The joint physician- and pharmacist-managed anticoagulation clinic is aiming to improve warfarin management in outpatients with atrial fibrillation in China: A prospective observational study

Zimo Sha; Youmei Shen; Duxiao Zhang; Jiaojiao Shi; Zidun Wang; Mingfang Li; Minglong Chen

doi:10.4103/ijhr.ijhr_13_20

ORIGINAL ARTICLE

Year : 2021 | Volume : 6 | Issue : 1 | Page : 67-72

The joint physician- and pharmacist-managed anticoagulation clinic is aiming to improve warfarin management in outpatients with atrial fibrillation in China: A prospective observational study

Zimo Sha¹, Youmei Shen², Duxiao Zhang¹, Jiaojiao Shi¹, Zidun Wang¹, Mingfang Li¹, Minglong Chen¹
¹ Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
² Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China

Date of Submission	14-Dec-2020
Date of Decision	02-Feb-2021
Date of Acceptance	02-Mar-2021
Date of Web Publication	30-Jun-2021

Correspondence Address:
Dr. Mingfang Li
Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ijhr.ijhr_13_20

Abstract

Background: Anticoagulation clinic (AC) is aimed at improving anticoagulation control and outcomes in patients with atrial fibrillation (AF). There is little published data on the benefits of providing an AC in China even if Asians have a higher risk of hemorrhage and stroke when taking warfarin. This study attempts to assess the impact of the AC on warfarin management in the Chinese population. Subjects and Methods: This prospective observational study was conducted in the First Affiliated Hospital of Nanjing Medical University and consecutively enrolled 42 AF patients from the joint physician-and pharmacist-managed AC from March 2017 to April 2018. The study protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Nanjing Medical University. Patients already on warfarin for at least 6 months before coming to the AC and unwilling to receive AF ablation or switch to non-Vitamin K antagonist oral anticoagulants were included. The anticoagulant activity of warfarin was monitored using the international normalized ratio (INR). The primary outcome of this study was INR control, which was defined by the time-in-therapeutic range (TTR). The TTR before and after visiting the AC was compared. Results: The mean age of the enrolled 42 patients was 68.3 ± 10.6 years and 25 (59.5%) were women. The mean CHA2DS2-VASc score and the mean HAS-BLED score were 3.43 ± 1.29 and 1.86 ± 0.80, respectively, in 28 (66.7%) patients with nonvalvular AF. The median follow-up time after visiting the AC was 298.5 days (interquartile range: 151.8–441.8 days). The TTR (% days) before and after visiting the AC was 44.1% ± 27.5% and 69.7% ± 23.3% (P < 0.001), respectively. Meanwhile, 6 (14.3%) and 25 (59.5%) patients had TTR (% days) >65% before and after visiting the AC (P = 0.001), respectively. Conclusions: TTR values were higher in AF patients taking warfarin after the AC. More patients reached satisfactory warfarin control after visiting the AC.

Keywords: Anticoagulants, anticoagulation clinic, atrial fibrillation, stroke prevention, time-in-therapeutic range

How to cite this article:
Sha Z, Shen Y, Zhang D, Shi J, Wang Z, Li M, Chen M. The joint physician- and pharmacist-managed anticoagulation clinic is aiming to improve warfarin management in outpatients with atrial fibrillation in China: A prospective observational study. Int J Heart Rhythm 2021;6:67-72

How to cite this URL:
Sha Z, Shen Y, Zhang D, Shi J, Wang Z, Li M, Chen M. The joint physician- and pharmacist-managed anticoagulation clinic is aiming to improve warfarin management in outpatients with atrial fibrillation in China: A prospective observational study. Int J Heart Rhythm [serial online] 2021 [cited 2023 Jun 3];6:67-72. Available from: https://www.ijhronline.org/text.asp?2021/6/1/67/319927

Introduction

Atrial fibrillation (AF) is associated with a 5- to 17-fold increased risk for ischemic stroke.^[1] Oral anticoagulants (OACs), consisting of warfarin and non-Vitamin K antagonist OACs (NOACs), are the cornerstone for primary and secondary stroke prevention in patients with AF.^[2],[3] However, a major concern with OACs is that they can cause severe bleeding, which increases mortality regardless of the bleeding site.^[4] NOACs have been used for the past few years. They overcome some of the limitations of warfarin and might have a lower risk of bleeding than that associated with warfarin.^[5] However, warfarin remains the first-line treatment for thromboprophylaxis in patients with AF in China due to its low price.

