Clopidogrel single antiplatelet therapy after PCI in East Asian patients

Patients with coronary artery disease (CAD) who have undergone percutaneous coronary intervention (PCI) and completed dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor typically receive aspirin as lifelong single antiplatelet therapy (SAPT). However, a growing body of evidence suggests that East Asian patients are prone to excess bleeding from antithrombotic therapy compared with their Western counterparts, and thus may require a different antithrombotic strategy. At a scientific symposium organized by the Hong Kong Society of Congenital and Structural Heart Disease (HKCASH), Professor Hyo-Soo Kim of the Cardiovascular Center, Seoul National University Hospital, Seoul, Korea, discussed emerging clinical data supporting use of clopidogrel as optimal maintenance therapy after PCI in East Asian patients.

Ethnic differences in response to antiplatelet therapy
East Asians have different ischaemic and bleeding thresholds compared with Westerners. An individual patient-level landmark meta-analysis of seven randomized controlled trials (RCTs) (n=16,518) comparing DAPT duration in PCI-treated patients revealed that ischaemic events occurred more frequently in non–East Asians (0.8 percent vs 1.8 percent for East Asians vs non–East Asians; p<0.001), while major bleeding events occurred more frequently in East Asians (0.6 percent vs 0.3 percent; p=0.001). [Thromb Haemost 2019;119:149-162]

“The duration of DAPT did not alter the incidence of ischaemic outcomes in either East Asians or non–East Asians,” noted Kim. “However, prolonged DAPT significantly increased the risk of major bleeding in East Asians [hazard ratio (HR), 2.843; 95 percent confidence interval (CI), 1.474–5.152; p=0.002], but not in non–East Asians [HR, 1.375; 95 percent CI, 0.523–3.616; p=0.523]. Furthermore, the proportion of patients with a higher probability of bleeding than ischaemia was significantly higher in East Asians [32.3 percent vs 0.4 percent; p<0.001].” [Thromb Haemost 2019;119:149-162]

“These distinct ischaemic and bleeding risk profiles suggest a different therapeutic window of antithrombotic treatment among East Asian vs non–East Asian patients,” pointed out Kim. [Thromb Haemost 2021;121:422-432]

In the PLATO and TRITON trials, DAPT with the potent P2Y₁₂ inhibitors, ticagrelor and prasugrel, were superior to clopidogrel. “These studies predominantly enrolled Westerners [≥91 percent],” remarked Kim. [N Engl J Med 2009;361:1045-1057; N Engl J Med 2007;357:2001-2015]

“In contrast, studies conducted in East Asian patients [eg, PHILO, KAMIR NIH, TICAKOREA, TALOS-AMI] showed comparable antithrombotic efficacy, but higher rates of bleeding, associated with ticagrelor and prasugrel vs clopidogrel,” he pointed out. [Circ J 2015;79:2452-2460; Thromb Haemost 2018;118:591-600; Circulation 2019;140:1865-1877; Lancet 2021;398:1305-1316]

Clopidogrel vs aspirin as SAPT after PCI
“Guidelines recommend indefinite SAPT [following initial DAPT] during the chronic maintenance phase after PCI,” highlighted Kim. “Aspirin is the most widely used antiplatelet agent, whilst clopidogrel is recommended as an alternative strategy.” [Eur Heart J 2019;40:87-165; Circulation 2011;124:2458-2473]

Clopidogrel and aspirin exert antithrombotic activity via different mechanisms. Clopidogrel prevents ADP-induced platelet aggregation by selectively and irreversibly binding to the P2Y₁₂ receptor. Aspirin targets cyclooxygenase-1 (COX-1) and inhibits thromboxane A2 (TXA2) synthesis, and thereby prevents platelet activation. [Semin Vasc Med 2003;3:113-122; Blood 2007;109:2285-2292]

“Unlike clopidogrel, aspirin has several off-target effects, such as inhibition of prostaglandins associated with gastric mucosal protection, which can be problematic,” noted Kim. “For example, nonspecific bleeding is more prevalent with aspirin than with clopidogrel in the postsurgical setting.” [N Engl J Med 2005;353:2373-2383]

HOST-EXAM study
HOST-EXAM was a randomized, open-label, multicentre trial conducted in South Korea that compared the efficacy and safety of aspirin vs clopidogrel monotherapy as chronic maintenance therapy in patients who underwent PCI with drug-eluting stents (DES). The study enrolled 5,530 patients who maintained DAPT without clinical events for 6–18 months after PCI. [Lancet 2021;397:2487-2496]

During 2-year follow-up, the primary composite outcome (ie, all-cause death, nonfatal myocardial infarction [MI], stroke, readmission due to acute coronary syndrome [ACS], and Bleeding Academic Research Consortium [BARC] bleeding type ≥3) occurred in 5.7 percent of patients in the clopidogrel group vs 7.7 percent in the aspirin group (HR, 0.73; 95 percent CI, 0.59–0.90; p=0.0035) in the intention-to-treat analysis. [Lancet 2021;397:2487-2496]

Clopidogrel was associated with a 32 percent reduction in risk of the secondary thrombotic composite endpoint (ie, cardiac death, nonfatal MI, ischaemic stroke, readmission due to ACS, and definite or probable stent thrombosis) (HR, 0.68; 95 percent CI, 0.52–0.87; p=0.003) and a 30 percent reduction in risk of any bleeding (BARC bleeding type ≥2) (HR, 0.70; 95 percent CI, 0.51–0.98; p=0.036). [Lancet 2021;397:2487-2496]

“Although not statistically significant, more deaths were reported in the clopidogrel vs aspirin arm [51 vs 36], which caused confusion in interpreting the results,” said Kim. “Given that SAPT is prescribed lifelong for secondary prevention, a long-term follow-up study was warranted to clarify this mortality issue.”

