Autoantibodies to phosphorylcholine and cardiovascular outcomes in patients with acute coronary syndromes in the ATLAS ACS-TIMI 46 trial

Abstract

Atherogenesis is a complex inflammatory process stemming from the accumulation and oxidation of low density lipoproteins (LDL). IgM autoantibodies against phosphorylcholine (anti-PC) bind to the PC epitope on oxidized LDL (OxLDL), inhibiting the uptake of oxLDL by macrophages in atherosclerotic lesions. Anti-PC autoantibodies have been reported to be protective against atherothrombosis. We investigated the relationship of anti-PC concentrations with cardiovascular outcomes in patients with acute coronary syndromes (ACS). We measured anti-PC levels within 7 days of an ACS in 3,356 patients enrolled in the ATLAS ACS-TIMI 46 trial, a randomized dose ranging study of rivaroxaban versus placebo. The primary endpoint was death, myocardial infarction (MI), stroke, or severe recurrent ischemia (SRI) requiring revascularization during 6 months. The median baseline anti-PC concentration was 40.9 U/mL (25th, 75th percentiles: 25.4, 67.4). There was no significant association between anti-PC levels and the primary endpoint (Q1: 6.8 %, Q2: 4.2 %, Q3: 7.8 %, Q4: 5.4 %, p-trend = 0.87), all-cause mortality (Q1: 1.4 %, Q2: 0.7 %, Q3: 2.4 %, Q4: 0.9 %, p-trend = 0. 96), or any of the other individual endpoint components (MI: p-trend = 0.87, Stroke: p-trend = 0.43, SRI: p-trend = 0.66). Using the previously reported anti-PC cutpoint of 17 U/mL did not reveal a significant relationship between anti-PC concentrations and cardiovascular outcomes (<17 U/mL: 8.1 % vs. ≥17 U/mL: 5.8 %; p = 0.11). Similarly, evaluation of anti-PC as a continuous variable did not reveal a significant association (p = 0.30). In this study of patients early after ACS undergoing intensive secondary preventive therapy, IgM anti-PC titers did not exhibit a significant relationship with cardiovascular outcomes.

Relationship of Autoantibodies to MDA-LDL and ApoB-Immune Complexes to Sex, Ethnicity, Subclinical Atherosclerosis, and Cardiovascular Events

“…11,12,38–40 However, these data are not entirely consistent, as other studies have shown no association. 11,36,39,41,42 Additionally, a recent study has shown that low levels of IgG to selected apoB-100 peptides and MDA-modified apoB-100 peptides (which may not reflect IgG titers to MDA epitopes) are associated with higher risk of CVD. 43 In a recent report from the Dallas Heart Study, we reported that lipoprotein(a) [Lp(a)], oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), apolipoprotein(a) isoforms and LPA snps varied significantly by ethnicity.…”

Rivaroxaban and other non-vitamin K antagonist oral anticoagulants in the emergency treatment of thromboembolism

“…When a parenteral agent is used initially, a VKA should be started concurrently and the parenteral agent discontinued after a minimum of 5 days’ treatment or when the international normalised ratio (INR) stabilises within the target range of 2.0-3.0 for 2 consecutive days [3,7]. In contrast, rivaroxaban is given alone at a dose of 15 mg twice daily for 3 weeks followed by 20 mg once daily for the remainder of treatment [5,6]. …”

“…They are administered orally, have a fast onset of action, and their predictable pharmacokinetics and pharmacodynamics across a broad range of patients allow for fixed doses without routine coagulation monitoring [4]. Currently, rivaroxaban is the only such agent to be approved in Europe and the US for the treatment of DVT and PE and the prevention of recurrent DVT and PE, at an initial dose of 15 mg twice daily for 3 weeks followed by 20 mg once daily for an individualised duration of anticoagulation [5,6]. …”

“…Rivaroxaban is a specific factor Xa-targeting anticoagulant that provides a comparable speed of onset to enoxaparin [5,23], but without the risk of heparin-induced side effects [4]. Unlike the indirect factor Xa inhibitor fondaparinux, rivaroxaban is administered orally, binds directly to factor Xa without the need for antithrombin [24], and inhibits free, prothrombinase-associated and clot-associated factor Xa [25].…”

“…These agents are effective but have limitations, some of which may be overcome by the more recently developed non-VKA oral anticoagulants (OACs) [4]. Based on the phase III EINSTEIN trials, the direct factor Xa inhibitor rivaroxaban is now approved in Europe and the US for the treatment of DVT and PE as well as the prevention of recurrent DVT and PE in adults [5,6]. In addition, treatment studies involving the direct thrombin inhibitor dabigatran have also been completed, and studies of the direct factor Xa inhibitors apixaban and edoxaban are ongoing.…”