Higher Bleeding Risk With Higher Peak Direct Oral Anticoagulant Levels Suggests Need for More Accurate Dosing

A study of patients with nonvalvular atrial fibrillation (NVAF) who were receiving a direct oral anticoagulant (DOAC) found that bleeding complications were more frequent among patients with high peak plasma anticoagulant levels, suggesting a need for a more accurate definition of the optimal therapeutic window in this population.

“Currently, DOACs are given at fixed doses and do not require laboratory monitoring … Nevertheless, a high interindividual variability in the drug blood levels [has been] shown with all DOACs,” wrote the authors, led by Sophie Testa, MD, from the Ospedale di Cremona in Italy. The study was published in the Journal of Thrombosis and Haemostasis.

In this trial, the researchers assessed a possible relationship between DOAC concentration trough (C-trough) and C‐peak levels (measured at steady state within the first month of treatment) and the bleeding events occurring during the year following blood sampling.

A total of 565 consecutive treatment-naïve patients with NVAF were enrolled in the observational, multicenter study. The distribution of patients across DOACs were as follows:

  • twice-daily dabigatran at 150 mg (n=82) or 110 mg (n=103)
  • once-daily rivaroxaban at 20 mg (n=100) or 15 mg (n=72)
  • twice-daily apixaban at 5 mg (n=154) or 2.5 mg (n=54)

Blood samples were obtained within the first 15 to 25 days of therapy administration. Measurements of both C-trough and C-peak DOAC levels were available in 411 patients (median age = 80 years; range not reported). Compliance and adherence to anticoagulant therapies were evaluated by manual pill counting at the first month of treatment and every three months for one year.

At one-year follow-up, rates of bleeding and thromboembolic complications were:

  • 3.4% for major bleeding (defined as fatal bleeding or symptomatic bleeding in critical area or organ, or a decrease in hemoglobin level of ≥20 g/L)
  • 1.1% for clinically relevant nonmajor bleeding (defined as any overt bleeding requiring a medical intervention and/or treatment discontinuation)
  • 8.3% for minor bleeding (defined as any overt bleeding reported by patients to the anticoagulation clinic that did not require medical intervention)

Approximately 20% of bleeding complications were noted within the first three months of DOAC treatment, the authors reported.

In multivariate analyses to determine risk factors for bleeding events, the researchers found that higher C-peak levels were associated with higher bleeding risk, compared with patients with the lowest C-peak levels (odds ratio [OR] = 2.7; 95% CI 1.3-5.4; p value not provided). However, there was no apparent association between bleeding risk and C-trough levels.

Patients with other “traditional” risk factors for bleeding and thromboembolic complications, such as high CHA2DS2VASc and HAS-BLED scores, were also at a greater bleeding risk (OR=1.6 and 2.9, respectively; p values not provided).

The results of the current study, the researchers added, suggest that the definition for the optimal treatment window of DOACs in patients with NVAF needs improvement. “DOACs are currently administered at fixed dose, without indications for individual dose adjustment based on specific laboratory testing, assuming a priori that a good anticoagulant level would be obtained in all patients,” Dr. Testa told ASH Clinical News. “In contrast, our studies confirmed that some patients are ‘poor responders’ and have low DOAC levels at C-trough with subsequently more thrombotic complications during follow-up.”

Conversely, she added, there are other “high-responder” patients with high levels of DOAC at C-peak and a higher risk of bleeding during treatment. “It is well-known that there is a high interindividual variability in response to the same DOAC dose and that the drug elimination rate may not be constant in all patients,” Dr. Testa noted. “A correlation between renal function and DOAC plasma levels has not always been found, yet an association between plasma levels and major events has been highlighted by U.S. Food and Drug Administration reports on DOAC phase III clinical studies and has been confirmed in the recent observational studies.”

Limitations of the study include its observational nature, the relatively small numbers of patients included in the study, the one-time measurement of DOAC levels at the steady state after anticoagulant treatment, and the lack of adjustment for adherence issues during the observational period.

Future research, Dr. Testa added, should attempt to find “the optimal therapeutic range to ensure DOAC efficacy and safety and to investigate how to reach and maintain that range in all patients.”

The study authors reported relationships with Bayer, Roche, Pfizer, CSL Behring, and Boehringer Ingelheim.

Reference

Testa S, Legnani C, Antonucci E, et al. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. 2019;17:1064-1072.