A retrospective study on the evaluation of the appropriateness of oral anticoagulant therapy for patients with atrial fibrillation.

BACKGROUND: The incidence of atrial fibrillation (AF) is increasing, and effective anticoagulation therapy can prevent adverse events. Selecting the appropriate OAC based on patient characteristics has become a challenge. Interventions are going to be a potential area of focus.
OBJECTIVES: To explore the discrepancies between clinician prescriptions and recommended guidelines of oral anticoagulants (OACs) for patients with atrial fibrillation (AF), and to provide direction for improving anticoagulation strategies for treating patients with AF.
MATERIALS AND METHODS: Data were collected from the electronic medical record system of Fuwai Yunnan Cardiovascular Hospital between July 2019 and January 2020. The suitability of prescribed OACs for patients with AF was assessed according to the Rules for Avoiding Prescription Inappropriateness, the prescribed medicine label, and any relevant antithrombotic guidelines for treating patients with AF.
RESULTS: A total of 460 patients met the inclusion criteria. Of these, 53.7% received an appropriate prescription and 46.3% received an inappropriate prescription. Of the patients who received inappropriate prescriptions, 15.4% were prescribed without the presenting appropriate indicators, 1.3% were prescribed inappropriate drug selection, and 29.6% were prescribed inappropriate drug doses. For patients prescribed without providing appropriate indicators, 2.2% had no indication for medication and 13.3% had an indication for medication, but not a specific OAC. For patients with inappropriate drug selection, 1, 5 patients were on rivaroxaban, dabigatran respectively. The distribution of NOAC doses was as follows: dabigatran standard dose (45.2%), the low dose (54.8%). Rivaroxaban standard dose (58.9%), low dose (36.8%), high dose (4.3%). A total of 44 patients (9.6%) experienced bleeding events, 12 patients (2.6%) experienced embolic events, and 7 patients experienced other adverse events after dosing.
CONCLUSIONS: In clinical practice, it is common for patients with AF to receive inappropriate prescriptions of OACs. Therefore there is a need to enhance anticoagulation management in patients with AF to improve the appropriate use of OACs.

Introduction

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and can lead to stroke, one of the most common and severe complications of AF [1]. AF increases the risk of stroke fivefold [2]. Stroke is characterized by high rates of disability, mortality and morbidity [3]. In addition, it places a significant burden on the healthcare systems, patients and their families [2].

Anticoagulation therapy is a cornerstone of stroke prevention in patients with AF [4]. With the widespread clinical use of new oral anticoagulants (NOACs) in recent years, there are many options for anticoagulation in patients with AF, and the quality of anticoagulation varies [5]. Most patients with AF have not received standardized anticoagulation therapy. In practice, oral anticoagulants (OACs) are underprescribed, and many patients with AF or a history of stroke have not received appropriate anticoagulation therapy [6, 7]. Furthermore, the choice of anticoagulants in many prescriptions is irrational, with poor anticoagulation control and inappropriate administration and dosing of OACs. This increases the incidence of adverse events such as thromboembolism and bleeding. A subgroup analysis of Chinese patients in the GARFIELD study showed that only 28.7% of patients received anticoagulation, of which 22.2% received warfarin, and 6.5% received NOACs [8]. 19.8% of patients did not receive any anticoagulation therapy, and 51.6% of patients received antiplatelet treatment. Globally, half of newly diagnosed low-risk AF patients receive OACs unnecessarily, which increases their risk of bleeding [9]. Franchi C et.al. assessment of the appropriateness of prescribing OACs and their correlates in hospitalized patients over 65 years of age showed that nearly 44% of patients were inappropriately prescribed OACs [10]. Most patients were underprescribed or prescribed inappropriate antithrombotic drugs.

With the increasing prevalence of AF, prescribing the appropriate OAC for each patient’s characteristics has become a challenge [7]. Improving clinicians’ prescribing of OACs for stroke prevention in patients with AF would be a potential area of focus for future interventions. In this study, the appropriateness of OAC prescriptions [warfarin and NOACs (dabigatran and rivaroxaban)] for patients with AF at Fuwai Yunnan Cardiovascular Hospital was evaluated according to atrial fibrillation guidelines and relevant information on the prescription drug label. [11, 12]. By exploring the differences between current clinician prescribing and guideline-recommended OACs for patients with AF, this study aims to provide insight into improving anticoagulation strategies for patients with AF.

Materials and methods

Study design

This research is a single-center, retrospective, cross-sectional real-world study. All patients with a diagnosis of AF admitted to the Fuwai Yunnan Cardiovascular Hospital between July 2019, and January 2020 were included. The inclusion criteria for this study were as follows: (i) All patients were diagnosed with AF by clinical presentations, physical examination and electrocardiogram (including patients currently receiving or previously receiving anticoagulation therapy). (ii) Age > 18 years. Exclusion criteria were as follows: patients with AF caused by transient factors including hyperthyroidism, acute pulmonary embolism, recent major surgery or acute myocardial infarction, and chest infections (pneumonia).

Data collection

Data were obtained from the electronic medical records system of Fuwai Yunnan Cardiovascular Hospital. The following basic data were recorded from the medical records for each patient: demographic characteristics (sex, age, weight, smoking history, bleeding history, etc.), comorbid conditions (congestive heart failure, hypertension, diabetes, vascular diseases, etc.), laboratory tests [serum creatinine, Hemoglobin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), left ventricular ejection fraction (LVEF)], and co-drugs (aspirin, clopidogrel, amiodarone, verapamil, digoxin, proton pump inhibitors, etc.). The CHA2DS2-VASc score, HAS-BLED score and SAMe-TT2R2 score were calculated for all patients (see Tables 1–3 for details).

