TWILIGHT: DAPT x3 months followed by ticagrelor monotherapy vs continued DAPT after PCI
Bottom Line:
Among patients at high risk of thrombosis who underwent PCI & tolerated ticagrelor + ASA for 3 months without thrombotic or major bleeding events, switching to ticagrelor monotherapy reduced the risk of bleeding (NNT=34) with similar risk of thrombotic events vs continued ticagrelor+ASA for up to 15 months.
It remains unclear how this “TWILIGHT” regimen compares to a standard regimen of ASA + clopidogrel, or other novel antiplatelet de-escalation strategies), in the era of 2nd-generation drug-eluting stents with low risk of stent thrombosis.
Patients (n=7119)
9006 enrolled at time of PCI -> 7119 randomized 3 months post-PCI
21% enrolled excluded before randomization, mostly due to non-adherence (13% of enrolled, 1/2 of related to dyspnea) or major thrombotic/bleeding event (3% of enrolled) in 1st 3 months post-PCI
Inclusion:
Underwent successful PCI with drug-eluting stent, with “intent to discharge the patient with a regimen of ticagrelor + ASA”
At least 1 clinical feature + 1 angiographic feature associated with high thrombotic or bleeding risk:
Clinical: Age >65 y, female, troponin+ ACS, established vascular disease (previous MI, known PAD or CAD/PAD revascularization), diabetes treated with medications, CKD
Angiographic: Multivessel CAD, total stent length >30 mm, thrombotic target lesion, bifurcation lesion treated with 2 stents, obstructive LM or pLAD lesion, or calcified target lesion treated with atherectomy
Did not experience major bleed (BARC 3b, 4 or 5) or thrombotic event (stroke, MI, coronary revascularization) in 1st 3 months post-PCI
Adherent to ticagrelor + ASA based on manual pill count after 1st 3 months
Excluded:
Presentation: STEMI, fibrinolytic therapy <24h of PCI, cardiogenic shock
PMHx: Prior stroke, dialysis-dependent CKD, cirrhosis, life expectancy <1 y contraindication to ASA/ticagrelor
Other: Ongoing OAC use, strong CYP3A inducer/inhibitor, active bleeding or “extreme” risk for major bleed, platelet count <100
Baseline
Age 65, female 24%, non-white 31%, North America 42%
Indication for PCI: NSTEMI 30%, UA 35%, stable angina 29%, asymptomatic 6%
Multivessel CAD 63%, previous MI 29%, previous PCI 42%, previous CABG 10%, PAD 7%
Smoker 22%, diabetes 37%, CKD 17%
Anemia 20%, previous major bleed 1%
Angiographic/procedural:
LM treated in ~5%, LAD in 56%
Mean # of vessels treated 1.3, mean total stent length 40 mm, mean minimum stent diameter 2.8 mm
Bifurcation 12%, thrombus ~10%, chronic total occlusion 6%, SVG 2%
2nd-generation drug-eluting stent used in >97%
Interventions & Controls
For the 1st 3 months after PCI, all patients received open-label enteric-coated ASA 81-100 mg/d + ticagrelor 90 mg BID
After the 1st 3 months, randomized to open-label ticagrelor plus 12 months of:
Intervention (ticagrelor monotherapy after 3 months of ticagrelor-based DAPT): Placebo
Control (continued ticagrelor-based DAPT): ASA
Similar % of patients took >80% of ticagrelor (86-87%) & study drug (82-83%)
Outcomes @ month 3 to 15 (during study intervention after 1st 3 months of DAPT)
No difference in thrombotic events
Death/MI/stroke (per-protocol analysis): 3.9% in both groups
Hazard ratio (HR) 0.99 (95% confidence interval [CI] 0.78-1.25)
Absolute difference -0.1 (-1% to +0.8), meeting non-inferiority criteria (see below)
Death: 1.0% vs 1.3%
MI: 2.7% in both groups
Stroke: 0.5% vs 0.2%
Stent thrombosis (definite/probable): 0.4% vs 0.6% (HR 0.74, 0.37-1.47)
Fewer bleeding events with abbreviated DAPT
BARC 2, 3 or 5 bleed (1o outcome) @ month 15 after PCI: 4.0% vs 7.1% (NNT 34)
HR 0.56 (0.45-0.68)
Identical results for TIMI minor/major definition
BARC 3 or 5: 1% vs 2% (HR 0.49, 0.33-0.74)
ISTH major: 1.1% vs 2.1% (HR 0.54, 0.37-0.80)
GUSTO moderate/severe: 0.7% vs 1.4% (HR 0.53, 0.33-0.85)
Subgroup analyses: No subgroup effect for bleeding or thrombotic outcomes.
Internal Validity
Low risk of
Allocation bias: Random sequence using permuted blocks stratified by site generated by independent statistician; concealed allocation via secure web-based system
Performance bias: Use of matching placebo (patients, clinicians, etc) unaware of treatment assignment
Detection bias: Outcomes adjudicated by committee unaware of study drug assignment
Unclear risk of attrition bias
Loss-to-follow-up 1.6% for the primary outcome & 0.3% for death
Bleeding outcome analyzed using intention-to-treat principle (low risk), but thrombotic outcome analyzed using per-protocol (unclear risk)
Other Considerations
Non-inferiority design for the key thrombotic endpoint (death/MI/stroke)
Pre-specified non-inferiority margin: Absolute difference of 1.6% assuming 8.0% incidence in the continued DAPT group
However, event rates lower than anticipated (3.9% instead of 8.0%). Ideally, a more conservative relative risk non-inferiority margin equivalent to a 1.6% increase above 8.0% would have been used (RR=9.6%/8.0%=1.20)
Using this stricter relative risk-based non-inferiority margin of 1.20, the study does not technically meet the study’s pre-specified non-inferiority criteria for this outcome.
Non-inferiority should only be concluded if both ITT & PP analyses consistently demonstrate non-inferiority; however, only PP analysis of thrombotic outcome reported in this trial.
Other Studies
PLATO: The landmark study demonstrating the superiority of ticagrelor + ASA vs clopidogrel + ASA among all-comer ACS patients (except STEMI patients treated with fibrinolytics) in the era of bare-metal & 1st-generation drug-eluting stents.
GLOBAL LEADERS: In a trial of patients who underwent PCI, ticagrelor-based DAPT x1 month, followed by ticagrelor monotherapy x23 months vs standard DAPT for ACS/stable angina did not reduce the risk of death/Q-wave MI.
In a contemporary population-based registry study of ACS patients who underwent PCI, ticagrelor + ASA was not associated with a lower risk of major adverse coronary events compared to clopidogrel + ASA. However, it was associated with significantly more major bleeding & dyspnea
Similar to TWILIGHT, this cohort study was done in the era of second-generation drug-eluting stents with low risk of stent thrombosis.