COMMENTARY

Direct-Acting Oral Anticoagulant Dos and Don'ts

Robert McBane, MD; Ariela Marshall, MD; Gayatri Acharya, MD

Disclosures

May 22, 2017

Editorial Collaboration

Medscape &

Gayatri Acharya, MD: Greetings! I'm Dr Gayatri Acharya, cardiology fellow at Mayo Clinic. During today's recording, we'll be discussing the recently released US Food and Drug Administration (FDA) drug watch list with advisories on the direct-acting oral anticoagulants, or DOACs [previously called novel OACs, or NOACs]. I'm joined today by my colleagues, Dr Robert McBane, cardiologist, and Dr Ariela Marshall, hematologist, at Mayo Clinic, who both specialize in this area. Welcome, great to have you today. Dr Marshall, we will start with you. What are the DOACs used for, and what are the FDA-approved indications?

Defining DOACs

Ariela Marshall, MD: When we talk about the DOACs as a class of drugs, we're actually referring to a number of different medications. One of them is dabigatran (Pradaxa, Boehringer Ingelheim), and that's in a class called the direct-thrombin inhibitors. The other medications are in a class called the direct factor Xa inhibitors, and that includes rivaroxaban (Xarelto, Janssen), apixaban (Eliquis, Bristol-Myers Squibb), and edoxaban (Savaysa, Daiichi-Sankyo).

We group these together and call them the DOACs because they are all oral agents. While there are differences [among them] in their mechanisms of action, most of the FDA-approved indications and the way that we use them clinically are similar.

A lot of DOACs were studied initially in large clinical trials in atrial fibrillation.[1,2,3,4] Just as you may have a patient who is on warfarin for stroke prevention in the setting of atrial fibrillation, the DOACs can be used for that indication as well—as long as it is for nonvalvular atrial fibrillation.

The second is my area: venous thromboembolic (VTE) disease. You can use DOACS for VTE, whether that is a deep venous thrombosis—usually in the lower extremity—or a pulmonary embolism.[5,6,7,8]

The third indication that many of these medications are FDA-approved [to treat] is clot prevention, and that is primarily after orthopedic surgery—a hip replacement or a knee replacement—and it can be used, usually, at lower doses for clot prevention.

Differences Among DOACs

Dr Acharya: Great. Dr McBane, Dr Marshall mentioned that there are different medications. What are the differences between these medications?

Dr McBane: For the first time in 50 years, we have a class of medications that do not need to be [directly] monitored, in comparison with warfarin. The second benefit of these medications is they do not tend to interact with food substances, and they do not tend to interact with very many medications. So for many reasons, these are very attractive medications and, in fact, quite easy to use.

Of the four, there are some subtle differences, however. The first medication the FDA approved, which was dabigatran in 2010, is cleared by the kidney predominantly. That makes it a little bit tougher to use in patients with renal impairment.

Then, as you add the factor Xa inhibitors, for example, apixaban and edoxaban as Dr Marshall mentioned, these tend to be less cleared by the kidney and more by other routes of metabolism, such as the liver and enteric secretion. One of the big differences among [drugs within] this class is how they are cleared.

All DOACs have about the same onset of action, which makes them attractive. Within 1 to 3 hours of taking these medications, they will be fully therapeutic. This is important when thinking about the use of DOACs, particularly in individuals who have recently had major surgery. You need to know that within an hour, they are going to be fully anticoagulated.

The half-lives of these medications are also long and differ to some degree, but in general, 10 to 17 hours for each. They vary in their efficacy. Although the efficacy differences are subtle, the major difference among these drugs is in their rates of bleeding. Their rates of major bleeding are more similar to warfarin; some of the medications, such as apixaban, are advantageous in that their rates of major bleeding are quite a bit lower than warfarin. As a class, these medications all have the overall benefit that, when compared with warfarin, they are much safer drugs, which makes them very attractive to practitioners.

DOACs vs Warfarin

Dr Acharya: Dr Marshall, are there any other pros or cons in comparison with warfarin, our standard medication that we have been using for anticoagulation?

Dr Marshall: Dr McBane has outlined a lot of the benefits, and we will discuss some of the risks later, but a major one is oral availability. For instance, in comparison with low-molecular-weight heparin—which can be painful for patients and expensive—the oral-acting agents are much easier to use. The ability to go without monitoring is attractive to patients on warfarin who are having their international normalized ratio (INR) monitored every couple of days or whose INR changes rapidly with other medication interactions or diet. Patients who have a more active lifestyle or travel may not be able to get their INRs checked regularly.

