Episode 148: Interference of oral Xa inhibitors with heparin Xa assays

In this episode I’ll discuss interference of oral Xa inhibitors with heparin Xa assays.

 

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In episode 57 I discussed the new CHEST Guideline recommendations which give preference to the new oral anticoagulants to treat VTE over warfarin in patients without cancer. Naturally, this new recommendation has increased the number of patients that come into the hospital on apixaban, edoxaban, and rivaroxaban.

Parallel to the increase in the use of oral factor Xa inhibitors is the use of anti-factor Xa assays to monitor heparin infusions in hospitalized patients instead of aPTT. I discussed this back in episode 126. To find the therapeutic aPTT range of heparin, the laboratory must compare aPTT and anti-Xa activity in a few samples, then find the best fit line that correlates aPTT to an anti-Xa level of 0.3-0.7 IU/mL.

The main benefits of monitoring heparin by anti-Xa are said to be:

• Better correlation to actual heparin level
• Better defined target that won’t change with each reagent batch (anti-Xa level of 0.3-0.7 IU/mL)
• Less interference from hemolysis, warfarin, liver disease

Current anti-Xa level assays are chromogenic. In the presence of factor Xa inhibition, the color change of the assay can be used to determine the exact heparin level. Color change will occur regardless of whether the factor Xa inhibition comes from heparin, apixaban, edoxaban, or rivaroxaban. Unfortunately, the assays are only calibrated to heparin and not the oral anticoagulants.

The increased use of oral Xa inhibitors and the increased use of anti-Xa level to monitor heparin infusions collide in the hospital to make for some complicated scenarios. The presence of any of the oral factor Xa inhibitors can lead to a falsely elevated anti-Xa level. When a heparin protocol is used, this will lead to an automatic holding or reduction in heparin dose. There is one report of this effect lasting 96 hours in a patient with poor renal function who was taking apixaban 5 mg po twice daily.

There are several reasons why a hospitalized patient may need to bridge from an oral factor Xa inhibitor to heparin. The two most common are:

– The patient has a surgical procedure scheduled and needs to be switched to an anticoagulant with a more rapid onset/offset.
– The patient had a thromboembolic event despite taking the oral factor Xa inhibitor and needs to be anti-coagulated with heparin.

In each of these scenarios, the ability to monitor the heparin infusion using anti-Xa level is hampered by the presence of oral Xa inhibitors. The aPTT however generally returns to normal or near-normal 12-18 hours after the oral factor Xa inhibitors are discontinued.  This means that in patients who were recently on oral factor Xa inhibitors, the aPTT may be a better way to monitor heparin than anti-Xa levels.

In a hospital that uses anti-Xa monitoring for heparin infusions, this makes for a complicated situation. It is common to have multiple heparin protocols for VTE, cardiac, and neuro-critical indications. Monitoring by aPTT in selected patients recently on oral Xa inhibitors would mean the number of protocols needs to double from 3 to 6.

As a recent Clinical Consultation in AJHSP highlights, there is almost no guidance in prescribing information or other references on how to handle this drug-laboratory assay interaction.  Until the laboratory interference can be controlled for, hospitals with anti-Xa heparin protocols will need to develop aPTT heparin protocols to use in patients who have recently received an oral Xa inhibitor.

 

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