Asians have a higher risk of hemorrhage and stroke while taking warfarin than Caucasians do.^[6],[7] The AF population is steadily increasing in China due to the prolonged life expectancy and large population.^[6],[8],[9] Unfortunately, warfarin management is still far from satisfactory in China.

An anticoagulation clinic (AC) is aimed at improving anticoagulation control and outcomes in AF patients.^[7] Different from usual medical care (UMC) provided by primary care physicians or cardiologists, an AC may be operated by nurse practitioners or pharmacists. It has been demonstrated that the availability of an AC can remarkably reduce the risk of bleeding and stroke.^[10],[11]

ACs has been introduced to China in the recent years. However, ACs have highly variable structure and staffing models in Mainland China.^[12] In addition, there is little published data on the benefits of providing an AC in China. The AC at this center started in March 2017. This study attempts to assess the impact of the joint physician-and pharmacist-managed AC on warfarin management among patients from China.

Subjects and Methods

Study design and population

This single-center, prospective, observational study was approved by the Institutional Review Board of the First Affiliated Hospital of Nanjing Medical University and conducted in accordance with the Declaration of Helsinki. Forty-two patients in the AC of the First Affiliated Hospital of Nanjing Medical University were consecutively enrolled from March 2017 to April 2018 without out any incentive given. The inclusion criteria were as follows: (1) Being documented AF by electrocardiogram, (2) already on warfarin for at least 6 months, and (3) unwilling to receive AF ablation or switch to NOACs. The exclusion criteria were as follows: (1) Less than six outpatient visits to the AC and (2) switch to NOACs or receive AF ablation during follow-up period, as shown in [Figure 1]. All of the enrolled patients signed written informed consent forms.

Figure 1: Study flow diagram. AC = Anticoagulation clinic, INR = International normalized ratio, NOAC = Non-Vitamin K antagonist oral anticoagulants, UMC = Usual medical care

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Usual medical care and the anticoagulation clinic

Patients on warfarin had been managed under UMC before they visited the AC. The management was at the discretion of specialist physicians in cardiovascular medicine, neurological medicine, gerontology medicine, or general medicine. There was no specified follow-up schedule or intensive education given for patients.

The AC jointly managed by a cardiologist who specializes in AF management and a clinical pharmacist has been established at the First Affiliated Hospital of Nanjing Medical University since March 2017. In addition, a research nurse collaborates with the cardiologist and pharmacist as a team. The AC is open once a week. The number of monthly patients visiting the AC was 40 in March 2017 (the start of data collection) and increased to 126 by April 2018 (the end of data collection). At the first visit, the patient's medical history, necessary physical examination, 30-second electrocardiogram using the KardiaMobile device (AliveCor, Mountain View, CA, USA) and medication review were completed. The patient's risks of bleeding and thromboembolism were evaluated. The nurse was to input the demographic information, risk factors for bleeding and thromboembolism, and the international normalized ratio (INR) values of each patient into the Electronic Medical Record System to provide valid medical decision-making support. The applicability of the thromboprophylaxis strategy was assessed and modified as indicated. Meanwhile, each patient received intensive verbal education about warfarin therapy for 30 min on average. The content of the verbal education includes basic knowledge of AF, treatment rationale of warfarin, medication administration of warfarin, side effects of warfarin, information on drug interactions when taking warfarin, and dietary guidance. In addition, patients were educated when to contact clinicians. Information brochures with written education material were provided to each patient. Patients were provided access to contact the nurse by a chat application using smartphones in case of emergency or with inquiries regarding the use of warfarin after AC visits. The follow-up schedule was determined by the cardiologist. During follow-up, the patient's thrombotic and bleeding events and INR values were collected. The necessary physical examination, 30-s electrocardiogram, and medication review were completed. The dosage of warfarin was adjusted at the discretion of the cardiologist after discussion with the clinical pharmacist. No algorithm was used to determine the warfarin dosage adjustment. Modification of other medications was also made as clinically indicated. Patients were usually required to visit the AC at intervals of ≤4 weeks, and their INR values were measured during each visit.

