Anticoagulation Therapy

Anticoagulation Management in the Oldest Old Population and Patients With ESRD

Direct-acting oral anticoagulation (DOAC) therapy is often prescribed to treat atrial fibrillation (AF). However, dosing and prescribing standards, as well as stroke risk, are unclear among the oldest old population and patients with end-stage renal disease (ESRD).

This was the topic of discussion during “Direct Oral Anticoagulant Dilemmas” at the 2021 American Society of Health-System Pharmacists Midyear Clinical Meeting & Exposition. The presenters included Barbara J. Zarowitz, PharmD, BCGP, BCPS, FASCP, who is the senior advisor of the Peter Lamy Center on Drug Therapy and Aging at the University of Maryland School of Pharmacy, and Zachary R. Noel, PharmD, BCPS, BCCP, who is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy.

DOAC Use Among the Oldest Old Population

Dr Zarowitz started the session by giving an overview of stroke risk by age category. She said that although the stroke risk is high among individuals aged 60 to 79 years, the risk increases exponentially among individuals aged 80 years or older. She also discussed the various, severe outcomes associated with post-stroke disability, including depression, epilepsy, and gait instability.

“Despite the severe outcomes, the AHA has stated that evidence-based treatments for this population are not often provided and that they are still a group that will benefit from and should be offered evidence-based treatment.”

She then went on to highlight the importance of preventing strokes in the oldest old population, saying that “someone in the United States has a stroke every 40 seconds … but more than 80% of strokes are preventable.” One way to prevent strokes is to follow the American Heart Association’s Life’s Simple 7 campaign, which includes managing blood pressure, being more active, and making small lifestyle changes that have a big impact.

Then she discussed the clinical trials that evaluated the efficacy and safety of different DOACs in patients with AF, although limited DOAC safety or efficacy data are available in the oldest old. The AVERROES trial showed that apixaban was more efficacious than aspirin for reducing strokes and systemic embolism among patients aged 75 years or older. And the ELDERCARE-AF trial showed that edoxaban was associated with more gastrointestinal bleeding in patients aged 80 years or older vs placebo. The strongest evidence supports apixaban, 2.5 mg twice daily or edoxaban, 15 mg once daily (off label) for oldest old patients with AF.

After a brief case report discussion, Dr Zarowitz continued on to discuss risk assessments for stroke and bleeding in the oldest old population. She said that neither the CHA2DS2‐VASc nor the HAS‐BLED score adequately predict bleeding risk and underestimate the risk in this population. And because bleeding risk is difficult to predict, she then turned attention toward the literature.

According to the American Geriatrics Society, dabigatran and rivaroxaban have an increased risk of gastrointestinal bleeding and are recommended to be used with caution in adults aged 75 years or older who have venous thromboembolism or AF. DOACs generally are not recommended, or are recommended at reduced doses, by the American Geriatrics Society for patients with varying levels of kidney function.

“Brand new, added this summer, to the ABIM Foundation’s Choosing Wisely campaign is [a recommendation] that pertains explicitly to the DOACs. It guides, ‘Don’t use 2 or more medications that are known to increase the risk of bleeding without evaluating the potential risks and benefits’ and then lists several of the medications.”

Next, Dr Zarowitz highlighted polypharmacy management and the most common mistakes of prescribing DOACs to the oldest old population. Polypharmacy (with prescribed and over-the-counter medications as well as supplements) is common, and therefore, drug-drug interactions are likely. SSRIs and SSNRIs negatively impact platelet medications.

Dr Zarowitz said the number 1 mistake made in practice is prescribing the wrong dose for indication, renal function, or other patient-specific factors. Important considerations for pharmacotherapy stewardship include identifying the indication for use; ensuring appropriate dosing, monitoring, and follow-up; evaluating renal and liver function, weight, and age; and performing medication reviews.

“Anticoagulants are the most common cause of adverse events in the United States, and the oldest old adults are particularly vulnerable to bleeding events,” she concluded. “We really have to be laser focused on what we do to minimize those risks. One of the ways we remain laser focused is recommending DOACs over warfarin or aspirin, because of the reduced risk of major bleeding.”

DOAC Use for Patients With ESRD

Dr Noel started his presentation by highlighting a case report and posing a question related to treatment of the patient. The question did not have a correct answer because, “We don’t have very robust data to suggest that routine anticoagulation is beneficial in patients with ESRD and AF,” he said. “We’re left with the conundrum of ‘do we anticoagulate and run the risk of bleeding?’ or ‘do we not anticoagulate and protect that risk of bleeding?’”

Compared with no anticoagulation or warfarin, Dr Noel says that DOACs are the best option. However, clinical outcomes for DOACs are not well established, the optimal dosing of DOACs is unclear, and the net clinical benefits of DOACs compared with warfarin are unclear.

He then highlighted the literature, which showed that apixaban and rivaroxaban are the least renally eliminated and are extensively protein bound, which makes them minimally dialyzable, Dr Noel said. Then he spoke about the specific clinical trials that examined the pharmacokinetics of DOACs in and clinical outcomes of patients on dialysis.

“What you’ll observe is that the relative risk of stroke isn’t that much higher [among patients with AF who are on dialysis], proportionally speaking, compared to those who don’t have atrial fibrillation.” But the mortality rate was higher.

Echoing Dr Zarowitz’s remarks about risk scores in the oldest old population, Dr Noel said, “The HAS-BLED score probably will underestimate the bleeding risk [in ESRD]…CHA2DS2‐VASc is poorly predictive of stroke, and the HAS‐BLED score is poorly predictive of bleeding,” according to the literature.

Digging into the guidelines, Dr Noel said the 2019 ACC/AHA/HRS AF guideline recommends prescribing apixaban for patients on dialysis, and rivaroxaban is not recommended. The 2018 CHEST guidelines generally do not recommend DOACs, but apixaban, 5 mg is approved for patients on dialysis. The 2018 KDIGO guideline cited “insufficient evidence” to recommend apixaban or rivaroxaban but recommend clinicians consider apixaban, 2.5 mg twice daily or rivaroxaban, 15 mg once daily. And finally, the 2020 ESC AF Guidelines make no comment on DOAC use.

“We’re left with observational data … It suggests that DOACs may be safer than warfarin [in ESRD], but we can’t definitively say. I think it’s reasonable to say that DOACs are probably no worse than warfarin,” Dr Noel stated.

Dr Noel said that shared decision-making is key when developing a treatment regimen. Regarding the mistakes made in clinical practice, he said that clinicians should:

  • Evaluate your patient’s antiplatelet medications and stop any unnecessary use (particularly aspirin) to avoid drug-drug interactions with DOACs.
  • Dose according to prescribing information (apixaban, 5 mg twice daily and rivaroxaban, 15 mg once daily with a large meal).
  • Avoid underdosing based on your clinical feeling or intuition.
  • Avoid DOAC use with strong inhibitors or inducers of CYP 3A4 and/or P-gp.


—Amanda Balbi


Noel ZR, Zarowitz BJ. Direct oral anticoagulant dilemmas: stroke prevention for atrial fibrillation in the oldest old and patients with end-stage renal disease. Talk presented at: 2021 American Society of Health-System Pharmacists Midyear Clinical Meeting & Exposition; December 5-9, 2021; Virtual.