Tag Archives: anticoagulation

Best Of EAST #8: Early vs Late Full Anticoagulation In TBI

Trauma professionals are always reluctant to anticoagulate TBI patients with demonstrated blood in their head. In recent years, we’ve become more comfortable providing prophylactic doses of low molecular weight heparin after a suitable period. This is typically 24-48 hours after a stable head CT in patients with select types of intracranial hemorrhage (ICH) who are at increased risk for venous thromboembolism.

But what about therapeutic dose anticoagulation in these patients? Let’s say that you have a patient with ICH who has developed a significant pulmonary embolism (PE)? Is is safe to give full dose anticoagulation? And if so, when?

The group at Shock Trauma in Baltimore attempted to answer this in one of the EAST Quick Shot presentations scheduled for this week. The did a retrospective review of 4.5 years of their own data on these patients. They specifically selected patients who had both ICH and PE and compared those who received full anticoagulation within 7 days of injury vs those who were dosed after 7 days. Outcomes studied included death, interventions for worsening ICH, and pulmonary complications.

Here are the factoids:

  • A total of 50 patients had both ICH and PE, but only the 46 who received therapeutic anticoagulation were analyzed
  • 19 patients (41%) received early anticoagulation, and 27 received it late (59%)
  • There were 4 deaths in the early group (2 from the PE, 1 from multi-system organ failure, 1 from the TBI) vs none in the late group, and this was statistically significant
  • 3 patients in the early group (18%) vs 2 in the late group (7%) had an increase in their ICH (p=0.3), and none required intervention

The authors concluded that their study failed to show any instances of clinically significant progression of ICH after anticoagulation, and that it is not associated with worse outcomes, even if started early. Thus they recommend that ICH should not preclude full anticoagulation, even early after injury.

My comment: I always say that you shouldn’t let one paper change your practice. Even a really good one. In order to ensure that you are providing the best care, more work must always be done to confirm (or refute) the findings of any provocative research. And this little Quick Shot, with little opportunity for questions from the audience, should definitely not change it!

The major issues to consider here are common ones: 

  • This was a retrospective study and it does not appear that any guideline was followed to determine who got early vs late anticoagulation. So who knows what kind of selection bias was occurring and how the surgeon decided to prescribe anticoagulation? It’s very possible that patients with a “bad CT” were put into the late group, and the not so bad ones in the early group. This would bias the results toward better outcomes in the early anticoagulation group.
  • It’s also a very small study that is extremely underpowered. The authors comment on the fact that the outcomes of the early group were not worse than the late group. However, looking at their sample size (46) shows that they would only be able to show differences if they were about 5x worse in the early group. They would realistically need about 350 total patients to truly show that the groups behaved the same. Their small numbers also preclude saying that there were no ICH progressions. There very well could have been if 300 more patients were added to the series.
  • And isn’t death a significant outcome? The authors indicated that 2 of the 4 deaths were a result of the PE. Yet there was a significant association (p=0.02) of increased death in the early anticoagulation patients that can’t be discounted.

Bottom line: It’s way too early to consider giving early anticoagulation to patients with ICH and pulmonary embolism. It may very well be shown to be acceptable, eventually. But not yet. And a much bigger prospective study will be required to confirm it.

Reference: Therapeutic anticoagulation in patients with traumatic brain injuries and pulmonary emboli. EAST Annual Assembly Quick Shot #7, 2020.

Reversing Direct Oral Anticoagulants With Andexxa

I just finished a summary of the Australian consensus paper regarding anticoagulants (and anti-platelet agents) in patients with hemorrhagic TBI. One of the issues addressed was reversal of these agents. Today I’m going to provide more specific information on one of the new reversal agents, Andexxa (recombinant Factor Xa, inactivated-zhzo).

First, maybe someone can help me here. What does zhzo mean? I’ve done a deep dive including a review of the FDA filings, and still can’t figure out what this is. I have a hard enough time with the thousands of something-umab monoclonal antibody products out there. Now we’re adding on a bunch of z’s to the end of drug names?

There are currently two classes of direct oral anticoagulant drugs (DOACs) available, direct thrombin inhibitors and Factor Xa inhibitors. Andexxa was designed to reverse the latter by providing a lookalike of Factor Xa to selectively bind to apixaban (Eliquis) and rivaroxaban (Xarelto).

The Austrian consensus paper I previously discussed recommended giving Andexxa in patients taking apixaban or rivaroxaban if it was not possible to show that the drugs were non-therapeutic. This means that if your lab could not measure anti-Factor Xa levels in a timely manner and the patient was known to be taking one of these agents, reversal should be considered.

Sounds cut and dried, right? Your patient is taking a Factor Xa inhibitor and they are bleeding, so give the reversal agent. Unfortunately, it’s much more complicated than that.

