Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism

Abstract

Background: Direct oral anticoagulants (DOACs) are increasingly prescribed for the treatment of venous thromboembolism (VTE). However, little is known regarding pharmacists’ practice patterns and preferences in clinical areas of contention, such as initiation dosing, obesity, and renal impairment. Objective: To determine pharmacist trends in practice regarding DOACs for the treatment of VTE overall and within areas of clinical controversy. Methods: An electronic survey was distributed to pharmacists in the United States through national and state pharmacy organizations. Responses were collected for 30 days. Results: One hundred fifty-three complete responses were submitted. The majority of pharmacists preferred apixaban (90.2%) for the oral treatment of venous thromboembolism. When initiating apixaban or rivaroxaban for a new VTE, 76% and 64% of pharmacists surveyed, respectively, state the duration of the initiation dose phases are reduced if the patient received parenteral anticoagulation. Fifty-eight percent of pharmacists used body mass index to evaluate the appropriateness of DOACs in obese patients whereas 42% used total body weight. Preference for rivaroxaban (31.4%) was higher in this population compared to the global population (10%). Apixaban was preferred for patients with renal impairment (92.2%). However, as creatinine clearance as calculated by the Cockcroft-Gault equation (CrCl) reduced to ≤15 milliliters/minute (mL/min), preference for warfarin increased (36%). Conclusion: This national survey of pharmacists demonstrated an overall preference for apixaban and significant variability in practice patterns regarding DOACs for patients with new VTE, patients with obesity, and patients with renal impairment. Further research is warranted to evaluate the efficacy and safety of DOAC initiation dosing phase modifications. Prospective evaluations of DOACs in obese and renal dysfunction populations would confirm the safety and efficacy of DOACs in these populations.

Keywords

anticoagulants physician prescribing cardiovascular

Background

Direct oral anticoagulants (DOACs) are increasingly prescribed for the treatment of venous thromboembolism (VTE), pulmonary embolism, atrial fibrillation (AF) and certain hypercoagulable conditions. Apixaban and rivaroxaban are indicated for the treatment of VTE and AF and are the most frequently prescribed DOACs.^1
-4 Despite trends toward increased DOAC utilization in the aforementioned disease states, the selection and management of oral anticoagulants is controversial in clinical practice with respect to the duration of the initiation dosing phase, upper extremes of body weight, and renal dysfunction.

In the treatment of VTE, apixaban and rivaroxaban require an initiation dose phase based on randomized controlled trials powered to assess safety and efficacy for this indication. Apixaban is dosed as 10 mg twice daily for 7 days followed by 5 mg twice daily thereafter,³ while rivaroxaban is dosed as 15 mg twice daily for 21 days followed by 20 mg daily with dinner thereafter.⁴ Patients with high-risk characteristics, such as right ventricular strain or hemodynamic compromise, may require initial treatment with parenteral anticoagulation prior to treatment with oral therapies.^5,6 Patients receiving more than 2 days of parenteral anticoagulation treatment were underrepresented in clinical trials, and the safety and efficacy of omitting, shortening, or completing the initiation dose phase is unknown.^7
-9 There are currently no published data describing the practice patterns of pharmacists and providers when patients receive an extended duration of parenteral anticoagulation prior to initiating a DOAC for VTE treatment. Furthermore, additional factors including perceived bleeding risk and patient adherence may impact the selected duration of the initiation dose, which warrants exploration.

The use of DOACs in special populations, such as in patients with obesity or renal insufficiency, is often cause for clinical debate. Historical guidance suggested the avoidance of DOACs in obesity.^10,11 Recently, data has been published using a variety of obesity definitions including body mass indices (BMI) >30 or 40 kg/m² and total body weight >100 or 120 kg.^10
-20 This led to updated guidance that apixaban and rivaroxaban may be used regardless of high BMI and weight.^10,11 Whether pharmacist practice aligns with the results of those studies is currently unknown. Furthermore, the apixaban and rivaroxaban clinical trials excluded patients with a creatinine clearance of less than 25 mL/min and 30 mL/min, respectively.^7
-9 However, pooled clinical data suggest that, in the treatment of acute VTE in patients with chronic kidney disease (CKD), outcomes of VTE or VTE-related death and major bleeding are similar between DOACs and warfarin.²¹ Since evidence is limited, practices may vary. Surveying pharmacists to identify trends in practice is important to identify areas of further research and advance patient care.

