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

Feb 15, 2022
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
AstraZeneca
Date Presented:
08/29/2021
Date Published:
02/07/2022
Date Updated:
02/15/2022
Original Posted Date:
09/26/2019
References

Contribution To Literature:

Highlighted text has been updated as of February 15, 2022.

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).

Sex differences: Women (23.9%); Ticagrelor monotherapy vs ticagrelor + aspirin reduced BARC type 2, 3, or 5 bleeding in women (5.0% vs. 8.6%; adjusted HR 0.62; 95% CI 0.42-0.92; p= 0.02) and in men (3.7% vs. 6.6%; adjusted HR 0.57; 95% CI 0.44-0.73; p< 0.001) (p for interaction = 0.69). Composite of death, MI, or stroke similar for ticagrelor monotherapy vs. ticagrelor plus aspirin in women (3.5% vs. 3.5%; adjusted HR 1.04, 95% CI 0.61-1.77; p = 0.88) and men (4.0% vs 4.1%; adjusted HR 1.06, 95% CI 0.80-1.39; p = 0.69) (p for interaction = 0.95).

High bleeding risk (HBR) patients (n = 1,064, 17.2%): Patients meeting ARC-HBR criteria were older, more likely to be female, non-White race, and had a higher burden of most comorbidities; they were also more likely to undergo complex PCI. BARC 2, 3, or 5 bleeding was significantly lower in the ticagrelor monotherapy arm compared with ticagrelor + aspirin in both HBR (6.3% vs. 11.4%, p = 0.004) and non-HBR (3.5% vs. 5.9%, p < 0.0001) patients (p for interaction = 0.67). TIMI major bleeding (0.4% vs. 2.2%, p for interaction = 0.021) and GUSTO moderate or severe bleeding (1.6% vs. 4.5%, p for interaction = 0.016) were significantly reduced among HBR patients with ticagrelor monotherapy. No difference in ischemic endpoints was noted in HBR and non-HBR patients.

Patients with prior MI (n = 1,937, 29.7%): At 1 year after randomization, patients with prior MI experienced higher rates of death, MI, or stroke (5.7% vs. 3.2%; p < 0.001) but similar BARC types 2-5 bleeding (5.0% vs. 5.5%; p = 0.68). Ticagrelor monotherapy consistently reduced the risk for the primary bleeding outcome in patients with (3.4% vs. 6.7%; HR 0.50, 95% CI 0.33-0.76) and without (4.2% vs. 7.0%; HR 0.58, 95% CI 0.45-0.76, p interaction = 0.54) prior MI. No differences were noted for individual ischemic endpoints including cardiovascular death, MI, ischemic stroke, and stent thrombosis.

TWILIGHT-CKD: Chronic kidney disease (CKD) was present in 16.3%. BARC type 2, 3, or 5 bleeding was lower for ticagrelor monotherapy vs. ticagrelor + aspirin among patients with CKD (4.6% vs. 9.0%; HR 0.50, 95% CI 0.31-0.80) and without CKD (4.0% vs. 6.7%; HR 0.59, 95% CI 0.47-0.75), p for interaction = 0.50. Death, MI, or stroke for ticagrelor monotherapy vs. ticagrelor + aspirin was similar among patients with CKD (7.9% vs. 5.7%; HR 1.40, 95% CI 0.88-2.22) and without CKD (3.2% vs. 3.6%; HR 0.90, 95% CI 0.68-1.20), p for interaction = 0.11.

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, men vs. women, those undergoing complex PCI, CKD, prior MI, and among patients at HBR. 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. On the other hand, in the STOPDAPT-2 ACS trial, clopidogrel monotherapy after 1 month of DAPT appeared to result in a higher risk of ischemic events (primarily MI) compared with 12 months of DAPT. These trials are thus likely to influence future guidelines regarding DAPT duration post-PCI.

References:

Chiarito M, Baber U, Cao D, et al. Ticagrelor Monotherapy After PCI in High-Risk Patients With Prior MI: A Prespecified TWILIGHT Substudy. JACC Cardiovasc Interv 2022;15:282-93.

Editorial Comment: Lev EI, Ben-Assa E. Dual Antiplatelet Therapy in Patients With Prior Myocardial Infarction: The Twilight of Prolonged DAPT Duration? JACC Cardiovasc Interv 2022;15:294-6.

Escaned J, Cao D, Baber U, et al. Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR. Eur Heart J 2021;42:4624-34.

TWILIGHT-HBR: Presented by Dr. Davide Cao at the European Society of Cardiology Virtual Congress, August 30, 2021.

Stefanini GG, Briguori C, Cao D, et al. Ticagrelor monotherapy in patients with chronic kidney disease undergoing percutaneous coronary intervention: TWILIGHT-CKD. Eur Heart J 2021;42:4683-93.

Vogel B, Baber U, Cohen DJ, et al. Sex Differences Among Patients With High Risk Receiving Ticagrelor With or Without Aspirin After Percutaneous Coronary Intervention: A Subgroup Analysis of the TWILIGHT Randomized Clinical Trial. JAMA Cardiol 2021;6:1032-41.

Presented by Dr. Kurt Huber at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 15, 2021.

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;75:2403-13.

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;75:2414-24.

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: ESC21, ESC Congress, Acute Coronary Syndrome, Adenosine, Angiography, Aspirin, Atherectomy, Brain Ischemia, Coronary Artery Disease, Diabetes Mellitus, Drug-Eluting Stents, Hemorrhage, Kidney Failure, Chronic, 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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