Purpose A case in which novel and traditional laboratory markers were successfully used to determine surgical intervention timing in an elderly patient receiving dabigatran for atrial fibrillation is reported.
Summary An 86-year-old woman who was taking dabigatran for atrial fibrillation suffered a right femoral neck fracture requiring surgical intervention. Dabigatran was withheld once the patient was admitted to the hospital, and the pharmacy inpatient anticoagulation management team was consulted for guidance on determining appropriate scheduling of surgical intervention with regard to the time since her most recent dabigatran dose to minimize bleeding complications. The team recommended delaying surgery, as dabigatran clearance would likely take 3–5 days and an ecarin chromogenic assay (ECA) dabigatran value of <50 ng/mL would be desirable before surgical intervention. During her hospitalization, novel and traditional laboratory markers for dabigatran, such as ECA value, activated partial thromboplastin time, thrombin time, and prothrombin time, were measured and followed closely to determine the best time to perform surgical intervention to minimize bleeding risk. Renal dysfunction likely delayed dabigatran elimination in the patient and may have led to potential accumulation of dabigatran. The patient ultimately had to wait 5 days after the last dabigatran dose for surgical intervention.
Conclusion Coagulation assay monitoring for dabigatran, with emphasis on an ECA dabigatran concentration of <50 ng/mL, was used to assess safety regarding bleeding risk before a nonemergent surgical procedure in an 86-year-old woman with a right femoral neck fracture.
Dabigatran etexilate was the first direct oral anticoagulant to receive Food and Drug Administration market approval in 2010 for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 Its approval was followed by market approval of additional direct oral anticoagulants: rivaroxaban, apixaban, and edoxaban. Despite the expanding use of these agents, before the approval of idarucizumab in 2015, no agent has been available to reverse bleeding or facilitate invasive procedures associated with these agents.2 Further, many clinicians struggle with how novel and traditional laboratory testing can be used to guide appropriate therapy or facilitate interventions.
The dabigatran package insert recommends therapy discontinuation 1–2 days before surgical procedures for patients with a creatinine clearance (CLcr) of ≥50 mL/min or therapy discontinuation 3–5 days before surgery when the CLcr is <50 mL/min.1 However, little practical evidence is available to assist in the interpretation of coagulation assays before a surgical procedure to assess safety with regard to bleeding risk. We report a case in which novel and traditional laboratory markers were successfully used to determine surgical intervention timing in an elderly patient receiving dabigatran for atrial fibrillation.
An 86-year-old, 99.8-kg woman (height, 167.6 cm) arrived at the emergency department (ED) with a right femoral neck fracture resulting from a fall while getting out of bed. The patient complained of significant right hip pain at presentation and was unable to bear weight. She denied having any other symptoms.
A radiograph taken on the day of her arrival to the ED (day 1) showed an impacted femoral neck fracture of the right hip. The patient was then admitted for surgical fracture repair. The patient reported taking her most recent dose of dabigatran on the morning of ED presentation.
Her medical history included atrial fibrillation, with a calculated CHADS2 score of 3 and a CHA2DS2VASc score of 5; hypertension; type 2 diabetes mellitus; macular degeneration of her right eye; a history of falls; and bilateral knee prosthesis replacement 14 years prior. Her home medications included dabigatran 150 mg twice daily, amlodipine 10 mg daily, atenolol 25 mg in the morning and 50 mg in the evening, losartan 100 mg daily, citalopram 10 mg daily, glimepiride 0.5 mg daily, tramadol 50 mg every 4–6 hours as needed for moderate pain, and cholecalciferol 2,000 units daily. She also reported taking a multivitamin capsule with lutein daily. Her only reported allergy was to penicillin.
On day 1, the patient’s laboratory test results were as follows: serum creatinine (SCr), 1.15 mg/dL; estimated CLcr, 33 mL/min using Cockcroft-Gault calculation; International Normalized Ratio (INR), 1.51; prothrombin time (PT), 17.8 seconds (normal, 11.8–14.5 seconds); hemoglobin concentration, 14.6 g/dL (normal, 11.5–15.8 g/dL); hematocrit value, 44.5% (normal, 35–45%); and platelet count, 231 × 103/μL (normal, 140–400 × 103/μL). The patient’s baseline SCr was unknown, and no other laboratory measures of anticoagulation were collected. Additional laboratory data are available in Table 1.
