Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention - TWILIGHT

Contribution To Literature:

The TWILIGHT trial showed that short-duration DAPT (3 months) followed by ticagrelor monotherapy for 12 months results in less bleeding compared with longer-duration DAPT (additional 12 months) among patients undergoing PCI with a DES and at high ischemic or bleeding risk; ischemic rates met criteria for noninferiority.

Description:

The goal of the trial was to compare the safety and efficacy of a short-duration dual antiplatelet therapy (DAPT) (3 months) followed by ticagrelor monotherapy compared with longer duration DAPT (12 months) among patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) and with ≥1 high risk feature of ischemia or bleeding.

Study Design

Eligible patients were randomized in a 1:1 double-blind fashion to either DAPT with aspirin and ticagrelor for 3 months followed by ticagrelor monotherapy (n = 3,555) or continued DAPT ticagrelor + aspirin (n = 3,564) for an additional 12 months. Aspirin dose was 81-100 mg daily, and ticagrelor dose was 90 mg BID.

  • Total number of enrollees: 7,119
  • Duration of follow-up: 12 months
  • Mean patient age: 65.2 years
  • Percentage female: 24%

Inclusion criteria:

  • Successful PCI with ≥1 locally approved DES and whom the treating clinician intended to discharge with a regimen of ticagrelor plus aspirin
  • ≥1 additional clinical feature and one angiographic feature associated with a high risk of ischemic or bleeding events
  • Clinical features: Age ≥65 years, female sex, troponin-positive acute coronary syndrome (ACS), established vascular disease, diabetes mellitus that was being treated with medication, chronic kidney disease
  • Angiographic features: Multivessel coronary artery disease, total stent length of >30 mm, thrombotic target lesion, bifurcation lesion treated with two stents, an obstructive left main or proximal left anterior descending lesion, calcified target lesion treated with atherectomy
  • No ischemic or bleeding event at 3 months after index hospital discharge

Exclusion criteria:

  • Presentation with ST-segment elevation myocardial infarction (STEMI)
  • Cardiogenic shock
  • Ongoing long-term treatment with oral anticoagulants
  • Contraindication to aspirin or ticagrelor

Other salient features/characteristics:

  • Previous MI: 29%, previous PCI: 42%
  • Unstable angina/non-STEMI (NSTEMI) presentation: 64%

Principal Findings:

The primary outcome of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 12 months, for ticagrelor monotherapy vs. aspirin + ticagrelor, was 4.0% vs. 7.1% (p < 0.001).

  • All-cause mortality, MI, stroke: 3.9% vs. 3.9% (p < 0.001 for noninferiority)
  • MI: 2.7% vs. 2.7%

Secondary outcomes for ticagrelor monotherapy vs. aspirin + ticagrelor:

  • Stent thrombosis, definite + probable: 0.4% vs. 0.6% (p < 0.05)
  • Ischemic stroke: 0.5% vs. 0.2% (p > 0.05)

Thrombogenicity platelet substudy: Ex vivo thrombogenicity measurements were performed in 42 patients. Platelet reactivity to collagen and arachidonic acid was increased in the absence of aspirin, while aggregation to adenosine diphosphate and thrombin was unchanged with or without aspirin. The adjusted mean difference in post-randomization thrombus area was similar between groups: −218.2 μm2; p = 0.22.

NSTE-ACS subset (n = 4,614): The primary endpoint for ticagrelor monotherapy vs. aspirin + ticagrelor was 3.6% vs. 7.6% (p < 0.001); TIMI major bleeding: 0.5% vs. 1.0% (p = 0.08); all-cause mortality, MI, stroke: 4.3% vs. 4.4% (p = 0.84); all-cause mortality: 1.0% vs. 1.5% (p = 0.14); any MI: 3.1% vs. 3.1% (p = 0.99); stent thrombosis: 0.4% vs. 0.6% (p = 0.38).

Diabetes mellitus subset (n = 2,620, 37%): BARC 2, 3, or 5 bleeding with ticagrelor vs. placebo was 4.5% vs. 6.7% (p = 0.012); ischemic events: 4.6% vs. 5.9% (p = 0.14).

Complex PCI (n = 2,342): Defined as 3 vessels treated, ≥3 lesions treated, total stent length >60 mm (52% of all), bifurcation with 2 stents implanted, atherectomy device use, left main PCI, surgical bypass graft, or chronic total occlusion as target lesions. BARC 2, 3, or 5 bleeding with ticagrelor vs. placebo was 4.2% vs. 7.7% (p < 0.05); ischemic events: 3.8% vs. 4.9% (p > 0.05); stent thrombosis: 0.4% vs. 0.8% (p > 0.05).

Interpretation:

The results of this trial indicate that short-duration DAPT (3 months) followed by ticagrelor monotherapy for 12 months results in less bleeding compared with longer-duration DAPT (additional 12 months) among patients undergoing PCI with a DES and at high ischemic or bleeding risk; ischemic rates met criteria for noninferiority.

These results were maintained even among the subgroup of patients presenting with NSTE-ACS (STEMI patients were excluded from the trial), diabetes mellitus, and those undergoing complex PCI. These are interesting findings, and help advance our understanding of the optimal duration and type of antiplatelet agent post-PCI. Similar findings were noted with clopidogrel in the SMART-CHOICE and STOPDAPT-2 trials. These trials are thus likely to influence future guidelines regarding DAPT duration post-PCI.

References:

Angiolillo DJ, Baber U, Sartori S, et al. Ticagrelor With or Without Aspirin in High-Risk Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention. J Am Coll Cardiol 2020;Mar 30:[Epub ahead of print].

Diabetes mellitus substudy: Presented by Dr. Dominick J. Angiolillo at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.

Dangas G, Baber U, Sharma S, et al. Ticagrelor With Aspirin or Alone After Complex PCI: The TWILIGHT-COMPLEX Analysis. J Am Coll Cardiol 2020;Mar 30:[Epub ahead of print].

TWILIGHT-COMPLEX analysis: Presented by Dr. George Dangas at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.

Baber U, Zafar U, Dangas G, et al. Ticagrelor With or Without Aspirin After PCI: The TWILIGHT Platelet Substudy. J Am Coll Cardiol 2020;75:578-86.

Editorial Comment: Becker RC, Sadayappan S. Designing Human In Vitro Models for Drug Development. J Am Coll Cardiol 2020;75:587-9.

Presented by Dr. Usman Baber at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.

Presented by Dr. Usman Baber at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2019), San Francisco, CA, September 26, 2019.

Mehran R, Baber U, Sharma SK, et al. Ticagrelor With or Without Aspirin in High-Risk Patients After PCI. N Engl J Med 2019;381:2032-42.

Presented by Dr. Roxana Mehran at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2019), San Francisco, CA, September 26, 2019.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Acute Coronary Syndrome, Adenosine, Angiography, Aspirin, Atherectomy, Brain Ischemia, Coronary Artery Disease, Diabetes Mellitus, Drug-Eluting Stents, Hemorrhage, Myocardial Infarction, Myocardial Ischemia, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Renal Insufficiency, Stroke, Thrombosis, Troponin, Transcatheter Cardiovascular Therapeutics, TCT19, Vascular Diseases


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