Rapid Reversal of Dabigatran in Patients Requiring Emergency Surgery

Dabigatran, a direct thrombin inhibitor, is used for stroke prevention in nonvalvular atrial fibrillation (AF) and the prevention and treatment of venous thromboembolism (VTE). RE-VERSE AD was a multicenter, open-label prospective study that enrolled 503 adults taking dabigatran at 173 centers in 39 countries. The trial examined the ability of idarucizumab, an antigen-binding fragment with a high affinity for dabigatran, to reverse the anticoagulant effect of dabigatran in patients with life-threatening bleeding or those requiring emergency surgery/invasive procedures.

Jerrold H. Levy, MD, of Duke, presented greater detail on patients undergoing emergency surgery or an invasive procedure in the RE-VERSE AD study at the American Heart Association's Scientific Sessions held November 11 to 15, 2017, in Anaheim, CA.

RE-VERSE AD enrolled 202 patients who required urgent surgery or a catheter-based procedure within 8 hours. Two infusions of idarucizumab 2.5 mg were administered no more than 15 minutes apart. Blood samples were taken at approximately 20 minutes, 1 hour, 2 hours, and 4 hours after the second infusion of idarucizumab. The primary endpoint was maximum reversal of dabigatran assessed using coagulation assays: diluted thrombin time and ecarin clotting time. Secondary endpoints included hemostasis during the surgery or procedure.

Patients enrolled in RE-VERSE AD were older. In addition, more than 90% of those undergoing surgery had AF; all patients in the drainage and catheter groups had AF. Diabetes, heart failure, coronary artery disease, and previous stroke or transient ischemic attack were common baseline characteristics.

"RE-VERSE AD had a complex, critical ill patient population. All patients had impaired creatinine clearance, which is important because dabigatran is principally cleared through the kidneys. Most patients had multiple comorbidities, with about one-third having heart failure," Levy commented. "This reflects the real-world patient population."

At baseline, patients undergoing surgery had an average dabigatran level of 80 to 90 ng/mL, with individuals in the catheter group having average levels of about 100 ng/mL. More than 95% of patients achieved maximum reversal of dabigatran within 4 hours. Levy noted, "There was rapid total reversal of dabigatran after administration of idarucizumab."

The majority (72%) of patients underwent surgery; 28% had a catheter-based procedure. Orthopaedic (n = 45), abdominal (n = 49), and vascular (n = 34) composed the majority of surgeries. The time from administration of the first vial of idarucizumab was 1.4 to 1.9 hours for surgery and 1.2 hours for catheter-based procedures.

The surgeon or interventionalist assessed hemostasis, the secondary endpoint of RE-VERSE AD. More than 90% of patients had normal hemostasis at the time of surgery or procedure. Mildly abnormal hemostasis, defined as oozing not requiring intervention, affected 3.4% of patients undergoing a catheter-based procedure and up to 6.7% of patients undergoing surgery. Hemostatic therapy was frequently used. For instance, fresh frozen plasma was given to 10% to 20% of patients, and packed red cells were given to 20% to 40% of patients.

TABLE 1. Key Data From RE-VERSE AD Emergency Surgery Patients

Characteristic Abdominal
(n = 49)
(n = 45)
(n = 34)
(n = 20)
(n = 29)
Median age 79 80 70.5 82.5 76
Time to surgery after idarucizumab (hours)a 1.7 1.9 1.4 1.3 1.2
Hemostasis (%)          
   Normal 91.8 91.1 94.1 95.0 93.1
   Mildly abnormal 6.1 6.7 5.9 5.0 3.4
   Moderately abnormal 2.0 2.2 0.0 0.0 3.4
   Severely abnormal 0.0 0.0 0.0 0.0 0.0
Use of hemostatic therapy (%)          
   Fresh frozen plasma 10.2 11.1 2.9 10.0 20.7
   Packed red cells 20.4 37.8 35.3 20.0 27.6
   Platelets 2.0 4.4 8.8 5.0 10.3
   Whole blood 0.0 2.2 2.9 0.0 3.4
   Volume expanders 12.2 11.1 11.8 20.0 20.0

aMeasured after administration of first idarucizumab vial.
Mildly abnormal = oozing not requiring intervention, moderately abnormal = controlled with local intervention,
severely abnormal = refractory hemorrhage.

Mortality rates were 5% to 10% at 30 days for patients who had surgery. Rates were higher in the catheter group, as 10 patients had sepsis at the time of enrollment, 9 of whom died within a few days. A few patients experienced a thrombotic event at 30 days; these patients had not been placed on VTE prophylaxis. About 80% of patients resumed oral anticoagulation within 5 to 10 days of the surgery or procedure.

RE-VERSE AD showed that idarucizumab quickly reverses the anticoagulant effect of dabigatran in more than 95% of patients. Surgery or invasive procedures were performed within 1.2 to 1.9 hours from administration of idarucizumab, and normal hemostasis was attained in more than 92% of patients. No safety concerns with idarucizumab were apparent. Levy concluded, "Idarucizumab facilitates management of patients requiring urgent procedures by providing specific and rapid reversal of dabigatran."

Source: Levy JH, Sellke FW, Reilly PA, et al. Idarucizumab in dabigatran-treated patients requiring emergency surgery or intervention: updated/final results from the RE-VERSE AD study. Presented at: American Heart Association Scientific Sessions 2017; November 11-15, 2017; Anaheim, CA. Abstract 297.