Idarucizumab rapidly reverses dabigatran anticoagulation in RE-VERSE AD
Idarucizumab, a dabigatran-reversing humanized monoclonal antibody fragment, rapidly, completely, and durably reversed the anticoagulant effect of dabigatran in elderly patients with life-threatening bleeding or undergoing invasive medical interventions, according to a full cohort analysis of the RE-VERSE AD* study presented at the ISTH 2017 Congress in Berlin, Germany.
Within 4 hours after idarucizumab administration, the median maximum percentage reversal of dabigatran ─ the primary endpoint ─ was 100 percent, as measured by diluted thrombin time or ecarin clotting time. [N Engl J Med 2017;doi:10.1056/NEJMoa1707278]
“A single 5-g dose of idarucizumab was sufficient in 98 percent of the patients, and reversal was maintained for 24 hours in most patients,” said the researchers. “Reversal was rapid and occurred independently of age, sex, renal function, and dabigatran concentration at baseline.”
Among bleeding patients (n=301, median age 79 years), the median time to haemostasis was 2.5 hours after idarucizumab administration.
In patients undergoing invasive procedures (n=202, median age 77 years), the median time to procedure initiation was 1.6 hours, with 93.4 percent of the patients being assessed as having normal periprocedural haemostasis, 5.1 percent being mildly abnormal, 1.5 percent being moderately abnormal, and none had severely abnormal haemostasis.
“The safety of idarucizumab observed in this study supports its urgent use even if patients later prove to have had little or no circulating dabigatran,” the researchers pointed out, noting that some patients had normal baseline clotting time because the study protocol did not mandate the baseline coagulation test results to be available before administering idarucizumab in order to mimic routine emergency care.
At 90 days, the rate of thrombotic events was 6.3 percent for bleeding patients and 7.4 percent for those undergoing invasive procedures, which the authors attributed to a low rate of anticoagulation re-initiation.
There were three potential hypersensitivity events ─ rash, hypotension, and vomiting and loss of consciousness within 5 days of idarucizumab use, which were deemed as being drug-related.
Serious adverse events within 5 days occurred in 23.3 percent of patients. The 30-day mortality rate was 13.5 percent for bleeding patients and 12.6 percent for patients undergoing invasive procedures, and the estimated 90-day mortality rate was 18.8 percent and 18.9 percent, respectively.
“Patients enrolled in this study were elderly, had numerous co-existing conditions, and presented with serious index events, such as intracranial haemorrhage, multiple trauma, sepsis, acute abdomen, or open fracture,” observed the researchers.
“Most of the [serious adverse events and] deaths that occurred within 5 days after enrolment appeared to be related to the severity of the index event or to co-existing conditions … whereas deaths that occurred after 30 days were more likely to be independent events or related to co-existing conditions,” they explained.
According to guidelines, prothrombin complex concentrate is recommended for dabigatran reversal when idarucizumab is unavailable (although with limited high-quality evidence), noted the researchers, and the absence of a control group in the study, therefore, constitutes a major limitation. [Europace 2015;17:1467-1507]
“Although case reports suggest that thrombolysis and thrombectomy can be performed safely after dabigatran reversal with idarucizumab, postmarketing surveillance would be helpful to monitor the effectiveness of idarucizumab for this and other indications and to further assess its safety,” the researchers added.
“The availability of specific reversal agents has the potential to improve the benefit–risk profile of long-term anticoagulant therapy and to increase patient and physician acceptance of such treatment,” they said.