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NEW YORK (Reuters Health) – When it comes to direct oral anticoagulants (DOACs), dose-adjustment and low-intensity treatment are two different forms of dose reduction, each with their own indications, researchers say.

“Not all ‘low’ doses are the same,” Dr. Behnood Bikdeli of Brigham and Women’s Hospital in Boston told Reuters Health by email. “Sometimes the dose is reduced with the goal of fully-therapeutic levels, such as the case of concomitant use of other drugs that increase the plasma DOAC levels. This is dose adjustment.”

“In contrast,” he said, diclofenac 150 g preisvergleich “in other cases, we intentionally plan for a lower intensity of anticoagulation to confer some protection, while posing a lower risk of bleeding compared with using full-intensity DOACs.”

“We think it is critical to distinguish these two,” he said.

“We noted that in many cases, data from large registries of routine practice do not align with high-quality existing evidence,” he noted. “One common error is to extrapolate and (mis)use dose adjustment criteria from trials of atrial fibrillation (AF) for the care of patients with venous thromboembolism (VTE).”

Dr. Bikdeli and colleagues studied randomized clinical trials (RCTs) for scenarios in which dose-adjusted or low-intensity DOACs were tested, and reviewed the labeled indications from regulatory authorities. They then used data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.

The review, published in JAMA Cardiology, included 35 RCTs that used dose-adjusted DOACs – dabigatran, apixaban, rivaroxaban, and edoxaban. Of these RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs.

“To our knowledge,” the authors write, “dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment.”

Low-intensity DOACs were used in 37 RCTs. According to guidelines, low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban); primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban); primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or post-discharge high-risk medical patients (rivaroxaban); in stable atherosclerotic vascular disease; or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban).

Although the team uncovered minor variations between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs, data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.

The authors conclude, “Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.”

Dr. Bikdeli said, “We also noted several areas of knowledge gap that need attention, including optimal use of dose-reduced DOACs for patients with advanced renal dysfunction (or ESRD) who have AF or VTE; what constitutes the optimal dose for treatment in patients of Asian descent (who may have a different risk/benefit profile); and particularly, what to do in patients who do not strictly meet criteria for ‘dose adjustment’ but are considered too frail to safely tolerate full-intensity anticoagulation.”

Dr. Howard Weintraub, clinical director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Health in New York City, commented on the study in an email to Reuters Health. “Hopefully, what this article will accomplish is to support making adjustments in therapy when it is appropriate, based on guidelines, but reduce the urge to do so when patients would be appropriate candidates for full-dose anticoagulation,” he said. “It is interesting that reduced-dose DOACs would be useful in patients with VTEs, but not in the acute phase.”

“The guidelines are there for the use of DOACs in AF, particularly as pertains to each of the four agents in the group,” he noted. “The role of reduced dosage DOAC’s in the treatment of VTE is something that should be made clearer.”

“I would encourage physicians to follow the recommendations and guidelines regarding each of these medications,” Dr. Weintraub concluded. “This is essentially what the authors recommended and I would think that this is good advice.”

SOURCE: JAMA Cardiology, online June 2, 2022.

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