Safety, Efficacy of Ticagrelor Monotherapy Confirmed in Complex PCI, Diabetes

Two prespecified analyses of the TWILIGHT trial show that a regimen of dropping aspirin and continuing ticagrelor monotherapy for 3 months following PCI is as beneficial for both diabetics and those undergoing complex procedures as it was in the overall study population.

The original TWILIGHT findings of more than 9,000 high-risk PCI patients, presented last year at TCT 2019, showed a 3.1% absolute reduction in BARC 2, 3, or 5 bleeding with no increase in death, MI, or stroke among those in the ticagrelor and placebo arm compared with those on ticagrelor and continued aspirin. Additionally, the ACS substudy confirmed a lower bleeding risk without an increase in ischemic events.

Both new studies were presented today during the virtual American College of Cardiology 2020 Scientific Session and simultaneously published in the Journal of the American College of Cardiology.

“We now have an enriched amount of knowledge for who we can safely use monotherapy in,” said Claire Duvernoy, MD (University of Michigan, Ann Arbor), during a press conference today. “What we've seen . . . are enough to change our guidelines. I think that we need to think about dropping aspirin and continuing monotherapy with potent P2Y12 inhibitors. I think we’re there.”

Complex PCI and Dropping Aspirin

For TWILIGHT-COMPLEX, George Dangas, MD, PhD (Icahn School of Medicine at Mount Sinai, New York), and colleagues looked at the 2,343 complex patients randomized in the original study, defined as having one of the following characteristics:

• 3 vessels treated (9.1%)
• ≥ 3 lesions treated (29.9%)
• Total stent length > 60 mm (51.8%)
• Bifurcation with two stents implanted (10.7%)
• Use of any atherectomy device (10.4%)
• Left main as target vessel (15.1%)
• Venous or arterial bypass graft as target lesion (6.9%)
• CTO of target lesion (19.0%)

Compared with the main TWILIGHT population, these patients were slightly older and more likely to have chronic kidney disease, anemia, and present with ACS.

We now have an enriched amount of knowledge for who we can safely use monotherapy in. Claire Duvernoy

With respect to the primary endpoint of BARC 2, 3, or 5 bleeding, complex patients (4.2% vs 7.7%; HR 0.54; 95% CI 0.38-0.76) saw the same decrease in events as noncomplex patients (3.9% vs 6.8%; HR 0.57; 95% CI 0.44-0.73) with ticagrelor plus placebo compared with ticagrelor and continued aspirin (P for interaction = 0.79). A similar finding was observed for BARC 3 or 5 bleeding with complex (1.1% vs 2.6%; HR 0.41; 95% CI 0.21-0.80) and noncomplex patients (0.9% vs 1.7%; HR 0.56; 95% CI 0.33-0.94; P for interaction = 0.47). TIMI minor or major, GUSTO moderate or severe, and ISTH major bleeding followed the same pattern (P for interaction > 0.05 for all).

There was no difference in death, MI, or stroke between the ticagrelor monotherapy or continued DAPT regimens in both complex (3.8% vs 4.9%; HR 0.77; 95% CI 0.52-1.15) and noncomplex patients (3.9% vs 3.5%; HR 1.13; 95% CI 0.84-1.53; P for interaction = 0.13). There were also no differences in CV death, MI or ischemic stroke; all-cause death; MI; ischemic stroke; and definite/probable stent thrombosis in complex patients in both arms (P for interaction > 0.05 for all).

Looking at the components of complex PCI, none favored a regimen of ticagrelor plus aspirin, while use of an atherectomy device clearly benefited from ticagrelor monotherapy (HR 0.16; 95% CI 0.04-0.73). There were also no differences in results depending on how many complex PCI criteria a given patient had.

Discussing the paper following its presentation, Glenn Levine, MD (Baylor College of Medicine, Houston, TX), said “this is an excellent analysis and the best one could do given the circumstances in the post hoc nature, but I think it's critically important because I think complex PCI will be on the minds of many.”

He asked Dangas that if he were on the revascularization guideline writing committee, “would you be comfortable based on your results as well as some other results writing a recommendation at this time that in patients undergoing complex PCI, including unprotected left main PCI, the recommended treatment is 3 months of DAPT followed by ticagrelor monotherapy?”

“Based on the type of data that we have, . . . the most prudent would be [to have] a more general guideline, but I would not call out the left main,” Dangas replied, explaining that unprotected left main patients were so few in the study. “Nobody wants to tout it as a left main specific intervention and I don’t think there should be a left main specific guideline.”

Katie Berlacher, MD (University of Pittsburgh, PA), noted that it’s important to consider pathophysiology when considering a post-PCI P2Y12 inhibitor regimen. “Why is it, you think, that even the people that have the more complex disease still have the same outcome?” she asked. “I would think, and a lot of us would say, that those patients are the ones that would do better potentially with dual antiplatelet therapy for an extended period of time.”

Dangas explained that the type of DAPT in TWILIGHT “is not the same” as other similar studies that “essentially tested interruption of the potent P2Y12 inhibitor. In that scenario, continuing the more important agent seemed to be conferring most of the benefit. In this study, this potent agent is not interrupted. So this study is very similar to other long DAPT studies in that, sure it’s not dual, but the potent agent continues and that may confer most of the ischemic endpoint and outcomes and the aspirin may be more related to long-term bleeding endpoints.”

