Dual pathway inhibition a new antithrombotic strategy for CAD and PAD

Dual pathway inhibition (DPI) is a new antithrombotic strategy in coronary artery disease (CAD) and peripheral artery disease (PAD), according to Professor Dominick Angiolillo from the University of Florida College of Medicine in Jacksonville, Florida, US, who discussed the latest updates and clinical implications of these treatment strategies at the 28th Annual Scientific Congress of the Hong Kong College of Cardiology.

“Advances in antiplatelet therapies for cardiovascular disease [CVD] have improved patient outcomes over time, but the challenge of balancing the risks of ischaemia and bleeding remains substantial,” said Angiolillo. “Moreover, many patients with CVD have a residual risk of ischaemic events despite receiving antiplatelet therapy. Novel strategies with an acceptable associated risk of bleeding are therefore needed to prevent clinical events through mechanisms beyond platelet inhibition.” [Nat Rev Cardiol 2020;17:242-257]

The REACH registry – an international, prospective, observational study of 67,888 patients ≥45 years of age at risk of or with atherothrombosis – showed that atherosclerosis is a polyvascular disease. More than three in five patients (61.5 percent) with PAD and almost a quarter (24.7 percent) of patients with CAD were found to have concomitant disease in other vascular beds. [JAMA 2006;295:180-189] “Polyvascular disease is associated with an increased risk of morbidity and mortality,” noted Angiolillo. [Eur Heart J 2010;32:992-999; Eur Heart J 2009;30:2318-2326; JAMA 2007;297:1197-1206]

“Aspirin monotherapy has been the standard of care for secondary prevention in patients with vascular disease manifestations, namely, stable CAD and PAD,” said Angiolillo. “However, ischaemic recurrences persist with aspirin monotherapy, and a number of other antiplatelet strategies have failed to reduce ischaemic mortality compared with aspirin alone.”

The advent of non-vitamin K antagonist oral anticoagulants (NOACs), which attenuate fibrin formation by selective inhibition of factor Xa or thrombin, has renewed the interest in DPI strategies that combine an antiplatelet agent with an anticoagulant. “Secondary and tertiary prevention of atherothrombotic complications beyond aspirin monotherapy is an emerging paradigm, based on the synergy of oral anticoagulant therapy, such as direct inhibitors of factor IIa and Xa, and antiplatelet therapy, such as aspirin and P2Y₁₂ inhibitors,” highlighted Angiolillo. [Nat Rev Cardiol 2018;15480-496]

The combination of aspirin with the NOAC rivaroxaban demonstrated efficacy in the large-scale, randomized COMPASS trial, which involved 27,395 patients with stable atherosclerotic CVD. The primary composite outcome of cardiovascular death, stroke, or myocardial infarction (MI) occurred in fewer patients in the rivaroxaban plus aspirin group vs the aspirin alone group (4.1 percent vs 5.4 percent; hazard ratio [HR], 0.76; p<0.001). While major bleeding events occurred in a greater proportion of patients receiving rivaroxaban plus aspirin (3.1 percent vs 1.9 percent; HR, 1.70; p<0.00), fatal or critical organ bleeding events did not increase significantly compared with aspirin alone. [N Engl J Med 2017;377:1319-1330]

“Overall, DPI with low-dose aspirin and rivaroxaban 2.5 mg twice daily is a suitable choice for patients with chronic coronary syndromes with or without previous ischaemic stroke or MI, who are not at high risk of bleeding, but who have additional risk factors, such as PAD or multivessel CAD, diabetes mellitus or chronic heart failure,” concluded Angiolillo. “In addition, patients with previous MI but no prior ischaemic stroke may be considered for dual antiplatelet therapy with low-dose aspirin plus ticagrelor 60 mg twice daily.” [Nat Rev Cardiol 2020;17:242-257]