Ticagrelor Monotherapy Affirmed in High-Risk ACS: TWILIGHT-ACS

Patrice Wendling

November 17, 2019

PHILADELPHIA — Patients with acute coronary syndrome (ACS) appear to derive the same benefits as other high-risk patients from ticagrelor monotherapy after percutaneous coronary intervention (PCI), according to TWILIGHT-ACS.

"Having a dedicated analysis focused exclusively on the acute coronary syndrome patients is very important for consideration of a treatment strategy that we might want to adopt of just 3 months of DAPT in ACS patients," Usman Baber, MD, MS, Icahn School of Medicine at Mount Sinai, New York City,  told theheart.org | Medscape Cardiology.

Current guidelines explicitly recommend dual antiplatelet therapy (DAPT) for 1 year in the presence of acute coronary syndrome (ACS), he noted. The parent TWILIGHT trial, however, recently showed that dropping aspirin after 3 months and continuing ticagrelor (Brilinta, AstraZeneca) monotherapy lowered the risk for bleeding without increasing ischemic events in PCI patients with at least one angiographic and one clinical high-risk feature.

The ACS substudy zeroed in on 4614 (64%) of the trial's 7119 randomly assigned patients who presented with unstable angina (n = 2494) or non–ST-segment elevation MI (NSTEMI; n = 2120). Almost half had four or five high-risk features and 17% had six or more, indicating a very high-risk phenotype, he said.

At 1 year, the primary endpoint of BARC (Bleeding Academic Research Consortium) 2, 3, or 5 bleeding occurred less often in the ticagrelor monotherapy group than it did in patients on ticagrelor plus aspirin (3.6% vs 7.6%; hazard ratio [HR], 0.47; 95% CI, 0.36 - 0.61).

Importantly, when the treatment effect was stratified by risk-factor burden, "relative reductions on the order of 50% to 60% indicated a uniform benefit of ticagrelor monotherapy, irrespective of underlying risk level," Baber said during a late-breaking trial session here at the American Heart Association (AHA) Scientific Sessions 2019.

Between-group differences, favoring ticagrelor monotherapy, were also present for the individual bleeding endpoints of

  • BARC 3 or 5 bleeding: 0.8% vs 2.1% (P < .0001)

  • TIMI major: 0.5% vs 1.0% (P = .08)

  • GUSTO moderate or severe: 0.6% vs 1.6% (P = .002)

  • ISTH major: 0.9% vs 2.2% (P = .001)

Ischemic Events

Rates of the secondary composite endpoint of death, MI, or stroke were almost identical across the ticagrelor monotherapy and ticagrelor/aspirin groups (4.3% vs 4.4%; HR, 0.97; 95% CI, 0.74 - 1.28), Baber noted. This included patients with NSTEMI) who were troponin positive (adjusted HR, 1.77; 95% CI, 1.23 - 2.55).

Further, there was no statistically significant incremental increase with ticagrelor monotherapy on the ischemic endpoint based on risk factor burden, including in those at highest risk, with six to nine risk factors (8.4% vs 9.8%; HR, 0.86; 95% CI, 0.54 - 1.36), he said.

Prespecified ischemic endpoints were also similar between the ticagrelor monotherapy and ticagrelor/aspirin groups:

  • All-cause death: 1.0% vs 1.5% (P = .14)

  • Any MI: 3.1% vs 3.1% (P = .99)

  • Ischemic stroke: 0.5% vs 0.3% (P = .21)

  • Definite/probable stent thrombosis: 0.4% vs 0.6% (P = .38)

Finally, results for the primary and secondary endpoints were unchanged for patients presenting with unstable angina or NSTEMI.

"I think this provides important reassurance that even for our highest-risk patients that a strategy of P2Y12 inhibitor monotherapy does not appear to increase the risk of MACE [major adverse cardiovascular events] when stopped 1 to 3 months post-PCI," Michelle O'Donoghue, MD, Brigham and Women's Hospital, Boston, Massachusetts, told theheart.org | Medscape Cardiology.

During her formal discussion of the results, O'Donoghue presented her own analysis of prior trials that looked at a strategy of P2Y12 monotherapy 1 to 3 months after PCI, including GLOBAL LEADERS, SMART CHOICE, STOP DAPT 2, and TWILIGHT. Overall, results show monotherapy with a P2Y12 inhibitor reduced bleeding by about 40% without a price in terms of increased MACE, with a hazard ratio of 0.91 favoring monotherapy, she noted.

Looking specifically at post-ACS patients in GLOBAL LEADERS ACS, SMART CHOICE ACS, and TWILIGHT-ACS, "again there was a consistent 51% reduction in bleeding and favorable trends for reducing MACE with the P2Y12 strategy [HR, 0.89]," she said.

Still Up in the Air

The choice of which P2Y12 inhibitor is best "remains up in the air," as does the question of whether genotyping or platelet function testing should be required for patients on clopidogrel monotherapy, given the significant interpatient variability in terms of pharmacodynamic response, O'Donoghue observed.

"The clopidogrel question in an important one because we don't know whether or not clopidogrel monotherapy would be adequate for people who are poor responders and should we do platelet function testing or genotyping for patients who fall in that category," she said when interviewed.

Adding an additional wrinkle to the choice of P2Y12 inhibitor are the recent ISAR-REACT 5 data, which, contrary to expectations, found that patients hospitalized with ACS scheduled for invasive coronary angiography who received prasugrel rather than ticagrelor were less likely to have an MI or stroke at 1 year and had a similar incidence of major bleeding.

"The data from ISAR-REACT 5 are certainly very controversial," O'Donoghue said. "Based on what we know about the pharmacodynamics effects of the two drugs, ticagrelor and prasugrel, they're both pretty much in line. So I think that before a decision is made to preferentially choose prasugrel over ticagrelor, I would want to see additional data to support that because it doesn't seem to be backed up by the pharmacology at this point."

Asked about ISAR-REACT 5 and the use of prasugrel in ACS, Baber said, "One of the confusing findings, at least to me, is that prasugrel lowered thrombotic risk. However, there was no excess bleeding. In all of our antiplatelet trials, we always see a reduction in thrombosis with a commensurate increase in bleeding. So that finding needs to be explored further and explained to really reconcile that literature with existing evidence."

Commenting further, he said, "Certainly people are using prasugrel in ACS, but in TWILIGHT we evaluated aspirin versus placebo, and I would caution against extrapolating the findings of TWILIGHT to a backbone of prasugrel."

TWILIGHT was funded by AstraZeneca. Baber reports advisory board/personal fees from Amgen, AstraZeneca, and Boston Scientific and research funding to his institution from AstraZeneca. O'Donoghue reports grant support from Amgen, Merck, AstraZeneca.

American Heart Association (AHA) Scientific Sessions 2019. Presented November 17, 2019.

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