Ticagrelor with or without aspirin in high-risk patients after PCI
Selected in The New England Journal of Medicine by E. Asher
The TWILIGHT trial was designed to test the hypothesis that in patients undergoing PCI who are at high risk for ischemic or hemorrhagic complications and who have completed a 3-month course of DAPT with ticagrelor plus aspirin, continued treatment with ticagrelor monotherapy would be superior to ticagrelor plus aspirin...
References
Authors
Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha JY, Collier T, Dangas G, Dudek D, Džavík V, Escaned J, Gil R, Gurbel P, Hamm CW, Henry T, Huber K, Kastrati A, Kaul U, Kornowski R, Krucoff M, Kunadian V, Marx SO, Mehta SR, Moliterno D, Ohman EM, Oldroyd K, Sardella G, Sartori S, Shlofmitz R, Steg PG, Weisz G, Witzenbichler B, Han YL, Pocock S, Gibson CM
Reference
N Engl J Med. 2019 Sep 26 [Epub ahead of print]
Published
September 2019
Link
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Why this study – the rationale/objective?
Monotherapy with a P2Y12 inhibitor after a short period of dual antiplatelet therapy (DAPT) is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI). In patients who have an acute coronary syndrome (ACS) or who have undergone PCI, the risk of thrombotic events is lower with DAPT (aspirin and a P2Y12 receptor inhibitor) than with aspirin alone. The use of more potent P2Y12 inhibitors or extension of the duration of dual antiplatelet therapy lowers residual ischemic risk among such patients but increases bleeding.
Hence, the Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention (TWILIGHT) trial was designed to test the hypothesis that in patients undergoing PCI who are at high risk for ischemic or hemorrhagic complications and who have completed a 3-month course of DAPT with ticagrelor plus aspirin, continued treatment with ticagrelor monotherapy would be superior to ticagrelor plus aspirin with respect to clinically relevant bleeding and would not lead to ischemic harm.
How was it executed – the methodology?
Randomized, placebo-controlled trial in 187 sites across 11 countries. Patients who underwent successful PCI with drug-eluting stent and were discharged with a regimen of ticagrelor plus aspirin were eligible to participate. Patients also had to have at least one additional clinical feature and one angiographic feature associated with a high risk of ischemic or bleeding events.
The clinical criteria for high risk were:
1) age ≥ 65 years, 2) female sex, 3) troponin-positive ACS, 4) established vascular disease, 5) diabetes mellitus and 6) chronic kidney disease.
Angiographic criteria included:
1) multivessel coronary artery disease, 2) a stent length > 30 mm, 3) a thrombotic target lesion, 4) a bifurcation lesion treated with two stents, 5) an obstructive left main or proximal left anterior descending lesion, and 6) a calcified target lesion treated with atherectomy.
Key exclusion criteria included:
1) presentation with ST-segment elevation myocardial infarction (STEMI), 2) cardiogenic shock, 3) ongoing long-term treatment with oral anticoagulants, or 4) contraindication to aspirin or ticagrelor.
Trial Regimen
All enrolled patients received DAPT ticagrelor (90 mg twice daily) and aspirin (81 to 100 mg daily) after the index PCI for 3 months. Thereafter, patients who had not had a major bleeding event or an ischemic event (stroke, myocardial infarction, or coronary revascularization) were eligible to randomized in a 1:1 ratio to receive aspirin or matching placebo for an additional 12 months along with continuation of open-label ticagrelor treatment.
Major bleeding event was defined as Bleeding Academic Research Consortium (BARC) type 3b or higher (type 3b indicates overt bleeding leading to a decrease in haemoglobin level of at least 5 mg per deciliter, cardiac tamponade, surgical intervention, or intravenous treatment with vasoactive drugs). Follow-up was performed by telephone at 1 month after randomization and in person at 6 and 12 months after randomization.
End Points
Primary endpoint: occurrence of BARC type 2, 3, or 5 bleeding between randomization and 1 year in a time-to-event analysis.