HOST-EXAM extended study
After the initial 2-year follow-up of the HOST-EXAM trial, an open-label extended follow-up study was designed to compare long-term outcomes (same primary and secondary endpoints as in HOST-EXAM) between clopidogrel and aspirin monotherapy. After a median follow-up of 5.8 years, per-protocol analysis was conducted using data from 4,717 patients who completed the study. [Circulation 2023;147:108-117]

“With nearly 6 years of follow-up, clopidogrel was still superior to aspirin in terms of the primary endpoint [12.8 percent vs 16.9 percent; HR, 0.74; 95 percent CI, 0.63–0.86; p<0.001], secondary thrombotic endpoint [8.1 percent vs 11.9 percent; HR, 0.66; 95 percent CI, 0.55–0.79; p<0.001], as well as any bleeding event [4.5 percent vs 6.1 percent; HR, 0.74; 95 percent CI, 0.57–0.94; p=0.016],” reported Kim. (Figure 1) “The landmark analysis of the primary endpoint showed consistent risk reduction of 31 percent in the in-trial period [HR, 0.69; 95 percent CI, 0.56–0.86; p=0.001] and 22 percent in the post-trial period [HR, 0.78; 95 percent CI, 0.63–0.97; p=0.022].” [Circulation 2023;147:108-117]

With extended follow-up, the incidence of all-cause death (6.2 percent vs 6.0 percent; p=0.742), cardiovascular (CV) death (2.8 percent vs 3.1 percent; p=0.602) and non-CV death (3.3 percent vs 2.8 percent; p=0.332) were similar between clopidogrel and aspirin, suggesting no significant difference in mortality risk. [Circulation 2023;147:108-117]

The incidence of major bleeding was significantly lower with clopidogrel vs aspirin (2.6 percent vs 3.9 percent; HR, 0.65; 95 percent CI, 0.47–0.90; p=0.008). In terms of bleeding sites, there were fewer gastrointestinal (2.2 percent vs 2.9 percent), intracranial (0.5 percent vs 1.0 percent), genitourinary (0.4 percent vs 0.7 percent), and respiratory (0.3 percent vs 0.5 percent) bleeding events in the clopidogrel group. [Circulation 2023;147:108-117]

“The most notable difference in bleeding between clopidogrel and aspirin was in the frequency of intracranial bleeding, which was reduced by half in the clopidogrel group,” noted Kim.

“The thrombotic events that we measured in [the HOST-EXAM] trial are associated with platelet activation inside the coronary artery. These are mediated by the P2Y₁₂ receptor, which is specifically targeted by clopidogrel,” explained Kim.“However, the actions of aspirin are not limited to inhibition of TXA2 synthesis. Aspirin also inhibits synthesis of prostacyclin and other prostaglandins that are essential for protection of the mucosal barrier. The off-target effects of aspirin can lead to nonspecific gastrointestinal, genitourinary or intracranial bleeding. The specific target of clopidogrel and off-target effects of aspirin account for better protection against ischaemic events and less bleeding risk with clopidogrel vs aspirin."

Kim also addressed a common physician concern regarding the use of clopidogrel in patients requiring surgery. “For emergency surgery, it is not necessary to stop clopidogrel if the surgical site is within the gastrointestinal, genitourinary or thorax region. However, for urgent neurovascular surgery, clopidogrel should be stopped and the timing of surgery should be adjusted,” advised Kim. “For elective surgery, I recommend stopping clopidogrel for 2 or 3 days before surgery and resuming it the day after surgery.

P2Y₁₂ inhibitor vs aspirin as SAPT for secondary prevention
PANTHER meta-analysis
A patient-level meta-analysis of seven RCTs (n=24,325) compared P2Y₁₂ inhibitor monotherapy (clopidogrel or ticagrelor) and aspirin monotherapy for secondary prevention in patients with established CAD. [J Am Coll Cardiol 2023;82:89-105]

P2Y₁₂ inhibitor monotherapy showed a significantly lower rate of the primary composite endpoint (ie, CV death, MI, and stroke) vs aspirin (5.5 percent vs 6.3 percent; HR, 0.88; 95 percent CI, 0.79–0.97; p=0.012). [J Am Coll Cardiol 2023;82:89-105] The frequency of major bleeding was comparable between P2Y₁₂ inhibitor monotherapy and aspirin (1.2 percent vs 1.4 percent; HR, 0.87; 95 percent CI, 0.70–1.09; p=0.23). “Results favoured P2Y₁₂ inhibitor monotherapy more in studies that used clopidogrel [eg, HOST-EXAM, CAPRIE, CADET], whereas aspirin was favoured more in studies using ticagrelor [eg, GLASSY, TiCAB],” pointed out Kim. (Figure 2) [J Am Coll Cardiol 2023;82:89-105]

Summary
East Asians exhibit a greater risk of bleeding than ischaemic events in response to antithrombotic therapy compared with Westerners, necessitating a tailored treatment approach in this population. For DAPT strategy, clopidogrel is associated with comparable ischaemic protection and lower rates of bleeding events than ticagrelor and prasugrel in East Asian patients. In addition, HOST-EXAM showed that clopidogrel monotherapy, as compared with aspirin monotherapy, significantly reduced the risk of thrombotic endpoints as well as bleeding events during the chronic maintenance period after PCI, suggesting clopidogrel should be the preferable SAPT over aspirin.