Efficacy and safety comparing prasugrel/ticagrelor and clopidogrel in Hong Kong post‐acute coronary syndrome patients–A 10‐year cohort study

Abstract Background Clinical evidence of prasugrel/ticagrelor in dual antiplatelet therapy (DAPT) in Asian acute coronary syndrome (ACS) population remains inconclusive. We aimed to compare the clinical efficacy and safety of prasugrel/ticagrelor compared to clopidogrel as part of DAPT in Hong Kong ACS population for 10 years. Hypothesis Prasugrel/ticagrelor, compared to clopidogrel, reduces risk of major adverse cardiovascular event (MACE) in Hong Kong ACS population. Methods The retrospective observational cohort study included patients admitted to seven institutions under Hospital Authority Hong Kong with diagnosis of ACS during 2008–2017. Risk of MACE, defined as composite of cardiovascular (CV) death, non‐fatal myocardial infarction (MI) and non‐fatal stroke, and risk of any bleeding leading to hospitalization were examined. Baseline characteristics difference was adjusted by propensity score (PS) matching. Adjusted Cox regression model was used to estimate hazard ratio of interested outcome. Results In PS matched cohort including 944 patients in each group, MACE risk reduction of 40% from 1 year to 5 years after index ACS event was observed in prasugrel/ticagrelor group (HR 0.60, 95% CI 0.39–0.91, p = .015). The risk reduction was highly driven by MI reduction (HR 0.54, 95% CI 0.33–0.91, p = .019). Lower bleeding risk was observed in prasugrel/ticagrelor group compared to clopidogrel from 1 year to 5 years (HR 0.46, 95% CI 0.21–1.00, p = .051). Conclusions Prasugrel/ticagrelor showed MACE risk reduction over clopidogrel as part of DAPT up to 5 years after index event, while prasugrel/ticagrelor was not associated with increased bleeding risk.


| INTRODUCTION
Dual antiplatelet therapy (DAPT) is indicated in post-acute coronary syndrome (ACS) patients, while use of prasugrel or ticagrelor is recommended over clopidogrel as suggested by international guideline recommendation. 1,2 Major clinical trials depicting benefit of prasugrel or ticagrelor over clopidogrel were mainly based on Caucasian population. 3 The landmark study for prasugrel in ACS patients, TRITON-TIMI 38, did not include Asian population, while in another prasugrel study for NSTE-ACS patients, TRILOGY-ACS, there was 8.1% (n = 571) of subjects from East Asia. 4,5 The PLATO study for ticagrelor recruited 1096 Asian patients to the study, which composed 5.9% of total cohort. 6 Yet, Asian population has lower thrombogenicity compared to Caucasian population. 3 Current evidence from real-world data and meta-analysis remained inconclusive on use of prasugrel or ticagrelor over clopidogrel in Asian population. 7 Table S1. Focus of current study was on post-discharge long term effect of antiplatelet therapy management. Patients who died at index hospitalization or missing drug dispensing record were excluded. Drug exposure during index hospitalization was captured only if the drug continued upon hospitalization discharge. Medication use only during index hospitalization yet not continued upon discharge was not described in this study. Time to event was defined as time from index hospitalization admission to interested event date, with censorship applied to patient's death or study end on 31 December 2018. The study design was based on intention to treat (ITT) approached. Dispensing duration of a drug was defined as sum of dispensing episode within study period after patient's index admission before interested event outcome or censorship. Discontinuation of a dispensing episode was defined as dispensing gap of a drug more than 28 days. As dispensing history was used in the study, to avoid any mistaken record of switching antiplatelet treatment (especially P2Y12 receptor antagonist) during an early follow-up, duration of continued drug exposure instead of number of daily doses dispensed was used.
Recruited subjects were categorized into DAPT with clopidogrel or DAPT with prasugrel or ticagrelor group. The primary efficacy outcome of the study was major adverse cardiovascular event (MACE), which was defined as composite of cardiovascular death, non-fatal myocardial infarction (MI, including non-ST-elevation MI (NSTEMI) and ST-elevation MI (STEMI)), and non-fatal ischemic stroke. The secondary efficacy outcome was occurrence of each primary efficacy outcome and all-cause mortality. The primary safety outcome was defined as occurrence of any bleeding leading to hos-    Table 1. No statistically significant difference in patients' demographics and comorbidities was observed after propensity score matching.
The duration of DAPT treatment was shorter in clopidogrel group (clopidogrel 308 days vs prasugrel/ticagrelor 366 days, p < .001), using MACE as outcome event. Duration of subjects follow up was longer in clopidogrel group (clopidogrel 1656 days vs. prasugrel/ ticagrelor 1014 days, p < .001). Duration of DAPT and concurrent use of other medication were different in clopidogrel and prasugrel/ ticagrelor group, and thus Cox regression model was adjusted accordingly with these variables (Table S2).
Subgroup analyses in the first time ACS patients and post-PCI patients showed prasugrel/ticagrelor reduced MACE risk and reduced MI risk from 1 year to 5 years compared to clopidogrel, similar to primary outcome analysis (Table S3). In patients aged 65 or above, reduction of MACE and MI using prasugrel/ticagrelor were not observed, while overall CV death and overall ischemic stroke risk were reduced. In all three subgroup analyses, reduction in all-cause mortality was observed, both overall and from 1 year to 5 years. This indicated the robustness of all-cause mortality reduction in prasugrel/ ticagrelor group compared to clopidogrel. No significant difference in T A B L E 1 Baseline characteristics of clopidogrel and prasugrel/ticagrelor groups bleeding risk was observed in all subgroup analyses comparing prasugrel/ticagrelor and clopidogrel. Comparable results were also obtained using PP approach and propensity score weighting, with or without trimming (Table S4).

| DISCUSSION
The study demonstrated the long-term clinical benefit of prasugrel/ticagrelor over clopidogrel as part of DAPT in Hong Kong ticagrelor versus clopidogrel was observed from SWEDEHEART registry in Sweden and a nationwide population-based study in Korea. 9,17 Gastro-intestinal tract was reported to be common site of bleeding in previous literatures. 9

CONFLICTS OF INTEREST
The authors declare no potential conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.