Pradaxa

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Pradaxa in VTE prevention
Clinical data from the RE-NOVATETM and RE-MODELTM trials, included in regulatory submissions to the European medicines Agency, support the clinical efficacy of Pradaxa in VTE prevention. At doses of 150mg or 220mg, orally administered Pradaxa proved as safe and effective as the injectable low-molecular weight heparin, enoxaparin 40mg, in preventing VTE and all cause mortality following total hip and knee replacement surgery.
"Patients given a 150mg dose of Pradaxa had a 34% lower risk of stroke or systemic embolism than patients given Wafarin
Incidence of major bleeding, the main safety concern with thromboprophylaxis, was comparable between treatment arms and low in both trials (range 1.3–2.0%). Likewise, the incidence of raised hepatic enzyme levels was similar between treatment arms.
Pradaxa's first indication is for VTE prevention. Boehringer completed the Phase III Randomised Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study of the drug in 2007, and the results were disclosed in 2009.
A total of 18,113 non-valvular atrial fibrillation patients with at least one risk factor for stroke were enrolled for two years and were administered randomised treatment with Wafarin or Pradaxa.
The results indicated that the patients who were administered with a 150mg dose of Pradaxa had a 34% lower risk of stroke or systemic embolism than patients given Wafarin.
"Two other oral anticoagulants are waiting in wings that are likely to challenge Pradaxa."
Marketing commentary
Developing a suitable alternative to Warfarin has been the driving force of anticoagulant research for years. Hopes were first raised at the end of 2003 when Exanta (ximelagatran), an oral direct thrombin inhibitor, was approved in Europe.
However, they were subsequently dashed when it was withdrawn from the market in 2006 because of hepatic toxicity.
Hopes have now been raised again with European Medicines Agency approval of Pradaxa. Two other oral anticoagulants are waiting in wings that are likely to challenge Pradaxa in the thromboprophylaxis market: Bayer's Xarelto (rivaroxaban) and Bristol-Myers Squibb's/Pfizer's apixaban.
 
http://healthcare.utah.edu/thrombosis/newagents/TS.Dabi_Provider.Info.pdf


Click on the above link. Until ASRA publishes recommendations (5 years from now?) my best guess is patients need to stop taking this class of drugs for 3 days prior to a Neuraxial Anesthetic. Maybe, patients with severe Renal impairment should stop taking it 4 days prior to a major surgery (open AAA) or an Epidural.

The use of a TEG or similar clotting device may be of use for those wanting to do a neuraxial block on patients only off this drug for 2 days or less. However, this is unchartered waters so I am going to keep it simple for now (KISS).
 
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Mechanism of Action


Dabigatran and its active metabolites are competitive, direct thrombin
inhibitors that inhibit both free and clot bound thrombin. Dabigatran prevents
thrombin-induced platelet aggregation.


pradaxa.png








Pharmacokinetics


Dabigatran is an oral medication that is ~35% plasma protein bound with
a 50-70 L volume of distribution. Dabigatran is a substrate of the efflux
transporter P-glycoprotein, but is not an inhibitor, inducer, or substrate of
CYP450 enzymes. Dabigatran is eliminated primarily in the urine. The half-life
of dabigatran is 12-17 hours in healthy subjects. Dabigatran prolongs the
activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and
thrombin time (TT) at recommended therapeutic doses. In patients receiving the
150 mg dose in the RE-LY trial, the median trough aPTT was 52 (40-76) seconds
and the median trough ECT was 63 (44-103) seconds. The INR may or may not be
elevated in patients receiving dabigatran and is relatively insensitive to the
activity of dabigatran.
 
IMHO, until more research is performed on these thrombin inhibitors the use of PTT monitoring to determine whether a patient "qualifies" for a Neuraxial block is insufficient.

The TEG could be abnormal and the activity of Pradaxa may be present even when the PTT normalizes. So, until we get more data patients should probably be off Pradaxa for 3-4 days and have a normal PTT prior to the administration of a Neuraxial anesthetic.

One could argue that the PTT isn't necessary (delay a case?) if the patient stopped his/her Pradaxa 3 days ago (normal renal function). What do you think?
 
For neuraxial, University of Washington says 72 hours if renal function normal.

I am planning on 4-7 days depending on patient's renal function.

If necessary, the patient could be bridged with another agent/ regimen.

If the need for neuraxial is truly critical (lung volume reduction etc) then I would consider a 3 day window with good preop counseling in the patient with normal renal function.

Withhold Pradaxa until 6-hours after the injection/ removal of catheter assuming no bloody tap. UW says 2 hours.

A more difficult question is what to do with the guy who received a DTI load and now needs emergent surgery.

