TTR-INR guided warfarin adjustment protocol: A strategy to improve time in therapeutic range in patients with atrial fibrillation receiving warfarin

doi:10.21203/rs.3.rs-2959158/v1

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TTR-INR guided warfarin adjustment protocol: A strategy to improve time in therapeutic range in patients with atrial fibrillation receiving warfarin

https://doi.org/10.21203/rs.3.rs-2959158/v1

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Background: Atrial fibrillation (AF) is a causing ischemic stroke. Warfarin remains a viable oral anticoagulant for many patients. Time in therapeutic range (TTR) is still not widely applied in clinical practice.

Purpose: To study the association of change of TTR after implementation of TTR-INR guided warfarin adjustment protocol in patients with AF receiving warfarin.

Methods: This is a prospective study of patients with AF at warfarin clinic of King Chulalongkorn Memorial Hospital. TTR was calculated by using Rosendaal linear interpolation method at baseline, 6 and 12 months after protocol implementation. Patient characteristics and outcomes (TTR improvement, embolic and bleeding events, and mortality) were collected. McNemar’s Chi-square test and paired t-test were used to evaluate the relationship between protocol implementation and outcomes.

Results: A total of 57 patients were primary analyzed (mean age of 72 years, 50% females). The TTR at baseline was 65% (53% of patients had TTR less than 65%). After 12 months of protocol implementation, TTR were significantly improved (80%) (p<0.001). Significant improvement of proportion of patients with TTR ³65% was shown after protocol implementation (from 47% to 88%) (p<0.001). Three patients died during the follow-up. No ischemic or major bleeding events were occurred during the follow-up in the first 12 months.

Conclusion: The TTR was significantly improved after 12 months of protocol implementation. This strategy may offer additional value in TTR improvement and good outcomes in patients with AF receiving warfarin.

Health sciences/Cardiology

Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Arrhythmias/Atrial fibrillation

Atrial fibrillation (AF)

Time in therapeutic range (TTR)

International normalized ratio (INR)

Vitamin K antagonist (VKA)

Oral anticoagulants (OACs)

Non-vitamin K antagonist oral anticoagulants (NOACs)

Atrial fibrillation (AF) is the most common cardiac arrhythmias in clinical practices. Its prevalence is approximately 1–2% for general population; however, increasing in prevalence is found in aging patients and varies among difference ethnicities and nationalities.^1–2 Severity of AF varies from mild to severe and is associated with an about 5 times increased risk of thrombotic event of the neurological system (stroke, in particular) and other systems.^3–4

Anti-coagulant therapy is a standard of practice for ischemic stroke prevention in patients with AF. The drugs can be classified into two major subgroups according to its mechanism of action: vitamin K antagonist anti-coagulants (VKA), and non-vitamin K antagonist oral anticoagulants (NOACs). In Thailand, the widely available VKA is warfarin.

Although there are studies comparing efficacy between warfarin and NOACs in prevention of ischemic events in neurovascular and other systems, and the results favor using NOACs over warfarin as they are at least non-inferior or even superior to warfarin in stroke prevention⁵ with better safety profile. (ESC 2020 recommended for using NOACs in patients with AF over warfarin, recommendation level IA⁶). NOACs are not on the Thailand National List of Essential Medicines (NLEM) while warfarin is on the list. Due to this problem, warfarin is still being widely used in clinical practice for AF patients for ischemic event prevention in Thailand.

To follow-up patients taking warfarin, International Normalized Ratio (INR) is measured, and Time in Therapeutic Range (TTR) is calculated from the duration that INR is within target range. Other measures include complications from the drug, particularly bleeding events.

Calculation of TTR by using Rosendaal linear interpolation method⁸ found that patient with TTR less than 60% have greater mortality rate and bleeding complications as compared to patients with TTR more than 75%, and patients with higher TTR have higher survival rate.⁹ Target TTR is accepted at 65–70% which will yield in good clinical outcome with less complication¹⁰ (ESC 2020 recommended that in patients taking warfarin, the target INR should be at level 2.0–3.0, with each patient TTR of at least 70% (evidence class IB), or should try to improve TTR by variable methods e.g. providing information, and frequent follow-up INR level (evidence class IIa). ⁶ Among Asian patients, the latest recommendation from 2021 Focused update of the 2017 consensus guidelines of the Asia Pacific Heart Rhythm Society (APHRS) on stroke prevention in atrial fibrillation stated that each patient should have TTR at 65% or higher, also is recommendation from 2016 Taiwan Heart Rhythm Society, and 2018 Korean Heart Rhythm Society. Still, there is lack of evidence in proper time to follow patients with lower-than-recommended TTR (lower than 65–70%).