Objective

To determine pharmacist trends in practice regarding DOACs for the treatment of VTE overall and within areas of clinical controversy including initiation dose phase duration, renal dysfunction, and obesity.

Methods

An electronic survey (Supplement 1) was distributed to pharmacists in the United States via email lists associated with the American College of Clinical Pharmacy (ACCP), American Society of Health-System Pharmacists (ASHP), Indiana Pharmacists Association (IPA), and Georgia Society of Health-System Pharmacists (GSHP). The Tennessee Pharmacists Association (TPA) posted the survey on its website. Survey invitations were sent once in March 2022, and any individual with the link could complete the survey. The survey was live for 1 month after distribution. The survey was developed by 2 authors and reviewed by all authors. A focus group consisting of select practicing pharmacists was utilized as a pilot group before distribution. The survey was reviewed by the University of Louisville Institutional Review Board (IRB) and Vanderbilt University Medical Center IRB prior to distribution and data collection. Results were analyzed using descriptive statistics. Post-hoc analysis of responses by geographic location was performed.

Results

One hundred fifty-five participants started the survey and 153 provided complete results. The median (interquartile range) time to survey completion was 4 minutes 56 seconds (3 minutes 39 seconds, 7 minutes 49 seconds). Pharmacists representing 35 states completed the survey with 30% of respondents residing in Georgia. Most pharmacists worked in an inpatient setting in an urban or suburban location. Fifty-one percent worked in an academic teaching hospital and 34% worked in a community hospital. Forty percent, 26%, and 7% of pharmacists specialized in internal medicine, cardiology, or anticoagulation, respectively. Twelve percent of respondents ascribed no specialty. Seventy-four percent of pharmacists were board certified. Sixty-six percent of pharmacists had 10 years or less of practice experience. All demographic information can be found in Table 1.

Table 1.

Demographics.

Survey completion time, minutes:seconds, median (IQR)	4:56 (3:39-7:49)
Practice setting
Inpatient, N (%)	131 (85.6)
Outpatient, N (%)	18 (11.8)
Both, N (%)	3 (2.1)
Emergency Department, N (%)	1 (0.7)
Institution type
Academic teaching hospital, N (%)	77 (50.7)
Community hospital, N (%)	51 (33.6)
Ambulatory care, N (%)	17 (11.2)
Community teaching hospital, N (%)	3 (2.1)
Community pharmacy, N (%)	1 (0.7)
Other, N (%)	3 (2.1)
Practice location
Urban, N (%)	91 (59.9)
Suburban, N (%)	46 (30.3)
Rural, N (%)	15 (9.9)
Practice region
Midwest, N (%)	33 (21.6)
Northeast, N (%)	12 (7.8)
South, N (%)	84 (55)
West, N (%)	21 (13.7)
International/No Location, N (%)	3 (1.9)
Specialty
Internal medicine, N (%)	60 (39.7)
Cardiology, N (%)	39 (25.8)
No specialty, N (%)	18 (11.9)
Anticoagulation, N (%)	10 (6.6)
Critical care, N (%)	10 (6.6)
Oncology, N (%)	4 (2.7)
Emergency medicine, N (%)	2 (1.3)
Antimicrobial stewardship, N (%)	1 (0.7)
Family medicine, N (%)	1 (0.7)
General medicine, N (%)	1 (0.7)
Geriatrics, N (%)	1 (0.7)
Hematology, N (%)	1 (0.7)
Long term acute care, N (%)	1 (0.7)
Stroke, N (%)	1 (0.7)
Transplant, N (%)	1 (0.7)
Board certification—yes, N (%)	112 (74.2)
Years in practice
≤2 years, N (%)	17 (11.2)
3-5 years, N (%)	38 (25)
6-10 years, N (%)	45 (29.6)
11-20 years, N (%)	34 (22.4)
≥21 years, N (%)	18 (11.8)

Note. IQR = interquartile range.

