East Asian Paradox: Balancing bleeding and clotting in ACS
East Asians with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) have a lower incidence of thrombotic events but a higher risk of bleeding compared with their Western counterparts in response to antiplatelet therapy, necessitating the need for guidance on antiplatelet treatment strategies specific for East Asian patients.
As the current clinical guidelines on antithrombotic strategies were based on randomized trials comprising mostly Caucasians, they might not be applicable across all races, said Dr Jeong Young-Hoon, director of the Cardiovascular Center at Gyeongsang National University Hospital, Changwon, South Korea, at the recent APSC Congress 2017 held in Singapore.
A paradigm shift from “one-guideline-fits-all races” to a more tailored strategy should be considered for East Asians, he urged.
“East Asians are different from Westerners, in terms of therapeutic window of antiplatelet agents and their response to P2Y12 inhibitors,” said Jeong.
Patients with a high on-treatment platelet reactivity (HPR) to adenosine diphosphate during dual antiplatelet therapy (DAPT), or poor responders, have been shown to have a higher risk of ischaemic events following PCI, in particular for those with ACS. Despite demonstrating a greater HPR during DAPT, East Asians showed a similar or even a lower ischaemic event rate after PCI compared with Caucasians ─ coined by Jeong as the “East Asian Paradox”. [Curr Cardiol Rep 2014;16:485-492]
Previous registry-based studies have shown that Asian patients who underwent coronary stent implantation had a lower risk for the composite endpoint of myocardial infarction, repeat revascularization, and death than Caucasian patients in the US NCDR* (adjusted hazard ratio, 0.89, 95 percent confidence interval, 0.82–0.96). [Circulation 2013;127:1395-1403] Also, incidence of stent thrombosis was lower in Japanese and South Korean registries (~0.2 percent per year) compared with Western registries (~0.6% per year) after stent implantation. [Lancet 2007;369:667-678; Circulation 2009;119:987-995; JACC Cardiovasc Interv 2008;1:494-503]
The difference in HPR could be attributed to a higher prevalence of the CYP2C19*2/*3 loss-of-function alleles among East Asians than Westerners (40.1–63.5 percent vs 20–35 percent), explained Jeong. These mutant alleles have been associated with a reduced response to clopidogrel compared with wild-type alleles in Asians with ACS. [J Thromb Haemost 2009;7:897-899]
Hence, a lower target international normalized ratio (INR) ─ a measure of how long a blood clot takes to form ─ has been suggested for East Asians (target INR for Japanese: 1.6–2.6 [especially for those aged ≥70 years], and for Chinese: 1.8–2.4) compared with the target for European or American patients (2.0–3.0). [Intern Med 2014;40:1183-1188; Br J Clin Pharmacol 2005;59:582-587]
While thrombosis risk was lower, bleeding risk was higher in East Asians compared with Caucasians, which Jeong attributed to the difference in response to P2Y12 inhibitors, among many other factors such as an increased exposure to active metabolites of antiplatelet agents (due to interethnic differences in the pharmacodynamics and pharmacokinetics of potent P2Y12 inhibitors).
“In East Asians, excessive inhibition of platelet function by potent P2Y12 receptor inhibitors may markedly increase the risk of serious bleeding without protection against post-PCI ischaemic event occurrence,” said Jeong.
“The findings also suggest that the optimal ‘therapeutic window’ of platelet reactivity might differ between [Caucasian] and East Asian patients,” he added.
To balance the risk of bleeding and ischaemia in the East Asian population, Jeong suggested several approaches: (i) de-escalating the dose of P2Y12 inhibitors tailored to individual patient based on clinical judgement and patient’s phenotype and genotype, or (ii) switching the use of newer-generation potent P2Y12 inhibitors (eg, ticagrelor, prasugrel) to clopidogrel in low-to-intermediate risk patients with ACS. Nonetheless, he also cautioned that the efficacy and safety of such approaches require further confirmation from larger clinical trials on East Asians.
“These observations … should be taken into consideration during the development of regional and national guidelines for East Asian patients with ACS or undergoing PCI,” said Jeong.