Secondary endpoint: first occurrence of death from any cause, nonfatal MI, or nonfatal stroke in a time-to-event analysis.
Secondary bleeding endpoints: BARC type 3 or 5 bleeding; TIMI major or minor bleeding; GUSTO moderate, severe, or life-threatening bleeding; or ISTH major bleeding.
Other secondary endpoints: death from cardiovascular causes, MI, ischemic stroke, and definite or probable stent thrombosis.
What is the main result?
- From July 2015 through to December 2017, 9006 patients were enrolled.
- Three months later 7119 were assigned to receive ticagrelor/placebo or ticagrelor/aspirin.
- Mean age was 65 years, 23.8% of the patients were females, 36.8% had diabetes mellitus, and 64.8% underwent PCI due to ACS.
- Adherence to ticagrelor treatment at 1 year was similar in the ticagrelor/placebo group and the ticagrelor/aspirin group (87.1% and 85.9%, respectively).
- The primary endpoint occurred in 141 patients (4.0%) who received ticagrelor/placebo, as compared with 250 patients (7.1%) who received ticagrelor/aspirin (HR, 0.56; 95% [CI], 0.45 to 0.68; P<0.001).
- The incidence of BARC type 3 or 5 bleeding was 1.0% in the ticagrelor/placebo group and 2.0% in the group the ticagrelor/aspirin group (HR, 0.49; 95% CI, 0.33 to 0.74).
- The incidence of death from any cause was similar in both groups (1.0% in the ticagrelor/placebo group and 1.3% in the ticagrelor/aspirin group), as were the incidences of MI (2.7% in both groups) and definite or probable stent thrombosis (0.4% and 0.6%, respectively).
- Ischemic stroke was found in 0.5% of patients in the ticagrelor/placebo group and in 0.2% in the ticagrelor/aspirin group.
Critical reading and the relevance for clinical practice
The current trial found that after 3 months of DAPT in patients who underwent PCI with DES and were at high risk for bleeding or ischemic events:
a) ticagrelor monotherapy was associated with a 44% lower risk of BARC type 2, 3, or 5 bleeding over 1 year than ticagrelor plus aspirin.
b) there was no evidence of a higher risk of death, MI, or stroke among patients who received ticagrelor monotherapy than among those who received ticagrelor plus aspirin.
c) the treatment effect with respect to both bleeding and ischemic endpoints was consistent across subgroups.
This means that a transition to an antiplatelet strategy of treatment with ticagrelor alone after a 3-month course of DAPT in high-risk patients who had undergone PCI provided a clinical benefit of less bleeding without ischemic harm.
In contrast to the SMART-CHOICE and the STOPDAPT-2 trials, the current trial enrolled a larger population of patients who more commonly had both clinical and angiographic high-risk criteria and were treated with a more potent P2Y12 inhibitor, ticagrelor instead of clopidogrel.
In contrast, the findings of the GLOBAL LEADERS trial showed that 1-month DAPT followed by ticagrelor monotherapy for an additional 23 months was not associated with a lower incidence of bleeding. Nevertheless, these results may be attributable to differences in trial design (double-blind vs. open-label), patient case mix (high-risk patients vs. all comers), duration of therapy after randomization (12 months vs. 23 months) or protocol adherence.
Should the guidelines be changed and include specific recommendations for monotherapy with a P2Y12 inhibitor after a short period of DAPT in high-risk patients to reduce the risk of bleeding after PCI with DES?
Although current guidelines recommend ticagrelor in the context of ACS alone, 33% of the trial participants were in stable condition at the time of enrollment. Moreover, the study had several limitations including lack of power to detect differences in stent thrombosis and stroke. Also, the authors suggest that the current trial results may not be generalizable to all patients who have undergone PCI, given the requirement for both high-risk (clinical and angiographic) features and a willingness to be treated with ticagrelor. On top of that, the observed treatment apply only to patients who were able to take 3 months of DAPT without any major adverse events. Lastly, the results do not apply to STEMI patients.
What is your approach regarding DAPT followed by monotherapy in high-risk patients after PCI with DES in daily practice?
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