For years, warfarin and aspirin have been standard therapies for prophylaxis of stroke in atrial fibrillation. In late 2010, dabigatran, an oral direct thrombin inhibitor, became available for use in nonvalvular atrial fibrillation. We sought to evaluate utilization and prescribing patterns of dabigatran in a physician group practice setting. We retrospectively collected prescription data from October 2010 to December 2011 including indication of use, dose, renal function, drug interactions, history of warfarin therapy, and risk assessment scores (CHADS 2 and HAS-BLED). Off-label use (history of valve disease or no diagnosis of atrial fibrillation) occurred in 20% (n = 34) of 174 patients. Renal function assessed by Cockcroft-Gault equation identified 1 case of contraindicated use and the need for initial renal dose adjustment in approximately 1/2 of the patients with reduced renal function (15-30 ml/min). Review of anticoagulant use revealed 68% of patients (n = 119) previously received warfarin and ultimately 20% of all patients on dabigatran resumed warfarin therapy. A significant increase in the use of permeability glycoprotein inhibitors and proton pump inhibitors after initiating dabigatran was observed. Nearly 10% of patients had a CHADS 2 score of 0. For patients receiving novel oral anticoagulants, prospective inclusion in anticoagulation services and guidance from specific “place in therapy” statements have potential to play a large role in maximizing safety while aiding in continued research.
Use of the Marshfield Clinic Anticoagulation Service, which manages approximately 10,000 unique patients annually or about 7,500 any given month, allows patients taking warfarin to be closely followed and monitored by specialists in anticoagulation. This provides improved management and prospective collection of patient data in a large population. The addition of novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban to anticoagulation monitoring services in any health-care setting may allow these new agents to be tracked closely as well, which could potentially offer data on prescribing practices, adverse events, and efficacy. At the time of this study, apixaban and rivaroxaban were still under review by the Food and Drug Administration (FDA) for the prevention of stroke in patients with nonvalvular atrial fibrillation; the primary objective of this quality improvement initiative was to assess the utilization and prescribing patterns of dabigatran in a physician group practice setting. As a secondary objective, this initiative assessed the benefit versus the risk of anticoagulation therapy by comparison of CHADS 2 and HAS-BLED scores.
Methods
This retrospective study included patients aged ≥18 years who had taken or were currently taking dabigatran from October 19, 2010 (FDA approval date) to December 2, 2011. Patients who did not have a primary care provider within the Marshfield Clinic System were excluded, and for all patients included, the specialty of the prescriber for dabigatran was collected. The study was approved by the Marshfield Clinic Institutional Review Board. Most data were extracted electronically, but consumption of alcohol and review of initial renal dose adjustments required manual chart review. Confirmation of atrial fibrillation diagnosis was also manually reviewed to confirm the accuracy of the electronic data extraction. Drug interactions were assessed by observing rates for interacting drugs starting 7 days before therapy and during dabigatran therapy in an attempt to see if dabigatran therapy influenced the interaction rates (95% confidence interval was derived using the exact binomial distribution). Storage of data was secured using computer files with restricted access.
Descriptive statistics included mean, SD, median, and range for the continuous variables (age, height, weight, creatinine clearance, estimated glomerular filtration rate, CHADS 2 score, and HAS-BLED score) and the frequency and percentage for the categorical variables (gender, race, and diagnosis of atrial fibrillation [valvular vs nonvalvular]). All statistical analyses were carried out using a commercially available statistical software package, SAS (version 9.2; English; Cary, North Carolina).
Results
The baseline characteristics of the 174 patients are displayed in Table 1 . Nearly all patients were white and approximately 1/2 were men. The mean age was 70.8 years with a range from 27 to 94. Notably, 40% (n = 70) of the patients were aged ≥75 years.
