Research Article: The daily practice of direct oral anticoagulant use in patients with atrial fibrillation; an observational cohort study

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Anouk J. W. Gulpen, Hugo ten Cate, Yvonne M. C. Henskens, René van Oerle, Rick Wetzels, Simon Schalla, Harry J. Crijns, Arina J. ten Cate-Hoek, Michael Nagler.


Direct oral anticoagulants (DOACs) are administered in fixed doses without monitoring. There is still little published data on the impact of the absence of monitoring on adherence to medication and stability of DOAC plasma levels over time.

To explore adherence and stability of DOAC plasma levels over time in patients with atrial fibrillation (NVAF) recently started on DOAC therapy.

A prospective observational cohort study with structured follow up including assessment of adherence to medication, plasma levels at baseline, 3,6 and 12 months and adverse events.

We included 164 patients; 89% were previous users of a vitamin K antagonist (VKA). One-year adherence was reasonably good: Morisky adherence measurement scores of 6–8 in 92%. The majority of DOAC plasma levels were within reported on-therapy ranges; dabigatran (median 104.4 ng/ml, IQR 110.2), rivaroxaban (median 185.2 ng/ml, IQR 216.1) and on average levels were not different for full and adjusted doses. There was significant variation between patients, but no significant differences over time within individuals. A substantial proportion of patients starting in the upper-or lower 20th percentiles remained there during the entire follow up. Seventeen bleedings (16 minor, 1 major) were reported, no ischemic events and bleeding or thrombotic events were not associated with DOAC plasma levels.

Adherence was reasonably good in the majority of patients. Our data confirm the stability of DOAC plasma levels over time. Knowledge of such data may, in the individual patient, contribute to optimal drug and dose selection.

Partial Text

Direct oral anticoagulants (DOACs) are increasingly used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). DOACs are at least as effective as vitamin k antagonists (VKA) and associated with less fatal and intracranial bleeding[1–4]. All DOACs are prescribed in fixed daily doses without the need for frequent laboratory-guided adjustment, with regular doses for patients without risk factors for bleeding and adjusted, lower doses for patients with reduced creatinine clearance, increased age or other risk factors for bleeding[5]. Due to their predictable pharmacokinetic and pharmacodynamic profiles, DOAC plasma levels will remain fairly stable within patients over the time, but high interindividual variability in plasma levels has been shown with all DOACs in defined study populations. However, in daily life patients experience changes in health status, variations in co-medication and problems with adherence, with reported non-adherence rates between 17% and 34% in patients with NVAF, which were similar to the warfarin discontinuation rates[6]. This may have substantial impact on the stability of DOAC plasma levels, potentially changing the efficacy and safety of anticoagulant management. Knowledge of variation in DOAC plasma levels in daily life may have impact on the setup of longterm follow up, which also receives increasing attention in international guidance documents[7]. Recommendations include at least annual monitoring of adherence, side effects, complications and blood tests for hemoglobin, renal and hepatic function; however, DOAC plasma level testing is not recommended. While an annual checkup may be sufficient in general, it may be insufficient in conditions such as illness, diminished adherence or fragile elderly subjects. The aim of this prospective cohort study was to assess the stability of DOAC plasma levels over time in relation to patient characteristics, outcomes and adherence to medication in patients with NVAF recently started on a DOAC. Secondary, we checked the prescribed doses in patients compared to the Dutch guidelines and the influence on DOAC plasma levels.

The focus of this observational cohort study was to assess the stability of DOAC plasma levels over time in relation to patient characteristics, dosing and adherence to medication. The reason for exploring this aspect was our initial concern that in day-to-day care in elderly subjects, due to variations in drug intake, drug interactions or comorbidity, the acclaimed pharmacokinetic stability of DOAC might be compromised.

Under conditions of reasonably good adherence the majority of patients in this observational study remained within therapeutic on-therapy plasma levels and experienced no thromboembolic and relatively few bleeding events. While our data support the assumption that frequent monitoring of DOACs in patients with NVAF is not required, one could argue that initial dose response evaluation may be of benefit in providing an individual patient’s “benchmark” for a particular type and dose of DOAC. Given the range of choices in DOACs (or VKA), optimization of drug and dose selection is feasible and might not be irrelevant.