No Fewer MACE With Ticagrelor vs Clopidogrel in ACS Patients After PCI: Registry

In the context of PCI performed mostly with second-generation DES in patients with ACS, there doesn’t appear to be much to gained by using ticagrelor (Brilinta; AstraZeneca) instead of clopidogrel as part of a dual antiplatelet therapy regimen, suggest registry data out of Alberta, Canada.

After accounting for differences in patient characteristics and adherence, MACE risk was not lower with ticagrelor versus clopidogrel (adjusted HR 0.97; 95% CI 0.85-1.10), lead author Ricky Turgeon, PharmD (Vancouver General Hospital, Canada), and colleagues report. Other clinical outcomes occurred at similar rates as well.

However, as seen in PLATO, the trial that supported ticagrelor’s approval back in 2011, the drug was associated with greater risks of major bleeding (adjusted HR 1.51; 95% CI 1.29-1.78) and dyspnea (adjusted HR 1.98; 95% CI 1.47-2.65).

Senior author Michelle Graham, MD (University of Alberta, Edmonton, Canada), noted that guidelines give a preference for ticagrelor over clopidogrel in patients with ACS regardless of whether they undergo an invasive procedure. This advice is based on the results of the PLATO trial, which demonstrated a lower MACE risk the newer drug.

Just because our results are different from PLATO doesn’t mean that PLATO was wrong or that we’re wrong. Michelle Graham

But a direct comparison between the current study and PLATO is hampered by differences centered around methodology, patient population, and technology. PLATO included all types of patients with ACS, not just those undergoing PCI, and those who underwent PCI in the trial mostly received BMS or first-generation DES. In this new study, all patients underwent PCI and most were treated with second-generation DES. Moreover, PLATO considered in-hospital outcomes, whereas the Canadian analysis picked up after discharge.

“Just because our results are different from PLATO doesn’t mean that PLATO was wrong or that we’re wrong,” Graham told TCTMD. “I think this is actually very reassuring that the technologies are safe and that perhaps you don’t need as potent an antiplatelet agent in the setting of patients with second-generation drug-eluting stents.”

Jurriën ten Berg, MD (St. Antonius Hospital, Nieuwegein, the Netherlands), who was not involved in the study, pointed out in an email to TCTMD that a more-potent agent might be needed earlier on. “In-hospital and early postdischarge is the higher-risk period where strong platelet inhibition is needed (PLATO),” he commented. “Maybe this stronger platelet inhibition with ticagrelor is not needed in all patients because a lot had a lower risk, and because this registry is postdischarge.”

I think personalized medicine is key. Jurriën ten Berg

In fact, a handful of studies in recent years have attempted to look at switching from more to less potent P2Y12 inhibition after PCI discharge, a strategy adopted in some centers where access to the higher-priced drug, taken long-term, is either not an option or adversely affects adherence.

TOPIC, for example, suggested that switching to clopidogrel from ticagrelor in ACS patients 1 month post-PCI may reduce bleeding without increasing the risk of later ischemic events. In TROPICAL-ACS, patients who’d undergone successful PCI for ACS underwent platelet testing 2 weeks after revascularization to determine whether they could be safely switched to clopidogrel from prasugrel, a strategy that appeared to have no trade-off in terms of ischemic events or bleeding. A “de-escalation” analysis of PRAGUE-18 also suggested that patients who switched to clopidogrel from prasugrel for economic reasons had lower risks of both ischemic events and bleeding. 

An adherence signal also was seen in the current study, published online January 13, 2020, ahead of print in JAMA Internal Medicine, Graham noted. Patients with high adherence during the study period—regardless of their P2Y12 inhibitor—had a lower MACE risk compared with those with worse adherence (adjusted HR 0.79; 95% CI 0.69-0.90).

“It really does reinforce the fact that you need to make sure that your patients are educated as to the rationale for the use of the meds and the rationale for the duration of therapy of the medication so that you can hopefully ensure that more patients are going to be adherent and persistent,” she said.

More Bleeding, Dyspnea With Ticagrelor

For the study, the investigators looked at data from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry on 11,185 patients with ACS who were discharged alive after undergoing PCI between April 2012 and March 2016 and who filled a first prescription for ticagrelor or clopidogrel within 31 days of the procedure. Median patient age was 61, and one-quarter were women.

