Debra Davis, CRNP

Jane Davis, DNP (left) and Kim Zuber, PA-C (right)
Credit: Self

Atrial fibrillation (AF) is linked to an increase in embolic strokes and thus most patients with AF will be prescribed anticoagulants to decrease this incidence.

AF is frequent in chronic kidney disease (CKD) with estimates ranging from 16-21% in non-dialysis patient and up to 40% in dialysis patients.1 AF is associated with both worse cardiac and kidney outcomes with an increased risk of CKD progression.

 The incidence of stroke in End Stage Kidney Disease (ESRD) is 7-9 times greater than in the general population and 3-fold more deadly.

For many years, warfarin was the drug of choice to decrease strokes in all populations but serum monitoring requirements, diet restrictions and narrow therapeutic window led to multiple complications. With the introduction of the direct oral anticoagulant (DOACs) medications, the complication rate in AF was significantly decreased.

As is true for most drug trials, patients with severe CKD (defined as an eGFR 

25 ml/min) were excluded from the DOAC trials.

 This is not unexpected; kidney patients have multiple comorbidities and are treated with multiple medications.

These comorbidities and medications add a level of complexity to the evaluation of adverse events during a drug trial. Yet, for a population where close to half of the population has AF, we do not have answers about the use of DOACs.

As there is no guidance from the pivotal DOAC trials for the CKD and ESRD patients, the kidney community has undertaken the collection of data from real world use of DOACs. We know that acute kidney injury (AKI) is significantly lower with the use of DOACs vs warfarin.

This is true for all stages of CKD, even in the elderly.

Using a meta-analysis approach, we have seen that DOACs have a better safety and effectiveness profile than warfarin.

 For this reason, the Kidney Disease Improving Global Outcomes (KDIGO) expert workgroup has developed recommendations for use of DOACs in CKD.

Adapted from KDIGO Controversies Conference

Legend: KDIGO-Kidney Disease Improving Global Outcomes, SCr-serum creatinine, eGFR-estimated glomerular filtration rate, bid-twice a day, qd-once a day. 

Yet, there is still a population that KDIGO recommendations did not address: the ESRD patient.

In the kidney failure patient, the incidence of AF is 40% and the stroke and sudden cardiac death are common.

 While cardiology defers to nephrology when treating ESRD, nephrology is divided on optimal treatment for this population. Most trials are retrospective and observational. However, recently randomized, controlled trials have been conducted.

With the most recent trial data available, the consensus is that warfarin is the most dangerous for this population whether it is used for AF prophylaxis or treatment for recurrent thromboembolism.

 Warfarin increases the incidence of bleeding without decreasing mortality. Two other large trials looking at DOAC vs warfarin both showed a better safety profile for apixaban but there were significant episodes of bleeding in the dialysis population.

 For this reason, the recently closed preliminary trial of three separate trial arms, which examine apixaban, warfarin, and no treatment, respectively, is being closely watched.

This Canadian/Australian trial included 151 participants and is a pilot to evaluate if we should 

 be treating the dialysis population with anticoagulants. The trial was completed in late December 2022. Results are pending.

If, as expected, the no treatment arm has a similar outcome profile with less bleeding complications, we will have to reassess our mantra of 

 while we stop treating the AF patient on dialysis with anticoagulants. A definite relearn for all of us.

Wanner C, Herzog CA, Turakhia MP; Conference Steering Committee. Chronic kidney disease and arrhythmias: highlights from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 

Bobot M, Suissa L, Hak JF, et al. Kidney disease and stroke: epidemiology and potential mechanisms of susceptibility. 

Garlo KG, Steele DJR, Nigwekar SU, et al. Demystifying the Benefits and Harms of Anticoagulation for Atrial Fibrillation in Chronic Kidney Disease. 

Harel Z, McArthur E, Jeyakumar N, et al. The Risk of Acute Kidney Injury with Oral Anticoagulants in Elderly Adults with Atrial Fibrillation. 

Malhotra K, Ishfaq MF, Goyal N, et al. Oral anticoagulation in patients with chronic kidney disease: A systematic review and meta-analysis. 

Wetmore JB, Herzog CA, Yan H, et al. Apixaban versus Warfarin for Treatment of Venous Thromboembolism in Patients Receiving Long-Term Dialysis. 

Mavrakanas TA. Should Oral Anticoagulation Be Used in ESKD Patients on Hemodialysis with Atrial Fibrillation?: COMMENTARY. 

Pokorney SD, Chertow GM, Al-Khalidi HR, et al for the RENAL-AF Investigators. Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial. 

Reinecke H, Engelbertz C, Bauersachs R, et al. A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study. 

Strategies for the management of atrial fibrillation in patients receiving dialysis (Safe-D) ClinicalTrials.gov identifier NCT03987711

Articles

Kim Zuber, PA-C, and Jane Davis, DNP, offer insight into the use of DOACs in people with atrial fibrillation and chronic kidney disease. 

