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Abstract

Aim:

Oral anticoagulants are the first-line drugs for treating thrombotic disorders related to nonvalvular atrial fibrillation and for treating deep vein thrombosis, diseases that increase in prevalence with age. Older patients have a greater risk of thrombotic and hemorrhagic events and are more prone to drug interactions. Given this backdrop, we wanted to determine the factors associated with the prescription of direct oral anticoagulants and vitamin K antagonists in older patients.

Methods:

We performed a cross-sectional observational study using a hospital prescription database. The study population consists of 405 older patients who were given oral anticoagulants. The 2 variables of interest were the prescription of 1 of the 2 classes of oral anticoagulants (direct oral anticoagulants vs vitamin K antagonists) and appropriateness of oral anticoagulant prescribing according to Summary of Product Characteristics (potentially inappropriate vs appropriate).

Results:

The factors associated with direct oral anticoagulant prescribing were the female gender (odds ratio [OR]: 1.87, 95% confidence interval [CI]: 1.22-2.88) and initiation during hospital stay (OR: 2.56, 95% CI: [1.52-4.32]). Stage 4 and 5 chronic kidney diseases (OR: 0.39, 95% CI: [0.19-0.79] and OR: 0.07, 95% CI: [0.01-0.53]) were factors favoring vitamin K antagonist prescription. Being 90 years of age or more (OR: 2.05, 95% CI: [1.06-3.98]) was a factor for potentially inappropriate anticoagulant prescribing. The gastroenterology department (OR: 2.91, 95% CI: [1.05-8.11]) was associated with potentially inappropriate anticoagulant prescribing.

Conclusions:

Direct oral anticoagulants are the drugs of choice for anticoagulant treatment, including in older adults. The female gender and the initiation during hospital stay increased the chances of being prescribed a direct oral anticoagulant in older adults. Stage 4 and 5 chronic kidney disease increased the likelihood of having a vitamin K antagonist prescribed. Our study also revealed a persistence of potentially inappropriate oral anticoagulant prescriptions in older patients.

Keywords

K oral anticoagulants older patients direct acting oral anticoagulants vitamin k antagonists observational study

Introduction

The prevalence of nonvalvular atrial fibrillation (AF) in France is about 1%, although it increases rapidly with age. It is 10% starting at 80 years and 17% beyond 87 years old.¹ Of all the people with nonvalvular AF in France, which numbered 600 000 to 1 million in 2011, two-thirds were older than 75 years old.² Similarly, the incidence of deep vein thrombosis (1% older than 75 years) and the mortality rate increase with age. In France in 2010, approximately 120 000 people were hospitalized for deep vein thrombosis and the mortality rate was 22.9 per 100 000, mostly due to pulmonary embolism.³ Since their introduction to the market, prescriptions for direct oral anticoagulants (DOAC) for treating thrombotic risks in patients with nonvalvular AF and venous thromboembolism have been steadily increasing, while those for vitamin K antagonist (VKA) have been declining.⁴ Currently, American and European medical associations recommend using first-line DOACs for these indications regardless of the patient’s age.^5,6

Older adults with AF who are treated with an oral anticoagulant have a greater risk of thrombotic and hemorrhagic events.⁷ These people are also more prone to drug interactions because they are often polymedicated.⁸ Given these elements, the factors that determine which oral anticoagulant class is prescribed in older patients are still poorly defined. Similarly, one may ask whether these oral anticoagulants are being appropriately prescribed in the elderly population. We hypothesized that different profiles of older patients can be identified based on the prescription of anticoagulants.

Our study therefore sought to analyze the use of DOAC and VKA in a population of patients older than 75 years. The main objective was to look for the factors associated with the DOAC (vs VKA) prescribing trend in people older than 75 years of age. The secondary objective of our study was to define which factors contribute to potentially inappropriate oral anticoagulant prescribing in elderly patients.

Materials and Methods

We performed a cross-sectional observational study using prescription data from a tertiary referral hospital.^9,10 We created a study database by extracting the medical records of patients older than 75 who were given oral anticoagulants and hospitalized between September 1, 2016, and August 31, 2017, in departments with computerized prescription systems (n = 405). We selected patients with indications common to both DOAC and VKA to compare the 2 populations. Two indications were used: thrombotic risk mitigation in nonvalvular AF and anticoagulant treatment in venous thromboembolism (VTE) secondary prevention. Only oral anticoagulants marketed in France were included (Acenocoumarol, Apixaban, Dabigatran, Fluindione, Rivaroxaban, Warfarin). The additional data needed to analyze the associated DOAC and VKA prescription factors were gathered from electronic medical records, clinical laboratory results, and prescription drug records.

