Btk inhibitors in atherosclerosis

In this issue of Blood, Busygina et al provide provocative evidence that there is a potential role for Bruton tyrosine kinase (Btk) inhibitors in inhibiting platelet aggregation specifically at the site of unstable atherosclerotic plaques.¹ 

Antiplatelet therapies are a mainstay for the prevention of atherosclerotic complications, particularly for secondary prevention of subsequent events in both the culprit and nonculprit vessels.²  Over the past several decades, there has been a transition in clinical practice to preferentially using antiplatelet over antithrombotic therapies for the chronic prevention of atherosclerotic events because of the recognition that platelet activation and aggregation are the key events in acute arterial thrombosis that occurs when plaques undergo rupture or erosion and the superior safety margin with regard to major bleeding. There is also increasing evidence that even in the absence of plaque rupture, platelet-endothelial interactions may be important in accelerated plaque progression.³ 

Efficacy of antiplatelet therapy can be modified by blocking different aspects of platelet function (eg, inhibitors of cyclooxygenase, adenosine 5′-diphosphate [ADP] receptors, protease-activated receptors, and α_IIbβ₃ integrin). The highly varied approaches for selecting antiplatelet therapy are based on the need to balance risk of bleeding with risk of arterial thrombosis in different patient categories (eg, coronary vs noncoronary disease, stable vs unstable phase, diabetic vs nondiabetic). In any patient category, preventing platelet adhesion and aggregation at the site of plaque rupture while preserving normal hemostatic function in hemorrhagic conditions such as trauma or aneurysm leak would be advantageous. The study by Busygina et al proposes that this could be possible with oral inhibitors of Btk. This concept is based on the known effects of Btk on platelet activation signaling from ligation of cell-surface adhesion molecules including glycoprotein VI (GPVI) and GPIb.⁴  Aggregometry has revealed that ibrutinib inhibits collagen (ie, GPVI-mediated) but not ADP-mediated platelet aggregation,⁵  which in part explains the increased bleeding with ibrutinib independent of thrombocytopenia, particularly in patients already receiving standard antiplatelet or antithrombotic therapy.⁶  Using high-throughput in vitro models, Busygina et al demonstrate that oral Btk inhibitors prevent platelet accumulation on exposed human plaque components selectively through GPVI signaling. Although it is already known that GPVI plays a critical role in platelet recruitment at sites of vascular injury,⁷  the implication of the current study is that aggregation can be reduced by inhibition of outside-in signaling by GPVI.

The observation that Btk inhibitors had a preferential effect in inhibiting platelet aggregation on plaque components rather than normal collagen was attributed to preservation of non-GPVI platelet collagen receptors (integrin α₂β₁) that are less selective for altered collagen within plaque. However, the notion that ibrutinib is safe must be tempered by known bleeding complications in oncology patients. One could argue that bleeding is a so-called price of doing business in secondary prevention and that selective inhibition of platelet-plaque interactions may be particularly useful in particularly high-risk settings such as iatrogenic plaque disruption in patients undergoing percutaneous mechanical revascularization.

There are some unsolved issues that must be addressed before directly applying results of this study in patients. The data provided on shear dependency of Btk inhibitors are insightful and informative with regard to effect in different vessel types. However, flow in large arteries is pulsatile, with low diastolic shears in noncoronary vessels, and shear in regions of plaque can be spatially heterogeneous and even oscillatory.⁸  Although platelet accumulation on plaque homogenates or sections is a reasonable ex vivo model, binding to collagen may not be entirely reflective of events that occur from disruption of nondiseased vessels. Another important consideration in humans is whether plaque-specific antiplatelet actions of Btk inhibitors could increase microhemorrhage within plaque neovessels, which has been implicated in plaque progression and risk for events.⁹  An additional consideration is the increased risk of cardiac arrhythmias, particularly a fourfold increase in risk of atrial fibrillation, with ibrutinib.¹⁰ 

The study by Busygina et al adds to our knowledge of the complex interplay between tyrosine kinase inhibitors and risk of cardiovascular disease. Whereas other kinase inhibitors (eg, ponatinib and nilotinib) have been associated with vascular events, the current study by Busygina et al implies a potentially beneficial role for Btk inhibitors as antiplatelet agents. The study also provides reassurance that the field of cardio-oncology can yield information beyond toxic effects of chemotherapeutics that may benefit patients with atherosclerotic disease, similar to the evolution of macrolide-coated coronary stents, which are now routinely used to inhibit adverse neointimal proliferation.