CANTOS and COMPASS: New Avenues for Secondary Cardiovascular Prevention

Reported from the European Society of Cardiology ESC Congress 2017 in Barcelona

Two large trials dominated Sunday’s discussions at the ESC Congress 2017 in Barcelona. CANTOS and COMPASS met their respective primary endpoints, although this came as no surprise because topline results were already in the public domain due to press releases earlier this year. Yet presentation of the complete results, along with simultaneous publications in the New England Journal of Medicine, tell us the full story and gives us important novel information to digest.

CANTOS: randomized, double blind trial of canakinumab

CANTOS was a randomized, double blind trial of canakinumab, a monoclonal antibody targeting interleukin-1β, administered subcutaneously every three months. A total of 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein were randomized to three doses of canakinumab or placebo. At 4 years, canakinumab reduced the high-sensitivity C-reactive protein level in a dose-dependent fashion, while the levels of lipids remained unchanged. At a median follow-up of 3.7 years, the primary efficacy endpoint (a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) was reduced significantly by the 150-mg dose with a 15% treatment effect driven by less myocardial infarction. The drug was associated with more infections than placebo, including mortality related to infections, but there were less cancer-related deaths that brought the mortality endpoint to no difference compared with controls.

This study proves for the first time the inflammatory hypothesis of atherosclerosis and represents a milestone in a field of considerable pathophysiological interest. In view of the modest treatment effect of the drug in CANTOS, and the safety findings with respect to infections, we now need more data on the net clinical benefit of using canakinumab. Implementation of this drug in clinical practice for selected patients (i.e. those with low LDL levels but high inflammatory markers) will also depend on cost-effectiveness considerations, because the drug is presently very expensive.

COMPASS: randomized, double blind study of rivaroxaban

COMPASS was a randomized, double blind study of rivaroxaban, a Factor Xa inhibitor oral anticoagulant, used alone or in combination with aspirin for secondary cardiovascular prevention. A total of 27,395 patients with stable atherosclerotic disease were randomized, and the study was stopped after a mean follow-up of 23 months for evidence of a 24% significant reduction in ischemic outcomes with the rivaroxaban 2.5-mg twice daily plus aspirin combination strategy, at the price of a 70% increase in major bleeding compared with placebo. Conversely, the use of rivaroxaban 5-mg alone (i.e. without aspirin) did not improve the clinical outcomes compared with placebo, and only increased bleeding. How this “dual pathway” strategy with rivaroxaban and aspirin compare versus dual antiplatelet therapy in patients with stable atherosclerosis? This is unknown and possibly the objective of future research in this field.