CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the ISAR-REACT 5 Trial

Table of contents for the ISAR-REACT 5 Trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

March 29, 2022

Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes

S. Schüpke, F.-J. Neumann, M. Menichelli, K. Mayer, I. Bernlochner, J. Wöhrle, G. Richardt, C. Liebetrau, B. Witzenbichler, D. Antoniucci, I. Akin, L. Bott-Flügel, M. Fischer, U. Landmesser, H.A. Katus, D. Sibbing, M. Seyfarth, M. Janisch, D. Boncompagni, R. Hilz, W. Rottbauer, R. Okrojek, H. Möllmann, W. Hochholzer, A. Migliorini, S. Cassese, P. Mollo, E. Xhepa, S. Kufner, A. Strehle, S. Leggewie, A. Allali, G. Ndrepepa, H. Schühlen, D.J. Angiolillo, C.W. Hamm, A. Hapfelmeier, R. Tölg, D. Trenk, H. Schunkert, K.-L. Laugwitz, and A. Kastrati, for the ISAR-REACT 5 Trial Investigators

https://www.nejm.org/doi/full/10.1056/NEJMoa1908973

Relevant Literature – ISAR-REACT 5 Trial

Relevant Guidelines

2021 ACC/AHA Coronary Artery Revascularization Guidelines ⁷

2014 ACC/AHA Non-STE ACS Guidelines⁸

Study Rationale

Dual antiplatelet therapy consists of aspirin combined with an adenosine diphosphatase receptor antagonist, which remains the cornerstone for the treatment of acute coronary syndromes (ACS). Both ticagrelor and prasugrel have proven to have more rapid and consistent inhibition of platelets compared to clopidogrel.However, no head-to-head trials have compared ticagrelor and prasugrel directly. This study was designed to be the first to compare the efficacy and safety of these two medications.

Objective

To assess if ticagrelor is superior to prasugrel in the management of ACS in patients with the planned intervention.

1. Trial: Prospective, randomized, open-label, multicenter (21 centers in Germany, 2 in Italy, N=4018). Enrollment September 2013-February 2018 with 1-year follow-up.
2. Intervention: Patients who presented with ACS and for whom invasive evaluation was planned received either ticagrelor or prasugrel*

*Upstream treatment with Prasugrel in STEMI but downstream administration (after angiography but before PCI) in NSTEMI and UA. Ticagrelor treatment occurred upstream in all cases.

Inclusion and Exclusion Criteria: – ISAR-REACT 5 Trial

Outcomes

1. Primary Outcome: Composite of death, myocardial infarction, or stroke 1 year after randomization
2. Secondary Outcomes:
   1. Safety endpoint: Bleeding (BARC class 3-5) –>see graphic below
   2. Incidence of individual components of the primary endpoint
   3. Stent thrombosis (ARC criteria: definite and probable)

Statistical Analysis

Sample size calculation based on assumed 10% and 12.9% incidence of primary endpoint in ticagrelor and prasugrel group respectively—intention-to-treat analysis (except primary safety endpoint which used modified intention to treat). The difference between the ticagrelor and prasugrel groups for the primary endpoint was tested in a Cox proportional-hazards model of the primary outcome using a two-sided significance level of 0.05.

Participant Characteristics:

• 1500 participants (757 underwent PCI, 743 underwent CABG)
• Mean age 65 years, 82% male, 29% had diabetes, 39% presented with acute coronary syndrome, and 13% had undergone previous PCI.
• Intravascular imaging was used in 11.7% of cases in the PCI arm.

Outcomes

• 4018 patients recruited from 23 centers (21 in Germany, 2 in Italy); 2012 patients assigned ticagrelor and 2006 patients assigned prasugrel
• Suspected diagnosis on admission: 41.1% STEMI, 46.2% NSTEMI, 12.7% unstable angina
• Before admission, 34.7% of patients in the ticagrelor group and 35.6% of patients in the prasugrel group were taking aspirin; 5.0% of patients in the ticagrelor group, and 4.7% of patients in the prasugrel group were taking clopidogrel
• No significant demographic differences between the two groups

Primary and Secondary End Points:

Adverse Events:

Incidence of bleeding at 1-year (included types 3,4 and 5 on BARC scale) seen in 95 patients in the ticagrelor group (5.4%) vs. 80 patients in the prasugrel group (4.8%) [HR 1.12, P=0.46]

ISAR-REACT 5 Trial Conclusions

In patients presenting with acute coronary syndrome with planned intervention, prasugrel was superior to ticagrelor in reducing the composite of death from any cause, myocardial infarction, or stroke at one year without a significant increase in the incidence of major bleeding.