Although evidence from studies recommend that TTR should be used in follow-up of patients taking VKA and should be targeted at 65–70% or higher, it is not being widely used resulting from lack of evidence that TTR usage provides benefit for Thai patients. Moreover, with the limitation to switch the class of anticoagulant from VKA to NOACs due to the Thailand NLEM problem as well as the patients’ socioeconomic status, warfarin is still major drug used in patients with AF in prevention of stroke in Thailand.

Study design

This prospective cohort, non-randomized, single-center study was conducted in Warfarin Clinic, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

The study was approved by the Institutional Review Board of the Research Ethics Review Committee for Research Involving Human Research Participants, Health Sciences Group, Chulalongkorn University (COA No. 202/2021, IRB No. 899/63), and is in accordance with the Helsinki Declaration of 1983, was registered in Thai Clinical Trials Registry (TCTR20201224003, Date of registration: 24/12/2020).

Study population and protocol

We enrolled consecutive patients with non-valvular AF confirmed by 12-lead ECG or ECG strip with \(\ge\)30 seconds of AF (including wearable-recorded ECGs) who were treated with warfarin. All patients must be 18 years of age or older. Enrollment was done in King Chulalongkorn Memorial Hospital from 1 February 2021 to 1 February 2022. Enrolled patients must had been using warfarin for at least 2 years, with at least 3 times INR measurement on different visits. Patients were excluded from this study if they had significant valvular heart disease including prosthetic valve replacement and moderate to severe rheumatic mitral stenosis, pregnancy, atrial fibrillation related to transient reversible cause (e.g., during respiratory tract infection), history of NOACs use within 2 years, unable or unwilling to attend follow-up, or refuse to participate

The percentage of time that a patient had an INR between 2 to 3 was calculated using the TTR by by using Rosendaal linear interpolation method. In this study, we defined poor anticoagulant control (group 1) with warfarin as TTR < 65% and good anticoagulant control (group 2) with warfarin as TTR ≥ 65%. All Participants was adjusted dose of warfarin by the Warfarin Dosing Nomogram (TTR-INR guided warfarin adjustment protocol) (according to table S5 in supplementary appendix)

The TTR was calculated by using Rosendaal linear interpolation method at baseline, at 6 months after protocol implementation, and at 12 months after protocol implementation. Clinical follow-up was performed each OPD visit up to 1 year at warfarin clinic by reviewing of hospital electronic medical records system or by telephone interview.

Protocol feasibility was collected by questionnaire and protocol violation was recorded.

The data from patient’s medical records were collected including baseline clinical characteristics such as sex, age, medical history, medication, left ventricular ejection fraction (LVEF) and laboratory tests (CBC, renal function tests, electrolytes, liver function tests, and INR), ischemic and bleeding risk scores, treatments, outcomes including TTR improvement, embolic event, bleeding events, hospitalization, and mortality.

We collected SAMe-TT2R2 score (table S1) as follow: S = Sex (female,1 point); A = Age (< 60 years,1 point); Me = medical history (at least two of diabetes, hypertension, heart failure, coronary artery disease, peripheral arterial disease, previous stroke, pulmonary disease, hepatic or renal disease, 1 point); T = treatment with interacting drugs such as amiodarone, non-steroidal anti-inflammatory drugs (NSAIDs), antifungal medications and many antibiotics (1point), T = tobacco use in 2 years (2 points); and, R = Race (non-Caucasian, 2 points).

Ischemic stroke risk was evaluated at baseline using CHA2DS2-VASc score (table S2) as follows: C = congestive heart failure (1 point); H = hypertension (1 point); A = age > 75 years (2 points); D = diabetes (1point); S = stroke (2 points); V = vascular disease (1 point); A = age 65–74 (1 point); and Sc = female sex category (1 point)).

Bleeding risk was evaluated at baseline using HAS-BLED score (table S3) as follows: H = uncontrolled hypertension; A = abnormal renal, or liver function; S = history of stroke; B = history of bleeding; L = labile INR (Unstable/high INRs or poor TTR < 60%); E = elderly (age above 65 years); and D = drugs or alcohol (1 point each).

Major bleeding, clinically relevant non-major bleeding (CRNM), and minor bleeding were categorized, defined by the 2005 International Society on Thrombosis and Haemostasis (ISTH).

We defined renal disease from the laboratory data in the last 6 months from glomerular filtration rate (GFR) below 60 ml/min/1.73m² by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or a diagnosis of CKD or end stage kidney disease (ESRD) in the medical record excluding acute kidney injury (AKI). For pulmonary disease, we defined as a diagnosis of chronic lung disease in the medical record. For liver disease, we defined from the laboratory data in the last 6 months as an at least 2 times increase in alanine aminotransferase (ALT) level from upper normal limit or a diagnosis of chronic liver disease or cirrhosis in the medical record.

