Advent of an antidoteJuly 16, 2018
How idarucizumab transforms the conventional anti-coagulation therapy using dabigatran
Patients with recurrent ischemic stroke are typically given anticoagulant drugs to prevent stroke. In India, one of the most commonly known anticoagulants amongst physicians is the vitamin K antagonist, warfarin. Warfarin, initially discovered as a rat poison and later approved for medical purposes, acts as a blood thinner by interfering with normal blood clotting pathways involving vitamin K. Several over-the-counter medications (drug-drug interactions) and foods rich in vitamin K (drug-food interactions) interfere with the effectiveness of warfarin and result in either under or over anticoagulation. Therefore, effects of warfarin must be frequently monitored by checking prothrombin time/international normalized ratio (PT/ INR). The need for regular monitoring is one of the major drawbacks of using warfarin.
The recent discovery of dabigatran, another oral anticoagulant, as an efficacious warfarin alternative that does not require regular monitoring has changed the treatment choice for stroke. Dabigatran directly inhibits thrombin function to prevent blood coagulation and was approved in India in late 2011. While clinical studies have shown that a 150-mg dose of dabigatran was superior to warfarin in preventing stroke, unlike warfarin, it has a predictable pharmacokinetic and pharmacodynamic profile with minimal drug-drug interactions and drug-food interactions. Thus, the use of dabigatran has eliminated the need for frequent PT/INR monitoring. However, until very recently, a major setback for dabigatran use was the absence of an antidote. Warfarin effects can be easily reversed by the administration of vitamin K, prothrombin complex concentrate, or fresh frozen plasma. The absence of such an antidote poses a huge risk for using dabigatran in life-threatening or uncontrolled bleeding and in emergency/urgent procedures, when the effect of dabigatran needs to be immediately neutralized. A 2015 study showed that a monoclonal antibody fragment, idarucizumab, that bound to free as well as thrombin-bound dabigatran, could reverse the anticoagulant effect of dabigatran in minutes. While the U.S. Food and Drug Administration gave accelerated approval for the use of this monoclonal antibody in 2015, it was only in 2018 that idarucizumab got full approval. A recent case in Amrita Hospital in Kochi truly illustrated the value of this monoclonal antibody fragment, which has been available in the Indian market only for the past few months.
A 60-year-old veteran patient with recurrent stroke came to the Stroke Division at Amrita Hospital, Kochi, with another incidence of stroke. Brain MRI and MR angiogram showed that there was a block in the left middle cerebral artery. This indication called for an emergency surgery. However, the patient was on dabigatran and had just taken the last dose on the morning of the incident. A few months ago, this would have lead to a delay in performing the surgery until dabigatran levels could be brought down (dabigatran should be stopped 2-4 days before a major surgery with a high risk of bleeding). However, since the reversal agent for dabigatran was available in India, the surgery could be performed without an unnecessary waiting period. Time to surgery can be a major determining factor in the effectiveness of clot-removing surgeries for stroke. In this case, idarucizumab was first given to neutralize dabigatran before the administration of the clot busting drug, alteplase. Alteplase is a tissue plasminogen activator that is involved in dissolving blood clots and improving blood flow to the deprived part of the brain. Prompt administration of clot-busting drugs can not only save lives, but also reduce the long-term effects of stroke. For effective use, alteplase must be administered within 3-4 hours after having stroke. Without idarucizumab, if the patient is on dabigatran, administration of alteplase within this time frame would be impossible, and this would have resulted in an unfavourable outcome for the patient. Alteplase was effective in the removal of the blood clot and the patient improved dramatically, regaining speech and communication in a short period of time.
‘The new discovery of idarucizumab has made a sea of change in the ease of effectively using the modern and convenient anticoagulant, dabigatran’, says Dr Vivek Nambiar, Head of Stroke Division at Amrita. ‘Our patient was extremely lucky that the antidote was available in the Kochi market when he needed it and that we were able to operate on him immediately’