Ticagrelor for DAPT Again Questioned in Current Era of PCI for ACS: CHANGE DAPT

Steve Stiles  

August 30, 2017

BARCELONA, SPAIN — Overall clinical risk at 1 year went up significantly in patients receiving PCI for acute coronary syndrome (ACS) after the European guidelines switched to recommending ticagrelor (Brilinta/Brilique, AstraZeneca) over clopidogrel in dual-antiplatelet therapy (DAPT), a single-center observational study indicates[1].

The risk increase was driven by a significant jump in major bleeding in the ticagrelor-DAPT era that was not balanced by reductions in ischemic events, it was reported here at the European Society of Cardiology (ESC) 2017 Congress.

Dr Clemens von Birgelen

That greater bleeding risk seemed in spite of practices increasingly used in the ticagrelor years that should have kept that risk down, including transradial-artery access for PCI, less reliance on GP IIb/IIIa inhibitors, and greater use of proton-pump inhibitors, Dr Clemens von Birgelen (Thoraxcentrum Twente, Enschede, the Netherlands) told theheart.org | Medscape Cardiology.

Von Birgelen is senior author on the publication of the registry study, Change of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome (CHANGE DAPT), in EuroIntervention timed to coincided with his ESC presentation of the results.

As he explained in an interview, his institution, a major PCI center, started to prefer the use of ticagrelor with aspirin in DAPT, instead of clopidogrel, in May 2014 on recommendation of guidelines following trials like PLATO. (US guidelines, in slight contrast, recommended ticagrelor for DAPT on equal footing with clopidogrel).

The randomized PLATO had suggested that ticagrelor was superior in PCI for ACS, although in patients receiving now-outmoded bare-metal or early-generation drug-eluting stents (DES).

But the CHANGE DAPT results are consistent with some studies conducted in the post-PLATO era with newer-generation, thinner-strut DES that are less likely to become blocked with thrombus, von Birgelen said. Such stents, he noted, were used in both the clopidogrel and ticagrelor eras of CHANGE DAPT.

And they were used in the recently reported TOPIC trial, von Birgelen noted, which saw fewer ischemic events in patients getting PCI for ACS using a biphasic DAPT strategy, as reported by theheart. org | Medscape Cardiology. It called for using either ticagrelor or another potent antiplatelet, prasugrel (Effient/Efient, Eli Lilly/Daiichi Sankyo) in the first month, when stent-related thrombosis is of special concern, but switching to clopidogrel thereafter.

"I think that our data contribute to this overall finding that the P2Y12 inhibitors may not be necessary in patients with ACS treated by PCI with modern drug-eluting stents," von Birgelen said.

Clinical recommendations shouldn't be changed based on an observational study, he added. "Nevertheless, if physicians, if cardiologists feel that they should treat patients with clopidogrel, rather than one of the more potent P2Y12 inhibitors, because they have some doubts, they should feel less guilty than they may have felt during the past few years."

"I'm Not Surprised"

A cowriter of US guidelines on DAPT with PCI, Dr Laura Mauri (Brigham & Women's Hospital, Boston, MA), told theheart.org | Medscape Cardiology that there were possible confounders in the CHANGE DAPT analysis despite its risk-propensity adjustments.

Patients were older in the ticagrelor era, for example. And with the more potent ticagrelor, "the risk of bleeding, I have to say, I'm not surprised, is higher over time, because we know that from randomized trials.

"So then I would question the lack of benefit. It could be that the patients [in the later cohort] are more complex in ways that were not foreseen or were not measured. We're being more aggressive about who we take for PCI in the setting of ACS."

Also, perhaps ischemic events were underestimated in the observational cohorts. Mauri, not associated with CHANGE DAPT, pointed out that in the randomized trials, "you had very regular and controlled ascertainment of the outcomes, mainly myocardial infarction."

In an observational cohort, "whether you're capturing all of that in follow-up, in terms of spontaneous myocardial infarction, is not clear to me. It's difficult to ascertain repeat infarction in someone who's had an infarct. And so maybe it's underestimated."

