Budget Impact Analysis of Warfarin Reversal Therapies Among Hip Fracture Patients in Finland

The present cost analysis of warfarin reversal therapies indicated that vitamin K and PCC were the least costly warfarin reversal treatment options if direct healthcare costs during hospitalization prior to the hip fracture surgery were considered. Vitamin K induced costs solely because of resource utilization due to operation delay, whereas PCC prompted extra drug costs. However, the drug costs of PCC were partly offset by savings in resource utilization, as the operation delay was avoided. According to the budget impact analysis, vitamin K, PCC, and FFP were profitable if the current treatment mix was replaced by a 100 % market share of each individual treatment option. However, different safety profiles and contraindications may affect the clinical implementation of treatment options, which cannot be defined in monetary terms. The present budget impact analysis was applied to the Finnish healthcare system. Utilization of local cost and resource use data is a relevant approach in economic evaluations. However, this may affect the generalizability of the results across regions. Potential bias arising from uncertainty in cost estimates was reduced by using two extremes of hip fracture treatment costs (DRG 211 and DRG 236) in the sensitivity analyses.

Most patients with hip fractures are frail and have comorbidities. Operation delays lengthen the hospital stay and may increase mortality [13‐15]. Early surgery reduces mortality; therefore, the current guidelines recommend surgery during the first 36–48 h after the hip fracture [5]. One reason that an operation may be delayed is the patient’s use of oral anticoagulants. The action of these anticoagulants should be reversed prior to the surgery to establish appropriate hemostatic function and to optimize the choice of anesthesia. The temporary withholding of warfarin is not feasible in emergency surgery, as it may take up to 5 days to establish appropriate hemostatic function. Proper reversal strategies include the administration of vitamin K, FFP, or a four-factor PCC, and the choice of treatment method depends on the urgency of the anticoagulant effect reversal [7, 8]. The various approaches may have significant budget impacts. Furthermore, in contrast to elective surgery, it is not consistently possible to predict when an emergency care patient can be admitted to surgery. Therefore, the system must be flexible so that the surgery can be performed in a timely manner.

The cost analysis favored vitamin K as an anticoagulation reversal therapy. The spontaneous reversal of anticoagulation by temporary warfarin cessation takes several days. As warfarin acts as a vitamin K antagonist, the reversal of anticoagulation is achieved more rapidly with the concomitant administration of oral vitamin K [7, 16, 17]. If 1 mg of oral vitamin K is given 24 h before surgery, an INR ratio can be normalized in some patients and correlates with short duration of bridging therapy [18]. However, one-third of patients fail to respond to these lower doses [19]. Intravenous vitamin K produces a more prompt and complete reduction in the INR ratio than does oral or subcutaneous vitamin K [7, 20‐22]. If 3 mg of intravenous vitamin K is administered in addition to the withholding of warfarin, appropriate hemostatic function can be restored within 24 h in 90 % of patients [9]. However, the desired ratio is not achieved in all patients. Vitamin K is less effective in patients with supratherapeutic INR ratios, and patients who receive vitamin K should have normal liver function to synthesize and activate vitamin K-dependent clotting factors. Moreover, after vitamin K administration it may take 2–11 days to re-establish a therapeutic INR ratio [9]. Therefore, patients may require bridging therapy with LMWH and repeated INR testing for up to 2 weeks after the surgery. Bridging therapy induces extra resource utilization and costs. Therefore, vitamin K administration is not an optimal approach in hip fracture surgery.

The cost analysis also favored PCC. The anticoagulant effect of warfarin is mediated by the reduced coagulant activity of four vitamin K-dependent clotting factors, II, VII, IX, and X [7]. Prothrombin complex concentrates are categorized as three- and four-factor products. Three-factor products contain low concentrations of factor VII, whereas four-factor PCCs contain factors II, VII, IX, and X and proteins C and S. Therefore, four-factor PCCs are highly effective in correcting INR ratios as soon as they are in circulation [7]. With PCCs, a blood type definition is not required. Furthermore, they are virally inactivated and can be administered as a short-term infusion with no risk of volume overload [7].

FFP products are indicated for the rapid reversal of the effects of oral anticoagulants if vitamin K is insufficient because of impaired liver function or in emergency situations. However, PCCs reverse anticoagulation more rapidly and effectively and have a better safety profile than FFP [23‐26]. Additionally, the therapeutic volume of PCC is 1–2 mL/kg, whereas FFP is administered in volumes of 15 mL/kg or higher [26]. These higher volumes are associated with an increased risk of volume overload; therefore, prolonged infusion times are required [26, 27]. Although FFP may be the treatment of choice in hypovolemic hip fracture patients with a normal hematocrit value, in patients with blood loss or anemia, large doses of FFP may impair hemostatic function by decreasing the hematocrit. Moreover, FFP may contain only 55–85 % of the physiological concentrations of clotting factors [28]. Therefore, to ensure that a patient is given, for example, 1000 IU of coagulation factor IX, the infusion volume should be between 1200 and 1800 mL. If the generally accepted starting dose of 15 mL/kg is given, a patient with a bodyweight of 70 kg may receive only 600–900 IU of factor IX. This value is significantly less than that of 1500 IU of 60 mL of PCC.

The various PCCs that are marketed in Finland have different dosing guidelines (according to the summaries of product characteristics [SPCs]), and different package sizes, and hence different costs; therefore, two commercial preparations were taken into account in the current treatment mix. The recommended doses of PCC1 vary between 0.4 and 1.3 mL/kg depending on the initial INR, bodyweight, and target INR [29, 30]. The recommended doses of PCC2 vary between 0.9 and 2.0 mL/kg (maximum dose 120 mL) [31]. Additionally, the availability of different package sizes (PCC1) potentially decreases drug wastage and thus decreases costs.

There are some limitations in the present study. Firstly, the budget impact analysis is based on the Finnish price level. Thus, the results should be interpreted with caution in other regions. Secondly, in respect of the treatment protocols, the study is based on a survey with a limited number of local anesthesiologists. Nevertheless, the budget impact analyses are according to dosages arising from summaries of product characteristics. Despite the limitations, the results provide a reasonable estimate of the local clinical situation. Also, in order to take into account the variation in dosage regimen, the sensitivity analyses were applied for various bodyweights and initial INR values.

New oral anticoagulants, apixaban, dabigatran and rivaroxaban, have recently been approved as an alternative for warfarin in some indications such as in patients with non-valvular atrial fibrillation. One of the limitations of these new compounds is that there are no specific antidotes for any of these new compounds. It is recommended to defer procedures that carry a risk for major bleeding or bleeding into a close compartment until at least 24–48 h after the last dose. However, no guidelines or strategies for the reversal of the anticoagulant effects of these compounds have ever been evaluated in clinical settings. Thus, no recommendation on how to handle hip fracture patients taking new oral anticoagulants can be given at this time [32].