Meeting NewsPerspective

TWILIGHT: Switching to ticagrelor monotherapy 3 months post-PCI lowers bleeding vs. DAPT

Roxana Mehran

SAN FRANCISCO — Among patients who underwent PCI with a drug-eluting stent and were prescribed dual antiplatelet therapy for 3 months, subsequent ticagrelor monotherapy lowered bleeding risk without raising ischemic risk compared with continued DAPT, according to results of the TWILIGHT trial presented at TCT 2019.

Among 7,119 patients who underwent randomization 3 months after PCI, the primary endpoint of Bleeding Academic Research Consortium type 2, 3 or 5 bleeding at 1 year was 4% in those assigned ticagrelor (Brilinta, AstraZeneca) plus placebo vs. 7.1% in those assigned DAPT with ticagrelor and aspirin (risk difference –3.08 percentage points; 95% CI, –4.15 to –2.01; HR = 0.56; 95% CI, 0.45-0.68), Roxana Mehran, MD, professor of medicine and director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Wiener Cardiovascular Institute at Icahn School of Medicine at Mount Sinai, and principal investigator of TWILIGHT, said during a press conference. Mehran noted that the treatment effect was consistent across all prespecified subgroups.

The composite ischemic endpoint of all-cause mortality, nonfatal MI and nonfatal stroke occurred at a rate of 3.9% in both groups at 1 year (difference, –0.06 percentage points; 95% CI, –0.97 to 0.84; HR = 0.99; 95% CI, 0.78-1.25), Mehran showed, again noting there was no variance across prespecified subgroups.

In other results, BARC type 3 or 5 bleeding occurred in 1% of the monotherapy group vs. 2% of the DAPT group (HR = 0.49; 95% CI, 0.33-0.74), according to results presented here.

The TWILIGHT data were simultaneously published in The New England Journal of Medicine.

“Balancing ischemic and bleeding complications after a coronary intervention is a very important dilemma for us clinicians,” Mehran said during the press conference. “The clinical imperative of lowering bleeding while preventing ischemic events requires a therapeutic strategy that decouples thrombotic from hemorrhagic risk.”

Among other ischemic endpoints, the researchers reported no significant difference between the groups in all-cause mortality, CV death, MI, ischemic stroke, definite or probable stent thrombosis, or CV death/nonfatal MI/nonfatal stroke, Mehran said.

Both groups had a mean age of 65 years and one-quarter of the study participants were women. All patients underwent successful PCI with at least one locally approved DES, and had at least one additional clinical risk factor and angiographic risk factor for bleeding or ischemic events. In addition, all patients included in the analysis were able to tolerate aspirin and ticagrelor for 3 months. Patients with STEMI, cardiogenic shock, long-term oral anticoagulant use or contraindication to ticagrelor or aspirin were excluded.

“In high-risk patients who underwent PCI and took ticagrelor and aspirin for 3 months and had no major events, an antiplatelet strategy of continuing ticagrelor monotherapy resulted in substantially less bleeding than ticagrelor plus aspirin without increasing ischemic harm over a 1-year period,” Mehran said.

Thrombogenicity substudy

Also presented at TCT was a substudy of 51 patients from TWILIGHT who underwent blood tests to compare the antithrombotic potency of both strategies.

The primary endpoint of the substudy was blood thrombogenicity as defined by platelet-dependent thrombus area. The secondary endpoint was platelet reactivity.

Platelet-dependent thrombus area did not differ between those assigned ticagrelor monotherapy and those assigned continued DAPT (mean difference, 218.2 μm2; 95% CI, 575.9 to 139.9), Cardiology Today Next Gen Innovator Usman Baber, MD, MS, assistant professor of medicine at Icahn School of Medicine at Mount Sinai, said during the press conference.

Platelet reactivity did not differ between the groups when assessed by adenosine diphosphate (P = .47) or thrombin receptor-activating peptide (P = .81), but platelet aggregation was higher in the monotherapy group when assessed by arachidonic acid (P = .02) and collagen (P = .03), he said.

“We concluded that ticagrelor monotherapy provides a similar antithrombotic effect to ticagrelor plus aspirin,” Baber said. “Platelet reactivity with collagen and arachidonic acid was increased, while aggregation of adenosine diphosphate and thrombin was not, and in our opinion, these findings indicate that aspirin withdrawal does not modulate ex vivo blood thrombogenicity in the presence of strong P2Y12 blockade, and it corroborates the clinical observations presented by Dr. Mehran with respect to no incremental ischemic risk.”

Generalizability

In a press release issued by Mount Sinai, Samin K. Sharma, MD, director of clinical and interventional cardiology for the Mount Sinai Health System, said: “The TWILIGHT trial is a landmark trial [that] will change our PCI practice by eliminating aspirin after 3 months in patients on ticagrelor with resultant lower vascular bleeding and no effect on ischemic endpoints. The findings are particularly important since this is the first study of its kind where a majority of patients were from the United States of America. The results are more generalizable to American patients and the practice of dropping aspirin may be widely and easily accepted in this country.” – by Erik Swain

References:

Baber U, et al. Late-Breaking Science 1.