Von Birgelen acknowledged that and other patient-related factors that might account for the results. "We have clearly a different patient population, which is real-world, while in the trials patients are motivated to participate in the trial, to count their pills, to have more [provider] contacts."

Also, patients aware that they are participating in a randomized trial tend to adhere to their medication more closely, he said. In the observational CHANGE DAPT, "We're afraid that this could have played a role. We should not forget that there are more side effects related to ticagrelor, like dyspnea and minor bleeding, that could trigger patients to stop the medication or take it less frequently." That could account for the lack of ischemic benefit, "but this is speculation."

Clinical Events and Complications in CHANGE DAPT, Propensity-Adjusted HR (95% CI) Ticagrelor Era vs Clopidogrel Era

End points HR (95% CI) P
Primary end point* 1.75 (1.20–2.55) 0.003
All-cause mortality 1.26 (0.71–2.22) 0.43
Any MI 1.39 (0.78–2.48) 0.26
Stroke 2.91 (0.75–11.27) 0.12
Major bleeding 2.75 (1.34–5.61) 0.01
Definite/probable stent thrombosis 1.03 (0.33–3.27) 0.96
*Net adverse clinical and cerebral events=death from any cause, any MI, stroke, or major bleeding (BARC class 3 or 5 and/or TIMI definition)

At baseline, the 1053 patients in the ticagrelor era were slightly older (mean 63.9 vs 62.9 years in earlier cohort, P=0.04) and less likely to have peripheral artery disease (5.5% vs 8.8%, P=0.003) than the 1009 in the clopidogrel era.

Importantly, the radial artery was used for PCI vascular access in 44.6% in the ticagrelor era and 17.7% in the clopidogrel era, procedural GP IIb/IIIa inhibitors in 24.7% and 43.7%, respectively, and proton-pump inhibitors (PPI) in 55.1% and 42.6% of patients, respectively. All three differences were significant (P<0.001) and, in theory, would be associated with reduced bleeding in the ticagrelor era, not an increase.

Patients in the two eras were similar in measured CV risk factors and history of CV events or stroke, prevalence of double- and triple-vessel coronary disease, and discharge meds (except for PPI).

With 1-year follow up data available for virtually all patients, rates for the "net adverse clinical and cerebral events" primary end point at 1 year were 7.8% with ticagrelor and 5.1% with clopidogrel.

For the major bleeding end point, defined the same way in both eras, the rates were 2.7% for ticagrelor and 1.2% for clopidogrel. Of note, there were 13 and six gastrointestinal bleeds, respectively; four and one access-site bleeds, respectively; and four and zero intracranial bleeds, respectively.

There were four intracranial hemorrhages (ICH) in the ticagrelor era, zero in when clopidogrel was dominant in DAPT. But in an analysis based on the regimens patients actually received, regardless of guidelines preference, only three of the ICHs were associated with ticagrelor, von Birgelen told theheart.org | Medscape Cardiology.

An editorial[2] accompanying the CHANGE DAPT publication contends that in light of the hypothesis-generating study's limitations, "there is therefore little evidence at present to sup­port a change toward the approach of 'downgrading' DAPT in clinical practice."

The writer, EuroIntervention deputy editor Dr Davide Capodanno, says, "In further test­ing of this concept, the efficacy of a stepwise antiplatelet therapy regimen is the objective of the upcoming GLOBAL-LEADERS trial, a large clinical trial of 16,000 all-comer patients undergoing PCI (also including ACS), aimed at investigat­ing whether switching from DAPT to ticagrelor alone at 30 days (another 'less-is-more' approach) significantly reduces the com­posite of death and myocardial infarction as compared with con­ventional DAPT."

The investigator-initiated CHANGE DAPT study was performed without external funding, it was reported. Von Birgelen reports that he does not personally receive any speaker honoraria. His institution has received research grants from AstraZeneca, Biotronik, Boston Scientific, and Medtronic. Disclosures for the coauthors are listed in the paper.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.