Study procedure (data collection)

Patients were referred to the AC for follow-up by their primary care physician. The collected data included patients' demographic information, risk factors for thromboembolism or bleeding, thromboembolic or bleeding events, mortality events, and all INR values before and after visiting the AC. The stroke risk in nonvalvular AF (NVAF) patients was evaluated by the CHA₂DS₂-VASc scoring system.^[13] The risk of major bleeding in patients taking anticoagulants with AF was assessed by the HAS-BLED scoring system.^[14]

In this study, INR testing was performed using ACL9000 coagulation analyzer (Beckman Coulter, Brea, CA, USA). INR determinations during hospitalization, emergency department visits, and physician office visits in addition to AC visits were all collected. Procedures requiring temporary discontinuation of warfarin during the follow-up were recorded. The target range of INR was 2.5–3.5 for patients with mechanical mitral valve replacement and 2.0–3.0 for other individuals.^[15] The quality of warfarin therapy was evaluated by time-in-therapeutic range (TTR), which was defined as the percentage of days within range (% days) and the percentage of tests (% tests) in range. The Rosendaal method was used to calculate the percentage of days within range.^[16] To calculate the percentage of tests in range, we added total visits within target range and divided the number by the total number of visits. TTR >65% was considered satisfactory warfarin control, for evidence suggests that TTR above 65% had a marked benefit against stroke and total vascular events for patients taking warfarin.^[17]

Outcomes

The primary outcome was TTR defined as the percentage of days within range (% days) and the percentage of tests (% tests) within range. The secondary outcomes were ischemic or hemorrhagic stroke, major bleeding or all-cause mortality.

Statistical analysis

Statistical analysis was performed using the SPSS software version 24.0 (IBM, Armonk, NY, USA). A paired Student's t-test was used to compare the TTR values of patients before and after AC. The number of patients with satisfactory warfarin control before and after AC was compared by a Chi-square test. A two-side P < 0.05 was considered to be a significant difference. Other clinical characteristics, such as age, CHA₂DS₂-VASc score or HAS-BLED score, were described as the mean ± standard deviation.

Results

Patient characteristics

The study included 42 AF patients on warfarin. The baseline clinical characteristics are summarized in [Table 1]. In the entire study, 25 (59.5%) patients were women, and 28 (66.7%) patients had NVAF. All patients took warfarin for at least half a year and had at least six outpatient visits to the AC. At baseline, the mean age was 68.3 ± 10.6 years. Among all the patients, 3 (7.14%) had congestive heart failure, 6 (14.3%) had diabetes mellitus, 23 (54.8%) had hypertension, and 7 (16.7%) had a history of stroke. The mean CHA₂DS₂-VASc score and the mean HAS-BLED score were 3.43 ± 1.29 and 1.86 ± 0.80 in patients with NVAF, respectively. The median follow-up time after visiting the AC was 298.5 days (interquartile range 151.8–441.8 days).

Table 1: Baseline clinical characteristics of the 42 participants

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Time-in-therapeutic range increased after patients visiting the anticoagulation clinic

The percentage of days within range was 44.1 ± 27.5% before visiting the AC, with an increase to 69.7 ± 23.3% after being seen at the AC (P < 0.001). The change in individual TTR (% days) before and after visiting the AC is shown in [Figure 2]. The percentage of tests within range was 38.7 ± 26.2% before visiting the AC, with an increase to 67.5 ± 20.4% after being seen at the AC (P < 0.001). The change in individual TTR (% tests) before and after visiting the AC is shown in [Figure 2]. TTR (% days) of patients with CHA₂DS₂-VASc ≥ 2 was 48.5 ± 29.9% and 70.0 ± 23.2% before and after visiting the AC (P = 0.003) and the TTR (% tests) of patients with CHA₂DS₂-VASc ≥2, before and after visiting the AC, was 43.3 ± 28.8% and 68.8 ± 21.1%, respectively (P = 0.001), while both TTR (% days) with CHA₂DS₂-VASc <2 were 36.3 ± 21.2% and 69.3 ± 24.2%, respectively (P = 0.007).

Figure 2: TTR value of patients before and after visiting the AC. (a) The percentage of days within therapeutic range (TTR of days). (b) The percentage of tests in therapeutic range (TTR of tests). Sample size is 42 and each color represents each patient's TTR value. The percentage of days and tests within range was increased after visiting the AC compared with before visiting the AC (P < 0.001; paired Student's t-test). AC = Anticoagulation clinic, TTR = Time-in-therapeutic range

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More patients reached satisfactory warfarin control after visiting the anticoagulation clinic

As shown in [Figure 3], 6 (14.3%) and 25 (59.5%) patients had TTR (% days) >65% before and after visiting the AC (P < 0.001), respectively. Meanwhile, 8 (19.0%) and 24 (57.1%) patients had TTR (% tests) >65% before and after the AC (P < 0.001), respectively.