We use the 20% event rate: change of TTR after protocol implementation (reference from a pilot study at KCMH) for calculating the adequate sample size, 93 patients were enrolled (power of study = 80%).

Outcomes

The primary end point was change of TTR after protocol implementation.

The secondary end points were protocol feasibility and protocol violation, proportion of patients who has been shifted to use NOACs, and incidence of ischemic stroke, bleeding events, and all-cause mortality.

Statistical analysis

Categorical data was presented as frequency and percentage. Continuous data was presented as mean ± standard deviation (SD) for normal distribution, and as median for skewed distribution.

Categorical data were compared using McNemar’s Chi-square test and continuous paired data was compared using paired t-test.

P-value < 0.05 was accepted as statistically significant. All statistical analysis was performed using SPSS version 28 statistical software.

From 1 February 2021 to 1 February 2022, total of 95 consecutive non-valvular atrial fibrillation patients (NVAF) were screened, 73 patients were being treated with warfarin at King Chulalongkorn Memorial Hospital, Bangkok, and were enrolled in this study. 16 patients were excluded from this study due to incomplete data (10 lost to follow-up, 2 refused to participate, 3 had reasons to target INR of more than 2.0–3.0, and 1 had high INR (> 4.99) at enrollment date. Total of 57 NVAF patients who were treated with warfarin had complete data for TTR calculation were included in this study.

Baseline characteristics

From 57 participants, mean age was 72 ± 11 years, and 50% were female. Mean left ventricular ejection fraction (LVEF) was 55.98 ± 15.39%, 17.31% of the patients had LVEF < 40%. Ischemic heart diseases (IHD) were reported in 32.4% (32.14% prior PCI, 14.29% had prior CABG), 57.14% had hypertension, 35.71% had diabetes mellitus, 46.43% had dyslipidemia, 21.43% had history of stroke, 21.43% had CKD at least stage III, 1.79% had end stage renal disease (ESRD), 3.57% had peripheral arterial disease (PAD), 3.57% had liver cirrhosis, 3.57% had chronic obstructive pulmonary disease (COPD), 7.14% had obstructive sleep apnea (OSA), 10.71% had cancer, and 44.64% had history of heart failure (HF).

All patients received warfarin (average dose was 21.02 ± 9.69 mg/week, median dose was 18 mg/week). Most patients received statin (82.14%), 71.21% of patients received beta blocker, 19.64% of patients received angiotensin converting enzyme inhibitor (ACEI), 28.57% of patients received angiotensin receptor blocker (ARB), 3.57% received ARNI. Only 3.57% of patients received concomitant aspirin and 3.57% of patients received concomitant P2Y12 inhibitor (clopidogrel), 50% of patients received diuretics (furosemide), 12.5% of patients received mineralocorticoid receptor antagonist (MRA, spironolactone), 12.5% of patients received digoxin, 3.57% of patients received hydralazine, and 7.14% of patients received nitrate.

History of cardiac implantable electronic device (CIED) implantation was recorded. Permanent pacemaker implantation (PPM) was reported in 16.07%. 3.57% of the patients had implantable cardioverter defibrillator (ICD). No patient was implanted with cardiac resynchronization therapy (CRT). 5.36% of patients had history of radiofrequency ablation (RFA) for AF.

The average laboratory investigation data consisted of hemoglobin 12.66 ± 2.00 g/dL, hematocrit 38.59 ± 5.69%, platelet 221,200 ± 70,560 cu.mm³, blood urea nitrogen (BUN) 20.31 ± 11.61 mg/dL, creatinine (Cr) 1.23 ± 0.67 mg/dL, sodium (Na) 140.04 ± 2.40 mmol/L, potassium (K) 4.11 ± 0.44 mmol/L, chloride (Cl) 104.62 ± 3.27 mmol/L, bicarbonate (HCO₃) 27.72 ± 11 mmol/L, albumin 3.78 ± 0.72 g/dL, total bilirubin 0.91 ± 0.54 mg/dL, direct bilirubin 0.44 ± 0.30 mg/dL, aspartate aminotransferase (AST, SGOT) 25.48 ± 9.75 U/L, alanine transaminase (ALT, SGPT) 22.28 ± 11.17 U/L, and alkaline phosphatase (ALP) 86.23 ± 39.27 U/L

The average CHA2DS2-VASc score, HAS-BLED, and SAMe-TT2R2 score was 3.82 ± 1.82, 2.13 ± 1.01 and 3.30 ± 0.74, respectively. The average of TTR was 64.69 ± 20.14% (mean = 62.78%) and 30 patients (52.63%) had poor anticoagulant controlled group (TTR < 65%), as shown in Table 2, and Table 3.

