TWILIGHT Benefits of Dropping Aspirin Hold Up in Diabetes

Patrice Wendling

April 01, 2020

Patients with diabetes are often the exception to the rule, but new findings suggest they derive the same benefits as other high-risk patients from ticagrelor monotherapy after percutaneous coronary intervention (PCI).

Discontinuing aspirin after 3 months on a background of ticagrelor (Brilinta, Brilique; AstraZeneca) reduced clinically relevant bleeding but also resulted in numerically fewer ischemic complications than taking both agents for 1 year in the TWILIGHT-DM study.

"Are we ready to implement this? The short answer is yes," said lead author Dominick Angiolillo, MD, PhD, University of Florida College of Medicine, Jacksonville. "We have a lot of data, not just from TWILIGHT, but from several other studies showing there aren't any signals of harm and we can reduce the bleeding."

"I'd definitely like to see this implemented within the upcoming guidelines, both on the European and the US side, as well as in the product label," he added.

The study was presented during the "virtual" American College of Cardiology 2020 Scientific Session/World Congress of Cardiology and published simultaneously in the Journal of the American College of Cardiology.

The results are "impactful and robust, notably showing that the benefits of ticagrelor monotherapy — previously shown within the primary TWILIGHT trial results and also within an ACS subgroup — extend to high-risk patients with diabetes," Sammy Elmariah, MD, MPH, director of interventional cardiology research at Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology in an email.

Patients with diabetes are known to have increased risks for both ischemic and bleeding complications after PCI, and their burden of coronary artery disease (CAD) is more extensive.

Indeed, nearly 70% of the diabetes subgroup had multivessel CAD and the mean total stent length was 40 mm. Yet even in this clearly high-risk cohort, ischemic events did not increase but were actually lower with ticagrelor monotherapy vs dual antiplatelet therapy (DAPT), he noted.

"The primary question that now remains to be answered is the optimal duration of antiplatelet monotherapy," Elmariah said. "Given the more favorable safety profile of ticagrelor monotherapy (over DAPT), longer durations of therapy beyond 12 months may provide a safe means of reducing long-term ischemic risk."

On a similar note, session co-chair Deepak Bhatt, MD, MPH, Brigham & Women's Hospital, Boston, asked how to reconcile the new results with those in THEMIS, suggesting that longer-term therapy in patients with diabetes with ticagrelor plus aspirin would be warranted.

"Do you think one could extrapolate from your study and say: maybe protracted ticagrelor beyond this 12- to 15-month period might, in fact, be in order in patients with diabetes, particularly those with ACS or PCI, or both?" Bhatt queried.

"Absolutely," replied Angiolillo, noting that the current results, as well as those from THEMIS and the diabetic analysis from the PEGASUS trial, led by Bhatt showing a mortality benefit, speak to some "specific benefits of ticagrelor" in patients with diabetes.

"One of these could be related to the twice-daily administration of the drug and, as we know, patients with diabetes do have higher platelet turnover," he said.

TWILIGHT-DM focused on 2620 high-risk patients with diabetes (mean age, 64.8 years) in the parent TWILIGHT trial, who were treated with ticagrelor plus aspirin for 3 months and, if event-free and adherent, were randomly assigned to ticagrelor plus aspirin or placebo for an additional 12 months.

Over 1-year follow-up in the intention-to-treat cohort, the rate of BARC 2, 3 or 5 bleeding was 4.5% in the ticagrelor plus placebo group and 6.7% in the ticagrelor plus aspirin group (hazard ratio [HR], 0.65; = .01).

No significant interaction was found for the primary end point when compared with 4499 nondiabetic patients (P = .23), "supporting consistency between the diabetic and nondiabetic cohorts," Angiolillo said.

Patients with diabetes assigned to ticagrelor monotherapy also had significant reductions in other bleeding definitions: BARC 3 or 5 (1.1% vs 1.3%), TIMI minor or major (4.5% vs 6.7%), GUSTO moderate to severe (0.7% vs 2.3%), and ISTH major (1.4% vs 3.1%). The interaction was positive only for GUSTO bleeding (P = .03).

In the per-protocol analysis of ischemic events, ticagrelor monotherapy was associated with a nonsignificant 23% reduction in the 1-year rate of all-cause death, MI, or stroke, compared with dual therapy (4.6% vs 5.9%; HR, 0.77; = .14; for interaction = .05).