In terms of cost, it varies from individual to individual based on insurance coverage, but in general, DOACs are probably less expensive than the injectable agents but more expensive than warfarin. But accounting for the monitoring visits with practitioners and the nursing with the dose changes required of warfarin, the overall cost of DOACs may actually be lower.

Dr Acharya: Absolutely, and I know for many of us in our practice, they are a very attractive option for our patients and one that they often ask about. Dr McBane, you mentioned bleeding risk for the DOACs. How do these bleeding risks compare with warfarin?

Dr Robert McBane: When thinking about effectiveness, these medications across the spectrum do not offer a huge benefit compared with warfarin. The major benefit for these medications, in addition to those that Dr Marshall has mentioned, is lower rates of intracranial hemorrhage, major hemorrhage, and bleeding from other sources.

Unfortunately, for gastrointestinal (GI) bleeding, two medications can be problematic. If you have a patient who is having difficulty with or a history of GI bleeding, then dabigatran and rivaroxaban probably are not the best choices. In fact, compared with warfarin, even for GI bleeding, low-dose edoxaban has been shown as superior. Apixaban is probably a wash or perhaps a bit better than warfarin therapy. So again, effectiveness is probably similar to warfarin. However, if you are looking for the major advantage, it would be a reduction in major bleeding. So that is where I think the biggest sell for these medications is.

Reversing Bleeding in DOACs

Dr Acharya: Dr Marshall, the next natural question is, if we have a patient bleeding, how do we reverse it?

Dr Marshall: There was lot of hesitation when these medications were first released and approved because, initially, they were thought to be irreversible in the setting of a bleed, whereas warfarin bleeding can be reversed within minutes with the use of a 4-factor prothrombin complex concentrate (PCC) and even within a couple of hours with the use of fresh frozen plasma. For heparin, if it is an unfractionated heparin that is being given continuously, just turn off the drip and protamine can be used to reverse that. Many medications are easily reversible, and at first, the fear was with these newer medications that they were not. If 5 to 10 years ago a patient had come in with a bleed while on dabigatran, knowing that it is mostly excreted by the kidney, we would try to dialyze the dabigatran off. Other approaches have been used, such as fresh frozen plasma or PCCs, but none of those are specific to the agent.

More recently, a specific reversal agent called idarucizumab(Praxbind) has been released for dabigatran. This is an antibody that actually binds to dabigatran and removes it from the system, so you can think of it as Digibind, the antidigoxin antibody. Idarucizumab is actually a specific antidabigatran antibody that removes it from the system within a couple of minutes. Most clinical trials have [focused on] laboratory end points, such as time-to-clot generation, but those clinical trials [investigating] patient-centered outcomes and bleeding [in particular] have shown that it is efficacious in reversing within a very short period of time. That benefit has become available only in the past year or so.[9]

For the factor Xa inhibitors, a reversal agent called andexanet alfa is in the pipeline. Again, the initial clinical trials were done more often in healthy patient populations and showed the drug's capacity to reverse [factor Xa inhibitors] in a period of minutes. More recently, we have seen clinical trials in patients who have required reversal in the setting either of emergent surgery or trauma-related bleeding, and the reversal agent has been efficacious in those settings.[10,11] They were early-[phase] trials, so we do not have the benefit of having hundreds of thousands of patients like we do in the efficacy trials for the DOACs. And andexanet alfa is still not yet FDA-approved, but it is certainly in the pipeline. I think that we will feel a bit better when there is a specific reversal agent available, but [in the meantime, I would still prescribe factor Xa inhibitors] because, as Dr McBane discussed, the risk of bleeding with these agents is actually somewhat lower than with warfarin.

Candidates for DOACs and the Importance of Compliance

Dr Acharya: Absolutely. That is very important for us as providers to convey to our patients because it is a frequent question from patients. Dr McBane, who would you consider to be a good candidate to prescribe a DOAC?

Dr McBane: That is a good question and [requires] somewhat of an intricate [answer]. The first [consideration] is—who does not need a DOAC? There are a number of patients who have been taking warfarin for years and they are doing fine: they have never had a bleed or clotting event. Often, patients will come and say, "Do I have to switch?" The answer is no. There are many, many patients who are doing just fine on warfarin. They do not mind the INR monitoring or maybe they have a home INR monitor. For those individuals, we definitely do not need to switch.

