Superiority of Ticagrelor Over Clopidogrel in ACS Questioned

Ticagrelor may not have an advantage over clopidogrel as part of a dual antiplatelet therapy (DAPT) regimen when it comes to treating ACS patients who have undergone PCI in everyday practice, a large US and Korean database study indicates.

Net adverse clinical events (NACE)—encompassing recurrent MI, revascularization, ischemic or hemorrhagic stroke, and GI bleeding—were not significantly different between the ticagrelor and clopidogrel groups at 1 year.

Ticagrelor, however, was associated with greater risks of hemorrhagic stroke, GI bleeding, and dyspnea, without an offsetting lower risk of ischemic events, compared with clopidogrel, lead author Seng Chan You, MD (Ajou University School of Medicine, Suwon, South Korea), and colleagues report.

The findings, published in the October 27, 2020, issue of JAMA, show “no benefit (and the suggestion of a harm) from ticagrelor, even taking into account that people are more likely to stop taking ticagrelor, the more-expensive drug,” You told TCTMD in an email.

Due to the retrospective nature of the data and the possibility of residual confounding despite extensive statistical adjustment, additional research is needed to compare the two drugs in patients with ACS after PCI, the researchers say.

“For now, until new information is available, we cannot assume that ticagrelor is superior in these patients,” You said. “And, because we know that people discontinue ticagrelor more often, the use of clopidogrel seems more appropriate. Some people have talked about pharmacogenomic testing, but that has also not yet been shown to be a beneficial strategy. We still have much to learn about whether there are selected patients who benefit from the more-expensive regimen, but with greater bleeding and more shortness of breath associated with ticagrelor, we should not favor it.”

Commenting for TCTMD, Bina Ahmed, MD (Santa Barbara Cardiovascular Medical Group, CA), said the study, though subject to the limitations of being retrospective, “speaks against the advantages of ticagrelor in real-world practice.”

That’s “a little perplexing because we know that ticagrelor is a more-potent antiplatelet and, for all intents and purposes, that should lead to better ischemic endpoints,” she said. “And in this instance it didn’t show that.”

Asked why, Ahmed said much of the blame can be placed on poorer adherence with ticagrelor versus clopidogrel due to dyspnea and other side effects. “Are we seeing less ischemic benefit because patients are taking the medication less or are being less adherent? That definitely could be a large part of the explanation,” she suggested.

Real-world Data

The findings appear to conflict with US and European guidelines, which give a preference to more-potent P2Y12 inhibition with ticagrelor or prasugrel over clopidogrel in patients with ACS. The ticagrelor recommendation is based mainly on the results of the PLATO trial, released in 2009.

But accumulating data since then have raised questions about the dominance of ticagrelor in the ACS population. In POPular AGE, ticagrelor increased bleeding without reducing thrombotic events compared to clopidogrel in older patients with NSTE ACS, with a similar finding seen among Korean ACS patients scheduled for early invasive management in the TICAKOREA trial. Earlier in 2020, a registry study showed that ticagrelor was associated with higher rates of major bleeding and dyspnea but not a lower risk of MACE relative to clopidogrel.

Even within the PLATO trial itself, You pointed out, ticagrelor was not superior to clopidogrel in the subsets of patients from North America and Asia. “This finding left some uncertainty about the superiority of ticagrelor in the US,” he said. “Meanwhile, rates of use increased dramatically.”

You et al set out to compare ticagrelor and clopidogrel using real-world data within the Observational Health Data Sciences and Informatics network. The analysis used two US electronic health record (EHR) databases—Optum EHR and IQVIA Hospital—and the South Korean Health Insurance Review and Assessment service, which contains national administrative claims data. It included patients with ACS who underwent PCI between November 2011 and March 2019. After matching using a large-scale propensity-score algorithm, there were 31,290 patients treated with ticagrelor and an equal number treated with clopidogrel (median age group 60 to 64 years; 29.3% women).

Most patients (95.5%) were also taking aspirin. By 1 year, lower adherence to P2Y12 inhibition was seen with ticagrelor versus clopidogrel, as indicated by a lower mean medication possession ratio (0.59 vs 0.77).

At that time point, there were no differences between the ticagrelor and clopidogrel groups in terms of NACE, individual ischemic endpoints, or all-cause mortality, although hemorrhagic events and dyspnea were more common with the more-potent agent.

Outcomes at 1 Year

^*Recurrent MI, revascularization, ischemic or hemorrhagic stroke, or GI bleeding.

The researchers note that the rates of individual ischemic and hemorrhagic events in the ticagrelor group were similar to what was observed in TICAKOREA and say that the overall findings of the analysis are consistent with those from that trial, POPular AGE, PHILO, and the North American PLATO cohort.

You speculated about the reasons ticagrelor was not associated with a benefit in the more-recent studies, pointing to improvements in the management of patients with ACS over time. “Now we use more-potent statins and DES for these patients,” he said. “Please note that the majority in PLATO received bare-metal stents, and most of the remaining patients received first-generation DES. When we dig into the result from PLATO, the significant benefit resulted from [a reduction in] stent thrombosis, which can be prevented by using second-generation DES.”

A second possibility, You said—echoing Ahmed—is lower adherence to ticagrelor versus clopidogrel, which could be related to cost, its twice-daily dosing, or adverse events like dyspnea.

And finally, it’s possible that residual confounding explains the result. “Still, we leveraged lots of state-of-the-art methods to assess systematic bias and avoid this,” You said.

Tailoring Antiplatelet Therapy

In an accompanying editorial, Eric Bates, MD (University of Michigan, Ann Arbor), acknowledges the limitations of the study but says “these results challenge the conventional wisdom promoted in clinical guidelines and communicated by thought leaders and in the media that ticagrelor is more effective than clopidogrel in DAPT.”

Ticagrelor does have a more-favorable pharmacodynamic profile compared with clopidogrel, Bates says. “However, compared with clopidogrel and prasugrel, ticagrelor may not demonstrate greater clinical benefit because of adverse effects (dyspnea), inconvenience (twice-daily dosing), or higher cost (clopidogrel and prasugrel are generics), which may decrease medication adherence.”

Bates suggests an approach to antiplatelet therapy for patients with ACS: prescribe up-front ticagrelor or prasugrel if the patient can tolerate and afford it and then consider switching to clopidogrel after a month (the initial high-risk period for ischemic events).

Ahmed said she uses a similar approach in her practice, typically giving ticagrelor plus aspirin for the first 4 weeks and then switching patients to clopidogrel plus aspirin for up to 1 year before continuing patients on antiplatelet monotherapy. In that way, “[I] feel that at least I’ve covered them for the higher risk of ischemia early on and then minimized their bleeding risk as they remain on dual antiplatelet therapy,” she explained.

Tailoring therapy based on patients’ ischemic and bleeding risks “may be a better approach than trying to prove that one antiplatelet agent or P2Y12 [inhibitor] is better than the other,” Ahmed said, acknowledging that there’s no randomized data to support this personalized approach. “But I think intuitively we’ve sort of tried to take the best that comes with ticagrelor, which is its more-potent platelet inhibition, early on, and then tried to minimize the risks that come with it, which are the bleeding and the adherence issues that come with continued use.”

Physicians should be thinking about the side effects of ticagrelor—the dyspnea, but also conduction deficits and atrioventricular block—more than they currently do, Ahmed added. “I think we do have to keep that in mind, especially as we’re trying to keep patients on ticagrelor for 12 months even if they’ve not had a PCI.”