An ecarin chromogenic assay dabigatran concentration of <50 ng/mL, along with monitoring of activated partial thromboplastin time, thrombin time, and prothrombin time, allowed for safe surgical outcomes in an 86-year-old woman with a right femoral neck fracture.
More information is needed regarding how to manage dabigatran when it needs to be stopped for bleeding or surgical intervention, particularly the impact of the 2-phase distribution model and renal impairment on laboratory values and other patient management decisions.
A clinician’s knowledge and appropriate application of anticoagulation assays in practice are essential to ensure safe patient care.
Dabigatran was withheld once the patient was admitted to the hospital, and the pharmacy inpatient anticoagulation management team was consulted for guidance on determining appropriate scheduling of surgical intervention with regard to the time since her most recent dabigatran dose to minimize bleeding complications. The team recommended delaying surgery, as dabigatran clearance would likely take 3–5 days and an ecarin chromogenic assay (ECA) dabigatran value of <50 ng/mL would be desirable before surgical intervention. The ECA dabigatran level was intended to provide a reference point before surgical intervention to ensure that most of the anticoagulant activity of dabigatran had subsided. Since the patient had most recently taken her dose of dabigatran the morning of ED presentation, it was highly likely that her ECA dabigatran level was above 50 ng/mL, so it was not measured on the first day.
On the morning of hospital day 2, the patient’s ECA dabigatran value was 130.91 ng/mL. Hospital day 3 revealed an unexpected increase in the ECA dabigatran level to 242.31 ng/mL, with a SCr of 0.84 mg/dL. The interprofessional team caring for the patient had initially planned to take the patient to surgery the next day, and this measurement put that plan in doubt.
On hospital day 4, the ECA dabigatran level increased to 254.68 ng/mL, and her SCr concentration rose to 0.97 mg/dL. Secondary to a continued increase in ECA dabigatran levels, an activated partial thromboplastin time (aPTT) was obtained to assess additional anticoagulation values and was recorded as 41.7 seconds (normal, 23.5–36.5 seconds). Therefore, the pharmacy inpatient anticoagulation management team recommended a further delay of surgery.
On hospital day 5, the patient’s laboratory test results were as follows: ECA dabigatran level, 200.4 ng/mL; aPTT, 39.1 seconds; thrombin time (TT), >120 seconds (normal, 10–21 seconds); and SCr concentration, 0.95 mg/dL. On hospital day 6, the patient’s ECA dabigatran level and aPTT continued to decrease (41.08 ng/dL and 31.5 seconds, respectively), and her TT was 117.3 seconds. Based on these laboratory test values and the passing of 5 days since the last dose of dabigatran, it was determined that it was now safe for surgery. The patient had a successful right hip hemiarthroplasty, with an estimated blood loss of 150 mL.
Postoperative day 1 allowed for drain removal and the initiation of enoxaparin 40 mg subcutaneously every 24 hours for deep vein thrombosis prophylaxis (roughly 18 hours after the end of surgery). The patient’s hemoglobin level remained stable for the rest of the hospitalization.
The patient remained stable in the hospital for the next 3 days before being discharged to a subacute care facility on postoperative day 4. Dabigatran was not restarted during the hospitalization or at discharge, with the plan to defer long-term anticoagulation decisions to her managing cardiologist.
The monitoring of ECA and other coagulation laboratory assays in this patient helped assess when surgical intervention could be safely performed in an elderly patient with reduced renal function. While routine monitoring of dabigatran is not a requirement with therapy, the agent has an effect on numerous anticoagulation assays such as the aPTT, PT, INR, TT, and ECA. These values have been shown to coincide with the plasma concentration–time curve for dabigatran.1,3–8 However, some of these measures are more helpful than others for use in a situation like this one.