  • The half-life of Andexxa is much shorter than that of the drugs it reverses. The reversal effect of Andexxa begins to wear off two hours after administration, and is gone by four hours. On the other hand, the half life of rivaroxaban is 10+ hours in the elderly. The half-life of apixaban is even longer, 12 hours. This means that it is likely that multiple doses of Andexxa would be necessary to maintain reversal.
  • There are no studies comparing use of Andexxa with the current standard of care (prothrombin complex concentrate, PCC). The ANNEXA-4 study tried to do this. It was a single-arm observational study with 352 subjects. These patients were given Andexxa if major bleeding occurred within 18 hours of their DOAC dose. Two thirds of the patients had intracranial bleeding. All were given a bolus followed by a two hour drip. All showed dramatic drops in anti-Factor Xa levels, and 82% of patients had good or excellent control of hemorrhage. However, 15% died and 10% developed thrombotic complications.
  • The FDA clinical reviewers recommended against approval due to the lack of evidence for clinical efficacy. The director for the Office of Tissues and Advanced Therapies overruled the reviewers and allowed approval until such time a definitive study was completed. So far there have been no justifiable claims that Andexxa is superior to PCC.
  • To be fair, PCC has not been compared to placebo either. So we don’t really know how useful it is when treating bleeding after DOAC administration.
  • Andexxa is very expensive. Old literature showed a single dose price of $49,500 but this has been revised downward. Effective in October 2019, Medicare agreed to reimburse a hospital about $18,000 for Andexxa over and above the DRG for the patient’s care. Remember, due to the half life of the Factor Xa inhibitors, two doses may be needed. This comes to about $36,000, which is much higher than the cost for PCC (about $4,000).

Bottom line: Any hospital considering adding Andexxa to their formulary should pay attention to all of the factors listed above and do the math for themselves. Given the growing number of patients being placed on DOACs, the financial and clinical impact will continue to grow. Is the cost and risk of this therapy justified by the meager clinical efficacy data available?

References:

  1. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM 380(14):1326-1335, 2019.
  2. Key Points to Consider When Evaluating Andexxa for Formulary Addition. Neurocrit Care epub ahead of print, 22 Oct 2019.

Best Practices For TBI Patients On Oral Anticoagulants: Part 4

In my last post, I started reviewing the anticoagulant reversal section of the Austrian consensus statement on TBI patients taking anticoagulants. Due to its length, I covered only anti-platelet agents. Today I’ll discuss their findings on reversing  Vitamin K antagonists.

Q1. Should Vitamin K antagonists (VKAs) be reversed in case of hemorrhagic TBI?

Answer: That’s simple. Yes!

Q2. Should Vitamin K be administered to reverse the effects of VKAs?

Answer: Yes, as an adjunct to other reversal agents. The usual dose is 5-10mg IV.

Adjuncts must always be used, because Vitamin K only enables the liver to produce factors II, VII, IX, and X. This is not an immediate process, and may take up to 24 hours for the INR to fall to reasonable levels. Additional treatment is needed to raise these factor levels quickly.

Q3. Should prothrombin complex concentrate (PCC) and/or plasma be used for reversal of VKAs?

Answer: Four-factor PCC is the treatment of choice, and is preferred over plasma. 

Reversal of VKAs with plasma requires administration of large volumes, and each unit is given over one to two hours. This results in a slower correction when compared to PCC, which occurs in less than 30 minutes. And many elderly patients with comorbidities cannot tolerate the colloid volume administered with multiple units of plasma. Multiple studies have shown that patients treated with PCC achieve their target INR significantly faster and have less hematoma progression than those treated with plasma.

Q4. Should recombinant activated factor VII (rFVIIa) be used for reversal of VKAs?

Answer: No.

This drug was the darling in trauma care around the turn of the century, but has since fallen into disuse. The few studies available show that there may be INR rebound and more frequent hematoma expansion compared to PCC.

Next post: Recommendations for reversal of DOACs.

Reference: Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care 23:62, 2019.

Best Practices For TBI Patients On Oral Anticoagulants: Part 3

My last post covered coagulation tests for oral anticoagulants and antiplatelet agents, as well as target levels of reversal. Today, I’ll share more of the Austrian consensus paper on actual reversal of anticoagulants. I’ll also add a little commentary to some of the answers.

This is a lengthy section in the paper, so I’ll split it into antiplatelet agents today, the vitamin K antagonists tomorrow, and the direct oral anticoagulants (DOACs) after that.

Q1. Should desmopressin (DDAVP) be administered to reverse the effect of platelet inhibitors?

