ISAR-REACT 5 Trial – Review

ISAR-REACT 5 Trial – Review

ISAR-REACT 5 Trial [1] was a multicenter study with randomized patients who presented which acute coronary syndrome for whom an invasive strategy was planned, to either ticagrelor or prasugrel. It was an open label trial. Primary end point was a composite of death, myocardial infarction or stroke at one year. A major secondary safety endpoint was bleeding. This was an investigator-initiated trial funded by German Center for Cardiovascular Research and Deutsches Herzzentrum München (German Heart Center Munich).

4,018 patients were randomized in the study. Primary composite endpoint occurred in 9.3% in ticagrelor group and 6.9% in the prasugrel group. Mortality was 4.5% in ticagrelor group and 3.7% in the prasugrel group. Definite stent thrombosis occurred in 1.1% in the ticagrelor group and 0.6% in the prasugrel group. Major bleeding occurred in 5.4% of patients in the ticagrelor group and 4.8% in prasugrel group (P=0.46).

The authors of the study report concluded that in acute coronary syndrome with or without ST segment elevation, the composite end point of death, myocardial infarction or stroke was significantly lower among those who received prasugrel than those who received ticagrelor. Incidence of major bleeding was similar in the two groups.

Both ticagrelor and prasugrel have been shown to be superior to clopidogrel in earlier randomized trials in acute coronary syndrome [2,3]. But prasugrel use was only in those scheduled for percutaneous coronary intervention (PCI) and it had a higher bleeding risk. Prasugrel was given only after the coronary anatomy was known and PCI planned.

A previous meta-analysis had shown that ticagrelor inhibits platelet reactivity more than prasugrel [4]. Ticagrelor inhibits cell uptake of adenosine. Hence it can increase adenosine mediated coronary blood flow velocity and dyspnea. While the latter is an adverse effect of ticagrelor, former is beneficial. These effects can be attenuated by theophylline [5].

Because of the beneficial effect on adenosine, which is a pleotropic effect, and higher inhibition of platelet reactivity by ticagrelor, one would have expected ticagrelor to perform better. On the contrary, in ISAR-REACT 5 trial prasugrel performed better. Patients with history of stroke, transient ischemic attack or intracranial hemorrhage were excluded from the study as has been the usual practice when prasugrel is given.

References

1. Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, Akin I, Bott-Flügel L, Fischer M, Landmesser U, Katus HA, Sibbing D, Seyfarth M, Janisch M, Boncompagni D, Hilz R, Rottbauer W, Okrojek R, Möllmann H, Hochholzer W, Migliorini A, Cassese S, Mollo P, Xhepa E, Kufner S, Strehle A, Leggewie S, Allali A, Ndrepepa G, Schühlen H, Angiolillo DJ, Hamm CW, Hapfelmeier A, Tölg R, Trenk D, Schunkert H, Laugwitz KL, Kastrati A; ISAR-REACT 5 Trial Investigators. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2019 Oct 17;381(16):1524-1534.
2. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57.
3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15.
4. 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 Jun;13(6):931-42.
5. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J, Nylander S, Gan LM. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol. 2013 Feb 19;61(7):723-7.