- pod
 
periopdoc said:
A more difficult question is what to do with the guy who received a DTI load and now needs emergent surgery.
Click to expand...

Yes. This situation is no bueno, and it will probably be as commonplace as it is with warfarin as the anticoagulant now.

You might imagine that someday MORE people will be on DTI's than were ever on warfarin since the therapeutic index is better and the "riskier" unreliable patients might get put on it.

An Fab to dabigatran (like Digibind) would be one way to "reverse" it.
 
before I get blasted for the 7 day recommendation, I am talking about the patient with previously normal renal function who is on full dose 150mg bid who presents in severe acute renal failure of unknown duration.


- pod
 
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periopdoc said:
before I get blasted for the 7 day recommendation, I am talking about the patient with previously normal renal function who is on full dose 150mg bid who presents in severe acute renal failure of unknown duration.


- pod
Click to expand...

Thanks for the post. I will stick with 72 hours since last dose of Pradaxa and normal PTT for Neuraxial blocks provided normal renal function.

As for restarting the DTIs that will be the next day after a spinal or at least several hours after removing an epidural catheter. The surgeon will likely withhold the DTI longer than my Epidural catheter remains in place anyway.

As for renal failure patients I agree with your one week recommendation and even then I will only do a single shot spinal provided the Coags are normal and the Platelets are greater than 100,000.
 
Pradaxa® – Management of Major Bleeding

Major and life-threatening bleeding is expected to occur in some patients treated with Pradaxa® (=Dabigatran). The question will then urgently arise how to best treat such catastrophic bleeding. As there have been no data published on this topic in the peer-reviewed medical literature, we don’t know how to best manage a patient with major and life-threatening bleeding on Pradaxa®, even though suggestions have been made in the absence of such data (ref 1,2). There (a) is no direct reversal agent available for Pradaxa®, and (b) have not been reversal strategies (backed up by clinical study data). It is key that the companies making these drugs and clinical investigators produce and publish data in peer-reviewed journals indicating how reversal of bleeding on these drugs can be treated effectively. In the event of bleeding complications in patients receiving Pradaxa®, management should, of course, be individualized according to the severity and location of the bleed. A lot of additional data are still needed to know how to best handle major bleeding events on Pradaxa®.
Treatment options

  1. Activated charcoal to prevent residual drug in the stomach to be absorbed
  2. Prothrombin complex concentrates (PCCs; in the U.S.: Bebulin®, Profilnine®) intravenously with or without additional fresh frozen plasma (FFP)
  3. Recombinant factor VIIa (NovoSeven®) i.v.
  4. Activated prothrombin complex concentrates (aPCCs; FEIBA®) i.v.
  5. Antifibrinolytic therapy (Amicar®=aminocaproic acid or Lysteda®=tranexamic acid)
  6. Consideration of 1-2 sessions of hemodialysis.
Published Data about management of bleeding on new oral anticoagulants


  • Xarelto®(Rivaroxaban): this drug also does not have a reversal drug. Noteworthy is a study presented at the Dec 2010 annual meeting of the American Society of Hematology (ASH) as an abstract, that showed that PCCs (50 U/kg of a 4-factor PCC) can reverse the anticoagulant effect of Xarelto® in healthy volunteers (ref 1). However, a lot of additional data are still needed to understand how to manage Xarelto®-associated bleeding.
  • Edoxaban (not FDA approved): this drug also does not have a reversal drug. A small, non-human ex vivo plasma-mixing study presented at the Dec 2010 annual meeting of the American Society of Hematology (ASH) shows that the anticoagulant effect of Edoxaban can be reversed by PCCs and by NovoSeven®(ref 2). The maximum recombinant factor VIIa dose used in this study was equivalent to 50 mcg/kg. A lot of additional data are still needed to understand how to manage Edoxaban-associated bleeding.

Personal Approach
At this point, not knowing what the most effective and safest treatment is, I would give the patient who has a life-threatening bleed on Pradaxa®:

  1. Charcoal to prevent residual drug in the stomach to be absorbed
  2. Prothrombin complex concentrate (PCC) – Bebulin® or Profilnine® (which are 3-factor concentrates), 50 U/kg x 1 plus FFP (2-4 U, depending on how much fluid the patient tolerates). However, whether the FFP with its factor VII is really needed in addition to the 3-factor PCC is not known.
  3. If I did not have PCCs available, I would consider recombinant factor VIIa (90 mcg/kg x1), but I would worry some about its prothrombotic effect, if the patient had had a recent thrombotic event or was very hypercoagulable by history. It is also important to realize that it is not clear what VIIa dose might be appropriate.
  4. If I did not have recombinant factor VIIa, I would give FFP, as much as possible.
  5. I would consider hemodialysis.