The following data were collected and analyzed: date of birth, age, weight, admission to inpatient unit, therapeutic category (DOAC or VKA), international nonproprietary name (INN), dosage, indication (prevention of AF or VTE), creatinine level, renal function (Cockcroft and Gault formula), occurrence of serious bleeding, possible change in dosage or INN during hospitalization, whether the oral anticoagulant was initiated during hospitalization. Chronic kidney disease (CKD) stages was defined according to Kidney Disease Outcomes Quality Initiative guideline.¹¹

The database was also used for the secondary purpose of identifying associated factors contributing to potentially inappropriate prescriptions, that is, overdose or underdose of DOAC or VKA compared to what is defined in the Summary of Product Characteristics (SPC).^12
-14 When collecting this information, some data were missing. We performed a full case analysis, so we chose to exclude patients for whom missing data were needed for statistical analysis (less than 3% of patients were excluded).

A potentially inappropriate prescription of oral anticoagulant was defined as:

– Any international normalized ratio (INR) less than 2 (without other anticoagulant like heparin) or greater than 3 at hospital discharge after at least 1 week of VKA exposure

– All doses of DOAC below or above those recommended in the SPC (taking into account kidney function [creatinine clearance, serum creatinine], age, weight and concomitant interacting medications).

We hypothesized that different profiles of older patients can be identified based on the prescription of anticoagulants.

The 2 variables to be explained were the class of oral anticoagulants prescribed (DOAC vs VKA [reference]) and appropriateness of oral anticoagulant prescribing as per the SPC (potentially inappropriate vs appropriate [reference]).

Comparisons between the 2 groups used the χ² or Fisher exact tests (for expected values < 5). We performed multivariate analyses (logistic regressions) to determine which factors were associated with the outcomes (primary outcome: DOAC vs VKA [reference] and secondary outcome: potentially inappropriate vs appropriate prescription as per the SPC [reference]).¹⁵ All the variables significantly associated with the outcome at a threshold of 20% in bivariate analyses were included in the multivariate models. Then, we used a backward stepwise regression procedure, with a significance level of .05, to exclude variables from the model. All models were adjusted for age, gender, and anticoagulant indication to control for potential confounding effects.¹⁶ Goodness-of-fit for the logistic regression models was considered acceptable if the Hosmer-and-Lemeshow test had a P value greater than .05 (non-rejection of the null hypothesis).¹⁷ All analyses were carried out using SAS version 9.3 software (SAS Institute, Inc, Cary, North Carolina).

Results

Descriptive Analysis

There were 173 patients with a DOAC (Apixaban [n = 101], Dabigatran [n = 23], Rivaroxaban [n = 49]) and 232 patients with a VKA (Acenocoumarol [n = 9], Fluindione [n = 120], Warfarin [n = 103]). There were no serious bleeding events during the observation period.

Factors Associated With Choice of Oral Anticoagulant Class

The bivariate analysis showed that the female gender (P = .002) and the initiation of treatment during hospitalization (P < .001) were associated with the prescription of a DOAC. In contrast, CKD was related to the prescription of a VKA (P < .001) (Table 1). We found the same significant factors in the multivariate analysis (female gender [OR: 1.87, 95% CI: 1.22-2.88]) and initiation during hospital stay (OR: 2.56, 95% CI: [1.52-4.32]). However, only CKD stages 4 and 5 were associated with the prescription of VKAs (OR: 0.39, 95% CI: [0.19-0.79] and OR: 0.07, 95% CI: [0.01-0.53]) (Table 2).

Table 1.

