Plasma D‐dimer concentrations predicting stroke risk and rivaroxaban benefit in patients with heart failure and sinus rhythm: an analysis from the COMMANDER‐HF trial

Abstract

Background: D-dimer is a marker of fibrin degradation that reflects intra-vascular coagulation. Therefore, plasma concentrations of D-dimer might predict thromboembolic risk and rivaroxaban treatment effect.Aims: To investigate the association between D-dimer levels and the risk of stroke and other thrombotic, bleeding and fatal events, and whether D-dimer concentrations could predict rivaroxaban 2.5mg/bd (vs. placebo) effect in patients enrolled in the COMMANDER-HF trial who were in sinus rhythm, had HFrEF and coronary artery disease.Methods: Survival models with treatment-by-plasma D-dimer interaction. Baseline measurement of D-dimer was available in 4,107 (82%) of 5,022 patients enrolled. Median (percentile 25-75 ) follow-up was 21 (12.9-32.8) months. Results:The median (percentile 25-75 ) plasma concentration of D-dimer was 360 (215-665)ng/mL. The D-dimer tertiles were: 1) ≤255; 2) 256-515; 3) >515ng/mL. Patients within the tertile-3 were older, and had lower BMI, blood pressure, hemoglobin, eGFR, and LVEF.Higher plasma D-dimer concentrations were independently associated with higher rates of death, stroke, and venous thromboembolism. For example, the all-cause death adjusted HR (95%CI) of tertile-3 vs. tertile-1 was 1.77 (1.48-2.11), p<0.001. The effect of rivaroxaban was similar in each tertile of D-dimer for all outcomes except stroke. Patients within the tertile-3 had the greatest absolute and relative stroke reduction (HR [95%CI] tertile-1=1.16 [0.49-2.74], tertile-2=1.45 [0.77-2.73], and tertile-3=0.36 [0.18-0.70]; interaction p =0.008). The number-needed-to-treat to prevent one stroke in tertile-3 was 36. Conclusion:In COMMANDER-HF, rivaroxaban reduced the risk of stroke but the benefit may be confined to patients with D-dimer concentrations above 515ng/mL. Prospective trials are warranted to confirm these findings.

April 2021 at a glance: focus on systolic function, quality of life and treatment in heart failure

“…Rivaroxaban 2.5 mg twice daily may be considered among treatment options for patients with HF, coronary artery disease and LVEF >30% 14 . An analysis of COMMANDER‐HF demonstrated that high plasma D‐dimer levels (>515 ng/mL) identify patients at high risk of stroke who can benefit from rivaroxaban administration 21 …”

“…14 An analysis of COMMANDER-HF demonstrated that high plasma D-dimer levels (>515 ng/mL) identify patients at high risk of stroke who can benefit from rivaroxaban administration. 21…”

Antithrombotic therapy in heart failure and sinus rhythm: the ongoing search for a better match of patients to therapy

“…In this issue of the Journal, Ferreira et al 11 . undertook a post‐hoc analysis of the COMMANDER‐HF trial assessing the association between baseline plasma D‐dimer concentrations and the risks of stroke and/or other fatal and non‐fatal athero‐thrombotic events as well as bleeding.…”

“…Moreover, in this analysis, D-dimer levels were measured at baseline after an episode of worsening HF and yet they were markers of events occurring at long-term follow-up. Most importantly, Ferreira et al 11 showed the effect of rivaroxaban was similar across D-dimer tertiles for all outcomes except for overall and ischaemic stroke whereas only patients with higher plasma D-dimer concentrations (above ≈500 ng/mL) appeared to benefit from rivaroxaban for stroke reduction (interaction P = 0.008).…”

Soluble fibrin monomer complex as a candidate sentinel for adverse events in patients with heart failure

“…Intruigingly, elevated suPAR seems to distinguish ischemia-driven heart failure from heart failure of non-ischemic causes [11] . Another fibrinolysis marker emerging as an independent sentinel predicting adverse outcome and death from all causes in patients with heart failure, is D-dimer [12] , [13] , [14] , [15] . D-dimer is a fibrin degradation product generated in the final stage of clot dissolution, and as such, its presence essentially indicates that thrombus formation has occurred and fibrinolysis has been initiated.…”