Increasing the dose can increase the biological effect of clopidogrel and reduce the incidence of CR. Simultaneously, large doses of clopidogrel can reduce patients’ platelet aggregation rate with CR [126]. For PCI patients, the 600 mg loading dose has a faster response than the 300 mg loading dose and has a more substantial platelet inhibitory effect. In this way, the incidence of CR is significantly reduced [127,128]. At the same time, studies have shown that CR or platelet hyperresponsiveness is still common after the administration of clopidogrel 600 mg load, but increasing the dose can reduce the risk of death from cardiovascular disease, myocardial infarction, and stent thrombosis [5]. In patients with stable coronary heart disease, CYP2C19*2 heterozygous carriers taking 225 mg of clopidogrel per day were shown to achieve the same antiplatelet effect with CYP2C19 wild-type patients taking 75 mg of clopidogrel per day. In contrast, CYP2C19*2 homozygous patients cannot achieve the desired antiplatelet effect even if they take the 300 mg clopidogrel maintenance dose [129]. CR in patients treated with PCI between high maintenance dose (150 mg · d ⁻¹) than conventional maintenance dose (75 mg · d ⁻¹) can more effectively prevent major adverse cardiac events (MACE). In the 1-month follow-up after PCI, the incidence of in-stent thrombosis was lower among the group receiving 150 mg · d ⁻¹ as compared to the group receiving 75 mg · d ⁻¹ (1.1% and 4.9%, p = 0.03). Simultaneously, cardiovascular events incidence was also significantly lower in the group with higher doses (2.7% and 7.6%, p = 0.03) [130]. However, some studies have shown that high-dose clopidogrel after PCI did not reduce the mortality of cardiovascular events or stent thrombosis incidence than standard doses [131]. Moreover, high-dose clopidogrel may lead to an increased probability of bleeding complications; therefore, the use of high-dose clopidogrel maintenance treatment to avoid treatment resistance requires further research.

Ainetdinova et al. [132] found that the probability of resistance to aspirin, clopidogrel, and the combination of these two drugs were 25.7%, 17.1%, and 5.7%, respectively. Therefore, DAPT with aspirin and clopidogrel was shown to reduce the occurrence of drug resistance. Another potential combination therapy uses the GPIIb/IIIa receptor antagonists (such as abciximab, tirofiban and eptifibatide), which can directly block the final pathway of platelet activation, adhesion, and aggregation. Based on clopidogrel therapy, the combined use of GPIIb/IIIa receptor antagonists can further inhibit platelet aggregation [133,134].

The new P2Y12 inhibitors, ticagrelor and prasugrel, will substantially reduce platelet hyperresponsiveness and improve clinical outcomes relative to the regular clopidogrel dose. Most patients who do not respond to clopidogrel can significantly inhibit the platelet aggregation rate after switching to prasugrel [135] because prasugrel can better inhibit ADP-induced platelet aggregation, which is faster and stronger than clopidogrel. The longer-lasting antiplatelet effect of prasugrel can significantly reduce the occurrence of ischemic events [136]. On the other hand, ticagrelor does not require liver metabolism and not affected by CYP2C19 gene polymorphism. It was also shown to significantly reduce mortality related to cardiovascular events, myocardial infarction [137]. A study showed that in STEMI patients undergoing PCI for the first time, a loading dose of 180 mg of ticagrelor was more effective than a loading dose of 600 mg of clopidogrel in reducing microvascular damage [138]. There is also literature mentioning that cangrelor has a powerful platelet inhibitory effect. Its effect may be more significant than clopidogrel. Moreover, its half-life is shorter, does not require liver activation, and is a direct antagonist of P2Y12 [26].

Active control of blood sugar in patients with coronary heart disease can reduce the incidence of CR. Avoiding the simultaneous application of other drugs that require CYP metabolisms, such as statins, calcium channel blockers, and PPI, would ensure a better response to clopidogrel therapy.

In a randomised trial of TROPICAL-ACS [139,140], a targeted de-escalation regimen with early switching from prasugrel to clopidogrel was established as an effective alternative treatment strategy in ACS patients. However, the study found that patient age was the primary determinant of outcome after PCI, [141,142], especially when using P2Y12 receptor inhibitors during and after PCI [143,144]. Therefore, TROPICAL-ACS performed a randomised assessment of the effect of age on reducing the escalation of antiplatelet therapy. Significant variation was found among the younger patients who showed an increased net clinical benefit resulting from reduced bleeding complications. These results suggest that targeted de-escalation may be a safe and attractive alternative therapy concept for all ACS patients after PCI, while a significant bleeding benefit could be achieved in younger patients [145].