Reversing Anticoagulant Effect of Dabigatran

SOURCE: Glund S, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: A randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015;386:680-690.

Dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) comprise what has been recently labeled the novel oral anticoagulants (NOACs). Their use has been popularized, particularly in atrial fibrillation, due to stroke reduction that equals or surpasses that of warfarin, with less risk of cerebral hemorrhage. Drug and food interactions with warfarin, as well as the requirement for ongoing monitoring, make its use somewhat complicated. Since no monitoring and minimal drug/food interactions occur with NOACs, use is simpler. All anticoagulant agents are associated with an increased risk of bleeding. The effects of excessive anticoagulation with warfarin may be reversed by the administration of vitamin K, or, when urgent warfarin reversal is indicated, by use of fresh frozen plasma or prothrombin complex concentrates. To date, no similar antidote to reverse the anticoagulant effects of NOACs has been available.

Idarucizumab is a monoclonal antibody to dabigatran. In this clinical dose-ranging study of idarucizumab, healthy volunteers were treated with dabigatran 220 mg twice per day and on the fourth day of dabigatran treatment, idarucizumab was administered to coincide with peak plasma levels of dabigatran.

At all idarucizumab doses of ≥ 2 g, the anticoagulant effects of dabigatran were immediately and completely reversed. Because dabigatran dissociates slowly from the dabigatran-idarucizumab complex, the reversal of anticoagulation was still fully in effect for 72 hours.

No serious adverse effects were seen with idarucizumab. These results are very encouraging. A tool for reversal of NOAC effects may soon be available.

Likelihood of Occult Cancer Causing Unprovoked DVT

SOURCE: Carrier M, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med 2015;373:697-704.

Recognized provocateurs of deep venous thrombosis (DVT) include prothrombotic disorders (e.g., antiphospholipid antibody syndrome), oral contraceptives, immobilization, trauma, long-haul air flight, and cancer. When DVT occurs absent recognized risk factors — so-called “unprovoked DVT” — should the clinician consider screening for occult cancer? Expert opinion ranges from “not useful” to “consider extended evaluation.”

Carrier et al report on their randomized controlled trial in Canadian adults who experienced new unprovoked DVT (n = 854) who were randomized to undergo either “limited screening” (complete history and physical, complete blood count, comprehensive metabolic panel, chest X-ray, and sex-specific screening such as mammography, if not previously performed) or “limited screening + CT.” A CT scan of the abdomen and pelvis included virtual colonoscopy/gastroscopy and enhanced CT of the liver, pancreas, and bladder.

At the end of a 1-year follow-up period, 3.9% of the total study group were newly diagnosed with cancer: 3.2% of the limited screen group and 4.5% of the limited screen + CT group (P = 0.28, not statistically significant).

The likelihood of identifying occult cancer in patients with new unprovoked DVT is not meaningfully enhanced by performing extended screening.

CAN Occurs Earlier in Type 2 Diabetes

SOURCE: Zoppini G, et al. Prevalence of cardiovascular autonomic neuropathy in a cohort of patients with newly diagnosed type 2 diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS). Diabetes Care 2015;38:1487-1493.

The most common neuropathy seen in type 2 diabetes (T2DM) is symmetrical distal neuropathy, which usually affects both lower extremities. T2DM is also characterized by a variety of autonomic neuropathies that have the potential to impact adrenergic, cholinergic, and dopaminergic pathways.

Cardiovascular autonomic neuropathy (CAN) may include neuropathy of the heart and vasculature. Sympathetic overactivity in CAN has been associated with arrhythmias and sudden cardiac death. Confirmation of CAN requires somewhat sophisticated tests, and there has been some inconsistency of diagnostic criteria, both of which have likely contributed to a low level of awareness of CAN and its consequences. The Verona Newly Diagnosed T2DM Study (n = 813) included a large subgroup of subjects who agreed to undergo cardiac autonomic testing (n = 557). Depending on the strictness of testing criteria, the prevalence of CAN was at least 1.8% at baseline (strict criteria), but as high as 15.3% when less strict criteria were utilized.

Clinicians typically have thought of neuropathic changes in T2DM as a reflection of long-term disease. This study is the largest population study of newly diagnosed persons with T2DM that studied CAN at baseline. These results suggest that CAN may occur quite early. Whether treatment of diabetes might alter the course of CAN remains unknown.