Source/Disclosures
Disclosures: The study was supported by an unrestricted research grant from Bayer AG to the Thrombosis Research Institute. Camm reports he received institutional grants and personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer/Bristol-Myers Squibb. Naccarelli reports he consulted for and participated in research funding from Janssen and consulted for Acesion, Milestone, Omeicos and Sanofi. Please see the study for all other authors’ relevant financial disclosures.
September 14, 2020
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Nonrecommended doses of direct oral anticoagulants may raise mortality risk

Source/Disclosures
Disclosures: The study was supported by an unrestricted research grant from Bayer AG to the Thrombosis Research Institute. Camm reports he received institutional grants and personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer/Bristol-Myers Squibb. Naccarelli reports he consulted for and participated in research funding from Janssen and consulted for Acesion, Milestone, Omeicos and Sanofi. Please see the study for all other authors’ relevant financial disclosures.
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Patients with atrial fibrillation who received nonrecommended doses of direct oral anticoagulants had increased risk for death compared with those who received recommended doses, according to new data from the GARFIELD-AF registry.

The excess deaths were driven by CV events such as HF and MI, according to the analysis published in the Journal of the American College of Cardiology. Most patients in the registry (72.9%) received the recommended dose of their direct oral anticoagulant.

Anticoagulants
Source: Adobe Stock.

“These findings from GARFIELD-AF remind physicians that they must recognize that stroke risk and mortality risk [are] high in patients with atrial fibrillation, and that the purpose of anticoagulant therapy is to reduce these adverse events,” Alan John Camm, MD, professor of clinical cardiology at St. George’s University of London, told Healio. “They must appreciate that it is important to prescribe anticoagulant at the correct dose in order to achieve the most effective results.”

Data from GARFIELD-AF registry

Researchers analyzed data from 10,426 patients with AF from the GARFIELD-AF registry taking direct oral anticoagulants, which included apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), rivaroxaban (Xarelto, Janssen/Bayer), dabigatran (Pradaxa, Boehringer Ingelheim) and edoxaban (Savaysa, Daiichi Sankyo). Rules on recommended dosing, underdosing and overdosing took into account baseline characteristics, including body weight, kidney function, bleeding risk and age.

Patients were stratified into three groups: underdosing (n = 2,423; median age, 77 years; 51% women), recommended dosing (n = 7,603; median age, 70 years; 42% women) and overdosing (n = 400; median age, 75 years; 49% women).

Clinical events assessed included vascular disease, chronic kidney disease and congestive HF.

The risk for all-cause mortality was higher in patients treated with nonrecommended dosing compared with those treated with the recommended dose (HR = 1.24; 95% CI, 1.04-1.48). Compared with the recommended-dose group, the HR for the underdosed group was 1.25 (95% CI, 1.04-1.5) and the HR for the overdosed group was 1.19 (95% CI, 0.83-1.71).

Most of the excess for all-cause death in the underdosed group compared with the recommended dosing group was due to high rates of CV death, specifically congestive HF and MI, according to the researchers.

There were no significant differences in risk for stroke/systolic embolism across the dosage groups. Patients who were underdosed had lower risk for major bleeding (HR = 0.5; 95% CI, 0.28-0.88). Patients treated with a higher dose than recommended had a trend toward higher risk for for major bleeding (HR = 1.29; 95% CI, 0.59-2.78) and stroke/systolic embolism (HR = 1.51; 95% CI, 0.79-2.91) compared with those prescribed the recommended dose.

Alan John Camm

“There have been several retrospective registry studies which have highlighted this problem, but GARFIELD-AF is the first prospective study to identify that there is a mortality increase associated with inappropriate dosing of [direct oral anticoagulants] and that major bleeding is not greatly reduced by using a lower dose,” Camm said in an interview.

Camm told Healio that further research needs to concentrate on achieving a balance between bleeding prevention and effective stroke reduction.

“The development and introduction of [direct oral anticoagulants] has significantly reduced bleeding risks associated with anticoagulant (with vitamin K antagonists, eg, warfarin),” he said in an interview. “However, bleeding still presents a difficult problem, which deters both physicians from prescribing the drug and patients from taking them. New anticoagulants with lower bleeding risks are already being evaluated, but they are some way off, likely to be expensive and difficult to afford. We already have some reversal agents for [direct oral anticoagulant] drugs which are highly effective, but they are too expensive for many patients and health care systems to afford.”

‘Careful with the art of practice’

Gerald V. Naccarelli

In a related editorial, Gerald V. Naccarelli, MD, professor of medicine and chief of the division of cardiology at Penn State Heart and Vascular Institute, wrote: “Treating patients is an art, and clinicians may rarely need to individualize a treatment for a given patient. However, the clinician should be careful with the art of practice. Ignoring the truth of the well-studied and recommend doses of direct oral anticoagulants can lead to dangerous consequences. The truth is that these doses have not been well-studied, and they can expose patients to thromboembolic events, leading to strokes. Primum non nocere (first, do no harm) is part of the original Hippocratic oath; underdosing of a direct oral anticoagulant may break that oath.”

Reference:

For more information:

Alan John Camm, MD, can be reached at jcamm.sgul.ac.uk.