Tuesday, January 11, 2011

ICU Rounds Report - Jan 11, 2011

The end of therapeutic rat poisoning is coming. Coumadin is great for preventing strokes in atrial fibrillation - it reduces overall stroke risk by 70% and clearly improves overall mortality. Yet, it's vastly underutilized (in one study only half of appropriate candidates got it) and it's notoriously difficult to dose. It has a very narrow therapeutic index, requires frequent monitoring and interacts unpredictably with drugs and diet. After decades of trying, big pharma appears to have finally come through with a safer oral substitute. And it will be big. FDA approved less then 3 months ago, it is widely expected to become a first-line recommendation by the ACC/AHA for the prevention of stroke in Afib sometime this year. The relevant European and Canadian heart societies have already made such recommendations.

Dabigatran is direct acting thrombin inhibitor (similar in action to argatroban or bivalirudin) that can be taken by mouth, twice daily. In the gigantic, industry-sponsored, 18,000 patient RE-LY trial, coumadin and dabigatran (at two doses) went head to head. Higher dose dabigatran was more effective at preventing embolic strokes, caused less hemorrhagic strokes and reduced overall mortality. Major bleed rates were equal for both drugs. Main side effects were dyspepsia and more heart attacks (but not enough to affect mortality). Perhaps best of all: it requires no blood monitoring and the dose is largely fixed.

Downside: It's crazy expensive. On the other hand, with frequent lab draws so is coumadin. In one cost analysis considering the indirect cost associated with coumadin (lab draws, travel time, lost productivity) it appears dabigatran is a bit cheaper, but that study used Canadian pricing (Americans pay more for drugs because of complicated political agreements that allow drug companies to charge essentially what they want). So cost remains a question. As do the long term effects - all published followup is 2 years or less.

Here's the relevant low down for when we start seeing ICU patients on it: There is no antidote or reversal apart from time.  Recombinant factor 7 appears effective in animal studies and has been described to work with other direct thrombin inhibitors. Prothrombin complex concentrates and FFP may have a role but nothing has been described or studied. Mechanistically no one expects vitamin K, protamine, amicar or desmopressin (and the like) to aid in reversal. It is easily dialysable.

Dabigatran is metabolized in the liver and excreted partially in the urine. It should be held for renal failure and dosages reduced for renal insufficiency. Mild liver impairment shouldn't effect dosing. Half time is 12 hours, which rises to >18 with kidney failure. Although no monitoring is needed, it usually affects the PTT (2.5x normal is considered an overdose). It has no effect on the INR and the thrombin time (TT) is the most sensitive test of its effect. Unlike heparin, it binds and inactivates thrombin already present in clot. For elective surgery, it should be held 24 hours prior for low risk procedures and 2-4 days for high risk.

N.B. It also appears to be as effective as enoxaparin for prevention and treatment of VTE but it is not approved for this use in the States. It's also fine for use (non-inferior) with Afib cardioversions.
Connolly, SJ, Ezekowitz, MD, Yusuf, S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139.
Schwartz NE. Dabigatran challenges warfarin's superiority for stroke prevention in atrial fibrillation. Stroke. 2010 Jun;41(6):1307-9.
Ryn S. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anti-coagulant activity. Thromb Haemost 2010; 103: 1116–1127

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