Latest anticoagulants—nuts and bolts for labs

February 2013—The list of anticoagulants has grown in recent years, which means there’s more to know about whether, when, and how to monitor. Last month in CAP TODAY, Michael Laposata, MD, PhD, spoke briefly about the newer drugs and explained how the older ones—warfarin, heparin, and low-molecular-weight heparin—work, and what that means for labs. This month, he returns to the newest of the major anticoagulants.

He presented this information last year in an AACC webinar and again at the CAP ’12 annual meeting, where he also covered antiplatelet drugs. His comments in CAP TODAY come from an edited and updated transcript of the webinar.

Dr. Laposata is the Edward and Nancy Fody professor of pathology; executive vice chair of pathology, microbiology, and immunology and professor of medicine, Vanderbilt University School of Medicine; and pathologist-in-chief, Vanderbilt University Hospital, Nashville.

In 2008, The Wall Street Journal Online followed a problem in which heparin, which had been received from China where it was made, was contaminated with another glycosaminoglycan. The coverage highlighted the process by which raw heparin was made: The company picks up barrels of pig intestines from slaughterhouses, and workers use a machine to wring the fecal material from inside those intestines. Most of us don’t want our IV drugs to sit next to fecal material, but that is where heparin and LMW heparin come from. Many years earlier it had been asked: If you can make heparin shorter, how short can you make it? They realized it had to be only five sugars long. This was fondaparinux (Arixtra). It’s a single chemical entity—it’s going just for factor X. And this is all that’s needed to back into the back of antithrombin and change that conformation. No one need worry about what the pigs are doing, and it can be made the same every time. Five sugars could be put together, cost-effectively, in a pharmaceutical operation.

Who would think that cutting several sugars off a low-molecular-weight heparin would change its pharmacokinetics much, but does it ever! One to three hours after a subcutaneous injection of fondaparinux, you get a nice anticoagulant effect—lasting about a day—and it’s predominately eliminated unchanged in the urine. Patients with impaired renal function have difficulty getting rid of this drug, so it must not be given to such patients.

There is no reversal agent, and when the drug was introduced, this new concept of an anticoagulant without a reversal agent was frightening. It has a long half-life of about 20 hours. Fondaparinux has been used as prophylaxis, often as we have used enoxaparin (Lovenox) and dalteparin (Fragmin). It can also be used therapeutically in a higher dose.

Lepirudin (Refludan) and argatroban are direct thrombin inhibitors that are administered intravenously. Lepirudin is derived from the leech compound hirudin. How does a leech suck blood? If you were a leech on someone’s skin, you would want to anticoagulate the blood so it’s easier to suck it out. So leeches were killed for their anticoagulant protein and a recombinant protein was made, and that’s what lepirudin is.

We can monitor it easily with a partial thromboplastin time (PTT) test (to 1.5–2.0 × mean of normal range). The drug is expensive because it’s recombinant, so why use it? If a patient has heparin-induced thrombocytopenia, he or she is allergic to heparin, and anything that is heparin or looks like heparin could be trouble. That is why lepirudin and argatroban surfaced with great flourish. The half-life is one hour if you have normal renal function. In end-stage renal disease it’s 52 hours on average, making it hard to compensate for a mistake of giving it to a patient with severe renal disease.

Argatroban is a synthetic chemical compound—it is not a recombination protein. It is monitored with a PTT, and it is administered intravenously.

We have to monitor it a lot, often about every six hours, to keep it in the window where the PTT needs to be (1.5 to 2.0 × mean of normal range). It’s for patients with heparin-induced thrombocytopenia, and especially those with impaired renal function because this drug is removed by the liver primarily, unlike lepirudin, which has renal elimination. This is the drug most physicians are going to use first with HIT if an intravenous line is in. The half-life is 20 minutes; that’s good if you make a mistake.

If you have bad hepatic function, you can cut the dose by, say, three-quarters, and you get the PTT where you want it and you can still use it. And importantly, it’s a bit forgiving, with the standard dose at 2 mg/kg per minute. So argatroban has won the battle over lepirudin for patients with HIT. As with fondaparinux and lepirudin, there is no reversal agent for argatroban.

Dabigatran (Pradaxa) is a newer drug. It inhibits factor IIa, the activated form of factor II. The drug is dabigatran etexilate, which is a prodrug that is converted in the liver to the active compound dabigatran. The antiplatelet agents Plavix and prasugrel are also prodrugs, which the liver converts into a drug that will slow blood clotting.

The RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) looked at dabigatran etexilate versus warfarin and found that 150 mg of dabigatran twice daily prevented more strokes or systemic embolisms than warfarin. And there were fewer major bleeds and far fewer intracerebral hemorrhages.

The half-life is 12 to 17 hours, and it’s only slightly longer at 15 to 18 hours in the elderly and others with mild to moderate renal impairment.

Here is what we didn’t know much about before dabigatran was released: A lot of people (10 to 20 percent) taking dabigatran have abdominal pain. In our practice it’s about 30 percent of patients. Some have even told us that as much as they do not want to return to warfarin and having INRs performed, and regulating their diets, they’re doing so.

Dabigatran has a Food and Drug Administration indication for atrial fibrillation. But studies have shown a good anticoagulant effect for postoperative thromboprophylaxis and a positive effect for other conditions such as venous thrombosis—all the things warfarin is used for, so new indications for dabigatran may arise.

There is no reversal agent for dabigatran. Some have begun to say they will try recombinant factor VIIa, NovoSeven, at about $1,000 per milligram—a very expensive way to reverse dabigatran—and possibly at a less than standard dose of 90 mg/kg. Another possibility: activated prothrombin complex concentrates.

Jack Ansell, MD, of Lenox Hill Hospital in New York, who has been involved in many of the studies of the new anticoagulants, has said that a dose of VIIa that is less than the full dose of 90 μg/kg, perhaps 30 mg/kg, might be used to treat the bleeding patients. The 90 μg/kg dose is used to stop bleeding in a patient with a factor VIII inhibitor. Alternatively, hemodialysis can remove about 60 percent over two to three hours. That is not an option for the other irreversible anticoagulants.

The FDA indication for dabigatran is for prevention of stroke and systemic embolism in patients with atrial fibrillation. If under age 80, the dose is 150 mg twice daily. For patients age 80 and older, it’s 110 mg twice daily. For those with severe renal impairment, it’s 75 mg twice daily.