Latest anticoagulants—nuts and bolts for labs

Let’s say a patient goes to a party and forgets to take her Coumadin at bedtime, as it’s supposed to be taken once a day. She wakes up in the morning and realizes she forgot. She can take her Coumadin, and her INR, if it was 2.5, might have gone down to 2.2 or 2.1, but she is still therapeutic. What if you have a drug where if the patient doesn’t take it, she’s fully coagulable at the time of the very next dose? If she forgot her dose, and the half-life is about 12 hours, she is well on her way toward normal again. And if she forgets it for a whole day, she’s almost fully coagulable. It’s very important that the patient not miss a dose of dabigatran. Twice daily dosed anticoagulants are more worrisome for the patients who are not highly compliant with their medications.

It’s easy to convert people from low-molecular-weight heparin or warfarin to dabigatran. For LMW heparin, if you’re giving it twice a day, you substitute the dabigatran when you were going to give the next dose of LMW heparin. If converting from warfarin, the INR must be less than 2.0 when the dabigatran is started.

How long before surgery must dabigatran be discontinued? It’s about a day for minor surgery and two days for larger procedures or ones when a small bleed may be very dangerous. It may require bridging therapy, using a shorter-acting anticoagulant before surgery, and that is something most doctors have yet to deal with. How long after surgery before you can re-start? Six hours is a common practice.

Patients on dabigatran need not be monitored routinely. That’s why some patients taking dabigatran are surprised others are still on warfarin therapy and having to still be tested for an INR value. But what happens if the patient’s blood dabigatran activity is unknown—we don’t use the INR for dabigatran—and he or she starts to bleed? Is it because the dabigatran level is too high? It is in this situation that a plasma dabigatran level can be highly informative. A dilute thrombin time test can be used to determine the anticoagulant effect of dabigatran because the relationship between plasma dabigatran and the clotting endpoint in the dilute thrombin time test is linear.

If you want to find out if residual dabigatran is present, because it’s a direct thrombin inhibitor, the standard thrombin time is highly sensitive for residual dabigatran. A normal thrombin time test in a patient who has been treated with dabigatran indicates the drug is no longer effective.

In the patient on dabigatran who develops a thrombotic stroke, the plasma concentration of dabigatran can be measured to determine if the patient suspected of poor compliance is taking the drug.

In Fig. 1, notice the thrombin time and how a little dabigatran pushes it way up. That’s why if the thrombin time is normal, there’s no dabigatran. You couldn’t use it to monitor, however, because it is not linear through the concentration of dabigatran that you might have in the blood. A dilute thrombin time works much better. The PTT is not linear, and the PT is not sensitive.
Dabigatran costs $5.46 per day for 150-mg tablets twice a day, and warfarin is 37 cents a day. That’s about $1,500 more per year than warfarin. If a large percentage of patients on warfarin were to switch to dabigatran—say 10 million people—the additional yearly cost would be $1.5 billion for the one medication switch.

The movement from warfarin to dabigatran has been substantial: millions of users. The return of dabigatran patients to Coumadin is not negligible, but it is small. So people are definitely moving forward with this. The dietary impact of eating foods with large amounts of vitamin K (broccoli, cauliflower, chick peas, and leafy vegetables as examples) and the interaction of warfarin with other drugs can create havoc because it can make the effect of warfarin larger or smaller. The logistics of life on Coumadin are challenging, so I think that the movement will continue, though I do not think everybody will come to use dabigatran, rivaroxaban, or apixaban [see page 11]. There will still be Coumadin users, because they’ve been using it and doing fine with it. However, a lot of the new users are likely to begin with other drugs.

Bivalirudin (Angiomax) is delivered intravenously, it inhibits thrombin (factor II), and it has a short half-life of 25 minutes. In a patient who has severe renal impairment, the half-life is about an hour. We can give it to those who have heparin-induced thrombocytopenia and have to undergo cardiac surgery. The bypass pump has to be used, and you don’t want to put whole blood through plastic and not have it anticoagulated because you can end up with clotting.

We typically don’t think of it as one of our routine anticoagulants because it’s monitored by an activated clotting time (ACT) rather than PT, INR, or PTT. It must be discontinued eight to 10 hours before surgery, and if we choose to continue with it postoperatively, we restart it two to four hours after surgery is completed. We monitor with the activated clotting time because bivalirudin prolongs the PTT to its maximum value. It is very expensive: $214 per treatment.

Rivaroxaban (Xarelto) is an oral direct inhibitor of factor Xa, so we use the anti-factor Xa assay. When compared with Lovenox, which is good at preventing clots in patients undergoing total hip arthroplasty, rivaroxaban is better. The RECORD1 study (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1) found it to be significantly more effective than Lovenox for preventing venous thromboembolic events. It was not associated with any significant increases in major bleeding or other bleeding events. So one FDA-approved clinical indication is postoperative thromboprophylaxis for patients undergoing elective total hip or knee replacement. It has more recently been approved by the FDA for treatment of venous thrombosis, primarily deep vein thrombosis in the extremities and pulmonary embolism. Like dabigatran, it is also approved for non-valvular atrial fibrillation.

It has a half-life of five to nine hours—a little shorter than dabigatran, and the elderly have a little longer half-life at 11 to 13 hours. We don’t have a good reversal agent, but there is evidence that prothrombin complex concentrates can be effective in reversing rivaroxaban. You’re dealing with major firepower, strong procoagulants, when shutting off dabigatran and rivaroxaban.

For recovery from hip or knee surgery, the patient might take Lovenox for 14 days. If the patient takes rivaroxaban for 35 days, he or she runs a lower postoperative DVT risk. We want to discontinue it 22 to 26 hours before surgery. The half-life is about five to eight hours. We’re still waiting four or five half-lives before surgery. After surgery, we are waiting four to six hours to restart the anticoagulant.

No routine monitoring is needed with rivaroxaban, though patients with extremes of body weight may require monitoring. The assay to use to monitor rivaroxaban therapy is the existing anti-factor Xa assay. The prothrombin time may correlate with rivaroxaban concentrations in the plasma, but it does not work for all PT reagents. There are far fewer drug interactions than with warfarin (Fig. 2). The thrombin time doesn’t rise much either. The prophylactic dose of 10 mg per day is $5.76.

Apixaban (Eliquis), another anti-factor Xa inhibitor, has been FDA-approved for stroke prevention in patients with atrial fibrillation, only for the past few months. More to come on apixaban as we gain clinical experience.

To sum up: Determine which anticoagulant is on board. Decide how to manage the patient based on the procedure to be performed. Perform monitoring for anticoagulant effect if it’s needed. For all patients, know what to do if they’re bleeding, possibly because they got too much. Know what to do if they’re clotting, meaning they probably don’t have enough. And know what to do in the laboratory to address both of those scenarios.

The biggest challenges are the anticoagulants that have no established reversal agents, or that have a powerful reversal agent that can induce thrombosis, moving the coagulation speedometer needle quickly from bleeding all the way to thrombosis.

Find part one of Dr. Laposata’s talk in the January 2013 issue of CAP TODAY.