Table 1

CHA2DS2-VASc score [2].

Risk factors	Points awarded
Congestive heart failure	1
Hypertension	1
Age ≥ 75	2
Diabetes mellitus	1
Stroke (Previous stroke, TIA or Thromboembolism)	2
Vascular disease	1
Age 65–74 years	1
Sex category (female)	1

TIA-: transient ischemic attack.

Table 3

SAMe-TT2R2 score [2].

Risk factors	Points awarded
Sex (female)	1
Age <60	1
Medical history of ≥ 2 comorbidities [hypertension, diabetes mellitus, CAD/myocardial infarction, PAD, Chronic heart failure, previous stroke, pulmonary disease, and hepatic or renal disease]	1
Treatment (interacting drugs, e.g. amiodarone)	1
Tobacco use	2
Race [non-Caucasian]	2

CAD-: coronary artery disease; PAD-: peripheral artery disease

Evaluation criteria for prescription suitability

The appropriateness of OACs in patients with AF was assessed according to the rules for evaluating prescription inappropriateness in the “Guidelines for the Management of Hospital Prescription Reviews (for trial implementation)” issued by the National Health and Family Planning Commission (Health Medical Development [2010] No. 28), and the labels of relevant antithrombotic drugs such as warfarin/rivaroxaban/dabigatran [11,12].

According to the current guidelines, the risk of stroke in patients with AF is estimated based on the CHA2DS2-VASc score. OAC should be considered for stroke prevention in AF patients with a CHA2DS2-VASc score of 1 for men or 2 for women [2]. For patients with a single non-sex CHA2DS2-VASc stroke risk factor, we suggest oral anticoagulation rather than no treatment. Aspirin, or a combination of aspirin and clopidogrel, antiplatelet therapy should not be used for stroke prevention in patients with AF. In addition, patients who undergo radiofrequency ablation in the perioperative period (within four weeks after surgery) need to receive anticoagulation therapy. Antithrombotic agents other than OACs should not be used in these patients unless anticoagulation is contraindicated [2, 4, 11, 12]. The combination of OAC and antiplatelet drugs (aspirin or clopidogrel) is considered “appropriate” only for 1–12 months after stent implantation.

The dose of NOACs and the suitability of the selected drug were evaluated according to renal function (creatinine clearance rate, CrCl), age, weight and concomitant interacting drugs. The evaluation criteria were as follows: (1) The standard dose of dabigatran was 150 mg/bid. The dose was reduced to 110 mg for patients (i) age ≥ 80 years, (ii) with CrCl 30–50 ml/min, (iii) treat with verapamil. The dose may be reduced to 110 mg when (i) 75–80 years of age, (ii) a high risk of bleeding (e.g., HAS-BLED ≥ 3 points), (iii) at high risk of gastrointestinal bleeding (with esophagitis, gastritis, gastroesophageal reflux disease). (2)The standard dose of rivaroxaban is 20 mg QD. The dose may be reduced to 15 mg when age is greater than 75 years or CrCl 15–50 ml/min, or when weight is low. The prescribed dose is divided into standard, low, and high doses.- Low and high doses are considered “inappropriate doses”. If a patient does not meet the above criteria for the use of NOACs, then “the selected drugs are inappropriate”. Warfarin remains the only treatment recognized as safe for patients with valvular AF for whom NOACs are prohibited. If patients with valvular AF that include moderate to severe rheumatic mitral valvular diseases and/ or an artificial heart valve [2] have prescribed NOACs, they are considered to be prescribed as an "inappropriate drug selection". The guideline recommends using the SAMe-TT2R2 score to help identify patients who are unlikely to have a good TTR (i.e. SAMe-TT2R2 score > 2) and use NOACs over warfarin treatment. If patients with a SAMe-TT2R2 score > 2 are treated with warfarin but not NOACs, their prescriptions are considered to be “inappropriate drug selection”Also, electronic medical records were retrieved to identify clinical results that may be associated with inappropriate medications, such as bleeding events and thromboembolic events, to evaluate the safety of patients with AF taking OACs.

Ethics committee

This study was conducted with the approval of the Ethics Committee of Fuwai Hospital, Chinese Academy of Medical Sciences, and Fuwai Yunnan Cardiovascular Hospital.

Reviewer

In this study, the prescriptions of OAC were all prescribed by cardiologists in our hospital after diagnosing the patients. The prescribing physicians have the title of attending physician or above, and the evaluation of the prescriptions was performed by clinical pharmacists with intermediate title or above.

Statistical analysis

Data were collated in Microsoft Excel spreadsheets. Statistical analyses were performed using SPSS17.0, with measures expressed as mean ± standard deviation (SD) and categorical variables expressed as the number of cases (n) and percentages. Univariate analysis (t-test or χ2 test) was used to analyze variables of interest when investigating the difference between NOACs dose and unreasonable dose, and significance was judged when P < 0.05.

Results

Baseline characteristics

A total of 460 patients were included in this study. 371 patients were treated with OACs, of which 72 patients received warfarin, 132 patients received dabigatran, 167 patients received rivaroxaban. And a total of 89 patients did not receive anticoagulation. Baseline characteristics of the patients are summarized in Table 4.