Table 1

Baseline characteristics of the study population compared between patients with TTR ≥ 65% and patients with TTR < 65%
Characteristics	All patients (n = 57) N (%) or Mean ± SD	TTR < 65% (n = 30) N (%) or Mean ± SD	TTR ≥ 65% (n = 27) N (%) or Mean ± SD	P-value¹
General information
Age (years)	72 ± 11	73 ± 12	70 ± 10	0.278
Female	28 (50)	16 (48.48)	12 (52.17)	0.786
LV systolic function (LVEF)	55.98 ± 15.39	55.76 ± 16.18	56.37 ± 14.32	0.892
LVEF ≤ 40%	9 (17.31)	6 (18.18)	3 (15.79)	0.911
LVEF 41–49%	7 (13.46)	5 (15.15)	2 (10.53)
LVEF ≥ 50%	36 (69.23)	22 (66.67)	14 (73.68)
Medical history
Heart failure	25 (44.64)	16 (48.48)	9 (39.13)	0.488
Diabetes mellitus	20 (35.71)	11 (33.33)	9 (39.13)	0.656
Coronary artery disease	18 (32.14)	11 (33.33)	7 (30.43)	0.819
Prior PCI	8 (14.29)	5 (15.15)	3 (13.04)	1.000
Prior CABG	5 (8.93)	2 (6.06)	3 (13.04)	0.392
Hypertension	32 (57.14)	17 (51.52)	15 (65.22)	0.308
Dyslipidemia	26 (46.43)	15 (45.45)	12 (52.17)	0.621
Old CVA	12 (21.43)	8 (24.24)	4 (17.39)	0.743
CKD stage ≥ 3	12 (21.43)	10 (30.30)	2 (8.70)	0.053
ESRD	1 (1.79)	1 (3.03)	0 (0)	1.000
PAD	1 (1.79)	1 (3.03)	0 (0)	1.000
Cirrhosis	2 (3.57)	1 (3.03)	1 (4.35)	1.000
COPD	2 (3.57)	1 (3.03)	1 (4.35)	1.000
OSA	4 (7.14)	1 (3.03)	3 (39.13)	0.295
Cancer	6 (10.71)	15 (15.15)	1 (4.35)	0.383
Cardiac implantable electronic device (CIED)
PPM	9 (16.07)	6 (18.18)	3 (13.04)	0.607
ICD	2 (3.57)	2 (6.06)	0 (0)	0.507
CRT	0 (0)	0 (0)	0 (0)	-
Procedure
AF RFA	3 (5.36)	1 (3.03)	2 (8.70)	0.562
AV node ablation	0 (0)	0 (0)	0 (0)	-
Medications
Furosemide	28 (50)	18 (54.55)	10 (43.48)	0.415
Spironolactone	7 (12.50)	5 (15.15)	2 (8.70)	0.688
Statin	46 (82.14)	29 (87.88)	17 (73.91)	0.179
Beta blocker	41 (73.21)	25 (75.76)	16 (69.57)	0.607
ACEI	11 (19.64)	7 (21.21)	3 (39.13)	0.723
ARB	16 (28.57)	7 (21.21)	4 (17.39)	0.144
Sacubitril/Valsartan (ARNI)	2 (3.57)	2 (6.06)	0 (0)	0.507
Digoxin	7 (12.50)	5 (15.15)	2 (8.70)	0.688
Hydralazine	2 (3.57)	2 (6.06)	0 (0)	0.507
Nitrate	4 (7.14)	4 (12.12)	0 (0)	0.136
Warfarin (dose: mg/week)	21.02 ± 9.69 (Mean 18)	22.33 ± 11.12 (Mean 19.5)	19.13 ± 9.98 (Mean 18)	0.363
Aspirin	1 (1.79)	0 (0)	1 (4.35)	0.411
P2Y12 inhibitor (Clopidogrel)	1 (1.79)	1 (3.03)	0 (0)	1.000
Laboratory investigation
Hemoglobin (g/dL)	12.66 ± 2.00	12.24 ± 2.10	13.27 ± 1.69	0.055
Hematocrit (%)	38.59 ± 5.69	37.36 ± 5.88	40.36 ± 5.00	0.055
Platelet (cu.mm²)	221,200 ± 70,560	229,180 ± 78,250	209,740 ± 57,530	0.315
Blood urea nitrogen (mg/dL)	20.31 ± 11.61	23.52 ± 13.75	15.50 ± 4.25	0.010
Creatinine (mg/dL)	1.23 ± 0.67	1.34 ± 0.82	1.06 ± 0.32	0.212
Sodium (mmol/L)	140.04 ± 2.40	139.70 ± 2.63	140.55 ± 1.95	0.314
Potassium (mmol/L)	4.11 ± 0.40	4.16 ± 0.41	4.03 ± 0.38	0.241
Chloride (mmol/L)	104.62 ± 3.27	104.15 ± 3.92	105.32 ± 1.81	0.144
Bicarbonate (mmol/L)	27.20 ± 2.93	27.24 ± 2.84	27.14 ± 3.12	0.897
Albumin (g/dL)	3.78 ± 0.72	3.73 ± 0.42	3.85 ± 1.01	0.046
Total bilirubin (mg/dL)	0.91 ± 0.54	0.97 ± 0.58	0.81 ± 0.45	0.353
Direct bilirubin (mg/dL)	0.44 ± 0.30	0.48 ± 0.34	0.37 ± 0.21	0.271
AST (SGOT) (U/L)	25.48 ± 9.75	25.36 ± 9.12	25.67 ± 10.90	0.901
ALT (SGPT) (U/L)	22.28 ± 11.17	20.15 ± 9.05	25.62 ± 13.44	0.126
ALP (U/L)	86.23 ± 39.27	94.36 ± 44.94	74.26 ± 25.64	0.068
¹P-value for comparison between patients with TTR ≥ 65% and TTR < 65%