The second group who is not a candidate for DOACs are patients with mechanical heart valves. We have some very early phase 2 clinical-trial data for dabigatran, and honestly it was a bust.[12] Dabigatran did not work for mechanical heart valves. If anything, one of the take-home messages was: if you have a patient with a mechanical heart valve, they should not be on a DOAC. They have to be treated with warfarin.

Beyond those conditions and [regarding] the FDA-approved indications—atrial fibrillation and venous thromboembolism—these medications are very advantageous. For those who are considering a DOAC and if they have an underlying indication of paroxysmal atrial fibrillation or chronic atrial fibrillation, then the issue is which nuances of each of these drugs would best serve that particular patient. For example, if the patient is a young individual with a high risk of thromboembolism but a reasonable risk of bleeding, then dabigatran is a very reasonable option.

For the patient who maybe has suffered a peripheral embolization—for example, an embolism to a brachial artery or maybe to a popliteal artery—there is clear evidence from the ROCKET-AF[3] trial that rivaroxaban is the preferred agent for that patient. On the other hand, if you have an older individual who may be at increased risk of bleeding, then apixaban would be a reasonable option. In prescribing these medications, we have to [emphasize] compliance and adherence to our patients. For an individual who might be very busy—a young executive, for example, who may not be able to do twice-daily dosing—once-daily dosing with either rivaroxaban or edoxaban is particularly attractive.

Compliance is a very big issue and something we all have to grapple with. One [consideration] is just how painful it was to monitor INR in our patients who were on chronic warfarin therapy and, yes, it was a setback and a disadvantage for this group of individuals. However, the advantage of regular INR monitoring was that you promoted compliance. If a patient came into the office and their INR was 1, then you did not have to guess [whether he or she was] really taking the medication. With these newer medications, we will not be checking compliance via regular monitoring, but we have to ensure that patients are both filling the prescription and taking the medication.

The European guidelines[13] recommend that you should see patients quarterly [or more often], do pill counts, and maybe have them sign a written document stating that they will take the medications. The worst-possible scenario would be to accept a phone call from the emergency room where your patient with atrial fibrillation comes in with a new stroke and they have not been taking their medications. Just because we are not doing INR monitoring, we have to be diligent with these patients and ensure that they are both picking up their prescription and filling them.

Dr Acharya: Dr Marshall, from a hematology perspective, any other insights into who would be a good or poor candidate?

Dr Marshall: It is a very important question. We see many patients who come in with either deep venous thrombosis (DVT) or pulmonary embolism (PE). Per the recent [American College of Chest Physicians] ACCP, or Chest, guidelines,[14] the DOACs are the preferred initial agent for treatment of DVT and PE, both for ease of use and safety considerations.

But in certain patient populations we still do not prefer the DOACs. One of them would be antiphospholipid antibody syndrome. This is a very prothrombotic condition. There have been case reports of patients with antiphospholipid syndrome who were managed with these DOACs and actually had recurrent thromboses. Now these were merely case reports—other case reports describe patients who have been safely managed on the DOACs—but until there are more clinical data from ongoing trials, we generally prefer to treat these patients with warfarin.

Another even larger group is the cancer population with VTE.[15,16,17,18,19,20] Up to 20% of first VTE [events] are actually cancer-related, and so it is a significant population. From ongoing studies comparing warfarin with low-molecular-weight heparin, we know that low-molecular-weight heparin is the preferred agent for treatment of cancer-related venous thromboembolic disease, and many ongoing trials compare the DOACs with low-molecular-weight heparin.[21,22,23] The DOACs have been compared with warfarin in cancer, and they are thought to be as efficacious as warfarin, but because low-molecular-weight heparin is still preferred, we need data from these ongoing trials before we can recommend DOACs for cancer-related VTE.

The last [scenario] I will mention is VTE in the setting of pregnancy. Obviously, warfarin is contraindicated during pregnancy, unless it is a very tough case such as a patient with a mechanical heart valve. But generally, we use low-molecular-weight heparin. There are no data from clinical trials in pregnant women. [DOACs are] actually contraindicated at this time because of the lack of available data. An open registry for patients who are pregnant and are, for some reason, treated with a DOAC will track outcomes both for the mother and the child, but for now, these drugs are not recommended in pregnancy.

Dr Acharya: Fantastic. This was a very educational discussion, and I thank you both so much for being here. Thank you to Dr McBane and Dr Marshall for these very important insights, and thank you for joining us on theheart.org on Medscape.

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