In the absence of other factors, the preferred oral anticoagulants for VTE treatment were apixaban (90%) and rivaroxaban (10%). Following parenteral anticoagulation, 76% and 64% of pharmacists stated the duration of the initiation dose phases of apixaban and rivaroxaban are reduced, respectively. Primary reasons for shortening the initiation dose phase included receipt of prior parenteral anticoagulation (67%), bleeding risk for the patient (34%), and simplifying the patient’s discharge medication regimen (20%). When presented with a patient who received 4 days of therapeutic enoxaparin, 47% of respondents chose to shorten the initiation dose period for apixaban to 3 days.

Regarding VTE treatment in obesity, pharmacists reported utilizing highly variable definitions of obesity. Fifty-eight percent used BMI while 42% used total body weight to define obesity. The most common BMI used to define obesity was 40 kg/m² (52%). The 2 most common total body weights used to define obesity were 120 kg (40%) and 150 kg (35%). Eighty-two percent of pharmacists preferred a DOAC over warfarin in obese patients. Of those who preferred a DOAC, 61% preferred apixaban and 38% preferred rivaroxaban. However, as body weight is a continuum, 65% of respondents reported that extent of obesity influences treatment selection. When presented with a 118 kg patient (BMI = 44.6 kg/m²) with a popliteal deep vein thrombosis; 63%, 31%, and 6% chose apixaban, rivaroxaban, and warfarin, respectively.

For VTE treatment in patients with renal impairment, apixaban was the preferred oral anticoagulant (92.2%). As creatinine clearance (CrCl) decreased, the preference to warfarin increased (Table 2), and 36% of pharmacists preferred warfarin for patients with a CrCl less than 15 mL/min. When presented with an 82-year-old male patient with a new VTE weighing 72 kg and with a SCr of 1.9 g/dL, most pharmacists elected to treat with the labeled dose of apixaban for VTE (86%). Six percent of pharmacists opted to omit the initiation dose phase and 7% opted for a half-dosed regimen consisting of apixaban 5 mg twice daily for 7 days followed by 2.5 mg twice daily thereafter.

Table 2.

Preferred Oral Anticoagulant by Patient Population.

	Apixaban (%)	Rivaroxaban (%)	Dabigatran (%)	Warfarin (%)
Baseline	90.2	9.8	0	0
Obesity	49.7	31.4	0.6	18.3
Renal impairment	92.2	0.7	0.7	6.5
CrCl 25-29 mL/minute	92.2	1.3	0.7	5.9
CrCl 15-24 mL/minute	79.1	1.3	0.7	19
CrCl < 15 mL/minute	62.9	0	0.7	36.4
Hemodialysis	70.4	0	0.7	28.9

Note. CrCl = creatinine clearance.

Discussion

Our survey of pharmacists reveals a clear preference for DOACs, particularly apixaban, in the treatment of VTE that may change in patient populations with obesity or severe renal impairment not on hemodialysis.

Additionally, this survey highlights a diverging opinion amongst pharmacists regarding clinical implementation of apixaban and rivaroxaban initiation doses. Though about three quarters of pharmacists reported reductions in the duration of initiation doses of apixaban, only about half chose to do so when presented with a patient who received 4 days of parenteral anticoagulation. Currently there are no published clinical data regarding the safety and efficacy of shortening the initiation dose phase. The only available data regarding using or omitting apixaban’s initiation dose phase is from computer simulations—no actual patients were evaluated.⁷ These simulations showed a modest reduction in VTE with a corresponding modest increase in bleeding with the initiation dose phase. Based on the results of this study, an increased initiation dose of 10 mg twice daily for 7 days was selected.⁷ Conversely, the initiation phase of 15 mg twice daily for 21 days for rivaroxaban resulted from a pharmacokinetic model that demonstrated lower troughs with twice-daily dosing and the concept that early after VTE more intense treatment may be needed to prevent disease progression or thrombosis extension.²²