Table 2

Risk scores of the study population compared between patients with TTR ≥ 65% and patients with TTR < 65%
Risk score	All patients (n = 57) N (%) or Mean ± SD	TTR < 65% (n = 30) N (%) or Mean ± SD	TTR ≥ 65% (n = 27) N (%) or Mean ± SD	P value¹
CHA2DS2-VASc score
Total score	3.82 ± 1.82	3.97 ± 1.90	3.61 ± 1.73	0.436
C	25 (44.64)	19 (57.58)	6 (26.09)	0.020
H	36 (64.29)	18 (54.55)	18 (78.26)	0.068
A2	24 (35.71)	16 (48.48)	8 (34.78)	0.308
D	20 (35.71)	12 (36.36)	8 (34.78)	0.903
S2	11 (19.64)	6 (18.18)	5 (21.74)	0.742
V	16 (28.57)	11 (33.33)	5 (21.74)	0.345
Risk score	All patients (n = 57) N (%) or Mean ± SD	TTR < 65% (n = 30) N (%) or Mean ± SD	TTR ≥ 65% (n = 27) N (%) or Mean ± SD	P value¹
CHA2DS2-VASc score (Cont.)
A	19 (33.93)	11 (33.33)	8 (34.78)	0.910
S	28 (50)	16 (48.48)	12 (52.17)	0.786
HAS-BLED score
Total score	2.13 ± 1.01	2.39 ± 1.09	1.74 ± 0.75	0.016
H	36 (64.29)	18 (54.55)	18 (78.26)	0.068
A	36 (64.29)	6 (18.18)	1 (4.35)	0.220
S	11 (19.64)	6 (18.18)	5 (21.74)	0.742
B	2 (3.57)	2 (6.06)	0 (0)	0.507
L	22 (39.29)	22 (66.67)	0 (0)	< 0.001
E	39 (69.64)	24 (72.73)	15 (65.22)	0.548
D	2 (3.57)	1 (3.03)	1 (4.35)	1.000
SAMe-TT2R2 score
Total score	3.30 ± 0.74	3.21 ± 0.60	3.43 ± 0.90	0.249
S	28 (50)	16 (48.48)	12 (52.17)	0.786
A	7 (12.5)	4 (12.12)	3 (13.04)	1.000
Me	33 (58.93)	20 (60.61)	13 (56.52)	0.261
T	1 (1.79)	0 (0)	1 (4.35)	0.411
T2	0 (0)	0 (0)	0 (0)	-
R2	56 (100)	33 (100)	23 (100)	-
¹P-value for comparison between patients with TTR ≥ 65% and TTR < 65%

Table 3

Baseline TTR of the study population compared between patients with TTR ≥ 65% and patients with TTR < 65%
Baseline TTR	All patients (n = 57)	TTR < 65% (n = 30)	TTR ≥ 65% (n = 27)	P-value¹
TTR (Mean ± SD)	64.69 ± 20.14	49.50 ± 13.15	81.56 ± 10.89	< 0.001
TTR (Median)	62.78	54.88	79.40	< 0.001
¹P-value for comparison between patients with TTR ≥ 65% and TTR < 65

Patients in poor anticoagulant controlled group (TTR < 65%) had higher BUN and HAS-BLED score as compared to good anticoagulant controlled group (TTR ≥ 65%) respectively (23.52 ± 13.75 vs 15.50 ± 4.25; p = 0.01), and 2.39 ± 1.09 vs 1.74 ± 0.75, p = 0.016).

Patients in poor anticoagulant controlled group (TTR < 65%) had lower serum albumin level than good anticoagulant controlled group (TTR ≥ 65%) (3.73 ± 0.42 vs 3.85 ± 1.01; p = 0.046.