Table 4

Baseline characteristics of the study population.

	warfarin	dabigatran	rivaroxaban	no OACs
	(n = 72)	(n = 132)	(n = 167)	(n = 89)
age (X¯±S), years	65.43±11.862	64.39±12.036	67.5±11.825	64.64±13.179
Male	37(51.4%)	79(59.8%)	108(64.7%)	53(59.6%)
Female	35(48.6%)	53(40.2%)	59(35.3%)	36(40.4%)
atrial fibrillation type
valvular AF	20(27.8%)	3(2.3%)	1(0.6%)	1(1.1%)
non-valvular AF	52(72.2%)	129(97.7%)	166(99.4%)	88(98.9%)
radiofrequency ablation	10(13.8%)	54(40.9%)	51(30.5%)	2(2.2%)
stent implantation	0	2(1.5%)	9(5.4%)	2(2.2%)
combined disease
congestive heart failure	16(22.2%)	23(17.4%)	15(8.9%)	10(1.2%)
hypertension	33(45.8%)	76(57.9%)	99(59.2%)	41(46.0%)
diabetes	11(15.2%)	30(22.7%)	27(16.1%)	10(11.2%)
stroke	17(23.6%)	31(23.4%)	55(32.9%)	16(17.9%)
vascular diseases	33(45.8%)	64(48.4%)	107(64.0%)	37(41.5%)
abnormal hepatic function	0	2(1.5%)	1(0.5%)	1(1.1%)
abnormal renal function	1(1.3%)	1(0.7%)	2(1.1%)	1(1.1%)
combined medication
clopidogrel	3(4.2%)	2(1.5%)	0	13(16.6%)
aspirin	2(2.8%)	0	3(1.8%)	20(22.5%)
aspirin+P2Y12 inhibitor	1(1.4%)	0	4(2.4%)	9(10.1%)
(clopidogrel or ticagrelor)

Suitability evaluation of prescriptions

From the current analysis, 247 (53.7%) of 460 patients‘ prescriptions were considered appropriate, and 213 (46.3%) were considered inappropriate. Of the patients who received inappropriate prescriptions, 71 (15.4%) were prescribed without presentation of appropriate indications, 6 (1.3%) were prescribed the inappropriate selection of medication, and 136 (29.6%) were prescribed the inappropriate dosage of medication.

For patients presenting with an inappropriate indication, 10 (2.2%) had no indication for medication, and 61 (13.3%) had an indication for medication but no OAC. For patients with an indication for medication but no OAC, the most commonly cited reason by clinicians was concern about the high risk of bleeding. The second most frequently cited reason was that some patients had low compliance and refused anticoagulant medications.

For patients with inappropriate drug selection in their prescriptions, 1, 5 patients were on rivaroxaban, dabigatran respectively. The reasons for these prescriptions were analyzed, as shown in Table 5.

Table 5

Reasons for the inappropriate selection of drugs.

	reasons for inappropriate	the number of cases
rivaroxaban	rivaroxaban is prohibited for valvular AF	1
dabigatran	dabigatran is prohibited for valvular AF	3
	dabigatran is contraindicated in patients with CrCl<30ml/min	2

Table 6 showed the relevant factors influencing drug dose selection. For patients taking dabigatran and rivaroxaban, there was a significant difference in age, stroke risk score and CrCI in the low-dose group compared with the standard-dose group (P<0.05). In patients taking rivaroxaban, there was a significant difference in CrCl in the low-dose group compared with the standard-dose group (P<0.05). Among patients taking rivaroxaban, there was no statistically significant difference in age, stroke and bleeding scores between the low-dose and standard-dose groups (P>0.05).

Table 6

Basic characteristics of NOACs dose.

	Dabigatran			Rivaroxaban			P
	(n = 126)		P	(n = 163)
	standard-dose	low-dose		standard-dose	low-dose	high-dose
				(n = 96,58.9%)	(n = 60,36.8%)	(n = 7,4.3%)
	(n = 57,45.2%)	(n = 69,54.8%)
age	68.86±12.914	60.61±9.687	0.0001	65.09±12.169	71.52±10.331	70.14±9.19	0.001a
							0.286b
<60	16 (28.1%)	34 (49.3%)		34 (35.4%)	7 (11.7%)	1 (14.3%)
60–69	5 (8.8%)	18 (26.1%)		26 (3.5%)	12 (20.0%)	4 (57.1%)
70–79	21 (36.8%)	17 (24.6%)		25 (27.1%)	28 (46.7%)	0
≥80	15 (26.3%)	0		11 (11.5%)	13 (21.7%)	2 (28.6%)
CHA2DS2-VASc	3.65±2.109	2.74±1.578	0.007	3.15±1.886	4.03±1.657	4.43±1.902	0.003a
							0.086b
0	2 (3.5%)	7 (10.1%)		7 (7.3%)	1 (1.7%)	0
1	8 (14.0%)	10 (14.4%)		15 (15.6%)	3 (5.0%)	0
2	11 (19.3%)	9 (13.0%)		17 (17.7%)	5 (8.3%)	2 (28.6%)
3	7 (12.3%)	22 (31.8%)		16 (16.7%)	13 (21.7%)	0
≥4	29 (50.9%)	21 (30.4%)		41 (42.7%)	38 (63.3%)	5 (71.4%)
HAS-BLED	2.16±1.279	1.41±0.828	0.0001	1.79±0.962	2.43±0.981	2.43±1.272	0.0001a
							0.101b
0	7 (12.2%)	8 (11.6%)		8 (8.3%)	2 (3.3%)	0
1	12 (21.0%)	32 (46.4%)		30 (31.3%)	6 (10.0%)	2 (28.6%)
2	12 (21.0%)	22 (31.9%)		34 (35.4%)	24 (40.0%)	2 (28.6%)
3	17 (29.8%)	7 (10.1%)		22 (22.9%)	21 (35.0%)	1 (14.3%)
≥4	9 (15.7%)	0		2 (2.1%)	7 (11.7%)	2 (28.6%)
CrCl	63.41±27.66	72.35±19.541	0.036	74.22±25.408	61.73±21.475	41.00±4.203	0.002a
							0.001b
>50	33 (57.9%)	64 (92.8%)		81 (84.4%)	43 (71.7%)	0
30–50	23 (40.4%)	5 (17.2%)		14 (14.6%)	16 (26.7%)	7 (100%)
15–30	1 (1.8%)	0		1 (1.0%)	1 (1.7%)	0
Bleeding event	7 (12.3%)	4 (5.8%)		5 (5.2%)	15 (25.0%)	1 (14.3%)
Thromboembolic events	2 (3.5%)	4 (5.8%)		2 (2.1%)	3 (5.0%)	0

