Per-Protocol Versus Intention-to-Treat in Clinical Trials: The Example of GLOBAL-LEADERS Trial

Carlos G. Santos-Gallego, Juan Antonio Requena-Ibanez, Juan Badimon

Research output: Contribution to journalEditorial

3 Scopus citations

Abstract

After drug-eluting stent implantation, the classic therapy was dual antiplatelet therapy (DAPT) for 1 year and then stopping P2Y12 inhibitor while maintaining aspirin forever. The main limitation is the increased risk of bleeding with prolonged DAPT strategy might offset the ischemic benefit. Given that ischemic risk is higher in the initial phase whereas bleeding risk is maintained in the long term, deescalation therapies have been proposed, either with shorter DAPT durations or with aspirin-free strategies.1 In fact, DAPT should follow the Goldilocks principle2 (not too short, not too long). Recent studies (GLOBAL-LEADERS,3 TWILIGHT [Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention],4 TICO [Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome],5 STOP-DAPT [Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting CobaltChromium Stent],6 SMART-CHOICE [Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs Dual Anti-platelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents]7) suggest that the deescalation strategy with an abbreviated DAPT period after percutaneous coronary intervention (1– 3 months) followed by aspirin cessation and P2Y12 inhibitor monotherapy mitigates bleeding risk without losing efficacy for ischemic prevention. Among all these trials, GLOBAL-LEADERS3 offers the largest sample size and is the only one designed as a superiority trial. Specifically, 15 991 patients undergoing percutaneous coronary intervention with a drug-eluting stent were randomized to deescalation therapy (1-month DAPT plus 23-month ticagrelor monotherapy) or to the control strategy (standard 12-month DAPT followed by 12-month aspirin monotherapy). At intention-to-treat analysis,3 the deescalation therapeutic strategy failed to show superiority at 2 years for the primary end point of the composite of all-cause mortality or nonfatal Q-wave myocardial infarction (rate ratio, 0.87; 95% CI, 0.75–1.01; P=0.07). In this issue of the Journal of the American Heart Association (JAHA), Gragnano et al.8 report the results of the per-protocol analysis of GLOBAL-LEADERS trial.

Original languageEnglish
Article numbere025561
JournalJournal of the American Heart Association
Volume11
Issue number10
DOIs
StatePublished - 17 May 2022

Keywords

  • Editorials
  • P2Y12 inhibitors
  • antiplatelet therapy
  • aspirin
  • clinical trial
  • intention-to-treat analysis

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