Acute coronary syndrome guidelines recommend adding intraprocedural low-dose anticoagulation during the urgent PCI in patients using regular DOACs, regardless of the time of the last DOAC dose.14,15 However, no prospective randomized study has specifically examined the management of intraprocedural anticoagulation in this situation. The purpose of this study was to determine whether an additional anticoagulant is needed, which anticoagulant should be used, and at what dose in patients taking DOACs who require urgent PCI. The anti-Xa level of the study group before rivaroxaban was higher than that of the control group. As expected, anti-Xa, ACT, PT, aPTT, and INR values in the study group were significantly higher than beginning at the 4th hour after 20 mg of rivaroxaban. All coagulation parameters significantly increased with the addition of 50 IU/kg UHF, 100 IU/kg UFH, 0.5 mg/kg enoxaparin, and 1 mg/kg enoxaparin 4 hours after rivaroxaban intake. Twelve hours after taking rivaroxaban, all anticoagulation parameters were still significantly higher than before the drug. The mean anti-Xa level at 12 hours was 0.94±1.21 IU/mL but less than 0.5 IU/mL in 24% (6/25) of patients. Among the anticoagulants added 12 hours after rivaroxaban, the best results were obtained with 0.5 mg/kg of enoxaparin (from 0.94±1.21 IU/mL to 2.00±1.02 IU/mL). The enoxaparin doses are given at 4 and 12 hours had a softer and more well-distributed anticoagulant effect than the UFH doses.
The American College of Chest Physicians’ consensus guideline states that the therapeutic anti-Xa activity for treating venous thromboembolism is between 0.3 and 0.7 IU/mL for UFH and 0.6 to 1.0 IU/mL using twice-daily low-molecular-weight heparins (LMWHs).18 Although the target for LMWH anticoagulant activity in PCI has not been clearly established, anti-Xa activity levels ranging from 0.5–1.8 IU/mL have been targeted in studies involving the administration of IV enoxaparin for PCI.19-21 In the STEEPLE (Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients, an International Randomized Evaluation) trial, 3528 patients undergoing elective PCI were randomized to receive 0.50 mg/kg IV enoxaparin, 0.75 mg/kg IV enoxaparin, or IV UFH.21 Anti-Xa levels of 0.5–1.8 IU/mL were targeted in the enoxaparin arms, while an ACT level of 300–350 seconds was targeted in the UFH arm (If glycoprotein IIb/IIIa inhibitors are also used, this value is 200-300 seconds). This study achieved target anticoagulation levels in 86% of patients receiving enoxaparin without monitoring, compared with 20% of patients receiving UFH with ACT monitoring. The STEEPLE study showed that both doses of enoxaparin (0.5 and 0.75 mg/kg) were highly effective, and the incidence of major bleeding was significantly lower in both enoxaparin groups than in the UFH group. The ATOLL (The Acute Myocardial Infarction Treated with Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischemic and Bleeding Events at Short- and Long-term Follow-up) trial compared an IV bolus of 0.5 mg/kg enoxaparin with UFH in 910 STEMI patients undergoing primary PCI. In the per-protocol analysis of the ATOLL trial, comprising more than 87% of the study population (795 patients), enoxaparin showed superiority over UFH in reducing the primary endpoint, mortality, and major bleeding and improved net clinical benefit.22 Compared to UFH, enoxaparin has been demonstrated to have a more stable and predictable anticoagulant effect, with almost all patients achieving an optimal level of anticoagulation during the procedure.
Routine monitoring is not required for DOAC therapy. If necessary, the anticoagulant effect of oral factor Xa inhibitors is evaluated by anti-Xa activity. The anti-Xa assay can be used to measure DOAC activity via chromogenic reagents and special DOAC calibrators.23,24 Studies have demonstrated a linear, dose-dependent, and strong correlation (R2= 0.95 to 1.00) between plasma rivaroxaban concentration and anti-Xa activity over a wide concentration range (20 to 660 ng/mL) when chromogenic reagents and rivaroxaban calibrators are used.23-25 A steady-state peak and trough anti-Xa activity range from 3.80 to 6.20 IU/mL and 0.60 to 1.00 IU/mL were calculated for rivaroxaban based on published drug concentrations in previous pharmacokinetic studies by Beyer et al.26 For apixaban 5 mg twice daily, these ranges are 1.80 to 2.20 IU/mL and 0.70 to 1.10 IU/mL, respectively. Our study group's mean anti-Xa level before rivaroxaban was 0.63±0.73 IU/ml. In this situation, it can be said that the coagulation parameters obtained 24 hours after 20 mg daily rivaroxaban taking in our study group are compatible with previous studies, and adequate anticoagulation continues even 24 hours after taking the drug. However, it should be noted that seven patients had anti-Xa levels less than 0.5 IU/mL in our study. The anti-Xa level 24 hours after rivaroxaban administration may be sufficient for prophylaxis of deep vein thrombosis or nonvalvular AF but not for elective or primary PCI.