| Characteristic | n (%) | Mean | SD | Median | Range |
|---|---|---|---|---|---|
| Age (yrs) | 174 (100) | 70.8 | 12.2 | 72 | 27–94 |
| Men | 97 (56) | — | — | — | — |
| Women | 77 (44) | — | — | — | — |
| White | 167 (96) | — | — | — | — |
| Asian | 2 (1.1) | — | — | — | — |
| Black | 1 (0.6) | — | — | — | — |
| Native Hawaiian/Pacific Islander | 1 (0.6) | — | — | — | — |
| Not specified | 3 (1.7) | — | — | — | — |
| Height (cm) | 173 (99) | 170.8 | 11 | 172.7 | 139.7–193 |
| Weight (kg) | 174 (100) | 92.6 | 25.9 | 90.4 | 44.5–178.1 |
| Renal function | |||||
| Creatinine clearance (ml/min) | 173 (99) | 61.1 | 25.6 | 57 | 13.3–142.1 |
| Estimated glomerular filtration rate (ml/min) | 146 (84) | 62 | 16 | 61 | 20.5–89.3 |
| CHADS 2 | 174 (100) | 2.0 | 1.3 | 2.0 | 0–6 |
| HAS-BLED | 174 (100) | 3.0 | 1.3 | 3.0 | 0–6 |
Results for assessment of indication for dabigatran therapy are displayed in Table 2 . Off-label use was identified at a rate of 20% and was defined as use in patients with a history of valve disease or no diagnosis of atrial fibrillation or atrial flutter. The primary prescribers of dabigatran included cardiology (38%) and internal medicine and/or family medicine (38%).
| Variable | Atrial Fibrillation | Total | |
|---|---|---|---|
| Yes | No | ||
| Nonvalvular | 140 (80.5) | 13 (7.5) | 153 (88) |
| Valvular disease | 19 (10.9) | 2 (1.1) | 21 (12.1) |
| Total | 159 (91.4) | 15 (8.6) | 174 (100) |
Use of the creatinine clearance identified 1 case of contraindicated use (<15 ml/min) and 13 candidates for renal dose adjustments (15 to 30 ml/min). More than 1/2 of those patients (n = 8, 62%) did not receive an initial renal dose adjustment for dabigatran. In contrast, the estimated glomerular filtration rate identified no cases of contraindicated use (<15 ml/min) and only 7 patients requiring a renal dose adjustment. Of these patients, just under 1/2 (n = 3, 43%) did not receive an initial renal dose adjustment for dabigatran.
Assessing history of anticoagulant use showed that 57% of patients (n = 99) had previously been using warfarin before using dabigatran, and 12% of patients (n = 20) were transferred from warfarin to dabigatran and then back to warfarin. Additionally, 24% of patients (n = 42) with no history of warfarin use were started on dabigatran therapy, and 8% of patients (n = 13) were initially started on dabigatran then later switched to warfarin. Reasons for the changes were not assessed. Most patients (98%) experienced “true switches,” whereas the remainder were “false switches.” An example of a false switch is a patient taking warfarin who is prescribed dabigatran but decides not to take it and continues on warfarin therapy, which would document a change within the electronic medical records but a change in therapy has not truly occurred.
The assessment of drug interactions is reported in Table 3 . Statistically significant increases in the prescribing rates for proton pump inhibitors and permeability glycoprotein inhibitors after initiation of dabigatran therapy were observed. The latter primarily consisted of cardiovascular drugs including amiodarone, dronedarone, diltiazem, and carvedilol.
| Drug | Patients | ||
|---|---|---|---|
| Before Prescribing Dabigatran | After Prescribing Dabigatran | 95% CI, % | |
| Proton pump inhibitors | 46 (26) | 59 (34) | 26.9–41.5 ∗ |
| P-glycoprotein inducers | 1 (1) | 1 (1) | 0.0–3.2 |
| P-glycoprotein inhibitors | 74 (43) | 116 (67) | 59.1–73.6 ∗ |
| Anticoagulants † | 4 (2) | 7 (4) | 1.6–8.1 |
| Platelet aggregation inhibitors | 16 (9) | 10 (6) | 2.8–10.3 |
| Nonsteroidal antiinflammatory drug (NSAID) | 30 (17) | 37 (21) | 15.4–28.1 |
∗ Statistically significant for the percentage after compared with the percentage before.
† Lepirudin and enoxaparin were the only anticoagulants identified, but it was not determined if these were actually used simultaneously with dabigatran or used when transitioning on or off dabigatran therapy.
The percentage of patients in each category of the CHADS 2 score (0 to 6) and HAS-BLED score (0 to 9) are presented in Figures 1 and 2 , respectively, and the results of the individual comparison of scores for each patient are depicted in Figure 3 .