References

  1. van Ryn J. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116–1127.
  2. Crowther MA. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009; 7 (Suppl 1):107–110.
  3. Eerenberg ES et al. Prothrombin Complex Concentrate reverses the anticoagulant effect of Rivaroxaban in healthy volunteers (abstract 1094; ASH annual meeting Dec 4-7, 2010, Orlando, FL).
  4. Morishima Y et al. Anti-Inhibitor Coagulant Complex, Prothrombin Complex Concentrate, and recombinant factor VIIa reverse prothrombin time prolonged by Edoxaban in human plasma (abstract 3319; ASH annual meeting Dec 4-7, 2010, Orlando, FL).
 
BEBULIN VH is used primarily to treat bleeds in patients with hemophilia B (Christmas disease), in which clotting Factor IX is either absent or not present in sufficient amounts.1

Indications

BEBULIN VH is indicated for the prevention and control of hemorrhagic episodes in hemophilia B patients.
BEBULIN VH is not indicated for use in the treatment of factor VII deficiency.1

Important Risk Information

The risk of thromboembolic complications including disseminated intravascular coagulation (DIC) and hyperfibrinolysis is present with the administration of Factor IX Complex, particularly in the postoperative period and in patients with risk factors predisposing to thrombosis. In such patients, the Factor IX level should not be raised to more than approximately 60 percent of normal.
As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. This risk has been reduced by effective donor screening, testing for the presence of certain virus infections, and inactivating and/or removing certain viruses. Anaphylactoid or anaphylactic reactions such as fever, urticarial rashes, nausea, retching, dyspnea, and anaphylactic shock may occur in rare cases.
 
Profilnine® SD
Factor IX Complex
Solvent Detergent Treated


A Solvent Detergent treated Factor IX complex for the prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B.
  • Profilnine® SD is a non-activated Factor IX complex concentrate consisting of Factor IX, II, X and low level of Factor VII and purified by DEAE cellulose adsorption for increased quality and safety.
  • Solvent Detergent treatment provides an extra measure of safety.
  • Wide range of presentations (500, 1000 and 1500 IU per vial) for easy and convenient administration.
 
BLADEMDA said:
Profilnine® SD
Factor IX Complex
Solvent Detergent Treated


A Solvent Detergent treated Factor IX complex for the prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B.
  • Profilnine® SD is a non-activated Factor IX complex concentrate consisting of Factor IX, II, X and low level of Factor VII and purified by DEAE cellulose adsorption for increased quality and safety.
  • Solvent Detergent treatment provides an extra measure of safety.
  • Wide range of presentations (500, 1000 and 1500 IU per vial) for easy and convenient administration.
Click to expand...


So for emergency surgery why not start with one 500 unit vial of profilnine and go from there? Have FFP ready and then add the expensive Factor 7A if needed.
 
"Factor VIIa use carries a heavy cost-burden," Dr. Mohammad said. "It is a significant expenditure."

"Factor VIIa is the number-one expenditure for hospital pharmacies because it is so expensive," meeting participant Ernest Alexander, PharmD, from Tampa General Hospital in Florida, asserted.

"We have adopted similar guidelines — it has resulted in $100,000 a year [in savings] with just this intervention," Dr. Alexander said. "If it is administered as ordered, that's 6 doses at a total cost of $90,000. With our guidelines, we got away with a cost of about $2,000 a patient, for a total annual cost of about $70,000."
"The reason [for the cost savings] is dose control," Dr. Alexander said. "We are currently conducting a prospective evaluation [much like Dr. Mohammad's] to determine just what the savings is with use of the guidelines.

"What wereally need is a gatekeeper, such as a hematologist," Dr. Alexander said. Dr. Mohammad agreed, noting that a gatekeeper reviews every case for which Factor VIIa is prescribed at the University of Michigan. "Our hematologists support the use of Factor VIIa guidelines.

"The main conclusion here is that guidelines for the appropriate use and dosing of Factor VIIa are necessary," Dr. Mohammed said, with Dr. Alexander in strong agreement.

Dr. Mohammad and Dr. Alexander report no relevant financial relationships. The research was not commercially supported.

http://www.ajhp.org/content/66/17/1554.abstract


http://www.hosp.uky.edu/pharmacy/formulary/criteria/Factor VIIa-Off label_9-16-08.pdf (worth looking at!)

 
I had to review some of the data to come up with reversal approaches for life threatening bleeding. The reversal data is basically limited to a few abstracts. In the animal bleeding models, neither PCC nor activated VII fully reversed the anticoagulant effect. The human models didn't really address bleeding.