No significant differences were observed for age, sex, LVEF, number of prior cardiovascular diseases, drugs used (statin, diuretic, betablocker, ACEI/ARB/ARNI, digoxin, hydralazine, nitrate, anticoagulant, aspirin, and P2Y12 inhibitor), CHA2DS2-VASc score, SAMe-TT2R2 score, history of CIED, and other laboratory testing.

Baseline characteristics of the study population compared between patients with TTR ≥ 65% and patients with TTR < 65% were shown in Table 1.

Primary outcome

Twelve months after protocol implementation, TTR was significantly improved (80.46 ± 16.51) (p < 0.001). Significant improvement of proportion of patients with TTR ≥65% was observed (from 47–88%) (p < 0.001), as showed in Table 4, Fig. 1–3.

Table 4

Change of TTR after 6 and 12 months of protocol implementation compared between patients with TTR ≥ 65% and patients with TTR < 65%
TTR	Before protocol	After protocol 6 months	After protocol 12 months	P-value¹
TTR (Mean ± SD) %	64.69 ± 20.14	70.08 ± 17.20	80.46 ± 16.51	< 0.001
TTR (Median) %	62.78	71.20	79.40	< 0.001
Group 1: TTR < 65%, n (%)	30 (52.63)	24 (42.11)	7 (12.28)	< 0.001
Group 2: TTR ≥ 65%, n (%)	27 (47.37)	33 (57.89)	50 (87.72)	< 0.001
¹P-value for comparison between patients with TTR ≥ 65% and TTR < 65%

Secondary outcomes

During follow up, there was 3 mortalities (a patient who deceased from severe acute pancreatitis, 2 patients died from severe sepsis) No ischemic or major bleeding events were occurred during follow-up in the first 12 months.

Protocol feasibility was assessed by questionnaire. Total 16 responses were collected (50% female, 50% male). Among these 16 participants; 2 were in the age between 21–30 years old, 12 were in the age between 31–40 years old, 1 was in the age between 41–50 years old, and 1 was in the age between 51–60 years old. Ten of the sixteen participant were in the fellowship training program, 3 were attending physician, 2 were pharmacists, and 1 was a nurse.

Detail of satisfaction of Warfarin Dosing Nomogram was classified into numerical data, with a scale from 1 to 5 as followings: 1 = strongly disagree, 2 = disagree, 3 = indifferent, 4 = agree, and 5 = strongly agree, as showed in Fig. 4.

Protocol’s accuracy: 12 strongly agreed, 3 agreed, and 1 was indifferent.
Protocol’s convenience: 12 strongly agreed, 3 agreed, and 1 was indifferent.
Protocol’s efficacy (Ability to decrease warfarin dose adjustment inaccuracy): 9 strongly agreed, and 7 agreed.
Readiness and rapidity of the protocol: 9 strongly agreed, 6 agreed, and 1 was indifferent.
Protocol provides more benefit as compared with usual calculation of warfarin dose adjustment: 12 strongly agreed, and 4 agreed.
Possibility to apply the protocol to other clinics: 8 strongly agreed, and 8 agreed.
Overall satisfactory of the protocol: 12 were strongly satisfied, and 4 were satisfied.

There were also suggestions from the questionnaire responders, as follows:

The protocol makes it easier to adjust the drug dose.
This protocol is interesting method to adjust warfarin dose and should be printed as a hard copy at the physician’s table.
Developing the protocol into digital system, or application for smart phone should be considered.
The protocol makes it easier to follow and adjust warfarin to achieve target INR.
For some patients, adjustment of warfarin should be more personalized according to the patient’s conditions.
This study only included patients with NVAF, there might be possibilities to apply for patient taking warfarin for other indications.
There might be some protocol violation especially in circumstances which patient’s INR is remarkably close to target and prior INR was within target range. For example, a patient with INR of 1.97 and prior INR was in target range, warfarin dose should be increased according to protocol, but in real life the physician might not follow the protocol.

This prospective study for patient with NVAF taking warfarin at warfarin clinic, King Chulalongkorn Memorial Hospital, dose adjustment of warfarin using TTR-INR adapted from Hamilton Dosing Nomogram and current Thai guidelines for patients taking oral anticoagulants, after 12 months follow-up (from February 2021 to February 2022), total of 57 patients were enrolled and were classified into 2 groups.

Group 1: patients with poor TTR (TTR lower than 65%)

Group 2: patients with good TTR (65% TTR 65% or higher)

After protocol implementation, the results at 12 months showed that mean TTR was significantly increased (p < 0.001) from 64.69 ± 20.14% to 80.46 ± 16.51%. The number of patients in group 2 (65% TTR or higher) was increased significantly from 27 patients (47.37%) to 50 patients (87.72%) (p < 0.001) when analyzed both as category and individually. This reflected effectiveness of using TTR-INR guided warfarin adjustment protocol after just 12 months of implementation.