ECA is specific for thrombin generation, since the assay’s activator, ecarin, is a compound that activates prothrombin to form meizothrombin. Direct thrombin inhibitors can inhibit the thrombin-like activity of meizothrombin, allowing the ECA test to portray a direct measure of dabigatran’s activity. ECA is similar to ecarin clotting time (ECT) in that meizothrombin generation is measured with a chromogenic substrate compared to its impact on the extent of ECT prolongation with ECT.9
Studies have shown a close linear correlation between ECT prolongation and plasma concentrations of direct thrombin inhibitors, allowing for quantification of plasma dabigatran levels.6 ECT is more sensitive than aPTT, particularly at low dabigatran concentrations, making it a better option to determine when it is safe to perform a surgical procedure. Interestingly, ECT is rarely used in clinical practice due to its limited availability at many institutions; however, some institutions do have the ability to measure ECA.3,4 The institution in which this patient was seen could perform the ECA, making it the primary monitoring value for dabigatran in this case. A calibration curve was constructed by running dabigatran calibrators with known drug concentrations. The plasma dabigatran concentration versus the color change of each of the standards was then plotted to obtain a dabigatran curve. The patient’s ECA dabigatran level trends from admission to the day of surgery are presented in Figure 1. While ECA dabigatran levels were used to help determine when it was safe to perform surgery in this case, guidance regarding specific laboratory levels on which to base this risk assessment are lacking.
This case was noteworthy since the anticoagulation team recommended surgical intervention based on analysis of time since last dose, package insert information, and specific ECA dabigatran level thresholds. The threshold recommendations were based on data obtained from pharmacokinetic analyses in relation to the RE-LY trial using ECT assays.8,10 Dabigatran trough concentrations of <50 ng/mL were shown to correlate with an increased risk of thromboembolism in these analyses, and this threshold has been used in further studies of dabigatran, such as the RE-ALIGN trial, to ensure safety. RE-LY trial data indicated a median dabigatran trough concentration of 116 ng/mL (46.7 and 269 ng/mL for the 10th and 90th percentiles, respectively) in patients with major bleeding. Patients with no major bleeding had a median dabigatran trough concentration of 75.3 ng/mL (30.7 and 176 ng/mL for the 10th and 90th percentiles, respectively).8,10,11 An ECA dabigatran value of <50 ng/mL falls below the median values for both of these bleeding categories and was deemed an acceptable goal signifying a diminished dabigatran effect, not absence of dabigatran, after comparison of drug concentrations related to bleeding frequency.
An increase in ECA dabigatran levels on days 3 and 4 provided an additional interesting aspect to this case. The patient’s last dose of dabigatran was on the morning of hospital day 1, but ECA dabigatran level elevations were documented as late as day 4. This phenomenon might be explained by dabigatran rebounding from tissues back into the plasma as a part of dabigatran’s 2-phase distribution model.2 Unfortunately, we had no need for an ECA dabigatran level on the day of admission; it would have been informative to see if that level was lower than on the following day to support this theory. There was no evidence of any decrease in renal function during this admission. Table 1 contains an overview of the anticoagulation assays monitored during the patient’s hospital stay.
The aPTT assay is also an option to detect dabigatran’s effects secondary to its wide availability. Variations in aPTT levels can be seen based on the type of coagulometer and the sensitivity of the reagent used; however, aPTT has less variability than does PT. With a long-term standard dabigatran etexilate dosage of 150 mg twice daily, median peak and trough aPTT levels of 2 and 1.5 times control values, respectively, may be seen. The aPTT has demonstrated a curvilinear prolongation of aPTT with dabigatran doses of up to 200 ng/mL and then leveled out above this range, favoring the notion that this assay may lack sensitivity to detect high and likely supratherapeutic dabigatran concentrations.3,4,12,13 The use of aPTT measurements to quantify the anticoagulation effect of dabigatran is not appropriate, especially with high plasma dabigatran concentrations. However, aPTT values may allow for a qualitative indication of dabigatran anticoagulation activity and may prove beneficial when assessed along with another test. In this case, concurrent normalization of the aPTT along with achievement of the target ECA dabigatran level gave us confidence the patient was ready for surgery. It is unclear if a normal aPTT alone is a safe indicator for surgery since it is not sensitive to low levels of dabigatran. However, a normal aPTT along with a normal or measurable TT might be another option to help determine when surgery is safe.
