Tuesday, May 05, 2015

Perioperative management of patients taking target specific oral anticoagulants

Although the target specific oral anticoagulants (TSOAC) have been validated in clinical trials and approved for several years in the U.S., high level data regarding certain aspects of their use are lacking.  As a result, clinicians have had to look to low level reports, expert opinion and pharmacokinetic information for guidance in situations such as bleeding and perioperative management.  Because the experience has grown and opinions change this has been a moving and controversial target.  Keeping up with continuously evolving recommendations has been a challenge.  Thus it is appropriate to revisit the topic of perioperative management. 

Key issues are:

How long to hold the drug before non-emergent surgery

How soon to restart the drug after surgery

How to assess for drug activity via laboratory testing

How to deal with bleeding

This post draws from two reviews, one published in the NEJM in 2013 and another just published review in Critical Care Forum.  Recommendations differ slightly between the two reviews.  Although the CCF article is more recent there's no reason to say one is better than the other since no high quality evidence came out during the interval.

How long to stop the drug before non-emergent surgery

NEJM review recommendations---

Dabigatran:  For creatinine clearance 50 and above 1-2 d;  for clearance below 50 3-5 d.  Consider holding longer for procedures deemed to be at high risk.

Rivaroxaban:  For normal clearance at least 1 day; for clearance of 60-90, 2 d; 30-59, 3 d; 15-29, 4 d.  Consider holding longer in high bleeding risk procedures.

Apixaban:  For clearance over 60, 1-2 d; 50-59, 3 d; 30-49, 5 d.  In this case a distinction between high and low bleeding risk procedures was not made, but the authors of the NEJM review vaguely suggest allowing more time in high risk procedures.  (In fact the NEJM authors make a blanket statement for all three drugs, regardless of procedure bleeding risk, to allow more time than the above statements recommend).

Note that the recommendations for the three drugs are inconsistent in their wording and categorization.  That's because they are derived largely from product labeling which is subject to various quirks in FDA approval terms and conditions for the respective drugs.

CCF review recommendations---

Dabigatran:  For clearance of 80 or above at least 24 hrs for low bleeding risk procedures and 48-72 hrs for high risk;  50-80, at least 36 hrs for low risk, at least 72-96 hrs for high;  30-50, at least 48 and 96 hs respectively.  If concomitant interacting drugs (anti-platelet agents, amiodarone) add 12 hrs.

Rivaroxaban and Apixaban (no distinction made, in contrast to the NEJM article):  Clearance of 80 or above, at least 24 hrs for low risk, at least 48 hrs for high;  50-80, at least 24 hrs for low, at least 48-72 hrs for high;  30-50, at least 24 hrs for low, at least 72-96 hrs for high; 16-30, at least 36 hrs for low, at least 96 hrs for high.  Add 12 hrs for the presence of interacting drugs (same drugs as for dabigatran). 

When to restart post op

No distinction among the three drugs applies to this recommendation.

From NEJM---no recommendation concerning low risk procedures; at least 48 hrs for high risk.

From CCF---6-8 hrs for low risk, 48-72 hrs for high risk.

Laboratory testing to assess residual drug effect

From NEJM---

Dabigatran:  aPTT  (normal value may rule out significant residual effect).

Rivaroxaban:  PT or anti-Xa  (normal values may rule out significant residual effect).

Apixaban:  Anti-Xa.

Differences in the recommendation for the latter two drugs, which are in the same class, may reflect labeling quirks rather than real biologic difference.

From CCF---

Dabigatran:  Thrombin time (Haemoclot).

The other two:  anti-Xa

Note:  Having blogged this topic extensively I can tell you that the recommendations on laboratory testing for drug effect are extremely variable.  Despite the convenience of the PT and PTT their use for this purpose is controversial.  On the other hand TT and anti-Xa assays are not readily available in many hospitals. 

How to deal with bleeding

From NEJM---

Dabigatran:  Consider factor VIII inhibitor bypass activity (FIBA), VIIa, and/or hemodialysis.

Rivaroxaban:  Consider PCC.

Apixaban:  Consider PCC or charcoal hemoperfusion.

From CCF---

No distinction made among the drugs.  For all, consider PCC or FIBA.  Dialysis is mentioned as a possible remedy in the body of the paper for dabigatran but not included in the final recommendations.

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