More than one-third of patients (36.4%) filled a prescription for ticagrelor, and this group tended to be younger and to have fewer cardiac and noncardiac comorbidities compared with clopidogrel users.

Before adjustment, ticagrelor was associated with a lower rate of MACE (all-cause death, hospitalization for ACS, unplanned coronary revascularization, or stent thrombosis) at 1 year (10.3% vs 11.6%), but there was no significant difference after adjustment. Higher rates of major bleeding (6.8% vs 6.3%) and of emergency department visits for dyspnea (2.9% vs 1.6%) continued to be seen with ticagrelor versus clopidogrel after adjustment.

There were no differences between P2Y12 inhibitors for any other outcomes, and the results were consistent in sensitivity and subgroup analyses.

The researchers also examined the impact of adherence, defined as a medication refill adherence of 80% or higher; this was more frequent in the ticagrelor group (81.6% vs 73.9%; P < 0.001). Although being adherent was associated with a lower MACE risk overall, there were no differences in MACE between ticagrelor and clopidogrel users regardless of adherence, persistence, or switching.

Findings ‘Should Not Challenge the Guidelines’

Asked about what the message is for selecting a P2Y12 inhibitor after PCI in patients with ACS, Graham called for individualization.

“You need to treat your patients keeping the guidelines in mind but also keeping in mind the reality of the patient sitting in front of you,” she said. “You have to have a careful consideration about whether or not they’re going to be adherent, whether they can afford the drugs, whether they’re more likely to take a once-daily drug compared to a bid drug. You do have to practice some personalized medicine here with these patients.”

She added that she often chooses ticagrelor, but that there are factors that might lead to making another choice. “I’m very cognizant of the dyspnea side effect in my patient population because I see a lot of elderly patients,” Graham said. “One of the goals of all of this therapy is not only to prolong life but to improve quality of life, and so you don’t want your therapy to be contributing to adverse quality of life.”

Ten Berg was senior investigator of the POPular AGE trial, which showed that in older patients with NSTE ACS, ticagrelor increased bleeding but did not reduce a composite of death, MI, or stroke compared with clopidogrel. He, too, called for a tailored approach to choosing a P2Y12 inhibitor in this setting.

“I think personalized medicine is key,” he said. “So [don’t] treat all patients with ticagrelor for 12 months post-ACS, but use characteristics such as older age (POPular AGE) and higher bleeding risk to use clopidogrel. Also, using CYP2C19 genetic testing to tailor P2Y12 inhibition to reduce bleeding has been shown to be effective (POPular Genetics).”

Commenting for TCTMD, Dominick Angiolillo, MD, PhD (University of Florida College of Medicine – Jacksonville), said that “the results of the study need to be taken with a grain of salt” and that “the study definitely will not affect my practice.”

He cited multiple limitations, including the smaller sample size compared with the PLATO trial (11,185 vs 18,624), the use of different endpoints and patient populations, and the possibility of confounding in an observational study, which cannot be completely overcome by statistical adjustment.

Clinicians should continue to abide with practice guidelines. Dominick Angiolillo

“Real-world [studies] are extremely important. I actually endorse them, but [only] when they are . . . conducted with a certain scientific rigor and a given sample size. And we don’t have this in this registry,” Angiolillo said. He noted that a previous analysis of the SWEDEHEART registry, which included 45,000 patients, provided results similar to those seen in PLATO.

For now, “clinicians should continue to abide with practice guidelines, which the authors in this investigation challenge,” he said. He acknowledged that there are some data supporting the concept of guided de-escalation from more- to less-potent antiplatelet therapy in patients with ACS based on the results of platelet function testing or point-of-care genotyping—from the TROPICAL-ACS and POPular Genetics trials, for instance.

“Nevertheless, I believe that the results of this specific investigation in JAMA Internal Medicine should not challenge the guidelines at all,” Angiolillo said.

For his part, Ten Berg said these data add to the evidence on optimal antiplatelet therapy, noting that real-world results can have an impact on guidelines because “we have to optimize antiplatelet treatment in many patients excluded from RCTs.”

The bottom line, he said, is that “clopidogrel is a valuable alternative to ticagrelor. We have to find out in whom clopidogrel is safer but with similar efficacy.”