Time for a Paradigm Shift in Vitamin K Antagonist Reversal - Embracing TGA over INR for Optimal Outcomes?

Abstract

Introduction: Vitamin K antagonist (VKA) anticoagulation reversal has relied on International Normalized Ratio (INR) as a standard parameter of coagulation status. Reversal of anticoagulation within INR ranges of 2 - 3 is usually achieved by 25 IU/kg of 4-Factor PCC (4F-PCC), resulting in INR <1.5. However, emerging evidence suggests that increases in coagulation factor activities may be more accurately reflected by the thrombin generation assay (TGA), paving the way for a different approach to assessing effectiveness of VKA reversal. To this effect, a Phase I/II clinical study was conducted to assess dose response of 4F-PCC in healthy subjects anticoagulated with a VKA agent. Methods: This was a prospective, randomized, open-label, placebo-controlled study involving healthy subjects aged 18 to 55 years. Participants were pre-treated for 10 days with acenocoumarol to achieve an INR between 2 and 3 (± 10% inclusive). Subsequently, they received a single iv bolus of 4F-PCC at doses of 12.5 IU/kg or 25 IU/kg, or placebo. Blood samples for TGA, INR, and blood clotting factors (FII, FVII, FIX, FX, protein C, and protein S) were assessed at specified intervals from pre-dose VKA (baseline) up to 15 days after 4F-PCC dose. Results: VKA for 10 days decreased plasma activities of blood clotting factors II, VII, IX and X as expected. Thirty minutes after infusion with 4F-PCC, clotting factor levels were increased in a dose-dependent manner, relative to pre-infusion levels. Placebo had no significant effect on any of the clotting factors. 4F-PCC at 12.5 IU/kg, or 25 IU/kg decreased mean INR values within 30 min after dosing from 2.39 to 1.37, and 2.45 to 1.17, respectively. Infusion with 25 IU/kg fully restored peak thrombin generation at 30 min after dosing compared to baseline (mean ratio: 1.08), while 12.5 IU/kg achieved partial restoration (mean ratio: 0.75). Factor II: Doses of 12.5 IU/kg or 25 IU/kg 4F-PCC increased mean FII values at 30 min post-dose from 32% to 65% and 32% to 89%, respectively (Figure 1). The median maximum concentration (Emax 0-12h) was 68% for 12.5 IU/kg, and 92% for 25 IU/kg (Table 1). Factor VII: Doses of 12.5 IU/kg and 25 IU/kg 4F-PCC increased mean FVII values at 30 min from 15% to 30%, and from 14% to 46%, respectively. The median Emax 0-12h was 32% for 12.5 IU/kg, and 46% for 25 IU/kg. Factor IX: Doses of 12.5 IU/kg and 25 IU/kg 4F-PCC increased mean FIX values at 30 min from 29% to 41% and from 29% to 52%, respectively. The median Emax 0-12h was 45% for 12.5 IU/kg, and 56% for 25 IU/kg. Factor X: Doses of 12.5 IU/kg and 25.0 IU/kg 4F-PCC increased mean FX values at 30 min, from 18% to 42% and 18% to 64%, respectively. The median Emax 0-12h was 45% for 12.5 IU/kg, and 66% for 25 IU/kg. Conclusion: After 4F-PCC infusion, clotting factors II, VII, IX and X showed dose-dependent increases at 30 min post-dose. Correspondingly, a dose-dependent TGA response was observed; 4F-PCC resulted in restoration to levels measured before anticoagulation with VKA. The degree of INR normalization appeared to be slightly more pronounced in the higher dosed 4F-PCC group. Factor II was almost normalized after 4F-PCC infusion and is known to be a main driver of the TGA response. Even though the other clotting factors, such as factor VII, remain in the range of approx. 50%, this does not represent a limitation for adequate activation of the coagulation system. Considering 4F-PCC characteristics and the mechanisms underlying either TGA or INR, the choice of TGA rather than INR appears to be more suitable to monitor appropriate restoration of the overall clotting potential after VKA reversal with 4F-PCC.