All coagulation parameters were significantly higher at 4 hours after taking 20 mg of rivaroxaban than before the drug (Table 3). Anti-Xa activity was measured on average at 1.96±1.35 IU/mL at the 4th hour after rivaroxaban intake. This value is slightly higher than the mean anti-Xa levels obtained in the elective PCI studies NICE-4 (The initial National Investigators Collaborating on Enoxaparin) and ELECT (Evaluating Enoxaparin Clotting Times) (1.7±0.9 IU/mL and 1.6±0.8 IU/mL, respectively).19,20 The X-PLORER (Evaluating Optimal Concomitant Anticoagulation in Rivaroxaban Treated Patients, an Oral Direct Factor Xa Inhibitor, During Percutaneous Coronary Revascularization) study has shown that rivaroxaban (with or without UFH) effectively inhibits coagulation activity during elective PCI in patients with chronic coronary syndrome compared with UFH alone.27 Periprocedural rivaroxaban given two to four hours prior to elective PCI appeared to provide adequate anticoagulation without an increased risk of bleeding. As a result, it is possible to achieve adequate anticoagulation for primary or elective PCI four hours after drug ingestion in patients using regular rivaroxaban.
The latest guidelines on coronary revascularization and ACS focus on reducing bleeding complications in PCI and antithrombotic therapies.15,28 Guidelines for anticoagulated patients undergoing primary PCI recommend some strategies to reduce the risk of bleeding: preferring the radial approach as the access site, performing primary PCI without interruption of oral anticoagulant, not applying UFH if INR > 2.5 in patients using VKA, and adding low-dose parenteral anticoagulation (e.g., enoxaparin 0.5 mg/kg or UFH 60 IU/kg) in patients using DOACs, regardless of the timing of the last DOAC administration.14,15 In our study, anti-Xa levels were significantly elevated by the addition of 50 IU/kg UHF, 100 IU/kg UFH, 0.5 mg/kg enoxaparin, and 1 mg/kg enoxaparin 4 hours after rivaroxaban intake (3.58±1.44 IU/mL, 5.79±1.21 IU/mL, 2.73±1.18 IU/mL, and 3.95±1.20 IU/mL, respectively) (Table 3 and Figure 2). These values are higher than the targeted and safe anti-Xa levels in previous primary or elective PCI studies with enoxaparin. A patient who regularly uses rivaroxaban 20 mg daily may not need additional intraprocedural anticoagulation 4 hours after taking the drug. Our findings contradict the guidelines' recommendation to give low-dose parenteral anticoagulation to patients who use DOACs, no matter when the last dose of DOACs was taken. Adding an anticoagulant 4 hours after rivaroxaban, even at a low dose, may shift the balance of major bleeding and thrombotic events in favor of bleeding in a STEMI patient who underwent primary PCI.
Twelve hours after rivaroxaban ingestion, all anticoagulation parameters remained significantly higher than before the drug. The mean anti-Xa level was 0.94±1.21 IU/mL at 12 hours after rivaroxaban. In patients receiving enoxaparin in the STEEPLE study, the median anti-Xa at the start and end of PCI was 0.94 and 0.82 IU/mL, respectively, and an anti-Xa level of approximately 0.9 IU/mL was associated with an optimal risk-benefit ratio.29 According to the STEEPLE study's findings, the mean anti-Xa level at the 12th hour of our patient group can be considered optimum. However, the distribution of the mean anti-Xa measurements at 12 hours in our study group was wide. Based on the target values of the STEEPLE study, the anti-Xa value of 6 patients (24%) was measured below 0.5 IU/mL, and the value of 2 patients (8%) was above 1.8 IU/mL. Additionally, primary PCI in patients with STEMI is performed in a more thrombotic environment than elective PCI. Inadequate anticoagulation, which occurs in approximately one-quarter of patients, may increase thrombotic risk. The addition of 50 IU/kg UHF, 100 IU/kg UFH, 0.5 mg/kg enoxaparin, and 1 mg/kg enoxaparin 12 hours after rivaroxaban administration significantly increased anti-Xa levels to 2.79±1.16 IU/mL, 5.62±1.53 IU/mL, 2.00±1.02 IU/mL, and 3.60±1.09 IU/mL, respectively (Table 4). When anti-Xa and other coagulation parameters are investigated, as shown in Table 4 and Figure 2, it is evident that the safest anticoagulant addition is 0.5 mg/kg enoxaparin. Also, previous randomized studies have shown that 0.5 mg/kg IV enoxaparin is superior to UFH in elective or primary PCI.21,22
Study Limitations
First, our study was carried out experimentally, and answers were sought to questions about clinical practices based on an in vitro study. However, the importance of such research prior to clinical trials is evident. Our study may guide future clinical studies. Second, we preferred rivaroxaban, an oral factor Xa inhibitor, taken once daily in our research. We do not know if our findings apply to apixaban, taken twice daily, and dabigatran, a direct thrombin inhibitor. Third, all DOACs currently present reach a peak plasma level within one to four hours after ingestion and reach their trough level between 12–24 hours. We examined the effects of anticoagulants added 4 and 12 hours after taking rivaroxaban. It is also possible to investigate different times, such as the 2nd, 8th, and 18th hours. Fourth, although we examined UFH and enoxaparin, the anticoagulants recommended by the guidelines and most frequently used in daily practice for PCI procedures,28,30 it would have been more beneficial to include bivalirudin in the study. Last, the control group consisting of five healthy individuals is a small sample size. However, the purpose of establishing a control group was to evaluate anticoagulants' efficacy and laboratory data's reliability rather than to compare the two groups. Consequently, the small sample size of the control group has no bearing on the study results.