Duvernoy noted that “really these are the patients in my own practice that we’ve been the most cautious about and the most worried about thrombotic risk and the most getting down on our house staff when they drop an antiplatelet agent. So this is very reassuring.”

Ticagrelor Monotherapy in Diabetes

Dominick J. Angiolillo, MD, PhD (University of Florida College of Medicine, Jacksonville), who presented the TWILIGHT-DM study told TCTMD that he would “absolutely” like to see the findings change practice. “I would like to see updates from practice guidelines and package inserts both in Europe and the United States to support a similar approach,” he said.

The analysis included the 2,620 patients with diabetes from the main trial who were randomized to ticagrelor plus placebo or continued DAPT. This cohort showed a similar lowering of BARC 2, 3, or 5 (4.5% vs 6.7%; HR 0.65; 95% CI 0.47-0.91) and BARC 3 or 5 bleeding risk (1.1% vs 3.1%; HR 0.34; 95% CI 0.19-0.63) among those on ticagrelor monotherapy compared with continued DAPT.

Again, there was no difference in the risk of death, MI, or stroke between the treatment groups (4.6% vs 5.9%; HR 0.77; 95% CI 0.55-1.09), nor in the risk of any other ischemic events. These findings held true when compared with patients without diabetes as well.

An exploratory analysis showed a number needed to treat of 30 to prevent one net adverse clinical event—BARC 3 or 5 bleeding, death, MI, or stroke—with ticagrelor monotherapy compared with continued aspirin (5.4% vs 8.7%; HR 0.61; 95% CI 0.45-0.82).

Finally, there were no clinical presentations or diabetes management strategies that specifically seemed to benefit from a regimen of continued aspirin.

Discussing the study during the session, Jacqueline E. Tamis-Holland, MD (Mount Sinai Saint Luke’s Hospital, New York, NY), called the findings “dramatic” even as a subgroup analysis. “Could you explain or give some insight to why if anything there was perhaps more of a benefit in the diabetic patients from the ischemic endpoint?” she asked.

“This ultimately derives from the potential harm that derives from bleeding,” Angiolillo responded. “When we look particularly at the bad bleeds, the BARC 3 or 5 bleeds, there was a clear difference and I think this all relates to the safety profile to aspirin or enteric coated aspirin in the patients with diabetes. There is literature suggesting that patients with diabetes may be more vulnerable to bleeding induced by enteric coated aspirin, mostly attributed to the integrity of the gastrointestinal mucosa derived by vascular disease. So, these patients are bleeding more and having big bleeds, and we know there's a clear link with ischemic events.”

For Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), these findings are “reassuring” in that the patients with diabetes did in fact have higher ischemic event rates. “That gives a lot of legitimacy to the analysis,” he said. “My question for you would be, how would you reconcile these results with the THEMIS results where that suggested that longer-term therapy in patients with diabetes with aspirin plus ticagrelor would be warranted? Do you think one could extrapolate from your study and say maybe protracted ticagrelor beyond this 12-15 month period might in fact be in order with patients with diabetes, in particular those with ACS or PCI or both?”

“There’s a nice link between our analysis and the THEMIS trial with the understanding that in THEMIS there was the adjunctive use of aspirin,” Angiolillo replied. “It does speak to some specific benefits of ticagrelor in patients with diabetes,” namely that having a twice daily dosed drug might be better for patients with diabetes, who are known to have higher platelet turnover rates.

Additionally, panelist Michelle O’Donoghue, MD, MPH (Brigham and Women’s Hospital, Boston, MA), commented that “it seems by and large that people have become more and more accustomed to dropping aspirin in the context of triple therapy, but perhaps a little bit slower to do so for patients who are just on dual antiplatelet therapy.” She asked about potentially cautioning the use of clopidogrel monotherapy, especially in patients with diabetes.

Angiolillo said he thought this strategy should definitely be avoided generally and in high-risk patients in particular. “Specifically in patients with diabetes, there’s a clear association with impaired response to clopidogrel in diabetic subjects which is mostly related to impaired metabolism of clopidogrel,” he explained. “We know that the exposure of the active metabolite . . . is approximately 30-40% lower in patients with diabetes. So definitely if you’re going to go with a monotherapy strategy, and particularly in patients with diabetes, this should not imply the use of clopidogrel.”

Lastly, Duvernoy asked about the potential for shortening DAPT to only 1 month. Also, she asked, “can we convince surgeons now to operate on patients on ticagrelor monotherapy where we are just now getting to the point where they are grudgingly operating on patients on aspirin monotherapy?”

“Perhaps” DAPT could be shortened to 1 month, Angiolillo said, citing no harm seen with this strategy in GLOBAL LEADERS. TWILIGHT was designed with regulatory agencies for 3 months to assess safety and adherence mostly, “but I think that shorter durations of DAPT are possible.”

As for surgery, “we would need to speak to the surgeons and understand their comfort level,” he said. “If you recall, almost two decades ago it was an absolute no-no to send patient to surgery while on clopidogrel. And then surgeons needed to learn how to operate on clopidogrel. So we’ll see with patients being on ticagrelor.”