BrainWaves #11 Which NOAC is best for secondary stroke prevention?

Transcript

Welcome back to Brainwaves Briefs.

I'm Jim Siegler.

We're going to do things a little bit differently in this episode.

We're going to discuss the novel oral anticoagulants in stroke prevention.

Mostly, what drug do you choose?

First of all, let's state the obvious.

Anticoagulation is indicated in non-valvular atrial fibrillation for secondary stroke prevention.

We know that aspirin plus clopidogrel was superior to aspirin alone in the active W trial.

However, the combination of antiplatelet therapy was less effective than warfarin.

That being said, we don't cut to the chase and immediately start patients on anticoagulation for secondary stroke prevention.

So we anticoagulate stroke patients in certain instances.

Low molecular weight heparin, ideally for hypercoagulability of malignancy.

Sometimes low molecular weight heparin or warfarin for cervical artery dissection, although cat is found no benefit over antiplatelet therapy.

We use warfarin for antifospholipin antibody syndrome or in select cases of heritable thrombophilias.

Warfarin only for valvular disease and for systolic heart failure with apical hypokinesis.

And then we have our non-valvular aphid.

When compared to warfarin, the new oral anticoagulants offer several advantages.

No routine blood tests, no interaction with food, limited interactions with other medications, and theoretically more time in the therapeutic range.

But there are several disadvantages to the NOACs.

Most require twice daily dosing, with the exceptions of rivroxiban and edoxiban, which despite their once daily dosing have a nearly identical half-life to epixiban.

Other disadvantages include that the reversal agents are currently unavailable, with the exception of the bigotran where you can treat with hydrosysmab.

Also, these NOACs can't be administered to patients on hemodialysis and expense can be limiting.

This may actually be the rate limiting factor for acquisition of some of these drugs.

So let's get started.

Which NOAC will you choose for a patient who has a fib and a stroke?

The answer is epixiban.

Alright, well I guess we can talk more about the different drugs.

For most of you, this episode can end here with epixiban.

But for the rest of you who want to know about the differences between the NOACs, I'm happy to go over these other drugs as well.

To make things more interesting, I've brought some toys with me this episode.

My triangle, my gong, and my toy train.

So they'll be joining us for this episode.

Let's start by discussing the factor 2a inhibitor, the bigotran.

It's dosed at 150 mg twice daily by mouth, and it can be reduced to 110 mg twice daily in patients with lower creatinine clans.

It is a half-life between 12 and 17 hours and can be reversed by hemodialysis and with a new agent called hydrosysmab.

We know that from the Relye trial, the rates of major bleeding were lower in the low dose to bigotran arm, but were similar in the high dose to bigotran arm when compared to warfarin.

Unfortunately, major GI bleeding was greater in the high dose to bigotran arm versus cumidin.

Rates of ICH were lower for both to bigotran arms compared to warfarin, and this was found to be a superior effect compared to warfarin.

Adverse events from the Relye trial included GI bleeding was greater for high dose to bigotran, and myocardial infarction was also more likely.

There was no overall mortality benefit, and no mortality benefit due to any death from cardiovascular disease in the bigotran study.

As in the Aristotle trial for epixaban, the rate of stroke, both hemorrhagic and ischemic, or systemic embolism were significantly lower in the high dose to bigotran arm versus cumidin.

Moving on to the factor 10a inhibitors, epixaban, one of the more favored factor 10a inhibitors, was associated with a lower risk of stroke or systemic embolism as well as intracerebral hemorrhage when compared to warfarin.

Rate of major bleeding was lower in the epixaban arm at 2.13% per year versus 3.09% per year, and the rates of GI bleeding were equivalent.

Epixaban users were also less likely to die from any cause when compared to users of warfarin, and to date only epixaban and low dose edoxaban have been associated with a lower rate of death.

Moving on to edoxaban, edoxaban also has a short half-life of 8-15 hours and is dosed once daily as is riveroxaban.

Currently there are no reversal agents for this drug, making any episode of bleeding a complicated event.

That being said, the rates of major bleeding are lower in edoxaban users when compared to warfarin by approximately 1% per year.

It was also associated with a lower rate of cardiovascular mortality and death from any cause for users of low dose edoxaban.

The risk of major bleeding is dose dependent, but overall the risk of bleeding is lower compared to warfarin users.

When using stroke as an outcome event, high dose edoxaban was found to be non-inferior to warfarin, but low dose edoxaban is certainly inferior to warfarin for stroke prevention.

The last of the direct factor 10a inhibitors is riveroxaban.

This drug has a shorter half-life than the remaining factor 10a inhibitors of 5-9 hours, and like edoxaban it's dosed once daily.

In the Rocket AF trial, the composite safety outcome of major and non-major clinically relevant bleeding was no different in riveroxaban versus warfarin.

It was also non-inferior to warfarin with regard to the primary outcome of stroke whether it's hemorrhagic or ischemic.

The rates of MI and death from any cause were also the same between groups.

Major bleeding was lower in riveroxaban users, as were rates of intracerebral hemorrhage, however major GI bleeding was more common in patients who were treated with riveroxaban.

When you try to conceptualize which drugs are more effective than warfarin for secondary stroke prevention, we look at the superiority data of each of the trials that have been performed.

To date, only a pixaban and the high-dose debigotran arm were found to be superior to warfarin.

Interestingly, these two drugs were also superior to warfarin for the prevention of intracerebral hemorrhage.

Riveroxaban was also associated with a lower risk of intracerebral hemorrhage as well, but was not superior to warfarin for the prevention of stroke.

When looking at the safety outcomes, a pixaban, edoxaban, and riveroxaban were superior to warfarin for major bleeding risk.

No drug was inferior to warfarin for major bleeding, interestingly.

However, major GI bleeding was more likely in the higher-dose debigotran arm as well as riveroxaban when compared to warfarin.

Patients who received debigotran were also more likely to have a myocardial infarction when compared to warfarin.

And finally, perhaps the ultimate outcome for clinical trials, death, was lower in patients who received a pixaban or low-dose edoxaban.

In summary, if you have a patient with stroke and non-valvular AFib, you can treat them with a novel oral anticoagulant as long as they're not on hematialysis.

For patients with a normal renal function, they should be treated with a pixaban.

Debigotran is a safe secondary alternative because it has a lower risk of secondary stroke.

For patients with a stroke and non-valvular AFib who have a DVT or PE, these people can be treated with a pixaban, riveroxaban, or debigotran.

Patients who have coexisting coronary artery disease or peripheral artery disease, warfarin has been best studied.

No comparisons have been made to date, but a NOAC is preferable.

For patients who have an acute coronary syndrome, also NOACs could be preferable, but dual anti-platelets may be necessary.

In patients with a high risk of GI bleeding, you want to avoid debigotran due to the major risk of GI bleeding, so a pixaban is preferred.

And given the reversibility of warfarin, you may want to choose warfarin over debigotran.

For patients with stage 3 kidney disease, a pixaban is preferred over riveroxaban and edoxaban, with debigotran and warfarin being less favorable.

[Music] You'll still probably want to go with a pixaban.

[Music] That's all we got for you today.

Thank you so much for listening to Brainwaves.

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This episode was produced by Jim Siegler, music by Josh Woodward.

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[Music] [Music]