Note

a: standard dose compared with low dose

b: standard dose compared with high dose.

Safety evaluation

Table 7 summarized the adverse events recorded in the electronic medical record system. A total of 44 patients (9.6%) experienced bleeding events after dosing, including 8, 21, 11 and 4 patients for warfarin, rivaroxaban, dabigatran and non-anticoagulated patients, respectively. As shown in Fig 1, rivaroxaban had the highest proportion of bleeding events after dosing. A total of 12 patients (2.6%) experienced embolic events, including 5 after rivaroxaban intake, 6 after dabigatran intake, and 1 after warfarin intake. Other adverse events occurred in 7 patients, with an incidence of 1.5%.

Table 7

Adverse events.

	adverse events and the number of cases
bleeding events	occult blood (22), subcutaneous hemorrhage (4), gastrointestinal bleeding (3), gingival bleeding (3), fundus bleeding (3), nose bleeding (2), hematuria (2), hemoptysis (1), subdural hematoma (1), urinary tract bleeding (1), ear mucosal bleeding (1), subarachnoid hemorrhage (1)
embolic events	atrial appendage thrombosis (5), recurrent symptoms (4), cerebral infarction (1), coronary embolism (1), ventricular thrombosis (1)
other events	increased digestive tract symptoms, abdominal distension, edema, stomach upset, allergies, dizziness, fatigue and other discomforts

Fig 1

Proportion of bleeding events in patients with AF.

Discussion

Dose appropriateness

In this study, we evaluated the appropriateness and safety of clinicians’ prescription of OACs to patients with AF. We found that 46.3% of patients were inappropriately prescribed OACs. Incorrect doses of dabigatran and rivaroxaban were the most common cases in this proportion, accounting for approximately 29.6%. In particular, inappropriately low doses were the most common, with 54.8% and 36.8% of patients being prescribed with low doses of dabigatran and rivaroxaban, respectively.

This result was consistent with the results reported in previous studies [10, 13]. All of their data showed that NOACs were clinically underdosed, and most patients were not adjusted according to the appropriate dose reduction index, but were dosed without an indication for dose reduction. Such inappropriate dose reductions may reduce the efficacy of stroke prevention. A retrospective cohort study from Korea showed that the combined effect of 20 mg/d was superior to 15 mg/d when prescribing rivaroxaban for NVAF patients with non-moderate renal insufficiency [14]. Similarly, a retrospective cohort study from Taiwan examined the efficacy and safety of the recommended dose (15 or 20 mg/d) and low-dose (10 mg/d) prescriptions of rivaroxaban in Asian patients with non-moderate renal insufficiency NVAF. The results showed the low dose did not significantly reduce the risk of intracranial hemorrhage compared with the recommended dose but rather increased the risk of ischemic stroke [15]. This study does not support the prescription of 10 mg/d of rivaroxaban in patients with normal or mild renal insufficiency with NVAF.

In our study, the specific decision basis for clinicians to prescribe NOACs is not clear. Analyzing the data collected, we found that the most common reason for patients taking low doses of dabigatran may be due to the pharmacy-packaged dose. The purchased dabigatran dose was a single dose of 110 mg of dabigatran, which somewhat limited the ability of clinicians to select an appropriate dose for their patients. Second, compared with the standard dose group, we found that patients taking low-dose prescription dabigatran had lower mean age, stroke risk, and bleeding risk scores, while their mean CrCI was at the high end of the normal range. In addition, the low-dose group had a relatively lower incidence of bleeding events and a relatively higher incidence of embolism. For patients taking rivaroxaban, their mean age, stroke risk and bleeding risk were higher in the low-dose group than in the standard-dose group, while CrCl was lower than in the standard-dose group. Both hemorrhagic and embolic events were higher. This suggests that because anticoagulation is usually a prophylactic treatment for patients with AF and there is concern about iatrogenic bleeding events caused by NOACs, clinicians tend to use low-dose NOACs to ensure safety and prevent bleeding. However, the trend toward low-dose NOACs may come at the cost of insufficient effectiveness in stroke prevention.

