CABG Safe 3 Days After Stopping Ticagrelor: RAPID CABG
Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.
The RAPID CABG trial found that early surgery 2 to 3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding compared with waiting 5 to 7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.
Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.
The study was presented today at the American Heart Association (AHA) Scientific Sessions 2021.
“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator, Derek So, MD.
So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, Ontario, Canada, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.
A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, So noted.
Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.
So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.
So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”
Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York City, said this was a “very important study,” being the only randomized trial to look at this issue to date.
Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”
However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.
RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2 to 3 days after ticagrelor cessation compared with a delay of 5 to 7 days among patients presenting with ACS who required nonemergency CABG surgery.
The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.
Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.
The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.
Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12 inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.
The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1000 mL in the first 12 hours, and reoperation for bleeding.
Results showed that 4.6% of the early surgery group had a primary outcome bleeding event compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).
Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.
In terms of other bleeding outcomes, TIMI CABG bleeding occurred in 2 patients (3.1%) in the early surgery group vs no patients in the delayed group; BARC 4 bleeding occurred in 2 patients (3.1%) in the early group vs none in the delayed group, and there were no BARC 5 bleeding events in either group.
In the intention-to-treat analysis, ischemic events before surgery occurred in 6 patients (8.7%) in the delayed group (1 myocardial infarction [MI], 4 cases of recurrent ischemia, and 1 ventricular tachycardia) vs none in the early group.
Cumulative 6-month ischemic events occurred in 9 patients (13.0%) in the delayed group vs 4 patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.
There were no cardiovascular deaths in either group and 1 all-cause death in both groups.
Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days vs 12 days in the delayed group.
Larger Trial Needed
Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the Cardiac Surgery Department in the Smidt Heart Institute at Cedars-Sinai Medical Center, Los Angeles, California, said the results were in line with her practice.
“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.”
Chikwe said her topline message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”
However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.
“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Chikwe noted.
She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”
The RAPID CABG study was funded by the Canadian Institutes of Health Research (CIHR). So reports research support, consultancy or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).
American Heart Association (AHA) Scientific Sessions 2021. Presented November 13, 2021. Abstract LBS1. Abstract
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