PT is another coagulation assay that represents clotting time in the extrinsic pathway. The PT assay provides little assistance in determining anticoagulation effects of dabigatran at therapeutic doses, with only a slight elevation in INR seen. Evidence of PT elevations with supratherapeutic dabigatran concentrations exists, but its use in guiding interventions or the need for reversal is unfavorable based on its poor sensitivity and assay variability.3,4 Due to our patient’s significantly elevated PT on admission, along with the timing of the last dose of dabigatran, no other coagulation laboratory assays were recommended for that day.
Another assay of consideration is TT, which provides a direct measure of dabigatran’s activity due to its direct assessment on thrombin’s activity in a plasma sample and linear dose–response to therapeutic concentrations of the agent; it is also more widely available than ECA. However, TT will rapidly reach a maximum response and is unable to identify excessively high dabigatran concentrations.7 The high sensitivity of this monitoring parameter limits its effectiveness in quantifying medication levels. However, in cases such as ours, it can be very useful to detect the presence of dabigatran in a patient’s blood.3,4,12 The drop in TT on hospital day 6 was yet another useful indicator that the patient was ready for surgery. While the TT on day 6 was not indicative of an absence of dabigatran in the patient’s serum, it provided confirmation that dabigatran concentrations had decreased, ECA dabigatran level was nearing our goal, and aPTT was declining to within normal range.
The effect of renal dysfunction on dabigatran clearance was clearly displayed in this case. Dabigatran undergoes 80% renal elimination and has a half-life of 12–17 hours in healthy subjects. In patients with moderate renal dysfunction (CLcr of 30–50 mL/min), the dabigatran half-life is 18 hours and the AUC increases to 3.2 times the AUC in normal renal function (CLcr of >80 mL/min). However, in patients with severe renal dysfunction (CLcr of <30 mL/min), a longer half-life of 27 hours has been seen, along with an AUC that is 6.3 times higher than in patients with normal renal function.1
This patient’s initial SCr was 1.15 mg/dL, which calculates to a CLcr of 33 mL/min, and she was previously receiving dabigatran 150 mg twice a day, the approved dose for patients with this CLcr value. It is important to recognize the effects that renal function may have on dabigatran elimination as accumulation of dabigatran may have occurred in this case secondary to the patient’s moderate renal dysfunction.
Utilization of reversal agents for dabigatran is another topic of interest. The package insert for dabigatran suggests that prothrombin complex concentrates (such as Feiba NF [Baxter Healthcare, Westlake Village, CA]) and recombinant factor VIIa may be considered for reversal.1 Feiba NF was available for our patient in case of bleeding during or after surgery but was not recommended for more active reversal since this was not an emergency situation and it would confer a thrombotic risk to the patient. Feiba NF was available in case of intraoperative or postsurgical bleeding in the operating room pharmacy but was never needed. Another option for dabigatran clearance is dialysis, which removes nearly 57% of dabigatran over 4 hours.1 However, there was not a strong desire to use this removal mechanism for the presented patient, especially due to the challenge of central line placement in a patient on dabigatran and the risk of bleeding.
More recently, idarucizumab has gained approval from the Food and Drug Administration for the use of dabigatran reversal for emergent procedures or in life-threatening or uncontrolled bleeding based on clinical trial data. This agent would have been useful in our case, as our patient showed signs of delirium on hospital days 4 and 5, and we were very concerned about further delays of surgery. The monitoring strategies we used in this case could be used if we had idarucizumab at our disposal. The ECA, aPTT, and TT levels could have been used after administration to demonstrate anticoagulation reversal and monitor for any postoperative rebound in dabigatran levels.2
Not all direct oral anticoagulants require routine anticoagulation monitoring during therapy. However, there are situations in which checking certain anticoagulation values can be helpful in clinical care. This is an important topic on which all clinicians who care for patients on anticoagulants should be well versed.
Coagulation assay monitoring for dabigatran, with emphasis on an ECA dabigatran concentration of <50 ng/mL, was used to assess safety regarding bleeding risk before a nonemergent surgical procedure in an 86-year-old woman with a right femoral neck fracture.
The authors have declared no potential conflicts of interest.
At the time of writing Dr. Byron was affiliated with South Dakota State University, Brookings, SD.
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