During follow up, there was 3 mortalities (a patient who deceased from severe acute pancreatitis, 2 patients died from severe sepsis). When focusing on treatment-related complications, there was no ischemic event or significant bleeding events along the first 12 months of follow up after implementation of TTR-INR guided warfarin adjustment protocol. This might reflect that its longer follow-up period might be required to elucidate the trend toward ischemic or bleeding complications from warfarin adjustment using the protocol. In other word, due to low event rate, prediction of ischemic or bleeding event is difficult.

Ten patients had low TTR (lower than 55%) after adjustment of warfarin according to protocol twice and had been switched from VKA to NOAC due to failure to reach target INR and TTR (higher than 65%). The corresponding patient considered changing the drug class which might reflected that the physician was highly considerate and careful follow-up of their patient while using warfarin especially for its efficacy perspective after follow-up of INR and TTR in each visit. Three Patients switched to NOAC due to cannot monitor INR.

Only one patient was excluded from the study due to protocol violation. This might prove that TTR-INR guided warfarin adjustment protocol has high feasibility and ease of use for most physicians. This result also corelated with the result from questionnaire which most responders agreed or highly agreed from the 7 perspectives questionnaire as mentioned above.

From a meta-analysis which collected 8 RCTs (total 3,647 patients) which compared warfarin with aspirin for patients with AF, the results show that warfarin had better efficacy in prevention of ischemic stroke with RRR 39% (95% CI, 19–53%). The result from this meta-analysis supported the use of warfarin over aspirin without significant differences in bleeding complications.¹¹

The efficacy to prevent acute ischemic stroke in patient with NVAF is best at INR target of 2.0–3.0 while TTR is a percent of duration which each patient had INR in the target range to total duration while the patient was taking warfarin. Calculation of TTR was derived from using Rosendaal linear interpolation method.⁸ The clinical importance of TTR was demonstrated from a post hoc analysis from the AF clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE A).¹² In this study, there was no difference in decreasing ischemic stroke when comparing between warfarin with combined antiplatelets (aspirin with clopidogrel) (RR 0.92, 95% CI 0.70–1.24%) when TTR was below 65%, but preferred using warfarin over combined antiplatelets when TTR was at higher level (65% or more) which able to significantly decrease vascular event (RR 2.14, 95% CI 1.61–2.85, p < 0.001). Another systemic review also supported the importance of TTR for both ischemic and bleeding outcomes.¹⁰ Data from the latest large worldwide observation study from 9,934 patients receiving warfarin from 35 countries during 2010–2015 also showed that the patients whom TTR was below 65% were at risk of developing ischemic stroke and other ischemic events at 2.6 times higher, and at risk of developing significant bleeding event 1.5 time higher, with overall mortality at 2.4 times higher when compared with the group of patients with TTR of 65% or more.¹³

Baker and colleagues had demonstrated a problem of controlling INR level in patients taking warfarin in the USA in a meta-analysis. His study showed that in the USA, there was only 55% of patients with AF had INR within target range.¹⁴ Later, Masaki and colleagues had demonstrated that optimizing warfarin dose to achieve within target INR level directedly associated with a decrease in incidence of ischemic stroke in elderly patients (70 years old, and older).¹⁵ The result was also the same from a study of Witt and colleagues which reported that patients with INR within target range during 6-month follow-up had a significant lower overall ischemic and bleeding event rate complications as compared with patients who did not achieve target level.¹⁶

Another important problem was the difficulty in adjust warfarin dose to achieve target INR and TTR (65% or higher). Even in studies with regular and close follow-up system still had average TTR of 55% and more than half of the patients in the USA had TTR lower than 65%¹³ which was lower than recommended in international guidelines. Furthermore, among university hospitals containing Warfarin Clinics, data from a real-world practice study had demonstrated difficulty in maintaining TTR at 65% or higher to achieve the target to prevent both ischemic and bleeding complications.

In Thailand, a study consisted of 132 patients who had warfarin from Samutprakarn General Hospital showed that only 22.1% of patients had INR within target range of 2.0–3.0.¹⁷ The same result of low proportion of patients who had INR within the target range was also observed from a study consisted of 97 patients from Songklanagarind University Hospital, which only 31.96% of the patients had achieved target INR.¹⁸

There are other studies in Thailand by Saokaew, et al.^19,20 which showed that TTR of patients with AF in warfarin clinic varied in the range of 30.9–55.9%.