Patients diagnosed with VTE may receive prolonged parenteral anticoagulation for a myriad of reasons including high-risk features such as right ventricular strain or hemodynamic compromise as well as pending diagnostic studies. Therefore, DOAC therapy is not immediately initiated in many patients with acute VTE. Approximately 1% of patients in the landmark apixaban and rivaroxaban randomized clinical trials for acute VTE received pretreatment with a parenteral anticoagulant for more than 2 days.^7
-9 In this patient population, can the initiation dose phase safely be shortened or omitted? Ultimately, this question remains unanswered; however, a substantial proportion of pharmacists report dosing these anticoagulants off-label in the setting of increased bleeding risk, prior parenteral anticoagulation, or regimen simplification. Based on our survey results, this is an area of research that merits further investigation.

The utilization of DOACs for the treatment of VTE in obesity has historically been discouraged owing to pharmacokinetic evidence suggesting suboptimal dosing and a lack of clinical outcomes data.¹⁰ For example, less than 20% of patients in the landmark apixaban and rivaroxaban randomized clinical trials for acute VTE weighed more than 100 kg.^7
-9 Subsequently, data emerged supporting the safety and efficacy of DOACs for VTE treatment in obese patients with various weight or BMI thresholds used including BMI > 30 kg/m², BMI > 40 kg/m², weight >100 kg, and weight >120 kg.^12
-20 Thus, the International Society on Thrombosis and Haemostasis suggests that apixaban or rivaroxaban may be used for acute VTE regardless of high BMI and weight.¹¹ Approximately 4 out of 5 pharmacists align with this suggestion. In those preferring a DOAC in obesity, 38% preferred rivaroxaban, which is higher than the global preference for rivaroxaban determined in this study. The discrepancy aligns with the increased availability of data supporting the use of rivaroxaban in obesity compared with other DOACs.¹⁷ However, there is a paucity of data at extremes of body weight, and nearly two-thirds of pharmacists reported that extent of obesity impacts treatment selection.¹¹ Furthermore, our survey revealed disagreement over which clinical parameter should be evaluated when assigning patients as obese, as well as significant variability amongst BMI or total body weight definitions. This is reflected in the available literature, as inclusion criteria vary with regard to BMI or total body weight.^12
-20 While 94% of respondents chose a DOAC when presented with a 118 kg patient with a BMI of 44.6 kg/m² with an acute VTE, this result must be interpreted with extreme caution given the self-reported variable obesity definitions and high influence of obesity extent.

Finally, as each DOAC is renally excreted, anticoagulant selection for the treatment of VTE in renal dysfunction presents a challenging clinical scenario. The exclusion of patients with severe renal impairment from the DOAC clinical trials has raised valid questions regarding the safety and efficacy of DOACs in this population. Recommended doses in renal impairment are largely based on pharmacokinetic data, and it is recommended to avoid the use of rivaroxaban in the setting of a creatinine clearance less than 15 mL/min.⁴ Although pharmacokinetic data for apixaban found a statistically significant increase in area under the curve for drug exposure in patients with severe renal impairment, there is no recommended dose adjustment for this indication and patient population.^3,23 Despite these recommendations, limited clinical data exist supporting DOACs in the treatment of VTE in patients with CKD stage 5 (ie, glomerular filtration rate <15 mL/min/1.73 m²) or dependent on dialysis.²⁴ While the majority of pharmacists surveyed preferred a DOAC in the setting of renal impairment, more than one-third of pharmacists preferred warfarin in patients with CKD stage 5. These data highlight that, despite FDA-approved labeling, a notable proportion of pharmacists are uncomfortable with DOAC utilization in patients with CKD stage 5 or dependent on dialysis. Additional retrospective analyses or a prospective study would help further characterize DOAC safety and efficacy in this population.