Bivariate Analysis of Oral Anticoagulant Therapeutic Class Prescribing.^a

Characteristics	DOAC (n = 173)	VKA (n = 232)	P Value
Age category, n (%)			.383
75-79	49 (28.3)	55 (23.7)
80-84	52 (30.1)	70 (30.2)
85-89	45 (26.0)	56 (24.1)
90 and up	27 (15.6)	51 (23.0)
Gender, n (%)			.002
Women	114 (65.9)	117 (50.4)
Men	59 (34.1)	115 (49.6)
Type of hospital department, n (%)			.089
Cardiology	65 (37.6)	89 (38.4)
Gastroenterology	11 (6.4)	9 (3.9)
Geriatrics	47 (27.2)	68 (29.3)
Internal medicine	13 (7.5)	16 (6.9)
Neurology	19 (10.9)	11 (4.7)
Other	18 (10.4)	39 (16.8)
Indication, n (%)			.523
AF prevention	159 (91.9)	217 (93.5)
VTE secondary prevention	14 (8.1)	15 (6.5)
Initiation during hospitalization, n (%)			<.001
Yes	55 (31.8)	34 (14.7)
No	118 (68.2)	198 (85.3)
Kidney function			<.001
CKD stages 1 or 2	62 (35.8)	63 (27.2)
CKD stage 3	93 (53.8)	104 (44.8)
CKD stage 4	17 (9.8)	49 (21.1)
CKD stage 5	1 (0.6)	16 (6.9)
Peptic ulcer or GERD, n (%)			.454
Yes	5 (2.9)	10 (4.3)
No	168 (97.1)	222 (95.7)
Fall in the last 3 months, n (%)			.656
Yes	17 (9.8)	26 (11.2)
No	156 (90.2)	206 (88.8)
Dementia, n (%)			.110
Yes	13 (7.5)	9 (3.9)
No	160 (92.5)	223 (96.1)

Abbreviations: AF, atrial fibrillation; CKD, chronic kidney disease, DOAC, direct oral anticoagulant; GERD, gastroesophageal reflux disease; VKA, vitamin K antagonist; VTE, venous thromboembolism. CKD stages 1 or 2 (≥60 mL/min), CKD stage 3 (30-59 mL/min), CKD stage 4 (15-29 mL/min), CKD stage 5 (<15 mL/min).

^a Reference: VKA.

Table 2.

Multivariate Analysis of Oral Anticoagulant Therapeutic Class Prescribing.^a

Parameters	Logistic Regression: DOAC vs VKA (Reference)		P Value
Parameters	Adjusted Odds Ratio	Confidence Interval at 95%	P Value
Age category			.360
75-79	Reference	Reference
80-84	0.79	0.45-1.39
85-89	0.96	0.52-1.74
90 and up	0.58	0.30-1.13
Gender			.004
Male	Reference	Reference
Female	1.87	1.22-2.88
Indication			.610
AF prevention	Reference	Reference
VTE secondary prevention	0.81	0.36-1.84
Initiation during hospitalization			<.001
No	Reference	Reference
Yes	2.56	1.52-4.32
Kidney function			.003
CKD stages 1 or 2	Reference	Reference
CKD stage 3	0.96	0.59-1.55
CKD stage 4	0.39	0.19-0.79
CKD stage 5	0.07	0.01-0.53

Abbreviations: AF, atrial fibrillation; CKD, chronic kidney disease; DOAC, direct oral anticoagulant; VKA, vitamin K antagonist; VTE, venous thromboembolism. CKD stages 1 or 2 (≥60 mL/min), CKD stage 3 (30-59 mL/min), CKD stage 4 (15-29 mL/min), and CKD stage 5 (<15 mL/min). Hosmer & Lemeshow test: P = .712.

^a Reference: VKA.

Factors Associated With Appropriateness of Oral Anticoagulant Prescribing

The bivariate analysis showed that the type of inpatient department was associated with the appropriateness of oral anticoagulant prescribing (P = .001) (Table 3). In the multivariate analysis, only the 90 years and up age-group (OR: 2.05, 95% CI: [1.06-3.98]) was linked to potentially inappropriate anticoagulant prescribing as per the SPC. The gastroenterology department (OR: 2.91, 95% CI: [1.05-8.11]) was associated with potentially inappropriate anticoagulant prescribing as per the SPC (reference: cardiology department) (Table 4). In the gastroenterology department, the potentially inappropriate anticoagulant prescribing as per the SPC consisted of underdosing in 78% of cases.

Table 3.

Bivariate Analysis of Patients With Potentially Inappropriate Oral Anticoagulant Prescribing.^a

