Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial

Objective: Dual pathway inhibition (DPI) by combining acetylsalicylic acid (ASA) with low-dose rivaroxaban has been shown to reduce cardiovascular events in patients with peripheral arterial disease (PAD) when compared to ASA monotherapy. A potential explanation is that inhibition of factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of cardiovascular events. We hypothesize that the addition of rivaroxaban to ASA in PAD patients leads to improved endothelial function. Design: An investigator-initiated, multicentre trial investigating the effect of DPI on endothelial function. Methods: Patients, diagnosed with PAD, were enrolled in two cohorts: cohort A (Rutherford I-III) and cohort B (Rutherford IV-VI). Participants received ASA monotherapy for a 4-weeks run-in period, followed by 12 weeks of DPI. Macro- and microvascular endothelial dysfunction were studied by measuring carotid artery reactivity upon sympathetic stimulus and by measuring plasma endothelin-1 concentrations, respectively. All measurements were performed during the use of ASA (baseline) and after 12 weeks of DPI. Results: 159 PAD patients (111 cohort A, 48 cohort B) were enrolled. Twenty patients discontinued study drugs early. Carotid artery constriction upon sympathetic stimulation at baseline (ASA) and after 12 weeks of DPI was similar in the total group, 22.0 vs. 22.7% (p = 1.000), and in the subgroups (Cohort A 22.6 vs. 23.7%, p = 1.000; cohort B 20.5 vs. 20.5%, p = 1.000), respectively. The mean concentration of plasma endothelin-1 at baseline and after 12 weeks of DPI did not differ, 1.70 ± 0.5 vs. 1.66 ± 0.64 pmol/L (p = 0.440) in the total group, 1.69 ± 0.59 vs. 1.62 ± 0.55 pmol/L in cohort A (p = 0.202), and 1.73 ± 0.53 vs. 1.77 ± 0.82 pmol/L in cohort B (p = 0.682), respectively. Conclusion: Macro- and microvascular endothelial dysfunction, as reflected by carotid artery reactivity and plasma endothelin-1 concentrations, are not influenced in PAD patients by addition of low-dose rivaroxaban to ASA monotherapy for 12 weeks. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04218656

Contrast Echocardiography Improves Interobserver Agreement for Wall Motion Score Index and Correlation with Ejection Fraction

Background: The wall motion score index (WMSI) is a surrogate for left ventricular ejection fraction (LV-EF), which becomes unreliable in poor echo windows. The value of contrast LV opacification (LVO) for WMSI assessment is not well known. Objectives: We sought to compare interobserver agreement for WMSI and the correlation between the LVO-WMSI and LV-EF using two-dimensional second harmonic (SH) and LVO echocardiography. Methods: The study comprised 100 consecutive patients (57 +/- 13 years, 85% males). Two independent physicians assessed LV segmental quality and wall motion for both the SH and LVO studies according to a 17-segment model. Systolic wall motion was defined as: normokinesia, hypokinesia (systolic inward endocardial motion < 7 mm), akinesia, and dyskinesia. LV-EF was assessed from the LVO images according to the biplane modified Simpson's method. Results: Of the 1,700 analyzed segments, 453 (26.6%) were poorly visualized with SH imaging, and 173 (10.2%) with LVO (P < 0.0001). The two observers agreed on segmental wall motion score in 1,299 segments (agreement 76%, Kappa 0.60) with SH imaging and in 1,491 segments (agreement 88%, Kappa 0.78) with LVO. Interobserver correlation (r2) was 0.86 for the SH-WMSI and 0.93 for the LVO-WMSI. The limits-of-agreement for interobserver LVO-WMSI (mean difference -1.0% +/- 6.8%, agreement -14.6%, 12.6%) was lower than that for SH-WMSI (mean difference -2.3% +/- 10.1%, agreement -22.5, 17.9). The LVO-WMSI correlated well with LV-EF (r2 = 0.71). LV-EF could be estimated according to the formula 1.01 - 0.32 x WMSI. Conclusion: Echo-contrast improves interobserver agreement for wall motion scoring and the WMSI. The LVO-imaged WMSI correlates well with LV-EF. (Echocardiography 2011;28:575-581)