East-Asian Paradox for Antithrombotics: Theory, Evidence and Next Strategy

August 6th, Highlight Session of TCTAP & AP VALVES 2020 VIRTUAL

Recommendations on P2Y12 inhibitor selection are largely consistent between the ACC/AHA and ESC updates. Both guidelines recommend that in patients with NSTE-ACS or STEMI without contraindications, aspirin therapy should be combined with ticagrelor or prasugrel in preference to clopidogrel. In particular, the results of the PLATO study supported changes of the US and European guidelines to include a preference for ticagrelor over clopidogrel as the P2Y12 inhibitor in antiplatelet regimens for ACS. In the PLATO, ticagrelor reduced the rate of death from vascular causes, MI, or stroke without increasing major bleeding in an international cohort of ACS patients. However, due to a greater susceptibility to bleeding and a lower likelihood of ischemic events for any given level of platelet inhibition in East-Asians compared with Western populations, which is called the "East Asian paradox", it would be difficult to unconditionally apply potent antiplatelet agents in East Asian population. Of note, only 6% of Asians were included in the PLATO study indicating that further research is needed for East Asians.

At the highlight session of TCTAP & AP VALVES 2020 VIRTUAL, Duk-Woo Park, MD spoke on this topic, entitled ¡®East-Asian Paradox for Antithrombotics: Theory, Evidence and Next Strategy.¡¯ He explained the proposed mechanisms of East-Asian paradox for antithrombotic therapy as follows; a small body size and lower BMI, a relatively lower renal clearance in East Asians, and genetic differences in metabolic or pharmacodynamic features such as genetic polymorphisms, plasma hemostatic factors, or endothelial activation markers. An important observation of the East-Asian Paradox is the ¡®decoupling¡¯ between the pharmacogenetics, PK/PD with the associated clinical presentation and outcomes. Asian population has a high prevalence of CYP2C19 loss-of-function (LOF) genotype compared with Western population. Despite a high prevalence of CYP2C19 LOF alleles which attenuates the antiplatelet effect of clopidogrel, several studies reported relatively low ischemic events in ACS or PCI among East Asians compared with Western population.

Clinical trials regarding the selection of P2Y12 inhibitors among patients with ACS have been conducted in East Asian countries. In PRASFIT-ACS study, 1,363 Japanese patients with ACS were randomized into clopidogrel 300/75 mg and prasugrel 20/3.75 mg to investigate the safety and efficacy of low-dose prasugrel. Low-dose prasugrel did not significantly increase the incidence of composite ischemic events compared with a standard clopidogrel dosing regimen at 24 weeks (prasugrel arm 9.4% vs. clopidogrel arm 11.8%; HR: 0.77; 95% CI: 0.56-1.07). Notably, the incidence of major bleeding was comparable between the two regimens (1.9% vs. 2.2%; HR: 0.82; 95% CI: 0.39-1.73). The PHILO study was a randomized controlled trial conducted in Japan, South Korea, and Taiwan to investigate the safety and efficacy of standard dose ticagrelor among 801 patients with ACS. In the PHILO trial, ticagrelor was associated with a numerically higher but statistically insignificant incidence of both composite ischemic events (ticagrelor arm 9.0% vs. clopidogrel arm 6.3%, HR 1.47; 95% CI: 0.88-2.44) and bleeding events (10.3% vs. 6.8%, HR 1.54; 95% CI: 0.94-2.53) compared with clopidogrel at 12 months. Recent individual patient-level meta-analysis evaluated seven RCTs including 16,518 patients (8,605 East Asians, 7,913 non-East Asians) to compare the benefit or harm between DAPT duration by race. In this study, there was a differential risk of ischemia and bleeding among East Asians and non-East Asians in that MACE occurred more frequently in non-East Asians (0.8% vs. 1.8%, p < 0.001), while major bleeding events occurred more frequently in East Asians (0.6% vs. 0.3%, p = 0.001). In the Cox proportional hazards model, prolonged DAPT significantly increased the risk of major bleeding in East Asians (HR 2.84; 95% CI: 1.47-5.15, p = 0.002), but not in non-East Asians (HR 1.38; 95% CI: 0.52-3.62, p = 0.52).

Several RCTs have been conducted to guide antithrombotic therapy for East Asians. In the pragmatic TICA-KOREA study, 800 Korean patients with ACS were randomized to compare the rates of ischemic and bleeding events between standard dose ticagrelor and clopidogrel. Ticagrelor was significantly associated with a higher incidence of bleeding events at 12 months (11.7% vs. 5.3%, HR 2.26; 95% CI: 1.34-3.79, p = 0.002). Similar to the PHILO trial, there was a statistically insignificant difference in the incidence of composite ischemic events between the two regimens (ticagrelor arm 9.2% vs. clopidogrel arm 5.8%, HR 1.62; 95% CI: 0.96-2.74, p = 0.07). In the TICO trial, of which was designed similar to the TWILIGHT study, 3,056 patients with ACS who underwent PCI were randomized to 12 months of DAPT with ticagrelor plus aspirin versus 3 months of DAPT followed by 9 months of ticagrelor monotherapy. The net adverse clinical events (death, MI, stent thrombosis, stroke, target vessel revascularization, or TIMI major bleeding) at 12 months were significantly lower in the ticagrelor monotherapy arm (3.9% vs 5.9%, HR 0.66; 95% CI: 0.48-0.92), mainly driven by a reduction in major bleeding (1.7% vs 3.0%; HR 0.56; 95% CI 0.34-0.91). Dr. Park also added that the TAILORED-CHIP trial is ongoing in Korea to determine the optimal antithrombotic regimen in East Asian patients undergoing complex high-risk PCI. Investigators planned to enroll 2,000 patients randomizing either to the conventional arm (clopidogrel and aspirin 12 months) or the tailored arm (ticagrelor 60 mg and aspirin early 6 months then clopidogrel alone late 6 months).

Duk-Woo Park, MD summarized this talk by concluding that

¡°the optimal antithrombotic therapy should be a balancing act between less ischemic and more bleeding risks. Further studies looking for an antiplatelet regimen with appropriate dosages, which may not be the same as the global dose, are needed for East Asians.¡±

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Editor: Benjamin Leo Cheang Leng, MD (Sultanah Aminah Hospital, Malaysia)