Characteristics	Appropriate Prescribing (n = 225)	Potentially Inappropriate Prescribing (n = 180)	P Value
Therapeutic category, n (%)			.703
DOAC	98 (43.6)	75 (41.7)
VKA	127 (56.4)	105 (58.3)
Age category, n (%)			.123
75-79	67 (29.8)	37 (20.5)
80-84	65 (28.9)	57 (31.7)
85-89	56 (24.9)	45 (25.0)
90 and up	37 (16.4)	41 (22.8)
Gender, n (%)			.121
Female	136 (60.4)	95 (52.8)
Male	89 (39.6)	85 (47.2)
Type of hospital department, n (%)			.001
Cardiology	85 (37.8)	69 (38.3)
Gastroenterology	6 (2.7)	14 (7.8)
Geriatrics	54 (24.0)	61 (33.9)
Internal medicine	21 (9.3)	8 (4.5)
Neurology	24 (10.7)	6 (3.3)
Other	35 (15.5)	22 (12.2)
Indication, n (%)			.464
AF prevention	207 (92.0)	169 (93.9)
VTE secondary prevention	18 (8.0)	11 (6.1)
Initiation during hospitalization, n (%)			.914
Yes	176 (78.2)	140 (77.8)
No	49 (21.8)	40 (22.2)
Kidney function			.128
CKD stages 1 or 2	80 (35.6)	45 (25.0)
CKD stage 3	100 (44.4)	97 (53.9)
CKD stage 4	35 (15.6)	31 (17.2)
CKD stage 5	10 (4.4)	7 (3.9)
Peptic ulcer or GERD, n (%)			.480
Yes	7 (3.1)	8 (4.4)
No	218 (96.9)	172 (95.6)
Fall in the last 3 months, n (%)			.493
Yes	26 (11.6)	17 (9.4)
No	199 (88.4)	163 (90.6)
Dementia, n (%)			.327
Yes	10 (4.4)	12 (6.7)
No	215 (95.6)	168 (93.3)

^a Reference: appropriate oral anticoagulant prescribing as per the Summary of Product Characteristics.

Table 4.

Multivariate Analysis of Patients with Potentially Inappropriate Oral Anticoagulant Prescribing.^a

Parameters	Logistic Regression: Potentially Inappropriate vs Appropriate Oral Anticoagulant Prescribing (Reference)		P Value
Parameters	Adjusted Odds Ratio	Confidence Interval at 95%	P Value
Therapeutic category			.804
VKA	Reference	Reference
DOAC	1.06	0.69-1.61
Age category			.171
75-79	Reference	Reference
80-84	1.59	0.91-2.78
85-89	1.39	0.76-2.53
90 and up	2.05	1.06-3.98
Gender			.060
Male	Reference	Reference
Female	0.67	0.44-1.02
Type of hospital department			.004
Cardiology	Reference	Reference
Gastroenterology	2.91	1.05-8.11
Geriatrics	1.26	0.74-2.13
Internal medicine	0.45	0.18-1.10
Neurology	0.31	0.12-0.80
Other	0.74	0.39-1.40
Indication			.551
AF prevention	Reference	Reference
VTE secondary prevention	0.78	0.35-1.75

Abbreviations: AF, atrial fibrillation; DOAC, direct oral anticoagulant; VKA, vitamin K antagonist; VTE, venous thromboembolism. Hosmer & Lemeshow test: P = .872.

^aReference: appropriate oral anticoagulant prescribing as per the Summary of Product Characteristics.

Discussion

Our study showed that the female gender, the initiation of anticoagulant treatment during hospitalization and CKD stages 4 and 5 were the 3 primary factors influencing the prescription of oral anticoagulants in older adult patients. The type of inpatient department was associated with appropriateness of oral anticoagulant prescribing as per the SPC.

In our study, female gender increased the chances of being prescribed a DOAC. This is consistent with the literature. The association of the female gender and the prescription of DOAC compared to the prescription of VKA became significant from 2013, while previous studies did not show any significant difference between men and women.¹⁶ This increase in DOAC prescriptions for women was correlated with an increase in apixaban prescriptions.¹⁶ According to a meta-analysis, this can be explained by the fact that women treated with DOAC have a lower risk of hemorrhage compared to men and those treated with warfarin have a greater risk of stroke and thromboembolic events.¹⁸ Another study demonstrated that in women, DOAC use was associated with a lower risk of intracranial hemorrhage and all-cause mortality when compared to warfarin.¹⁹ Throughout their lives, women are more aware of their health status and closer to the health-care system than men; more of them consult medical doctors.²⁰ This also can explain why DOACs are prescribed in women more than in men—the women’s drug prescriptions may be more up-to-date and consistent with medical association guidelines.

The second notable factor in our study was that DOACs were more often prescribed than VKAs when treatment is initiated during hospitalization. This suggests more recommended oral anticoagulant prescribing occurs at the hospital. Indeed, since 2016, DOACs have been recommended in Europe as the first-line treatment for thromboembolic risk related to nonvalvular AF.⁵ To explain this result, we hypothesize that hospital specialists prescribed more DOAC (vs VKA) than private practice doctors because they are better informed about the medical association guidelines through their university affiliations, the research conducted and their collaboration with other health professionals. Support for our hypothesis was found in the literature, namely one study showing that cardiologists more readily prescribed DOAC than general practitioners.²¹ Also, the initial prescription of DOAC for VTE facilitates the hospital discharge compared to the heparin overlap during the initiation of VKA and the initial INR monitoring.^12,14

