By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
SYNOPSIS: In a trial that included acute coronary syndrome patients treated with ticagrelor, undergoing coronary bypass surgery within two to three days was noninferior to the guideline-recommended five to seven days regarding severe bleeding.
SOURCE: So DYF, Wells GA, Lordkipanidze M, et al. A randomized study of early vs. delayed coronary artery bypass surgery among patients with acute coronary syndromes treated with ticagrelor: The RAPID CABG study. Presented at American Heart Association Scientific Sessions, Nov. 13, 2021.
Current American College of Cardiology/American Heart Association guidelines recommend instituting dual antiplatelet therapy early in the hospital course for eligible patients presenting with acute coronary syndrome (ACS).1 This recommendation can conflict with bleeding risk in the roughly 10% of ACS patients who are referred for coronary artery bypass grafting (CABG). Perioperative bleeding is a major concern, highlighted by the higher mortality seen in the PLATO trial among patients who underwent CABG within one day of stopping ticagrelor.2 Although the mechanisms of action and elimination of ticagrelor are fundamentally different than that of the thienopyridines clopidogrel and prasugrel, U.S. guidelines continue to recommend a minimum waiting period of five days after cessation of ticagrelor prior to non-urgent CABG.3 This recommendation carries a class IB designation, even though it is based on retrospective and pharmacodynamic data. The European Society of Cardiology (ESC) guidelines recommend a shorter waiting period of only three days.4
RAPID CABG was designed to test the safety of early vs. delayed CABG in patients presenting with ACS who have received ticagrelor. ACS patients treated with ticagrelor who were determined to require CABG after angiography were randomized in a 1:1 fashion to either early surgery (day 2-3 after ticagrelor) or delayed surgery (day 5-7). The primary outcome was the occurrence of severe or massive perioperative bleeding, according to the universal definition for perioperative bleeding (UDPB). A total of 143 patients were enrolled, of whom 72 were randomized to early surgery and 71 to late surgery. The mean age was 64 years, 57% were men, and the mean BMI was just under 30 kg/m2. The median time to surgery was three days in the early surgery group and six days in the late group. Platelet reactivity before CABG was evaluated via the Pre-CABG VerifyNow P2Y12 (PRU) test and was found to be significantly lower in the early surgery group compared to the late group (PRU 200 vs. 251; P < 0.001).
The primary outcome of severe or massive bleeding occurred in 4.6% of the early CABG group and 5.2% of the delayed CABG group. This met the prespecified noninferiority margin of 8% (P = 0.025). Notably, all bleeding events in the trial were classified as severe, with no massive bleeding events recorded. Only one patient in the early CABG group required re-exploration, while none in the delayed group did.
Although no presurgical ischemic events were recorded in the early surgery group, six such events were reported in patients waiting for later CABG. These events included one myocardial infarction, four episodes of recurrent angina, and one occurrence of ventricular tachycardia. This difference was the main driver behind a lower six-month major adverse cardiovascular event rate in the early vs. delayed surgery group (5.6% vs. 13.0%). Hospitalization time also was significantly shorter in the early CABG group, with a median length of stay of nine days vs. 12 days in the delayed group. The authors concluded CABG two to three days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding vs. waiting five to seven days.
COMMENTARY
Relatively few randomized trials carry the potential to solve a known issue and change clinical practice, but RAPID CABG clearly falls into this category. Many cardiologists can relate to the scenario of managing an ACS patient who needs CABG for days while the P2Y12 inhibitor washes out. Current U.S. guidelines call for waiting for at least five days after cessation of ticagrelor, but the results of this trial suggest proceeding with CABG within two to three days of stopping ticagrelor is safe.
For some, this trial will confirm already-held beliefs and allow a shift toward the shorter ESC recommendation. For others, however, the small size of the trial represents an undeniable weakness. Of the 71 patients assigned to the early group, six went later and one was treated medically, leaving 65 patients treated per protocol. Of 72 patients in the late group, two refused surgery, seven went to CABG earlier than the assigned window, and four went even later than assigned, leaving only 58 patients per protocol. The total number of bleeding events was small — three in each group using the UDPB definition. The use of alternate bleeding definitions yielded even fewer events. For example, thrombolysis in myocardial infarction CABG bleeding and Bleeding Academic Research Consortium Type 4 (CABG-related) bleeding each occurred in two patients in the early group and zero patients in the late group (which were not significantly different).
Regardless, this represents the best available evidence on this issue. For the ACS patient who has been treated with ticagrelor and is awaiting CABG, earlier surgery could prevent ischemic events and shorten hospital stay, with what appears to be minimal added bleeding risk.
REFERENCES
- Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2016;134:e123-155.
- Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: Results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011;57:672-684.
- Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:e652-735.
- Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J 2018;39:213-260.
In a trial that included acute coronary syndrome patients treated with ticagrelor, undergoing coronary bypass surgery within two to three days was noninferior to the guideline-recommended five to seven days regarding severe bleeding.
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