NOACs have predictable pharmacokinetics, fixed-dose regimens. They do not require frequent dose adjustments or routine pharmacodynamic monitoring, but each NOAC has a recommended dose based on clinical characteristics (e.g. sex, age, body weight, renal function, and concomitant medications). To ensure the safety and efficacy of NOACs for patients, prescribing practices in clinical practice should follow the results of clinical studies and the drug label instructions approved for different NOACs indications, combined with individualized dosing for clinical benefit. Also, pharmacies need to be fully aware of the dose variations of dabigatran to meet clinical needs when purchasing drugs.

Appropriateness of indications in this study, approximately 15.4% of patients were prescribed medication without appropriate indication for its use. The presence of insufficient or excessive anticoagulants was one of the reasons for prescribing. Approximately 2.2% of patients had no indication for medication, and the prescription of medication leads to excessive anticoagulation. The reason for this may be due to the subjective experience of the clinician. About 13.3% of patients presented with an indication for medication but were not prescribed an anticoagulant, which led to underprescribing of anticoagulation. Of these patients, 52.9% were at high risk of bleeding. Clinicians’ caution in preventing patients from bleeding may have contributed to the lack of anticoagulant prescriptions. Secondly, 27.1% of patients had poor compliance and refused anticoagulation therapy, meaning that these patients used only antiplatelets for stroke prevention.

Hypertension, age, and history of stroke are overlapping risk factors for stroke, and bleeding in patients with AF. As the CHA2DS2-VASc score increases, the risk of bleeding increases accordingly. The increased risk of bleeding is often accompanied by an increased risk of embolism. If patients present with an indication for anticoagulation therapy and are also at high risk for bleeding, it is necessary to conduct a risk and benefit assessment to actively correct the reversible factors contributing to bleeding risk while closely monitoring and developing an appropriate anticoagulation regimen. In patients at high risk of bleeding, the benefits of appropriate anticoagulation therapy can outweigh the risks, so bleeding risk is not necessarily a contraindication to anticoagulation therapy [16]. Furthermore, an anticoagulant is the cornerstone of the treatment for patients with AF and antiplatelet therapy alone is not recommended. The BAFTA study showed that aspirin has little benefit compared to warfarin in the anticoagulation of elderly patients with AF [17]. The rate of the primary endpoint of fatal/disabling stroke (ischemic or hemorrhagic) was 52% higher than warfarin, while the difference of incidence of bleeding events between warfarin and aspirin was not statistically significant. For patients with AF undergoing radiofrequency ablation, the four-week postoperative period is a high-risk period for thrombosis. Therefore, anticoagulation must be started regardless of CHA2DS2-VASc score and continued for at least four weeks after cardioversion. The need for long-term anticoagulation after four weeks should be determined by the assessment of the risk for thromboembolism and bleeding. In this study, 2.2% of the patients were in the perioperative phase of radiofrequency ablation but were not on anticoagulation therapy.

Therefore, to effectively outperform and manage anticoagulation therapy for patients with AF, the proper indications should be correctly captured to determine which patients require anticoagulation therapy. In addition, the relevant guidelines and instructions should be strictly followed. Physicians or pharmacists can educate patients about the use of OAC medications to eliminate their fears and concerns about the risks of bleeding and to improve their medication compliance. With regular follow-ups, dynamic assessment of embolic and bleeding risks, and close monitoring, clinicians can properly determine when the benefits of anticoagulation will outweigh the risks of bleeding.

Medicine selection

The main OACs used in our hospital are mainly warfarin, rivaroxaban and dabigatran. We found that a total of 6 patients were prescribed inappropriate drug selection. Both warfarin and NOACs were effective in preventing stroke in patients with AF. However, NOACs were effective in reducing the risk of stroke and systemic embolism compared with warfarin, unlike their risk of bleeding. Currently, 12 guidelines recommend NOACs for NVAF only [12]. Prescribing NOACs is contraindicated in patients with valvular AF. In this study, four patients with moderate-to-severe rheumatic mitral valvular diseases and/or an artificial heart valve were prescribed NOACs, indicating that the clinician performing the medical prescription did not have a grasp of which indications were suitable for prescribing NOACs. Therefore, there may have been inadequate knowledge or clinical assessment, which presents a potential therapeutic risk. NOACs are primarily excreted by the kidneys, particularly dabigatran. Dabigatran is contraindicated in patients with CrCl less than 30 ml/min. In this study, two patients with CrCl < 30 ml/min were prescribed dabigatran, which was an inappropriate choice. Many factors can affect the anticoagulant strength of warfarin during its use. Guidelines recommend the use of the SAME-TT2R2 score to help identify patients who are less likely to achieve good TTR with VKA therapy and who would benefit more from NOACs. Studies have shown that the SAMe-TT2R2 score is strongly associated with TTR in Chinese patients with AF [18]. These patients required increased follow-up and regular monitoring of coagulation indicators to obtain good TTR during warfarin use. For these patients, NOACs may be a better option.