Finally, our study showed that kidney failure decreased the likelihood of having a DOAC prescribed. This is because the DOAC dose must be adjusted in patients with CKD. The dabigatran dosage should be decreased in patients with CKD stage 3 and is contraindicated in CKD stages 4 and 5.¹³ As for rivaroxaban, the dosage should be adjusted in CKD stage 3 (and CKD stage 4).¹⁴ The CKD is one of the criteria taken into account for adjusting the apixaban dosage in AF.¹² Finally, the DOAC are not clinically studied in CKD stage 5.^12
-14 These findings are consistent with those in the literature.²² Vitamin K antagonists, with close monitoring of the INR, are the drugs of choice in patients with CKD stages 4 and 5 because DOACs are currently not recommended in these situations. Here again, our study showed that the SPCs were generally followed at the hospital.

Regarding the secondary objective of our study, we noticed that a potentially inappropriate anticoagulant treatment as per the SPC does not correlate to the treatment class used. The specialty of the practitioner taking care of the patient has an effect on the risk of having a potentially inappropriate prescription as per the SPC. Indeed, gastroenterology was the only unit with a greater odds ratio of potentially inappropriate anticoagulant prescribing (vs the cardiology department). In the gastroenterology department, the potentially inappropriate anticoagulant prescribing consisted of underdosing in 78% of cases. We can explain this difference by the fact that gastroenterologists fear iatrogenic bleeding more than other specialties.²³ The proportion of potentially inappropriate anticoagulant prescriptions in the other units examined did not differ from that of the cardiology department. A study with similar results to ours found that cardiologists complied with DOAC dose recommendations in the SPC more than other practitioners.²¹ A second study, involving 266 patients and 178 physicians and comparing apixaban, rivaroxaban, and warfarin, ranked the importance of oral anticoagulant prescribing factors for the physicians surveyed (mostly cardiologists and internists). The first determinant was the risk of hemorrhage, the second was the risk of drug and food interactions, while the effectiveness of the proposed treatment only came in eighth place.²⁴ Finally, a third study showed that doctors frequently prescribe a potentially inappropriate dose of oral anticoagulant as per the SPC because of concerns over the risk of bleeding.²⁵ These results are consistent with our study.

These results led us to ask questions about the management of older patients treated with oral anticoagulants. Indeed, one study showed that DOAC underdosing is often linked to having more comorbidities and the patients’ sociodemographic characteristics.²¹ It was also shown that a potentially inappropriate dose reduction of apixaban was associated with a higher risk of stroke and also a bleeding risk identical to the standard dose.²⁶

Our study focused on older adults. It is the first study in France to investigate factors associated with DOAC prescribing and to compare the prescriptions of DOAC and VKA within a French university hospital over a 1-year period. It is also the first French study to compare the proportions of prescriptions for oral anticoagulants that do not comply with the SPC compared with appropriate prescriptions in older adults.

This is an observational study, which provides information on a population less often studied. Older adults are often excluded from clinical studies even though they are a large part of the target population for drugs. In terms of prescriptions for anticoagulants and their follow-up in the elderly patients, there are differences in prescriptions between the various departments of the same hospital. The results of this study could be generalized to other countries with similar health-care systems, although the economic aspects (and cost-effectiveness analysis results) may have a different influence on the choice between DOAC and VKA in various countries.²⁷

Nevertheless, our study has some limitations. It was a retrospective observational study. Missing data were to be expected because of this design, but they were limited in our study (about 3% of excluded patients). Unfortunately, some results were at the limit of significance probably because of a lack of power in connection with the relatively small sample size. We did not observe serious bleeding in patients with potentially inappropriate prescriptions as per the SPC because of this number and the follow-up period being too short to detect the occurrence of rare adverse events, such as serious bleeding attributed to oral anticoagulants. The results are likely to change in the future, as DOACs will be increasingly prescribed compared to VKA. Our database did not contain measures of frailty, although it would have been interesting to add this variable to our study.

Conclusion

Direct oral anticoagulants are drugs of choice for anticoagulant therapy, including in older adults. Gender, place of initiation (hospital vs ambulatory care), and renal function are factors associated with different oral anticoagulant prescribing choices in these patients. Our study also revealed a persistence of potentially inappropriate oral anticoagulant prescriptions as per the SPC in older adults.

Footnotes

Acknowledgments

The authors thank Philippe Lambéa for extracting the data from Disporao software.

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 iD

Arnaud Pagès

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Factors Associated With the Choice of Oral Anticoagulant Class in the Older Patients: An Observational Study