Mehran R, et al. Late-Breaking Trials 1. Both presented at: TCT Scientific Symposium; Sept. 25-29, 2019; San Francisco.

Mehran R, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908419.

Disclosures: The study was funded by AstraZeneca. Mehran reports she has financial ties with Abbott Vascular, AstraZeneca, Bayer, Boston Scientific, Bracco Group, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, Janssen, Medscape/WebMD, Medtronic, Novartis, OrbusNeich, Osprey Medical, Philips/Volcano/Spectranetics, PLC/RenalGuard, Roivant Sciences, Sanofi, Siemens Medical Solutions and Watermark Research Funding. Baber reports he receives consultant fees/honoraria from AstraZeneca and Boston Scientific. Sharma reports he holds equity in Eternal Heart Care Centre and Research Institute Private Ltd. and has lectured at events sponsored by Abbott, Boston Scientific and Cardiovascular Systems Inc. Please see the study for the other authors’ relevant financial disclosures.

Roxana Mehran

SAN FRANCISCO — Among patients who underwent PCI with a drug-eluting stent and were prescribed dual antiplatelet therapy for 3 months, subsequent ticagrelor monotherapy lowered bleeding risk without raising ischemic risk compared with continued DAPT, according to results of the TWILIGHT trial presented at TCT 2019.

Among 7,119 patients who underwent randomization 3 months after PCI, the primary endpoint of Bleeding Academic Research Consortium type 2, 3 or 5 bleeding at 1 year was 4% in those assigned ticagrelor (Brilinta, AstraZeneca) plus placebo vs. 7.1% in those assigned DAPT with ticagrelor and aspirin (risk difference –3.08 percentage points; 95% CI, –4.15 to –2.01; HR = 0.56; 95% CI, 0.45-0.68), Roxana Mehran, MD, professor of medicine and director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Wiener Cardiovascular Institute at Icahn School of Medicine at Mount Sinai, and principal investigator of TWILIGHT, said during a press conference. Mehran noted that the treatment effect was consistent across all prespecified subgroups.

The composite ischemic endpoint of all-cause mortality, nonfatal MI and nonfatal stroke occurred at a rate of 3.9% in both groups at 1 year (difference, –0.06 percentage points; 95% CI, –0.97 to 0.84; HR = 0.99; 95% CI, 0.78-1.25), Mehran showed, again noting there was no variance across prespecified subgroups.

In other results, BARC type 3 or 5 bleeding occurred in 1% of the monotherapy group vs. 2% of the DAPT group (HR = 0.49; 95% CI, 0.33-0.74), according to results presented here.

The TWILIGHT data were simultaneously published in The New England Journal of Medicine.

“Balancing ischemic and bleeding complications after a coronary intervention is a very important dilemma for us clinicians,” Mehran said during the press conference. “The clinical imperative of lowering bleeding while preventing ischemic events requires a therapeutic strategy that decouples thrombotic from hemorrhagic risk.”

Among other ischemic endpoints, the researchers reported no significant difference between the groups in all-cause mortality, CV death, MI, ischemic stroke, definite or probable stent thrombosis, or CV death/nonfatal MI/nonfatal stroke, Mehran said.

Both groups had a mean age of 65 years and one-quarter of the study participants were women. All patients underwent successful PCI with at least one locally approved DES, and had at least one additional clinical risk factor and angiographic risk factor for bleeding or ischemic events. In addition, all patients included in the analysis were able to tolerate aspirin and ticagrelor for 3 months. Patients with STEMI, cardiogenic shock, long-term oral anticoagulant use or contraindication to ticagrelor or aspirin were excluded.

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“In high-risk patients who underwent PCI and took ticagrelor and aspirin for 3 months and had no major events, an antiplatelet strategy of continuing ticagrelor monotherapy resulted in substantially less bleeding than ticagrelor plus aspirin without increasing ischemic harm over a 1-year period,” Mehran said.

Thrombogenicity substudy

Also presented at TCT was a substudy of 51 patients from TWILIGHT who underwent blood tests to compare the antithrombotic potency of both strategies.

The primary endpoint of the substudy was blood thrombogenicity as defined by platelet-dependent thrombus area. The secondary endpoint was platelet reactivity.

Platelet-dependent thrombus area did not differ between those assigned ticagrelor monotherapy and those assigned continued DAPT (mean difference, 218.2 μm2; 95% CI, 575.9 to 139.9), Cardiology Today Next Gen Innovator Usman Baber, MD, MS, assistant professor of medicine at Icahn School of Medicine at Mount Sinai, said during the press conference.

Platelet reactivity did not differ between the groups when assessed by adenosine diphosphate (P = .47) or thrombin receptor-activating peptide (P = .81), but platelet aggregation was higher in the monotherapy group when assessed by arachidonic acid (P = .02) and collagen (P = .03), he said.