From a systematic review by Wan, et al.¹⁰ which collected studies published during January 1990 to January 2008 from MEDLINE, EMBASE, and Cochrane database to find correlation between the result of controlling INR and unexpected adverse events (UAEs) in patients with AF taking warfarin showed that TTR could be used as a predictor of UAEs. After analysis retrospectively from 21,540 patients found that with an increase in TTR of 7% was associated with a decrease in severe bleeding complications events, and with an increase in TTR of 22% was associated with a decrease in ischemic events.

From a recommendation from The American College of Chest Physicians (ACCP) emphasized systematic warfarin dose adjustment which related with its efficacy in warfarin clinic using, the method of dose adjustment was adapted from Hamilton Dosing Nomogram which adjustment was done considering INR of the patient each visit and calculated dose as mg/week. Data from a prospective, randomized trial revealed that using Hamilton Dosing Nomogram was able to increase TTR into target (TTR = 72%).

RE-LY trial, which studied differences in TTR among countries and correlation of warfarin dose adjustment and clinical result, found that every 10% increase of algorithm-consistent dosing of warfarin dose adjustment was able to increase TTR of 6.12% (95% CI, 5.65–6.59), and was associated with a decrease in both ischemic stroke and severe bleeding complications 8% (HR 0.92, 95% CI, 0.85-1.00).

Data from our study showed that TTR was increase 17% after implementation of TTR-INR guided warfarin adjustment protocol for 6 months, but clinical outcomes was not observed. This might be due to the short follow-up duration. However, our study result was correlated with a study of Harriete G.C., et al which demonstrated that warfarin dose adjustment systematically was associated with an increase in TTR.

Study strength

Our study is a prospective study which use a protocol-based for adjustment of warfarin dose in patients with NVAF who had warfarin as anticoagulant. While TTR is a standard of care for patient with AF taking warfarin, its implementation is not widely used in Thailand. Also, there was no prior study in Thailand which demonstrated the efficacy of using Warfarin Dosing Nomogram (TTR-INR guided warfarin adjustment protocol). As showed in many studies, algorithm-consistent dosing was effective, help decreasing human error in calculation, and easy-to-use. The result of our study might emphasize the use of protocol-based dose adjustment in Thailand in the future.

Limitations

This study was a non-randomized single center, collected patients only from Warfarin Clinic at King Chulalongkorn Memorial Hospital. This clinic consisted of cardiologists, pharmacists, and nurses who were familiar with warfarin and had experiences in educating the patients about the drug information, this might result in higher TTR from baseline as compared with other studies from different center or clinic.

Also, due to the COVID-19 pandemic situation, the clinic was temporally closed, and was able to open again in June 2021. So, recruiting the patients was delayed and TTR calculation at 12 months was not able to calculate or interpreted. Further result is expected to be completed by the time this study has finished.

Also, due to the COVID-19 pandemic situation, some of the patients was lost to follow up, or required to postpone a scheduled visit with the physicians. This might result in an error calculating TTR, and sample size was less than calculated (data was calculated from 56 patients, from an initial expected sample size was 93).

Future research

In order to gather more precise and reflect real practice in Thailand, prospective multicenter study of similar study design might be useful. To obtain more patients from both warfarin clinic and other clinics and longer follow-up time might be required to elucidate clinical outcomes.

Warfarin is among the common use of oral anticoagulants in patients with atrial fibrillation. The TTR was significantly improved after 12 months of protocol implementation. This strategy may offer additional value in TTR improvement and good outcomes in patients with atrial fibrillation receiving vitamin K antagonist oral anticoagulant.

Acknowledgement

We thank Chonlada Phathong for her assistance in designed study and statistical analysis.

Supplementary data

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Conflict of interest statement

All authors have no conflicts of interest to declare.

Funding

This study was supported in part by the Ratchadapiseksompotch Fund (2021), Chulalongkorn University (Grant No. RA 64/025).

Conflict of interest and potential competing interests

None

Authors’ contributions

PK designed the study, recruited the patients, acquired, analyzed, and interpreted the data, and drafted the article; NS recruited the patients, acquired, analyzed, and interpreted the data; KN, WL, and WS interpreted the data and revised the manuscript for important intellectual content, KT, RA, and AS acquired the data, VR designed the study, analyzed, and interpreted the data, and critically revised the manuscript for important intellectual content; All authors have read and approved the final manuscript.

Institutional review board statement

Ethics approval was obtained from the Institutional Review Board and the Ethics Committee of Faculty of Medicine, Chulalongkorn University (COA No. 202/2021, IRB No. 899/63).

Informed consent statement

Informed consent was obtained from all individual participants included in the study.

Financial support

This study was supported in part by the Ratchadapiseksompotch Fund (2021), Chulalongkorn University (Grant No. RA 64/025)

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No competing interests reported.

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TTR-INR guided warfarin adjustment protocol: A strategy to improve time in therapeutic range in patients with atrial fibrillation receiving warfarin

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