Ticagrelor Monotherapy or Dual Antiplatelet Therapy After Drug‐Eluting Stent Implantation: Per‐Protocol Analysis of the GLOBAL LEADERS Trial

Abstract

Background In the GLOBAL LEADERS trial, ticagrelor monotherapy beyond 1 month compared with standard antiplatelet regimens after coronary stent implantation did not improve outcomes at intention‐to‐treat analysis. Considerable differences in treatment adherence between the experimental and control groups may have affected the intention‐to‐treat results. In this reanalysis of the GLOBAL LEADERS trial, we compared the experimental and control treatment strategies in a per‐protocol analysis of patients who did not deviate from the study protocol. Methods and Results Baseline and postrandomization information were used to classify whether and when patients were deviating from the study protocol. With logistic regressions, we derived time‐varying inverse probabilities of nondeviation from protocol to reconstruct the trial population without protocol deviation. The primary end point was a composite of all‐cause mortality or nonfatal Q‐wave myocardial infarction at 2 years. At 2‐year follow‐up, 1103 (13.8%) of 7980 patients in the experimental group and 785 (9.8%) of 7988 patients in the control group qualified as protocol deviators. At per‐protocol analysis, the rate ratio for the primary end point was 0.88 (95% CI, 0.75–1.03; P =0.10) on the basis of 274 versus 325 events in the experimental versus control group. The rate ratio for the key safety end point of major bleeding was 1.00 (95% CI, 0.79–1.26; P =0.99). The per‐protocol and intention‐to‐treat effect estimates were overall consistent. Conclusions Among patients who complied with the study protocol in the GLOBAL LEADERS trial, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1‐year standard dual antiplatelet therapy followed by aspirin alone at 2 years after coronary stenting. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01813435.

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

“…Strong points of this article 8 include the large sample size, the similar results obtained in intention‐to‐treat and per‐protocol analysis, and the fact that the positive net adverse clinical events results with the deescalation strategy are confirmed in independent trials (TWILIGHT, TICO, STOP‐DAPT and SMART‐CHOICE). 4 , 5 , 6 , 7 As with all studies, this also has limitations.…”

“…Third, adjustment should be made for confounding due to incomplete adherence (a naïve per‐protocol analysis without adjustment for confounding will be valid only if adherence occurred completely at random); as adherent and nonadherent participants generally differ with respect to prognostic factors, a per‐protocol analysis must adjust for prerandomization and postrandomization prognostic factors that predict adherence. It is reassuring that the authors of the current article 8 have followed all these rules in their per‐protocol analysis of the GLOBAL‐LEADERS trial.…”

“…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.…”

“…This strategy is actually followed in the current analysis of GLOBAL‐LEADERS trial. 8 In order to augment the probability that per‐protocol analysis yields a valid estimate of the treatment, 3 general rules need to be followed. 9 First, data from participants should not be censored when they stop treatment for clinical reasons; no protocol would expect to continue statin treatment if rhabdomyolysis is developed.…”

“…Given the high rate of noncompliance with treatment in the GLOBAL‐LEADERS study 3 (22% in the experimental arm—perhaps influenced by potential dyspnea induced by ticagrelor—and 7% in the control arm,), the intention‐to‐treat analysis might have underestimated the true effect of the experimental strategy, as just explained. This the reason for the authors to perform a per‐protocol analysis 8 to learn whether the novel deescalation strategy was superior in patients who were actually compliant with the strategy and did not deviate from medication decisions.…”