Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With COVID-19: Implications From Clinical Features to Pathologic Findings

On March 11, 2020, the World Health Organization officially declared the novel coronavirus disease 2019 (COVID-19) a global pandemic. Considering that ≈5 million percutaneous coronary interventions (PCIs) are performed worldwide annually, safety concerns exist about the effect of dual antiplatelet therapy (DAPT) on bleeding complications, especially the risk for diffuse alveolar hemorrhage, among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

SARS-CoV-2 and SARS-CoV have a shared cellular target: angiotensin-converting enzyme 2. When comparing the clinical manifestations of infections with these viruses, we found that thrombocytopenia (platelet count <150 000/μL), prolonged thrombin time, and elevated D-dimer levels were observed frequently in both,^1,2 suggestive of high likelihood of disseminated intravascular coagulation or pre–disseminated intravascular coagulation. Diffuse alveolar hemorrhage was reported as a common finding in lung pathology in severe acute respiratory syndrome and COVID-19.^3,4

Although incompletely understood, previous findings from influenza pneumonia revealed a mechanistic link between virus infection and the risk for diffuse alveolar hemorrhage (summarized in the Figure), which starts with virus replication and dissemination, followed by alveolar endothelial dysfunction, platelet activation, generation of neutrophil–platelet aggregates, neutrophil migration, and fibrin and microthrombus formation; if left uncontrolled, these alterations would trigger secondary fibrinolysis, coagulation factors depletion, and consequently disseminated intravascular coagulation and diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage refers to a distinct form of life-threatening pulmonary hemorrhage that originates from pulmonary microcirculation (alveolar arterioles, capillaries, and venules) and should be distinguished from other causes of pulmonary hemorrhage caused by localized abnormalities (bronchiectasis, malignancy, and tuberculosis). Although alveolar hemorrhage can be localized, there are generally multiple areas of involvement; therefore, the term “diffuse alveolar hemorrhage” is preferred. In the rapid progressive and life-threatening form of viral pneumonia, the underlying pathologic process is often diffuse alveolar hemorrhage. Collectively, the pathologic and clinical features of COVID-19 are mechanistically linked to high risk for disseminated intravascular coagulation and propensity for diffuse alveolar hemorrhage.

In addition to thrombosis and hemostasis, emerging evidence supports a putative role of platelets in the host defense against infections, which adds a greater layer of complexity in evaluating the role of antiplatelet therapy in the setting of viral pneumonia. The following 3 issues should be taken into account when interpreting the effect of antiplatelet therapy on disease progression. First, the timing of administration is important. As summarized in the Figure, in the early phase of infection, platelet inhibition may reduce intravascular fibrin and thrombus formation, thereby preventing the ensuing consequences. Aspirin use before hospitalization, but not after hospitalization, was associated with lower risk of developing severe acute respiratory distress syndrome and mortality in patients with community-acquired pneumonia. Second, the choice of oral P2Y₁₂ inhibitors deserves consideration. Although all P2Y₁₂ inhibitors reduce platelet–leukocyte aggregates and platelet-derived proinflammatory cytokines from α-granules, ticagrelor is unique in having the only well-documented additional target of inhibition ENT1 (equilibrative nucleoside transporter 1), contributing to inhibition of cellular adenosine uptake. Therefore, ticagrelor confers more potent anti-inflammatory properties by inhibiting platelet P2Y₁₂ receptor and ENT1. The XANTHIPPE trial (Targeting Platelet–Leukocyte Aggregates in Pneumonia With Ticagrelor; URL:https://www.clinicaltrials.gov; Unique identifier: NCT01883869), as well as post hoc analyses of the PLATO study (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome; URL:https://www.clinicaltrials.gov; Unique identifier: NCT00391872) and basic research, provide evidence demonstrating the clinical benefit of ticagrelor in the management of pneumonia by preventing the complications of sepsis and reducing lung injury. Third, circulating platelet counts are important. Both primary thrombocytopenia (immune thrombocytopenia) and secondary thrombocytopenia (enhanced consumption) are associated with increased risk of infection (including pneumonia) and worsened clinical outcomes associated with acute respiratory distress syndrome. Thrombocytopenia leads to loss of the ability to deposit fibrinogen and to seal the damaged pulmonary vasculature. Expert consensus warrants taking proactive measures or stopping antiplatelet therapy in patients with a platelet count <100 000/μL or <50 000/μL, respectively.

Emerging evidence suggests DAPT as an important aggravating factor for diffuse alveolar hemorrhage, which could be mistaken as pneumonia initially because of similarities in clinical manifestations (ie, coughing, radiographic evidence of mild infiltration, and fever). Given the high bleeding risk in patients with COVID-19 after PCI, shorter-duration DAPT may be beneficial in this population.

To counterbalance the increased bleeding risk associated with DAPT, emerging findings from large randomized controlled trials provide evidence supporting a net benefit of aspirin-free strategies after PCI for patients at low, intermediate, and high risk for both ischemia and bleeding, which is mainly driven by reduction in bleeding events. This strategy reduces the duration of aspirin use (1 to 3 months) and allows for more prolonged use of potent P2Y₁₂ inhibitors. When faced with the challenge of the COVID-19 pandemic with insufficient evidence regarding appropriate antithrombotic regimens for patients after PCI, we must extrapolate information from related clinical scenarios to assist in decision making. Among patients on DAPT, maintaining P2Y₁₂ inhibitor monotherapy (preferably ticagrelor) may be scientifically reasonable for ≥3 months after PCI. DAPT should not be discontinued <3 months after PCI. Considering recent experience from China demonstrating the effectiveness of low-molecular-weight heparin in reversing disseminated intravascular coagulation in COVID-19,⁵ the International Society of Thrombosis and Hemostasis disseminated intravascular coagulation scoring system and platelet counting should be performed daily or more frequently to identify patients who would benefit from early low-molecular-weight heparin administration or from discontinuation of P2Y₁₂ antagonists because of clinically meaningful thrombocytopenia. The trade-off between ischemia and bleeding may be challenging when patients take an oral P2Y₁₂ inhibitor concomitantly with an indication for low-molecular-weight heparin prophylaxis. An alternative approach in this setting would involve using an intravenous P2Y₁₂ inhibitor such as cangrelor as bridge therapy.

The COVID-19 pandemic presents a unique opportunity to study key questions concerning the preventive, therapeutic, or aggravating effects of antiplatelet therapy on viral pneumonia on the basis of nonrandomized real-world data. Clinicians must be cognizant of the effects of antiplatelet therapy in patients with COVID-19.