Dual Antiplatelet Therapy or Dual Pathway Inhibition

Switching from Dual Antiplatelet Therapy with Aspirin Plus a P2Y₁₂ Inhibitor to Dual Pathway Inhibition with Aspirin Plus Vascular-Dose Rivaroxaban: The Switching Anti-Platelet and Anti-Coagulant Therapy (SWAP-AC) Study

Both antiplatelet and anticoagulation therapies have an unique history of preventing acute myocardial infarction. A landmark randomized clinical trial, namely, the Second International Study of Infarct Survival (ISIS-2), had a strong impact on the medical community because the authors showed that the risk of in-hospital death rate could be reduced by more than 20% by only taking aspirin, which is a widely available oral antiplatelet agent.[1] ISIS-2 also showed that the fibrinolytic agent streptokinase also decreases the risk of in-hospital death. When combined with aspirin, it further reduced in-hospital mortality by almost 50%.[1]

Hence, platelets play a crucial role in the recurrence of myocardial infarction, supported by the fact that antiplatelet agents (aspirin) reduce in-hospital mortality. Second, fibrin plays an important role in myocardial infarction, which is supported by the reduction in the risk of in-hospital mortality by fibrinolytic therapy. Indeed, both platelets and fibrin and their interaction[2] play important roles in myocardial infarction.[3]

Antiplatelet therapy reduces the risk of thrombosis but increases the risk of serious bleeding.[4] Dual antiplatelet therapy (DAPT) further increases the risk of serious bleeding. Thus, various studies have attempted to shorten the DAPT period after stenting, especially in stable patients.[5] It has been recognized that East Asians have a higher risk of bleeding, the so-called East Asian paradox.[6] In an analysis by Gorog et al, reduction of bleeding without increasing the risk of cardiovascular events could be expected by shortening DAPT, especially in the East Asia region.[7]

Also, various attempts were made to find new drug targets, such as platelet PAR-1 thrombin receptor inhibitors[8] [9] to improve the balance between protection against thrombosis and risk of bleeding complications. However, antiplatelet agents with a safer profile compared with P2Y₁₂ inhibitors are yet to be found.

Heparin is a commonly used anticoagulant that has been proven to reduce the risk of myocardial infarction in patients with unstable angina.[10] In the chronic phase, oral anticoagulation with warfarin reduces the risk of myocardial infarction, regardless of whether it is used alone or in combination with aspirin.[11] The major limitation of the use of warfarin in coronary artery disease (CAD) patients is the increased risk of serious bleeding complications. Recently developed specific and reversible coagulation Xa inhibitors showed a lower risk of serious bleeding as compared with warfarin targeting PT-INR of 2 to 3.[12] [13] [14] Accordingly, it was hypothesized that the risk of myocardial infarction may effectively be reduced by dual pathway inhibition (DPI) by the addition of low-dose anti-Xa on top of antiplatelet therapy in a reasonable risk-to-benefit ratio ([Fig. 1]).[15] [16] For acute coronary syndrome patients, the addition of low-dose anti-Xa reduced the risk of thrombotic events but substantially increased the risk of bleeding.[17] In selected patients with stable CAD and peripheral artery disease (PAD), DPI effectively prevents thrombotic events with an acceptable increase in the risk of serious bleeding complications.[18] The authors aimed to provide clinical and pharmacodynamic (PD) information regarding switching DAPT to DPI in CAD patients in this trial. The sample size of the study was too small (n = 90) to draw any meaningful conclusions in regard to clinical endpoints. Moreover, the feasibility of switching DAPT to DPI in CAD patients was not clear from this study because the number of adverse events in both groups was small and not substantially different. (One BARC type 2 bleeding in DPI and no adverse events in the DAPT group.)

Fig. 1 Concept of dual antiplatelet therapy (DAPT) and dual pathway inhibition (DPI). Coronary arterial thrombus is composed of both activated platelets and fibrin. The coagulation cascade and platelet activation interact with each other. Aspirin is the baseline therapy for both arms. The DAPT was achieved by preventing platelet activation by additional blockage of the platelet P2Y12 receptor. The DPI, on the other hand, is achieved by blocking the function of coagulation factor Xa. Both DAPT and DPI can reduce the risk of myocardial infarction but increase the risk of serious bleeding complications. The best balance between antithrombotic and bleeding is hard to achieve even when measuring various hemostatic parameters.

In their study, Ortega-Paz et al[19] reported the results of various platelet and coagulation function testing, including VerifyNow P2Y12 reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor (TF), and a combination of collagen, ADP, and TF (CATF; maximum platelet aggregation %); and thrombin generation (TG). The authors should be commended for conducting these detailed evaluations of the pharmacokinetic (PK) parameters in their randomized trial. Currently, the majority of CAD patients who undergo coronary stents are treated by shorter-term DAPT to subsequent single antiplatelet therapy (SAPT). The Cardiovascular outcomes for people using Anticoagulation Strategies (COMPASS) trial included CAD patients,[18] but did not focus on patients switching from DAPT to DPI. In this regard, the authors provided the first comprehensive evidence supporting the feasibility of switching DAPT to DPI in CAD patients.

There are important limitations in this study. First, the DAPT group was not uniform and was a little complicated. The second antiplatelet agent that was added to aspirin was a mix of clopidogrel, prasugrel, and ticagrelor. While these three P2Y₁₂ inhibitors are commonly used in a similar manner in patients after coronary stenting,[20] the results supporting the authors' conclusion are complicated by these mixed agents because the results of platelet-mediated global thrombogenicity comparing between DPI and clopidogrel differ from the comparison of DPI with ticagrelor and prasugrel. Second, all the platelet function assays were conducted in artificial conditions that reduced calcium ion concentration by using a chelator of calcium ions. Despite the fact that the authors conducted a lot of hemostatic function assays in a careful manner, these assays rather evaluated the potentials of platelet functions upon stimulation by various agonists such as ADP or thrombin rather than reflecting the platelet function states in vivo. The same is true for the TG assay. The interpretation of the integrated results shown by the authors is not easy.

Publication History

Received: 12 October 2023

Accepted: 12 October 2023

Accepted Manuscript online:
13 October 2023

Article published online:
15 November 2023

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