Patients with high-risk features undergoing elective PCI and treated with
the more-potent antiplatelet agent ticagrelor (Brilinta; AstraZeneca)
instead of clopidogrel fared no better with respect to protection from
periprocedural myocardial infarction or major myocardial injury, according
to the results of the ALPHEUS study.
And while use of ticagrelor in the elective setting wasn’t associated
with an increase in major bleeding, there was more minor or nuisance bleeding
when compared with those who received clopidogrel. For this reason, investigators
say their results support the continued use of clopidogrel as the standard
of care for elective PCI.
Speaking during a morning press conference at the American Heart Association
2020 Scientific Sessions, lead investigator Johanne Silvain, MD, PhD (Sorbonne
Université/Pitié-Salpêtrière Hospital, Paris,
France), said the group figured that periprocedural myocardial necrosis
resulting from atherothrombotic complications could be reduced with the
more-potent antiplatelet agent. Since side-branch occlusion, slow coronary
flow, and embolization may have an atherothrombotic component, ticagrelor,
they hypothesized, might prove superior to clopidogrel.
“We were surprised by the results of the trial,” Silvain said.
“It does not confirm the thrombotic mechanism.” Silvain said
researchers plan to study the angiograms collected by the core laboratory
in the hopes of identifying the underlying mechanism for the resulting
myocardial infarction and injury.
Stephen Wiviott, MD (Brigham and Women’s Hospital, Boston, MA), who
commented on the study during the morning press conference, said that
more-intensive antiplatelet therapy can generally be expected to reduce
platelet-mediated thrombotic events, such as MI and stent thrombosis,
as studied in ALPHEUS, and to increase the risk of bleeding. In the setting
of PCI for stable CAD, however, clopidogrel is the preferred agent and
should remain so after ALPHEUS, he argued.
“There was no evidence of ischemic benefit regardless of the specific
endpoint that was chosen,” said Wiviott. “As we put this all
together, I would conclude that this trial does not support the use of
a more-potent P2Y12 antagonist for elective PCI given that there was no
ischemic benefit and a tendency toward more risk with bleeding. Based
on these results, and consistent with similar trials, aspirin and clopidogrel
should remain the standard of care in this population.”
For patients with NSTE ACS undergoing PCI, ticagrelor, prasugrel, and clopidogrel
all have a class I recommendation for use in the US and European guidelines,
with the American College of Cardiology/American Heart Association (ACC/AHA)
also stating that it is reasonable to give preference to ticagrelor and
prasugrel over clopidogrel. In elective PCI for stable CAD, however, clopidogrel
has a class I indication from both the ACC/AHA and European Society of
Cardiology. The US guidelines offer no recommendations on the use of ticagrelor
or prasugrel in elective PCI, while the European guidelines state there
is a divergence of opinion on its use in this setting.
Consistent Findings Across Endpoints
The ALPHEUS trial, presented during the late-breaking clinical trials session
and published simultaneously in the
Lancet, was conducted at 49 hospitals, the vast majority in France. The trial
included 1,910 patients randomly assigned to ticagrelor or clopidogrel.
Patients were included if they had normal cardiac troponin levels (or
decreasing levels if troponin was mildly elevated) and at least one high-risk
characteristic, among them the presence of complex lesions, multivessel
disease, or longer stent lengths. Diabetes, another high-risk patient
characteristic, was present in more than one-third of patients.
Patients received a loading dose of ticagrelor 180 mg before PCI and 90
mg twice daily thereafter for 30 days or a loading dose of clopidogrel
300 to 600 mg at the physician’s discretion followed by 75 mg daily.
Two-thirds of patients received at least 600 mg of clopidogrel as the
loading dose.
The primary outcome, which was PCI-related myocardial infarction using
the 3rd Universal Definition or major myocardial injury within 48 hours
of the procedure (or at the time of discharge if earlier), occurred in
35.5% of those treated with ticagrelor and 36.2% in the clopidogrel group (P = 0.75). Periprocedural MI (type 4a) rates were similar in both treatment
arms (8.5% with ticagrelor vs 8.2% with clopidogrel;
P = 0.79), while the rate of stent thrombosis (type 4b) was identical at
0.3% in both arms. Major myocardial injury occurred in equal numbers in
both treatment groups (26.7% with ticagrelor vs 27.7% with clopidogrel;
P = 0.61). There was also no difference in rates of minor myocardial injury.
“There was a consistency in all components of the primary outcome,”
said Silvain. When investigators employed the 4th Universal Definition
of MI, which emerged on the scene during the course of the study, periprocedural
event rates were significantly higher but similar in the ticagrelor- and
clopidogrel-treated patients.
With respect to safety, there was no difference in rates of bleeding classified
as major (BARC type 3 or 5) or nuisance or minor (BARC 1 or 2), or of
any bleeding (BARC 1 to 5), at 48 hours. At 30 days, there remained no
difference in the risk of major bleeding, but the rate of nuisance or
minor bleeding was 11% in the ticagrelor arm and 8% with clopidogrel (P = 0.007). Rates of dyspnea were also higher with ticagrelor.
In pooling the ALPHEUS results with SASSICAIA, a study published earlier
this year testing intensified antiplatelet therapy with prasugrel before
elective PCI, researchers showed there was no difference in the risk of
death, any MI, or stent thrombosis, among other endpoints, with ticagrelor
or prasugrel compared with clopidogrel.
Dipti Itchhaporia, MD (Hoag Memorial Hospital Presbyterian, Newport Beach, CA), said the trial should make interventional cardiologists think, particularly
since many have grown more comfortable over the years using ticagrelor
and prasugrel for patients with ACS and even in stable CAD patients with
high-risk, complex anatomy. In one review, almost one-third of patients
without ACS undergoing PCI between 2009 to 2016 were treated with prasugrel
or ticagrelor, she said.
For that reason, “ALPHEUS is a really important data,” she
told TCTMD. “I think the data does really make you pause and ask
if [more potent antiplatelet therapy] is really necessary because it is
more expensive, although prasugrel is generic so that’s not as big
an issue, but if you’re using ticagrelor, [cost] is an issue.”
For Itchhaporia, there is still a need for more research in this area.
For example, while the patients in ALPHEUS were classified as high-risk
cases, there is an opportunity to study the more-potent antiplatelet agent
in stable CAD patients with even more complex anatomy. Nonetheless, from
a clinical perspective, ALPHEUS shows that “if you have a pretty
straightforward patient that you’re planning on discharging home
the same day, you can just use Plavix in these stable patients,”
she said. “There is no reason to use the more-potent agent. Even
if it’s just more minor bleeding, why put them through it?”
In her practice, Itchhaporia noted they are treating fewer stable patients
with CAD and that the majority of cases are patients with ACS.
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