Safety

We observed bleeding events in about 9.6% of patients and embolic events in 2.6% of patients. Of the bleeding events, rivaroxaban, dabigatran, warfarin, and non-anticoagulated non-anticoagulation accounted for 12.6%, 8.3%, 11.1%, and 4.5% of patients, respectively. Of these, occult blood was the most common, followed by gastrointestinal bleeding. 5 occurred major bleeding or fatal bleeding(include 3 fundal bleeding, 1 subdural hematoma and 1 subarachnoid hemorrhage). Embolic events were relatively rare. We analyzed the dose difference of NOACs by hemorrhagic and embolic events. We found that bleeding events were higher in the standard dose group of dabigatran than in the low dose group, whereas embolic events were lower than in the low dose group. In contrast, bleeding events and embolic events were lower in the standard dose of rivaroxaban than in the low dose group. However, since this study did not follow up with patients, it cannot be determined whether these safety outcomes were associated with inappropriate prescribing. This should be verified by further studies, such as prospective studies with large samples.

Limitation

This study has some limitations. Because it was a retrospective study, not all clinical results were registered and the registered results may have been biased by inaccurate or incomplete information. We did not follow up with the patients during the study period, and the number of bleeding and thromboembolic events may have been underestimated. Also, we did not directly question the prescribing physicians to determine their methods and intentions for dose adjustment, making it difficult to explain why inappropriate prescriptions would be so. Nonetheless, our data are representative enough of results from an Asian hospital specializing in cardiovascular medicine to indicate whether OAC prescribing was appropriate for patients with AF at this hospital.

Conclusion

Our study found that under- and over-anticoagulation in patients with AF seem to occur frequently and that improper dose selection of NOACs is common. One of the greatest risks of AF is stroke. To reduce stroke caused by AF, anticoagulation therapy is needed for patients at a high risk of stroke. However, there are still some misconceptions about anticoagulation therapy for the treatment of AF in clinical practice due to insufficient understanding of the risk assessment of stroke and bleeding in patients with AF. In order to standardize anticoagulation therapy, it is necessary to clarify which patients need anticoagulation therapy and to standardized the use of anticoagulant doses. Therefore, the number of follow-up visits should be increased while assessing the risk of stroke and bleeding. And to monitor changes in clinically relevant risk factors during the follow-up period according to the patient’s actual situation. The complexity of the dose of NOACs depends on relevant factors, such as renal function, age, the combination of drugs. Since there is no corresponding efficacy judgment index for NOACs, clinicians may feel that using low doses can reduce the risk of bleeding and thus lead to underdosing. Therefore, it is important to prescribe NOACs in strict accordance with study results and dosing guidelines to effectively utilize their anticoagulant effects while avoiding drug-related problems in clinical practice.

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22 Jun 2021

PONE-D-21-18099

REVIEW ORIGINAL RESEARCH CASE REPORT CASE SERIES RAPID A retrospective study on the evaluation of the appropriateness of oral anticoagulant therapy prescription for patients with atrial fibrillation

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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Reviewer #2: No

Reviewer #3: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Line 78: S capital

Line 106: citations at the beginning of the sentence

Line 112 and 113 are repetitive

citation needed for line 114 to 119.

164 should be prescription instead of description.

This research review provides light on how frequently OAC is mismanaged in patients with Atrial fibrillation.

It is important to state if the majority of the patients were managed by cardiologists or primary care providers. It would be interesting to see if the cardiologist were handling the OAC doses better than their primary care colleagues.

Interesting to note that although apixaban is the most widely used OAC in the world, it was not included in the study [ author to clarify reason of not including apixaban in the review].

Overall, well conducted study.

Reviewer #2: Review comments according to the number(against the serial number): 4: Omit the word 'prescription'. 22: Replace the word 'patients and' by the word 'materials'. 27: 57.7% is the wrong typing, it will be 53.7%. 29: Replace the world 'description' by the word 'prescription'. 37: Bleeding events are 44, but I find it is 43 according to table 6. 84: Transient factors may include chest infections(pneumonia) also. 134 & 135: The term 'valvular AF' is less appropriate term at present because most of the recent study(AF) for NOACs(according to ESC guidelines for AF-2020) include other valvular AF except moderate to severe Rheumatic Mitral valvular diseases and/ or an artificial heart valve. 137: Use of NOAC with Warfarin- I think the word 'with' is replaced by the word 'over'. 159: In Table 4- Only male sex; what's about female sex? no information about female sex. 162: 56.7% will be corrected by 53.7%. 164:'Description' will be corrected by 'prescription'. 175: Regarding prohibition-Dabigartan(RE-LY trial) and Rivaroxaban(ROCKET- AF trial) is used other valvular AF except moderate to severe Rheumatic Mitral valvular diseases and/ or an artificial heart valve. 184: Table 6-shows Dabigartan(n=126), Rivaroxaban(n=163), but description shows Dabigartan was given to 132 patients and Rivaroxaban was given to 167 patients(there is discrepancy). 188: Table 6 shows bleeding events in Rivaroxaban group is 20 but description shows it is 21. 190: Rivaroxaban had the highest proportion of bleeding events but ROCKET-AF trial(ESC guidelines for AF-2020) shows that Rivaroxaban causes less intracranial bleeding than warfarin. Though this study is a retrospective study, but it should explain the possible underlying factors/ causes for (is there any history of low platelets or concomitant use of NSAID/ effects of abnormal liver or renal function?) high bleeding events than warfarin. 196: Figure 1 - shows Dabigartan causes high rate of bleeding events than warfarin, but RE-LY trail shows that Dabigartan causes less intracranial bleeding but high GIT bleeding than warfarin. Though this study is a retrospective study, but it should explain the possible underlying factors/ causes (is there any history of low platelets or concomitant use of NSAID/effects of abnormal liver or renal function?) for high bleeding events than warfarin. 288: Contraindication to NOAC therapy in valvular AF-according to ESC guidelines for AF-2020 that include other valvular AF except moderate to severe Rheumatic Mitral valvular diseases and/ or an artificial heart valve. 306: Description shows no major/fatal bleeding but Table 7 shows there are 3 fundal bleeding, 1 subdural hematoma and 1 subarachnoid haemorrhage- I think it should be included as a major bleeding events.