I don't have PCC available to me, so I've recommended going to Factor VII. The doses used in the animal studies were greater than the 90 mcg/kg (from 10% more to double that dose). FFP may be of benefit, but you'd need quite a bit to get good reversal and it will take time to infuse. In the patient on dabigatran, there are likely concerns with volume overload. Just to make dosing more fun, the different thrombin inhibitors seem to get differing amounts of reversal from the various agents. The human studies are also all limited and underpowered.

Charcoal hemoperfusion, if available, is probably a more rapid modality for removal of the dabigatran, then hemodialysis.
 
BADMD said:
I had to review some of the data to come up with reversal approaches for life threatening bleeding. The reversal data is basically limited to a few abstracts. In the animal bleeding models, neither PCC nor activated VII fully reversed the anticoagulant effect. The human models didn't really address bleeding.

I don't have PCC available to me, so I've recommended going to Factor VII. The doses used in the animal studies were greater than the 90 mcg/kg (from 10% more to double that dose). FFP may be of benefit, but you'd need quite a bit to get good reversal and it will take time to infuse. In the patient on dabigatran, there are likely concerns with volume overload. Just to make dosing more fun, the different thrombin inhibitors seem to get differing amounts of reversal from the various agents. The human studies are also all limited and underpowered.

Charcoal hemoperfusion, if available, is probably a more rapid modality for removal of the dabigatran, then hemodialysis.
Click to expand...

Sooner or later one of us will post a real case and its management. My bet is you are correct in that these DTIs will require Factor 7A, FFP and some PCC if available. Then, if the patient has a stroke on POD#2 after surving Emergency Surgery it will be your fault.😉🙄
 
Regarding Pradaxa... I have not seen anything that specifically addresses it's use and neuraxials on the ASRA website.

So is everyone still waiting 3 days before neuraxials?

Are you guys also getting coags?
 
I've seen 3 days as the recommendation before a neuraxial blockade.

My question is if there is an emergency surgery, is there a reversal for Pradaxa? Or is it like Plavix where do reversal exists.
 
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According to ASRA and other sources we should base our decision on the half life (~17hrs). 48 hrs should theoretically be enough and 72 hrs is a good time frame to be on the safe side. Of course this assumes normal renal function and degredation of the drug. ASRA does NOT provide specific guidelines for this type of drug but some of the european societies are saying 48hrs should be enough. As PMPMD mentioned in his link, there is not specific reversal for this drug and there's not much we can do about it. The upside of course is that there really aren't too many places you "NEED" to do regional in the emergency pt and these pts can usually go to sleep.
 
PCCs look like the only pharmacotherapy of any potential value for life-threatening bleeding. Beriplex worked in rat models of ICH to attenuate hemorrhagic expansion. I would never use Factor VII and only FFP as part of a massive transfusion protocol.

In the few human studies, no pharmacotherapy has worked in terms of reversal of measurable coagulation parameters, but those were all surrogate markers for bleeding.
 
Our institution has chosen to go with:

Wait 5 days (renal excretion: half life 12-17hrs: normal dose 150mg PO BID) get a thrombin time. If it is normal (TT<22) then it’s indicative of safe levels
 
I met a Pradaxa rep the other day and she was telling me that the package insert recommends 3-5 days for neuraxial anesthetics (although I have not had a chance to verify this myself yet). As said before, she also said that the only way to rapidly get rid of it is to dialyze it out in the case of emergency surgery or massive bleeding.

I hate anticoagulants with no reversal options!!!
 
TrustMe said:
I met a Pradaxa rep the other day and she was telling me that the package insert recommends 3-5 days for neuraxial anesthetics (although I have not had a chance to verify this myself yet). As said before, she also said that the only way to rapidly get rid of it is to dialyze it out in the case of emergency surgery or massive bleeding.

I hate anticoagulants with no reversal options!!!
Click to expand...

Anybody out there done an emergency CABG with this s h it on board yet?
 
jetproppilot said:
Anybody out there done an emergency CABG with this s h it on board yet?
Click to expand...

If it's anything like plavix.... nothing good will come of it. Haven't had the pleasure of pradaxa + emrg. cabg... but they will come as coumadin gets replaced by pradaxa once the patent is up (excluding drug product s/e like what happened to vioxx, aprotonin and now xigris).

I've seen a good number of patientns on it... the only thing really inhibiting it's wide spread use is cost. Good ? Jet. I'm also curious.

Sounds like 3-5 days for pradaxa. Nice link blade. 👍
 
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sevoflurane said:
If it's anything like plavix.... nothing good will come of it.
Click to expand...

Plavix wasn't all that effective: only 30% compared to the 80% of the newer anti platlets agents prasugrel/effient.

Oral anticoagulants (Pradaxa/Xarelto) are a major advance for patients needing chronic anticoagulation, i wouldn't hold back on them just because someone might want to do a spinal instead of of GA.

Bleeding is a surgical problem.
 
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