Limitations of this survey include the disproportionate number of responses from pharmacists in the state of Georgia. This is potentially explained by utilizing the Georgia Society of Health-System Pharmacists email list as 1 of 5 distribution methods, which is mostly distributed to pharmacists residing in Georgia. Though many responses came from Georgia, when Georgian respondents were removed from the dataset, the results were consistent with the rest of the surveyed pharmacists (Supplement 3). As the survey was distributed via professional organizations, it is possible that survey results are not representative of all practicing pharmacists. Our survey consisted primarily of pharmacists practicing in an inpatient setting. So, the results may not be representative of pharmacists practicing primarily in an outpatient or community setting. Our survey attempted to capture pharmacists practicing in hematology and/or oncology, but this population comprised only 3% of the dataset. Our survey did not validate that respondents were practicing pharmacists. However, the survey was distributed to groups that should include primarily actively practicing pharmacists. Because our survey was voluntary and distributed via selected distribution groups, we cannot exclude a component of nonresponse bias. Similarly, we cannot calculate a response rate as it is unknown how many pharmacists may have seen the survey link. Finally, response bias may have influenced results, but we attempted to identify this through utilization of example patient scenarios.

Conclusion

This national survey of pharmacists demonstrated a preference for apixaban and significant variability in practice patterns regarding DOACs for patients with new VTE, patients with obesity, and patients with renal impairment. Further research is warranted to evaluate the efficacy and safety of DOAC initiation dose duration modifications. Prospective evaluations of DOACs in patients with obesity and renal dysfunction would confirm the safety and efficacy of DOACs in these populations. Selected additional opportunities for evaluation of pharmacist practice patterns relating to DOACs include periprocedural management, use in hepatic dysfunction, and use in malignancy-associated thrombosis.

Supplemental Material

sj-docx-1-hpx-10.1177_00185787221127612 – Supplemental material for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism

Supplemental material, sj-docx-1-hpx-10.1177_00185787221127612 for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism by David M. Kaylor, Andrew J. Johnson, Sarah L. Berardi, Vanessa M. VanArsdale and Meredith H. Niemann in Hospital Pharmacy

Supplemental Material

sj-docx-2-hpx-10.1177_00185787221127612 – Supplemental material for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism

Supplemental material, sj-docx-2-hpx-10.1177_00185787221127612 for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism by David M. Kaylor, Andrew J. Johnson, Sarah L. Berardi, Vanessa M. VanArsdale and Meredith H. Niemann in Hospital Pharmacy

Supplemental Material

sj-docx-3-hpx-10.1177_00185787221127612 – Supplemental material for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism

Supplemental material, sj-docx-3-hpx-10.1177_00185787221127612 for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism by David M. Kaylor, Andrew J. Johnson, Sarah L. Berardi, Vanessa M. VanArsdale and Meredith H. Niemann in Hospital Pharmacy

Supplemental Material

sj-docx-4-hpx-10.1177_00185787221127612 – Supplemental material for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism

Supplemental material, sj-docx-4-hpx-10.1177_00185787221127612 for Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism by David M. Kaylor, Andrew J. Johnson, Sarah L. Berardi, Vanessa M. VanArsdale and Meredith H. Niemann in Hospital Pharmacy

Footnotes

Author Contribution

David M. Kaylor: Conceptualization, methodology, formal analysis, investigation, data curation, writing—original draft Andrew J Johnson: Conceptualization, methodology, formal analysis, investigation, writing—original draft Sarah L. Berardi: Methodology, writing—review & editing, supervision Vanessa M. VanArsdale: Methodology, writing—review & editing, supervision Meredith H. Niemann: Conceptualization, methodology, writing—review & editing, supervision.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

David M. Kaylor

Andrew J. Johnson

Supplemental Material

Supplemental material for this article is available online.

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