Rates for the majority of other ischemic events were numerically lower with ticagrelor monotherapy, without a significant interaction:

  • cardiovascular death, MI, or ischemic stroke (4.4% vs 5.5%)

  • all-cause death (1.3% vs 2.0%)

  • cardiovascular death (1.2% vs 1.5%)

  • MI (3.1% vs 4.1%)

  • definite/probable stent thrombosis (0.5% vs 0.7%)

  • ischemic stroke (0.6% vs 0.4%).

In an exploratory analysis of net clinical adverse events, defined as BARC 3 or 5, death, MI, or stroke, rates were 5.4% for ticagrelor plus placebo and 8.7% for ticagrelor plus aspirin (HR, 0.61; P = .001), resulting in a number needed to treat with ticagrelor monotherapy of 30 to prevent a net clinical adverse event.

In subgroup analyses, outcomes were consistent in patients who presented with acute coronary syndrome (ACS) versus stable CAD and in patients treated with and without insulin.

Randomization, however, did not stratify patients by diabetes status and did not account for multiplicity, thus increasing the chance for a type 1 error, Angiolillo said. Other limitations are that serum glucose and hemoglobin A1c were not collected, patients with ST-segment elevation MI were excluded from the trial, and the findings may not generalize to patients treated with other oral P2Y12 inhibitors, particularly clopidogrel.

As part of the discussion, panelist Jacqueline Tamis-Holland, MD, Mount Sinai/St. Luke's Hospital, New York City, asked why there was more of a benefit in the diabetic patients with regard to the ischemic end points.

"This ultimately derives from the potential harm from bleeding," said Angiolillo, noting that there was a clear difference in BARC 3 or 5 bleeds between the two groups. There is also 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.

"So these patients are bleeding more and having big bleeds; we know that there is a clear link with ischemic events," he said.

"That makes sense," Tamis-Holland said. "I guess that's always been the question: When you're getting the bleeding, are you stopping all the antiplatelets and having a higher ischemic risk?"

Session co-chair Michelle O'Donoghue, MD, also from Brigham & Women's Hospital, noted that clinicians are more cautious in dropping aspirin in patients on dual vs triple therapy, adding: "Would you caution people against using clopidogrel as monotherapy if they are going to pick a strategy of dropping aspirin?"

"Absolutely," replied Angiolillo, noting that in patients with diabetes, there is an impaired response to clopidogrel, with exposure to the active metabolite about 30% to 40% lower.

"So, definitely if you're going to go with a monotherapy strategy, particularly in patients with diabetes, this should not imply the use of clopidogrel," he said

During a media briefing later that morning, Claire Duvernoy, MD, ACC Board of Trustee member and professor of medicine at the University of Michigan, Ann Arbor, said: "We now have an enriched amount of knowledge for who we can safely use monotherapy. We heard about ACS patients, we heard about complex PCI patients, and now about diabetics, which as you know is an increasing number of patients in the United States. So I think this is critically important."

She agreed that one of the important unknowns is the optimal duration of dual therapy with ticagrelor.

"Can we cut that back, can we go down to one month?" Duvernoy said. "The other question is can we convince surgeons now to operate on patients on ticagrelor monotherapy when we're just now getting to the point where they are grudgingly operating on patients on aspirin monotherapy?"

The 3-month use of ticagrelor was designed in alliance with regulatory authorities and allowed for better understanding of adherence, but "I think that shorter durations of dual therapy are possible," Angiolillo said.

With regard to surgeons' hesitation, he noted that roughly 2 decades ago, it was an "absolute no-no" to send a patient to surgery on clopidogrel and that a specific antidote for ticagrelor is under development with positive preliminary results.

TWILIGHT was funded by AstraZeneca. Angiolillo reports receiving grant support, consulting fees, and honoraria from Amgen, Aralez, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Janssen, Merck, and Sanofi; and consulting fees and honoraria from Haemonetics, PhaseBio, PLx Pharma, Pfizer, and the Medicines Company. He also reports grant support and fees for review activities from CeloNova, fees for review activities from St. Jude Medical, and grant support from CSL Behring, Eisai, Gilead , Idorsia Pharmaceuticals, Matsutani Chemical Industry, Novartis, Osprey Medical, and RenalGuard Solutions. Elmariah reports no relevant financial relationship. Bhatt reports relationships with multiple companies, including receiving honoraria from WebMD. O'Donoghue reports consultant fees/honoraria from Amgen, CVD Caremark, Janssen Pharmaceuticals, and Novartis; serving on the data safety monitoring board for Merck; and research/research grants from Amgen, AZ Medimmune, Eisai, Janssen, The Medicines Company, and Merck.

J Am Coll Cardiol. Published online March 30, 2020. Abstract

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC): Abstract 410-16. Presented March 30, 2020.

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