Using DOACs in People with Chronic Kidney Disease, with Kim Zuber, PA-C, and Jane Davis, DNP

Wendy L. Wright, DNP, ANP-BC, FNP-BC, FAANP, FAAN, FNAP:

 We’re going to wrap this up. If you could leave 1 parting bit of advice for our colleagues, our APRNs [advanced practice registered nurses], our physician assistants, the nursing staff that are listening, what advice do you have about managing sleep disorders?

 I loved the part where we talked about the chicken or the egg. When someone comes to you and can’t control their blood pressure, or they’re talking to you about the stress in their life, I think if you always have that tickler in the back of your brain that says, "Are they sleeping? Should I ask if they are sleeping?” I think that that would just go a long way to helping the population to be healthier and having a good night of restorative rest.

Wendy L. Wright, DNP, ANP-BC, FNP-BC, FAANP, FAAN, FNAP: 

And my parting advice to all of our colleagues is don’t be afraid to open Pandora’s box and ask about sleep because you’re going to struggle in getting their pain under control, in treating their depression and anxiety, if we’re not addressing part of the underlying issue, which is not being able to sleep and not getting that restorative sleep. Remember, oftentimes, these people have suffered from sleep issues for years, and you can really make a difference, not just in the short term, but in their long-term health outcomes.

Debbie, it’s truly been my pleasure to sit here and have a dialogue with you about insomnia. It’s been really fun, and I want to thank you on behalf of myself and our colleagues for joining me.

Thank you, Wendy. I have really enjoyed it, and I have learned a lot in preparing for this talk. I just want to move forward in treating our patients as best we can. I’ve learned a lot from you as well. Thank you for your time.

Right back at you. Thank you so much. And to those of you who are joining us, goodbye for now.

Videos

Advanced practice practitioners share final pearls with their colleagues for the management of sleep disorders.

Advice for Advanced Practice Providers in Managing Sleep Disorders

We’ve just got a couple of questions left that I want to ask you. What do you think are the remaining unmet needs out there for people with insomnia?

That they’re not bringing it up when they come in. I think that so many times they think it’s just not important or, often, especially in my world of hormones, patients want a more natural option, and so they think if they mention it, I’m just going to give them a drug for that. And I think that they don’t want that; they just want to try to work through it themselves. I think that that’s a problem.

Other times maybe you’ve got a list of 4 other things that you want to talk about that you think are more pressing, and maybe you think that I won’t think it’s very important, but I do. I think that a lot of times the problem is today’s rushed visit, even though I always try to sit down and really answer your questions. Often it gets put on the back burner, and patients just think it’s not as important.

I think for years there have been medicines out there that will put people to sleep or help them stay asleep, but the risks of those medicines, oftentimes, in my opinion, outweigh the benefits.

So, moving forward, I think that continuing to see that medication development for these people who are suffering is key. We’re not asking people who don’t sleep 1 night in their lives to take medicine; we’re talking about people who for 10 years have suffered with 3 nights or longer of insomnia, whether it’s difficulty falling or staying asleep. And we now have medicines that are safer and that can be used long term, and I think that we need to just continue to move forward as a country in trying to develop those products, to give options to people who truly suffer from chronic insomnia.

I agree 100 percent. I think that if they only knew that this was safe and a very good option, they would be willing to try it. And I think that our colleagues would be willing to prescribe it if they only knew that the DORAs [dual orexin receptor antagonists] really are just orexin inhibitors—they’re not hypnotics, they’re not sedatives, they’re not going to do harm to your patient. But because they’re in this “controlled” box, a lot of times prescribers are like, "Well, no, I’d rather give them something that is not a controlled substance," when in this case, the controlled substance is much safer.

Dr Wendy Wright and Debra Davis comment on unmet needs in insomnia and other sleep disorders.

Unmet Needs in Management of Sleep Disorders

We’ve talked, and we’ve given our colleagues a lot of different options for medicines. We’ve talked about the benefits of all the different medicines and some of the adverse effects, etc. But here’s my question to you as we’re wrapping up our discussion today, how do you determine efficacy in insomnia? What do you use to determine efficacy, if anything?

What a good question, and the honest truth is, and I probably should be a little embarrassed about this, is the patient report. I don’t have an IDSIQ [Insomnia Daytime Symptoms and Impacts Questionnaire]; I don’t have a scoring system. Now, I do that on hormones, because so many times when you bring someone to normalcy, they say, “I’m no better.” I say, “Oh really, you’re still having hot flashes and night sweats?” “No, I haven’t had that since you put me on medicine.” “Really, you’re not sleeping at night?” “No, I sleep just fine.” When somebody feels normal, they’re like, “I’m no better,” and so in my world a lot of times I really do rely on that, “How are you feeling? Are you feeling better? Are you sleeping better?” When really, it probably should be a bit more of a scoring system, of pointing out to them, “Remember, you were only sleeping 4 to 6 hours, and now you’re sleeping 7 to 8 hours.” Because so many times when people feel normal, they’re like, “Well, I don’t know. I don’t think I’m better,” when really, you’re a lot better.