This is a retrospective study and the researchers had no direct contact with the study subjects (rely on the papers only). But it shows clearly the inappropriateness of prescription that will help the physicians for selecting the appropriate anticoagulation therapy during management of AF.

Reviewer #3: Dear Author, this is a retrospective cross sectional study analyzing the prescriptions of patients with AF from the electronic medical records for the appropriateness of medication indication and dosage. It is small study with good analysis and the discussion is also appropriate. Overall study and paper is presented nicely but there are some sentences are conveying with ambiguous and confusing meaning. There also some minor spell checks and grammatical errors which need correction. I request the authors to go through the document with corrections and check uploaded by me. I would like you consider your title which includes "REVIEW ORIGINAL RESEARCH CASE REPORT CASE SERIES RAPID" in it. Is this phrase needed in the title ?.

**********

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Reviewer #1: Yes: Deepti Bhandare

Reviewer #2: Yes: Nirmol Kumar Biswas

Reviewer #3: Yes: BHAVANADHAR PENTA

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Submitted filename: PONE-D-21-18099_reviewer with comments.pdf

Click here for additional data file.

21 Aug 2021

Dear Editor,

We very much appreciate your consideration of this manuscript. We are also very grateful for the reviewers’ careful reading and constructive suggestions, which have been very helpful in improving our revision. We have studied comments carefully and have made corrections which we hope meet with approval. we present our response to each comment point by point as following:

Response to Editor:

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

According to the requirements of PLOS One, we have modified the format of the manuscript to meet the requirements.

Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (a) whether consent was informed and (b) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

We strictly follow the ethical procedure and provided all patients with written informed consent before study entry. We also add the ethics committee approval letter in the ethics statement in Methods section and online submission form.

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"YES-Correspondence"

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

We already removed the funding information from the Acknowledgments section and other parts of our manuscript. We would like update our funding statement in the online submission. The context of the statement is: "This research was funded by Scientific Research Fund Project of Yunnan Provincial Department of Education (Program No.2018JS245) and Hospital-level scientific research fund project of Fuwai Yunnan Cardiovascular Hospital (Program No.2019YFKT-08)."

We also include this statement in our cover letter.

5. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager.

We provide ORCID iD of the corresponding author in the submission system

Response to Reviewer #1:

Line 78: S capital

Edited

Line 106: citations at the beginning of the sentence

Added

Line 112 and 113 are repetitive

Deleted

citation needed for line 114 to 119.

Added

164 should be prescription instead of description.

Edited

This research review provides light on how frequently OAC is mismanaged in patients with Atrial fibrillation.

It is important to state if the majority of the patients were managed by cardiologists or primary care providers. It would be interesting to see if the cardiologist were handling the OAC doses better than their primary care colleagues.

We thank the reviewer for his positive assessment. In this study, the OAC was prescribed by a cardiologist at our hospital. The prescribing physicians had at least the title of chief physician, and the evaluation of the prescriptions was performed by clinical pharmacists with intermediate or higher titles. The details are added in the Reviewer section of the article. Our hospital is a grade A tertiary hospital specializing in cardiology. No primary care physicians were involved in this study

Interesting to note that although apixaban is the most widely used OAC in the world, it was not included in the study [ author to clarify reason of not including apixaban in the review].

Apixaban has been approved for marketing by the Chinese Food and Drug Administration but has not been purchased at our hospital. Since apixaban was not available in our hospital, it was not included in this study.

Overall, well conducted study.

We thank the reviewer for his kind comments and useful insights.

Response to Reviewer #2:

4: Omit the word 'prescription'.

Done

22: Replace the word 'patients and' by the word 'materials'.

Done

27: 57.7% is the wrong typing, it will be 53.7%.

Edited

29: Replace the world 'description' by the word 'prescription'.

Edited

37: Bleeding events are 44, but I find it is 43 according to table 6.

Table 6 only lists the information of patients taking dabigatran and rivaroxaban. A total of 32 cases of bleeding occurred. There were also 12 cases of bleeding events in patients taking warfarin and those who did not take anticoagulants. So there are 44 cases for the total number of patients.

84: Transient factors may include chest infections(pneumonia) also.

Added

134 & 135: The term 'valvular AF' is less appropriate term at present because most of the recent study(AF) for NOACs(according to ESC guidelines for AF-2020) include other valvular AF except moderate to severe Rheumatic Mitral valvular diseases and/ or an artificial heart valve.

Edited

137: Use of NOAC with Warfarin- I think the word 'with' is replaced by the word 'over'.

Edited

159: In Table 4- Only male sex; what's about female sex? no information about female sex.

Female data added

162: 56.7% will be corrected by 53.7%.

Corrected

164:'Description' will be corrected by 'prescription'.

Corrected

175: Regarding prohibition-Dabigartan(RE-LY trial) and Rivaroxaban(ROCKET- AF trial) is used other valvular AF except moderate to severe Rheumatic Mitral valvular diseases and/ or an artificial heart valve.

