Effect of Low-Dose Rivaroxaban Plus Aspirin on Carotid Plaque Inflammation (SPIRIT): A Randomized 18F-FDG PET/CT Trial

BackgroundAspirin plus rivaroxaban reduces cardiovascular events in patients with stable atherosclerosis; however, whether Factor Xa inhibition attenuates arterial wall inflammation in humans remains unclear. MethodsWe conducted a single-center, randomized, open-label, proof-of-concept study with blinded endpoint assessment using {superscript 1}F-fluorodeoxyglucose positron emission tomography/computed tomography ({superscript 1}F-FDG PET/CT). Adults with asymptomatic carotid stenosis (20-80%) and baseline carotid inflammation (target-to-background ratio [TBR] [≥]1.6) were randomly assigned in a 1:1 ratio to receive either aspirin (100 mg/day) plus rivaroxaban (2.5 mg twice daily) or aspirin (100 mg/day) alone. The primary endpoint was the percent change in the most diseased segment (MDS) TBR of the index carotid artery from baseline to 12 months. Secondary endpoints included whole-vessel carotid TBR, aortic TBR, and changes in lipids and high-sensitivity C-reactive protein. ResultsBetween September 2021 and December 2023, 92 patients were randomized (mean age 69.4 years; 88% men); 81 (88%) completed 12-month imaging. Mean percent changes in carotid MDS TBR were -7.25% (95% CI, -11.03 to -3.48) and -7.36% (95% CI, -11.06 to -3.67) in the combination therapy and aspirin-alone groups, respectively. The adjusted between-group difference (combination therapy minus aspirin alone) was -1.50 percentage points (95% CI, -6.20 to 3.21; P=0.53). No significant between-group differences were observed in whole-vessel carotid or aortic TBR, or in laboratory parameters. Minor bleeding occurred in four patients (8.7%) receiving combination therapy and in one (2.2%) receiving aspirin alone, with no major bleeding or deaths. ConclusionsIn patients with carotid atherosclerosis, adding low-dose rivaroxaban to aspirin did not reduce arterial inflammation beyond aspirin alone over 12 months on {superscript 1}F-FDG PET/CT. Clinical Trial RegistrationClinicalTrials.gov NCT05797376 CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIThis is the first randomized trial using serial 18F-FDG PET/CT imaging to directly evaluate whether dual-pathway inhibition with low-dose rivaroxaban plus aspirin reduces arterial inflammation compared with aspirin alone. C_LIO_LIDespite proven cardiovascular benefits in the COMPASS trial, the addition of rivaroxaban to aspirin did not confer additional anti-inflammatory effects on human atherosclerotic plaques over 12 months. C_LIO_LIBoth treatment groups showed similar reductions in arterial inflammation, likely reflecting the anti-inflammatory effects of background statin therapy and aspirin. C_LI What are the clinical implications?O_LIThe cardiovascular benefits of dual-pathway inhibition are likely mediated primarily by prevention of thrombotic events rather than by plaque stabilization through reduced inflammation. C_LIO_LIOptimal cardiovascular risk reduction requires a complementary approach: antithrombotic therapy to prevent acute events and anti-inflammatory interventions to stabilize atherosclerotic plaques. C_LIO_LIFuture studies should explore whether combining dual-pathway inhibition with targeted anti-inflammatory therapies (such as colchicine, IL-1{beta} inhibition) provides synergistic cardiovascular protection. C_LI