Absolutely. I don’t use a real scoring tool either, I just ask, “Do you feel like it’s helped you? In what way? How long is it taking you to fall asleep? How much longer are you asleep in the middle of the night?” But what I also have asked people to do is, I’ll say to them, “If 10 was the worst you’ve ever thought your sleep was, and you had to rate your sleep today, where are you? With 0 being the best sleep you envision.” And that gives me a sense of, if they say, “I was a 10, and I’m a 5 now,” I say to them, “That sounds like a 50% improvement. Let’s see what we can do tweak that.” Which brings us to our next question, when would you change treatments? What would provoke you? What would be the instigator for you to change a treatment?

Often with the DORAs [dual orexin receptor antagonists] especially, they are supposed to take them every night. If someone says, like when the suvorexant first came out and people were like, “This did not work for me at all.” Then, I’m going to have to make some changes. But if they’re 50% better, I often will pull up a scale and show them that this really improves over time, to stay with it, keep doing the same things. And we always do talk about, “What are you doing before you go to bed at night? Are you watching TV? Are you looking at your phone?” Because remember, the light shuts off melatonin, you need to have a time before bed where you’re not engaging in being on your phone, having that light in your eyes, you really do need a dark room. “What are you doing to prepare for sleep?”

I agree with you, and I would add that for me, what would cause me to change my treatment would be some of those complex sleep behaviors, right? Or if they were reporting sleep paralysis, where they feel like they can’t move when they wake up, or hypnopompic, hypnagogic hallucinations, if they’re seeing things as they’re falling asleep or as they’re waking. Some adverse event, or if they say to me, “I slept through my baby crying.” Those are all reasons that I would switch, and obviously, if they’re not working, then I would move to a different agent.

I want to talk for a moment about adherence to our treatment regimen, and you just mentioned something, Debbie, where you said we really want people taking the DORAs every night. Now, you said that, but historically, we’ve said, “Oh, we don’t want people on sleep medications every night.” So, I think as we’re getting newer options that are safer, our philosophy on how we treat sleep is evolving. Would you agree?

I would agree completely because you would never take your antihypertensive medication every 3 days, or just when you felt like you needed it. You need to take this drug as it’s prescribed, and it’s prescribed for nightly use, because it shows that it really does get better over time. And if you stick with it, and you want to take it properly, take it every night, and I think you’ll find that it gets better and better. You were saying that sometimes people have really adverse events. At what moment, or time, do you say, “Hey, it’s time for you to see a sleep specialist,” and how does that happen?

Certainly, once we’ve diagnosed them with sleep apnea, we will get them in to see a nurse practitioner specializing in sleep so she can titrate up their CPAP [continuous positive airway pressure] machine. If I’m concerned regarding narcolepsy, if I’ve tried the standard of care and these folks are not getting better. If the sleep study was inconclusive, and maybe they need an in-house sleep study. Those are some of the reasons that I send people over for sleep medicine. Does that seem similar to what you’re doing for sleep medicine?

Yes, it is, especially I like what you said about the inconclusive studies, because sometimes it’s, is this mild, or is this moderate, or was it done properly because it was done in the home? Then referring them out I think is a much better idea at that juncture.

As we talk about adherence to the regimen, and you talked about the fact that it’s important people take this once a night, there are different kinds of tools out there. I wanted to share with you a couple of tools we have in our clinic. We now have a bidirectional interface with a patient’s pharmacy. So I click on this cute little button, it’s called “fill history” in our EHR [electronic health record], and I can see any drug the patient has filled at a pharmacy. And if it hasn’t been prescribed by my clinic, it’s in a bold category, so I know someone else is prescribing it. What that helps me to do is drug-to-drug interactions checks, but I can also say, “Look, I’m seeing here that you last filled this drug 6 months ago. Are you still taking it? What’s going on?” Are there other tools that you have for tracking adherence?

We have the same option in our EMR [electronic medical record] system, which is great, because you can, like you said, see drug-to-drug interactions and find out what else they’re taking. Because so many times, patients will say, “No, I haven’t had it filled, but I have plenty.” I can say, “You should not have plenty; how is that you have plenty?” And so, that is a way to bring up the conversation of, “You really should.” I hate to

people, but “I would really like it if you tried taking this every night because it would work better, you would sleep better, and you would feel better.”

Advanced practice practitioners discuss how they assess treatment response and patient adherence in insomnia, and considerations for changing treatment.