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
(n = 49)
(n = 45)
(n = 34)
(n = 20)
(n = 29)
|Time to surgery after idarucizumab (hours)a||1.7||1.9||1.4||1.3||1.2|
|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|
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.