Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease. The X-PLORER trial

Abstract

Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6-8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin-antithrombin complex values at 2 h post-PCI were 3.90 [6.8]µg/l and 3.90 [10.1] µg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin-antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting.

Keywords: Anticoagulation; coronary artery disease; rivaroxaban; thrombosis.

Conflict of interest statement

Conflicts of interest Pascal Vranckx has received research grants from Bayer Health-Care, Boehringer Ingelheim and Daiichi Sankyo; honoraria for advisory board and lectures from BMS-Pfizer. Freek W. A. Verheugt has received honoraria for consulting and speaking from Bayer HealthCare, Boehringer Ingelheim, BMS/Pfizer and Daiichi Sankyo. So-Young Kim, Bodo Kirsch, Martin van Eickels and Frank Misselwitz report being employees of Bayer HealthCare. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1: Study flow

. One patient in the rivaroxaban + UFH arm did not receive any rivaroxaban and was removed from the analysis. PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

Figure 2: Median vs time curves plotted by individual treatment

. Median prothrombin fragment 1+2 levels (A); thrombin–antithrombin complex levels (B); anti-factor Xa activity (C); prothrombin time (D); activated partial thromboplastin time (E); endogenous thrombin potential (F) per treatment. Anti-Xa, anti-factor Xa; aPTT, activated partial thromboplastin time; ETP, endogenous thrombin potential; F1+2, prothrombin fragment 1+2; PCI, percutaneous coronary intervention; PT, prothrombin time; TAT, thrombin-antithrombin; UFH, unfractionated heparin.

Figure 3: Cumulative curves for thrombin–antithrombin III complex (A, B) and prothrombin fragment 1+2 (C, D) at 2 (A, C) and 48 (B, D) h after the start of the percutaneous coronary intervention

. Start PCI = baseline. F1+2, prothrombin fragment 1+2; PCI, percutaneous coronary intervention; TAT, thrombin–antithrombin; UFH, unfractionated heparin.

Figure 4: Relationship between rivaroxaban plasma level and the result of coagulation tests

. Anti-factor Xa activity (A); prothrombin time (B); activated partial thromboplastin time (C); endogenous thrombin potential (D). aPTT, activated partial thromboplastin time; ETP, endogenous thrombin potential; PT, prothrombin time; UFH, unfractionated heparin.