“We concluded that ticagrelor monotherapy provides a similar antithrombotic effect to ticagrelor plus aspirin,” Baber said. “Platelet reactivity with collagen and arachidonic acid was increased, while aggregation of adenosine diphosphate and thrombin was not, and in our opinion, these findings indicate that aspirin withdrawal does not modulate ex vivo blood thrombogenicity in the presence of strong P2Y12 blockade, and it corroborates the clinical observations presented by Dr. Mehran with respect to no incremental ischemic risk.”

Generalizability

In a press release issued by Mount Sinai, Samin K. Sharma, MD, director of clinical and interventional cardiology for the Mount Sinai Health System, said: “The TWILIGHT trial is a landmark trial [that] will change our PCI practice by eliminating aspirin after 3 months in patients on ticagrelor with resultant lower vascular bleeding and no effect on ischemic endpoints. The findings are particularly important since this is the first study of its kind where a majority of patients were from the United States of America. The results are more generalizable to American patients and the practice of dropping aspirin may be widely and easily accepted in this country.” – by Erik Swain

References:

Baber U, et al. Late-Breaking Science 1.

Mehran R, et al. Late-Breaking Trials 1. Both presented at: TCT Scientific Symposium; Sept. 25-29, 2019; San Francisco.

Mehran R, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908419.

Disclosures: The study was funded by AstraZeneca. Mehran reports she has financial ties with Abbott Vascular, AstraZeneca, Bayer, Boston Scientific, Bracco Group, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, Janssen, Medscape/WebMD, Medtronic, Novartis, OrbusNeich, Osprey Medical, Philips/Volcano/Spectranetics, PLC/RenalGuard, Roivant Sciences, Sanofi, Siemens Medical Solutions and Watermark Research Funding. Baber reports he receives consultant fees/honoraria from AstraZeneca and Boston Scientific. Sharma reports he holds equity in Eternal Heart Care Centre and Research Institute Private Ltd. and has lectured at events sponsored by Abbott, Boston Scientific and Cardiovascular Systems Inc. Please see the study for the other authors’ relevant financial disclosures.

    Perspective
    Davide Capodanno

    Davide Capodanno

    In a population of patients with who had complex PCI, including coronary stents for multivessel disease and/or long lesions, dropping aspirin but keeping ticagrelor monotherapy after 3 months of DAPT is safer overall than the standard of care. We must learn to select appropriate patients for this strategy, for example those at high bleeding risk, but it is something we now can consider. 

    We cannot imagine that the uptake to routine clinical practice will be immediate because people are fairly used to DAPT and stopping the P2Y12 inhibitor rather than aspirin. But there are patients who could benefit because of high thrombotic risk and bleeding risk. We now have a practice validated in a large study that may be an indication for some patients.

    The thrombogenicity substudy provides an explanation for what we have seen. That is reassuring. The mechanism shows that with the P2Y12 inhibitor, you sufficiently address the thrombosis risk, and when you add something like aspirin on top of that, you are basically just adding to the risk for bleeding.

    • Davide Capodanno, MD, PhD
    • Professor of Cardiology
      Azienda Ospedaliero-Universitaria
      Policlinico-Vittorio Emanuele
      Catania, Italy

    Disclosures: Capodanno reports he receives consultant fees, speaker fees or honoraria from AstraZeneca, Bayer, Daiichi Sankyo/Eli Lilly and Sanofi Aventis.

    Perspective
    Ori Ben-Yehuda

    Ori Ben-Yehuda

    There are still a lot of questions. Was this a ticagrelor study or a short duration of DAPT study? Would the results be the same if the patients were on clopidogrel or aspirin monotherapy? I understand why it was conducted, but I regret that there was not an aspirin-only arm. That would have provided additional useful information. So, we have more work to do. The major concern with DAPT has always been bleeding, and the ability to go to a single agent is helpful. We also know from the PLATO study that there were benefits of ticagrelor in the setting of DAPT in terms of having a reduced event rate, so it would be interesting to see a comparison of ticagrelor vs. aspirin as a single agent. Based on CAPRI, it would stand to reason that there would be greater benefit of the P2Y12 inhibitor, and maybe an advantage in terms of bleeding. We need a head-to-head study. CAPRI has to be done again with other agents. The thrombogenicity substudy was useful. We see there is no difference in thrombogenicity. That relates to the ischemic risk, for which there was no difference in the overall study. One would have perhaps expected also that there would be some relation to bleeding, so it’s a little incongruent to the difference in bleeding results. If the antiplatelet effect is the same in both arms, why is there a difference in bleeding? One explanation might be because of the gastrointestinal effect of aspirin. That is not an antiplatelet effect, but the erosive effect of aspirin on the GI tract.

    • Ori Ben-Yehuda, MD
    • Executive Director, Clinical Trials Section
      Cardiovascular Research Foundation

    Disclosures: Ben-Yehuda reports no relevant financial disclosures.

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