A randomized, double-blinded, placebo-controlled trial which enrolled 7119 high risk patients with coronary artery disease who had undergone recent percutaneous coronary intervention (PCI) has shown that, after 3 months of dual anti-platelet therapy (DAPT) using a P2Y12 receptor blocker (ticagrelor) and aspirin, continuing secondary prevention with a single anti-platelet therapy (SAPT) with ticagrelor alone reduces bleeding as compared to extended DAPT.
The results of the trial were presented at TCT 2019 by Dr. Roxana Mehran (Icahn School of Medicine at Mount Sinai Hospital, New York, NY) and simultaneously published in New England Journal of Medicine. The TWILIGHT trial enrolled 7119 participants ≥ 65 years of age (24% females) who presented with troponin positive ACS or stable coronary artery disease and had successful coronary stenting in the recent past. Patients had at least 1 additional clinical and angiographic feature associated with a high risk of ischemic or bleeding events such as multi-vessel disease (63.1%), concomitant chronic kidney disease (CKD), diabetes (37.7%), and established peripheral vascular disease (7.9%). Patients with ST-elevation myocardial infarction (STEMI), ongoing hemodynamic instability and intake of oral anti-coagulants were excluded from the study. Following PCI and 3 months of initial DAPT, patients were randomized in 1:1 fashion to receive either ticagrelor (90 mg twice a day) alone (SAPT) OR continue treatment with DAPT (81-100 mg aspirin once daily plus 90 mg ticagrelor twice a day). The primary outcome was time to clinically relevant bleeding between randomization and 12 months post-randomization (defined as Bleeding Academic Research Consortium [BARC] types 2, 3 or 5 [fatal and non-fatal]).
The investigators found that continuation of secondary prevention with ticagrelor monotherapy (SAPT) after initially treating with 3 months of DAPT was associated with a 3.08% reduction in the incidence of clinically relevant BARC 2, 3 or 5 bleeding (4.0% for the SAPT group vs. 7.1% for the DAPT group – HR [95%Confidence interval (CI)]: 0.56, 0.45 to 0.68; P < 0.001). An additional analysis revealed that the difference in incidence between the groups was similar for BARC type 3 or 5 bleeding (1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; HR [95% CI]: 0.49, 0.33 to 0.74]). Secondary outcome for the trial was the determination of SAPT non-inferior ischemia prevention efficacy with the outcome defined as time to first occurrence of confirmed all-cause death, non-fatal MI or stroke. In terms of the secondary outcome, the authors found that incidence of secondary outcome was 3.9% in both groups (difference, −0.06%; HR [95% CI]: 0.99, −0.97 to 0.84; P < 0.001 for noninferiority).
Dual anti-platelet therapy (DAPT) is the cornerstone of secondary prevention for patients with coronary artery disease and limits ischemic events following PCI. However, treatment with DAPT presents itself as a dilemma for clinicians as this treatment regimen is associated with an elevated risk of bleeding complications due to its potent anti-platelet effect. The current standard of care recommends 6 to 12 months of DAPT followed by life-long aspirin monotherapy in this patient population which puts the patients at risk of gastric erosions, out-of-hospital bleeding, and fatal bleeding due to aspirin mediated prostaglandin inhibition. Results from the TWILIGHT study advocate a shorter duration of DAPT followed by a switch to ticagrelor monotherapy in order to uncouple the anti-ischemic benefit from the elevated bleeding risk, thereby optimizing the net clinical benefit. Similar findings were noted with clopidogrel in the SMART-CHOICE (3000 participants) and STOPDAPT-2 (3,045 participants) trials. Results from these trials, when taken together, carry the potential to change clinical practice and recommend a shorter duration of DAPT following PCI for better patient outcomes.
The limitations of the trial include the lack of generalizability to all patients undergoing PCI due to inclusion of only patients with high risk (angiographic and clinical) receiving background therapy with P2Y12 inhibitors. In addition, the trial lacked adequate power to detect differences in important ischemic events such as stent thrombosis and stroke and a lower than predicted incidence of the composite end point of death, MI, or stroke may have biased the results for this key secondary end point toward the null.
To watch the complete interview of Dr. Roxana Mehran with Dr. C. Michael Gibson, click here.