Answer: No recommendation. (My answer: no)

DDAVP accelerates platelet adhesion. Very few papers have looked at using DDAVP in patients with platelet inhibition, and those that did had low numbers of subjects. The only positive study showed a reduction in hematoma of only 0.5 cc (in hemorrhagic stroke patients, by the way, not trauma). This is not clinically significant. It is likely that the nonfunctional platelets do not really respond to DDAVP, so this drug is not very useful.

Q2. Should TXA be used in patients receiving platelet inhibitors?

Answer: No recommendation. (My answer: no)

There are few, if any, studies that address this. A CRASH-2 subset with TBI showed no significant difference in intracranial hematoma size after TXA. Only one very small (80 patient) study showed a decreased total hematoma after TXA administration (2cc vs 4cc). I’m not sure how clinically significant this is. CRASH-3 did not address it. Overall there is too little data to make a decision regarding this one. It’s value, if any, is very subtle.

Q3. Should platelet concentrate be administered to reverse the effect of platelet inhibitors?

Answer: No

There are no studies that have shown any clear benefit to giving units of platelets to these patients. And a meta-analysis showed no survival benefit. Giving platelets sounds like a good idea, but remember that the drug that poisoned the patient’s platelets is still circulating. It can and does poison the new platelets as well. So adding more platelets that are destined to stop functioning doesn’t seem like a good idea.

In my next post, I’ll dig into the recommendations for reversing Vitamin K antagonists (warfarin).

Reference: Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care 23:62, 2019.

Best Practices For TBI Patients On Oral Anticoagulants: Part 1

Over the past five years, there has been a tremendous increase in the number of patients presenting to hospitals with traumatic brain injury. The bulk of these injuries occur in the elderly, and a rapidly growing number of them are taking anticoagulants for management of their medical comorbidities. Although there is a growing body of literature addressing this issue, many practical questions remained unanswered. This is due to the lack of randomized controlled studies of the clinical problems involved. And given the ethical issues of obtaining consent for them, there likely never will be.

An interdisciplinary group of Austrian experts was convened last year to consider the most common questions asked about TBI and concomitant anticoagulant use. They reviewed the existing literature from 2007 to 2018 and combined it with their own expertise to construct some initial answers to those questions.

Over the course of my next few posts, I’ll dig into each of the questions and review their suggested answers. And remember, all these Q&A apply to patients with known/suspected TBI with known/suspected oral anticoagulant use.

Let’s start with some diagnosis questions.

Q1. Should head CT be performed in all patients with known or suspected TBI and suspected or known use of anticoagulants?

Answer: All patients with TBI and potential or known use of anticoagulants should undergo an initial screening CT scan of the head.

A number of systems that predict the utility of head CT already exist (e.g. Canadian head CT rules). However, they do not and cannot take into account the various permutations of drugs and other medical conditions that may influence coagulation status. Vitamin K antagonists (VKA) like warfarin have been clearly shown to increase mortality after TBI. Data involving the use of anti-platelet agents or direct oral anticoagulants (DOAC) are a bit less clear.

Q2. Should a repeat head CT scan be repeated in these patients, and if so, when?

Answer: Patients with intracranial hemorrhage on their initial scan should have a repeat within 6-24 hours, based on the location of the bleed.

The natural course of patients who have an identified intracranial hemorrhage is extremely unpredictable. For that reason, a repeat scan is suggested. However, there are no consistent data that would indicate when this should occur. Indications and potential for progression vary by type of bleed (subarachnoid, subdural, epidural, intraparenchymal). Thus, you must work with your neurosurgeons to arrive at a reasonable repeat interval, and it may be different for a high-risk location (epidural) vs one with low risk (subarachnoid).

Q3. Should a patient with an initial head CT that is negative be admitted for neurologic monitoring?

Answer: Patients taking only aspirin with GCS 15 and initially negative head CT may be discharged. All other patients should be admitted for at least 24 hours for neurologic monitoring as follows (q1 hr x 4 hrs, q2 hr x 8 hrs, q4 hr x 12 hrs). Repeat head CT is indicated if there is any deterioration in neurologic exam.

Multiple papers have described the occurrence of delayed intracranial hemorrhage in patients taking oral anticoagulants other than aspirin. Although some bleeds may develop days or weeks after the initial injury, the majority occur during the first 24 hours. Routine repeat head CT in this group of patients with an initially negative scan has not been found to be helpful.

Q4. What about patients with an initially negative head CT who cannot be examined neurologically (intubation, sedation, dementia)?

Answer: Unexaminable patients should undergo a repeat head CT within 6-24 hours based on the underlying risk factors for development of delayed hemorrhage.

There is no real literature on this topic, but this statement makes sense. Each center should pick a reasonable time interval and include it in their own practice guideline.

In my next post, I’ll review the panel’s recommendations on coagulation tests and target levels for reversal of the various classes of anticoagulants.

Reference: Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care 23:62, 2019.