction versus clopidogrel, respectively. Despite the difference in populations, such a high benefit with prasugrel appears extravagant. In addition, the expected ischemic event rates in the prasugrel arm, particularly MIs were slightly less than in results from earlier trials, which were likely due to chance, thus inflating the ischemic benefit much in favor of prasugrel.[1],[2]

With respect to the bleeding endpoints, a potential confounder is the high percentage of femoral access used in the trial (62%). This could have inflated the bleeding rates in the ticagrelor arm, where patients had been preloaded with a loading dose of ticagrelor before access. This could potentially and at least partially explain the numerically less major bleeding observed in the prasugrel arm which was counterintuitive.

There was asymmetry in the proportion of individuals who stopped therapy (15% in the ticagrelor group and 12% in prasugrel group), which may be overestimated the benefit of prasugrel. Furthermore, >80% of individuals underwent PCI; therefore, the findings cannot be projected to medical therapy for ACS.

The unavoidable open-label design, the different aspirin doses in previous studies, and a large number of patients (~20%) not being on the assigned agent at discharge all makes interpretation difficult.

Other factors need to be weighed in. The different pharmacokinetic profiles of the drugs, particularly the rapid onset and offset of ticagrelor, its reversible nature of binding, along with the possibility of interactions make it more susceptible to lower platelet inhibition and more ischemic events. Any noncompliance in the ticagrelor arm potentially will lead to more ischemic events.

With that being said, it still remains the first major randomized controlled trial performing a head-to-head comparison of the two agents in all ACS patients and remains to date, the only hard data available.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.  Back to cited text no. 1
    
2.
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.  Back to cited text no. 2
    
3.
Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367:1297-309.  Back to cited text no. 3
    
4.
Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013;369:999-1010.  Back to cited text no. 4
    
5.
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.  Back to cited text no. 5
    
6.
Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87-165.  Back to cited text no. 6
    
7.
O'Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:e362-425.  Back to cited text no. 7
    
8.
Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013;369:999-1010.  Back to cited text no. 8
    
9.
Schulz S, Angiolillo DJ, Antoniucci D, Bernlochner I, Hamm C, Jaitner J, et al. Randomized comparison of ticagrelor versus prasugrel in patients with acute coronary syndrome and planned invasive strategy-design and rationale of the iNtracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial. J Cardiovasc Transl Res 2014;7:91-100.  Back to cited text no. 9
    
10.
Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47.  Back to cited text no. 10
    
11.
Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation 2007;115:2344-51.  Back to cited text no. 11
    
12.
James SK, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: Substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ 2011;342:d3527.  Back to cited text no. 12
    
13.
Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367:1297-309.  Back to cited text no. 13
    
14.
Lemesle G, Schurtz G, Bauters C, Hamon M. High on-treatment platelet reactivity with ticagrelor versus prasugrel: A systematic review and meta-analysis. J Thromb Haemost 2015;13:931-42.  Back to cited text no. 14
    


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