Limitations & Considerations

• Open label trial making it more subject to bias
• Population included patients ≥ 75 years and < 60 kg who received reduced prasugrel maintenance dose of 5 mg daily instead of 10 mg daily after initial 60 mg load without documented increased risk of bleeding; this information could potentially change our management in this patient population by encouraging more frequent use of prasugrel
• High compliance rates at 99.6% and 99.1% in ticagrelor and prasugrel groups, respectively, raise concern for potential over-reporting of medication adherence, particularly in the setting of only 10% of follow-ups being face-to-face (with the remaining 83% being over the phone and 7% in written correspondence).
• Questionable skewed results given intention-to-treat model due to 20.4% of patients in each of the ticagrelor and prasugrel groups being discharged without the antiplatelet therapy they were initially assigned. Additionally, 243 patients from the ticagrelor group and 199 patients from the prasugrel group discontinued treatment after discharge. 37 patients were lost to follow-up, resulting in  1299 patients included in the analysis who were not receiving their assigned medication.
• 233 patients (11.6%) from the prasugrel group were excluded from safety analysis vs. 23 (1.14%) in the ticagrelor group, potentially underestimating the rate of major bleeding with prasugrel.
• Ticagrelor was discontinued more frequently and earlier on in the trial than prasugrel possibly biasing the primary outcome away from ticagrelor
• Despite the fact that ticagrelor was administered immediately vs delayed administration of prasugrel, rate of primary outcome was still significantly lower in the prasugrel group. This may be due to the irreversible activity of prasugrel which last a platelets lifetime (10 days) vs reversible binding of ticagrelor to P2Y12 receptors. This also highlights that immediate loading by P2Y12 inhibitors in the setting of ACS may not be necessary.
• Important to note that difference in primary outcome was largely due to individual component of myocardial infarction (higher rates of type 4a and 4b myocardial infarction in ticagrelor arm) raising question of compliance in ticagrelor patients or effect of patients being switched from initial ticagrelor dose at discharge
• When compared to their orignical major studies, primary end point for ticagrelor was similar to PLATO trial (9.3% vs 9.8%) while prasugrel was different when compated to TRITON-TIMI38 trial (6.9% vs 9.9%)

1. Cannon CP, Husted S, Harrington RA, et al; DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007 Nov 6;50(19):1844-51. doi: 10.1016/j.jacc.2007.07.053. Epub 2007 Oct 23. Erratum in: J Am Coll Cardiol. 2007 Nov 27;50(22):2196.
2. James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009 Apr;157(4):599-605. doi: 10.1016/j.ahj.2009.01.003.
3. Wiviott SD, Antman EM, Gibson CM, et al; TRITON-TIMI 38 Investigators. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006 Oct;152(4):627-35. doi: 10.1016/j.ahj.2006.04.012.
4. Wiviott SD, Trenk D, Frelinger AL, et al; PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007 Dec 18;116(25):2923-32. doi: 10.1161/CIRCULATIONAHA.107.740324.
5. Roe MT, Armstrong PW, Fox KA, et al; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012 Oct 4;367(14):1297-309. doi: 10.1056/NEJMoa1205512. Epub 2012 Aug 25. PMID: 22920930.
6. Motovska Z, Hlinomaz O, Miklik R, Hromadka M, Varvarovsky I, Dusek J, Knot J, Jarkovsky J, Kala P, Rokyta R, Tousek F, Kramarikova P, Majtan B, Simek S, Branny M, Mrozek J, Cervinka P, Ostransky J, Widimsky P; PRAGUE-18 Study Group. Prasugrel Versus Ticagrelor in Patients With Acute Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention: Multicenter Randomized PRAGUE-18 Study. Circulation. 2016 Nov 22;134(21):1603-1612. doi: 10.1161/CIRCULATIONAHA.116.024823. Epub 2016 Aug 30. PMID: 27576777.
7. Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022 Jan, 79 (2) e21–e129. doi: 10.1016/j.jacc.2021.09.006
8. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec, 64 (24) e139–e228

The published archive features curated twitter highlights from the journal club event.