Corrected

184: Table 6-shows Dabigartan(n=126), Rivaroxaban(n=163), but description shows Dabigartan was given to 132 patients and Rivaroxaban was given to 167 patients(there is discrepancy).

Of the 460 patients with AF, 132 were selected with dabigatran and 6 others had indications or inappropriate drug selection. Therefore, only 126 cases taking dabigatran were analyzed.

Of the 167 cases using rivaroxaban, 4 had indications or inappropriate drug selection, so only the 163 patients taking rivaroxaban were analyzed for rivaroxaban dosage.

188: Table 6 shows bleeding events in Rivaroxaban group is 20 but description shows it is 21.

We rechecked the data in Table 6 for a total of 21 cases of rivaroxaban bleeding events. It has been modified in Table 6.

190: Rivaroxaban had the highest proportion of bleeding events but ROCKET-AF trial(ESC guidelines for AF-2020) shows that Rivaroxaban causes less intracranial bleeding than warfarin. Though this study is a retrospective study, but it should explain the possible underlying factors/ causes for (is there any history of low platelets or concomitant use of NSAID/ effects of abnormal liver or renal function?) high bleeding events than warfarin.

196: Figure 1 - shows Dabigartan causes high rate of bleeding events than warfarin, but RE-LY trail shows that Dabigartan causes less intracranial bleeding but high GIT bleeding than warfarin. Though this study is a retrospective study, but it should explain the possible underlying factors/ causes (is there any history of low platelets or concomitant use of NSAID/effects of abnormal liver or renal function?) for high bleeding events than warfarin.

190 and 196：

This study showed that the proportion of hemorrhage was higher in patients treated with rivaroxaban than in those treated with warfarin, and the data were objective and conclusive. However, the baseline of factors such as CHA2DS2-VASc score and HAS-BLED score were not always consistent due to the different groups of anticoagulation regimens of patients. Therefore, we do not consider this to be in conflict with the findings of the RE-LY study and the ROCKET-AF study. Also, due to the small sample of patients in this study and the limitations of the subgroup statistics, we have adjusted the discussion in this conclusion.

288: Contraindication to NOAC therapy in valvular AF-according to ESC guidelines for AF-2020 that include other valvular AF except moderate to severe Rheumatic Mitral valvular diseases and/ or an artificial heart valve.

Corrected

306: Description shows no major/fatal bleeding but Table 7 shows there are 3 fundal bleeding, 1 subdural hematoma and 1 subarachnoid hemorrhage- I think it should be included as a major bleeding events.

We understand and agree with this suggestion. We have included these 5 bleeding cases in Table 7 as major bleeding events.

This is a retrospective study and the researchers had no direct contact with the study subjects (rely on the papers only). But it shows clearly the inappropriateness of prescription that will help the physicians for selecting the appropriate anticoagulation therapy during management of AF.

We appreciate the reviewer for this positive insight, careful reading, and detailed comments here.

Response to Reviewer #3:

Dear Author, this is a retrospective cross sectional study analyzing the prescriptions of patients with AF from the electronic medical records for the appropriateness of medication indication and dosage. It is small study with good analysis and the discussion is also appropriate. Overall study and paper is presented nicely but there are some sentences are conveying with ambiguous and confusing meaning. There also some minor spell checks and grammatical errors which need correction. I request the authors to go through the document with corrections and check uploaded by me. I would like you consider your title which includes "REVIEW ORIGINAL RESEARCH CASE REPORT CASE SERIES RAPID" in it. Is this phrase needed in the title?

We thank the reviewer’s appreciation and all the inputs about our study. We have carefully checked and revised the manuscript according to the reviewer's comments, and also have re-scrutinized to correct spell and grammatical errors in the manuscript. We agree and appreciate with reviewer’s suggestion of the title, we deleted the “REVIEW ORIGINAL RESEARCH CASE REPORT CASE SERIES RAPID” and the current title is “A retrospective study on the evaluation of the appropriateness of oral anticoagulant therapy prescription for patients with atrial fibrillation”.

Submitted filename: rebuttal letter.docx

Click here for additional data file.

15 Oct 2021

A retrospective study on the evaluation of the appropriateness of oral anticoagulant therapy prescription for patients with atrial fibrillation

PONE-D-21-18099R1

Dear Dr. Qian,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: all comments have been answered

well written case

interesting aspect of engaging pharmacists to discuss safety profile of medications

Reviewer #2: The corrections that is made by the Authors is upto the mark for publication and fulfill the expectation.

Reviewer #3: Dear Author, the title of edited version manuscript is now according to the PLOS ONE guidelines. The corrections suggested by the reviewers and editor have been addressed.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Deepti Bhandare

Reviewer #2: Yes: Nirmol Kumar Biswas

Reviewer #3: Yes: PENTA BHAVANADHAR

2 Nov 2021

PONE-D-21-18099R1

A retrospective study on the evaluation of the appropriateness of oral anticoagulant therapy for patients with atrial fibrillation

Dear Dr. Qian:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Vijayaprakash Suppiah

Academic Editor

PLOS ONE

Table 2

HAS-BLED score [2].

Risk factors	Points awarded
Uncontrolled hypertension	1
Abnormal renal and/or hepatic function	1 point for each
Stroke	1
Bleeding history or predisposition	1
Labile INR	1
Aged >65 years or extreme frailty	1
Drugs or excessive alcohol drinking	1 point for each

INR-: international normalized ratio.