Figure 3: Percentage of patients who had TTR > 65% before and after visiting the AC. (a) The percentage of patients having TTR (of days) >65%. (b) The percentage of patients having TTR (of tests) >65%. Numbers in the bar mean the amount of patients in each category. A Chi-square test was used to compare the percentage of patients reaching satisfactory warfarin control after visiting the AC compared with before visiting the AC (P < 0.001). AC = Anticoagulation clinic, TTR = Time-in-therapeutic range

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No patients were withdrawn from therapy due to serious adverse effects. No patients had thromboembolic events, major bleeding events or death during the study period. No patients switched from warfarin to NOACs.

Discussion

This study showed that compared with UMC, the joint physician- and pharmacist-managed AC at this center significantly improved the TTR values in terms of both the percentage of days within range (% days) and the percentage of tests (% tests) within range for AF patients taking warfarin.

The disease burden of AF is high in China. Although the age-standardized prevalence of AF in China is 0.77%, which is lower than that in the Caucasian population of the Western world, the overall risk of stroke is even higher in the Chinese population, particularly hemorrhagic stroke.^{[9],[18],[19],[20]} The higher morbidity and mortality do not, however, translate into the awareness of anticoagulation therapy among Chinese patients. Previous hospital-based studies showed that more than 40% of patients discontinued warfarin within the 1^st year of initiation.^[21] Only 6.75% of patients receive appropriate anticoagulation therapy.^[22] Most nontertiary hospitals do not have a consecutive record of the previous INR values, especially for outpatients. The absence of family doctors and low education levels among older patients make it difficult to reduce the prevalence of stroke and the risk of bleeding in patients taking warfarin. Therefore, it is urgent for China to have a system to provide intensive care to such a population. However, ACs have been established at only a few centers of China in recent years.

The impact of AC on anticoagulation control and patient outcome has been evaluated effectively in the Western world. A meta-analysis including four randomized control trials showed that the mean %TTR values in AC was 3.66 higher than that in UMC (P < 0.001).^[23] Our study was a prospective historical control trial that first reported the effectiveness of ACs in China. The TTR values after patients were seen in the AC were similar to those in another study.^[23] Patients enrolled in this study had good medication compliance. However, according to their prior TTR values, we could assume that they had not found an appropriate health-care provider to help them manage the use of warfarin. These patients received marked benefits after they transferred to the AC from UMC. The exquisite skills of warfarin management by the cardiologists and the clinical pharmacist in the AC, the intensive patient education provided by the AC and the online connection with patients after the visit are the main reasons for the improvement of TTR after patients are seen in the AC.

Of all 42 patients in the present study, both TTR (% days) and TTR (% tests) in 6 patients decreased after they were seen at the AC. Two of them had TTR >95% before they came to the AC and >85% after the AC and one of these 6 patients came to the AC for just 1 month. Others with unsatisfactory TTR values were older than 75 years. It is difficult for aged people to fully understand caution when taking warfarin even after intensive patient education. We should bear in mind that aged patients with AF are at both a high risk of stroke and a high risk of bleeding. Therefore, more effort should be put in this specific group of patients. NOACs or nonpharmacological strategies, such as left atrial appendage occlusion, may be a better choice for aged patients with AF. It is also worth noting that the difference of TTR value between AC and UMC was larger in high-risk patients (CHA₂DS₂-VASc score ≥2). Therefore, AC should be strongly recommended to these high-risk patients.

Limitations

The major limitation of the study is that the sample size of the study could not provide enough power to compare the clinical outcomes such as thromboembolic events, bleeding events, or all-cause mortality before and after patients visited the AC. Thus, we alternatively used TTR to evaluate the impact of the AC on anticoagulation management.

Conclusions

TTR values were higher in AF patients taking warfarin after AC. Therefore, more joint physician- and pharmacist-managed ACs are encouraged to open in China.

Financial support and sponsorship

The study was supported by the Construction Program of Jiangsu Provincial Clinical Research Center Support System and Basic Research Program Natural Science Foundation of Jiangsu Province. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

There are no conflicts of interest.

Editor note: MC is an Editorial Board member of International Journal of Heart Rhythm. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

Institutional review board statement

This study was approved by the Institutional Review Board of the First Affiliated Hospital of Nanjing Medical University.

Declaration of patient consent

The authors certify that they have obtained all appropriate consent from patients. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity forms.

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