Relationship Between Infarct Volume and Prothrombin Time-International Normalized Ratio in Ischemic Stroke Patients With Nonvalvular Atrial Fibrillation

Abstract

Background: In Japan, warfarin treatment at prothrombin time-international normalized ratio (PT-INR) of 1.60–2.60 is recommended for elderly patients with nonvalvular atrial fibrillation (NVAF). But it remains unknown whether PT-INR 1.60–1.99 has a similar effect on stroke severity as a value >2.0. The purpose of this study was to clarify the association between infarct volume and PT-INR levels.

Methods and Results: The 180 patients (mean age, 76 years [SD, 10 years], 53% male) selected from 429 consecutive ischemic stroke patients admitted within 48 h of onset between 2004 and 2014 with NVAF were included. We classified them into 4 groups according to their PT-INR values on admission: no warfarin (NW), 129 patients; PT-INR <1.60 (poor control: PC), 29 patients; PT-INR 1.60–1.99 (low-intensity control: LC), 14 patients; and PT-INR ≥2.00 (high-intensity control: HC), 8 patients. Median (interquartile range: IQR) of infarct volume was 55 mL (IQR 14–175) in the NW, 42 mL (IQR 27–170) in the PC, 36 mL (IQR 6–130) in the LC, and 11 mL (IQR 0–39) in the HC groups. The infarct volume of the HC group was significantly smaller than in the other 3 groups, but no difference existed between the LC and PC groups or the LC and NW groups.

Conclusions: Warfarin control at PT-INR of 1.60–1.99 is not effective for reducing the severity of ischemic stroke in NVAF patients.

Establishing appropriate anticoagulation treatment prior to the onset of cerebral infarction is associated with better clinical outcome in cardioembolic stroke patients.^1–4 A target prothrombin time-international normalized ratio (PT-INR) of 2.0–3.0 is recommended in Western countries,^5,6 whereas in Japan it is recommended that patients aged >70 years be treated with lower intensity, at a PT-INR of 1.60–2.60⁷ because the risk of intracranial hemorrhage suddenly increases with a PT-INR >2.60⁸ in Japanese patients. In the Stroke Prevention in Atrial Fibrillation (SPAF) III study, the rate of ischemic stroke was effectively inhibited in patients with a PT-INR of 1.50–1.99.⁹ Inoue et al recently reported that the rate of ischemic stroke was similar between low-intensity (PT-INR, 1.6–1.99) and high-intensity (PT-INR, 2.0–2.59) warfarin therapy in 7,406 Japanese patients with nonvalvular atrial fibrillation (NVAF).¹⁰ In line with these findings, we previously demonstrated that the infarct size was smaller at a PT-INR ≥1.60 than at a PT-INR <1.60 in 68 ischemic stroke patients with NVAF.¹¹ However, the clinical outcome after an ischemic stroke seems to be better in those with a PT-INR ≥2.00 than in those with a PT-INR of 1.50–1.99.¹ Although it is already known that a better outcome is associated with a smaller lesion size,¹² it is unclear whether a PT-INR ≥2.00 is better for inhibiting infarct size than PT-INR of 1.60–1.99. Therefore, the aim of this study was to evaluate the relationship between cerebral infarct volume and PT-INR among acute cardioembolic patients with NVAF.

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Methods

Patient Selection

We retrospectively reviewed the medical records of consecutive patients admitted to the Stroke Centers at Osaka University Hospital, Osaka National Hospital, and Hoshigaoka Medical Center between January 2004 and March 2014. Patients diagnosed with acute ischemic stroke within 48 h of symptom onset and AF were selected. We identified 188 patients from Osaka University Hospital, 124 patients from Osaka National Hospital, and 117 patients from Hoshigaoka Medical Center. The total number of suitable candidates was 429. Of them, 249 were excluded from the analysis as follows: patients that did not have computed tomography (CT) performed in 3±1 days (n=53), patients without serum measurements (n=17) on admission, and patients with a history of valve replacement (n=22), implantation of a left ventricular assist device (n=14), hypertrophic cardiomyopathy (n=4), nonbacterial thrombotic endocarditis or cancer (n=9), cardiac catheterization (n=2), pacemaker insertion (n=2), cardiac valvular disease (n=10), or infective endocarditis (n=7). Patients who received thrombolytic therapy (n=92) were also excluded because thrombolysis treatment is likely to enhance recanalization and affect infarct size. Patients with moyamoya disease (n=1), carotid artery stenosis (n=6), clearly diagnosed as branch athreomataus disease (n=3), aortogenic embolism (n=1), and atherothrombolic brain infarction (n=2) were excluded because of other possible causes of cerebral infarction (Figure 1).

Figure 1.

Flow chart of included and excluded patients in a study of the relationship between infarct volume and prothrombin time-international normalized ratio in ischemic stroke patients with nonvalvular atrial fibrillation.

The patients were classified into 4 groups according to their PT-INR values on admission and whether or not they were treated with warfarin: no warfarin (NW), 129 patients; PT-INR <1.60 (poor control: PC), 29 patients; PT-INR 1.60–1.99 (low-intensity control: LC), 14 patients; and PT-INR ≥2.00 (high-intensity control: HC), 8 patients. We set a cut-off PT-INR of 1.60 for comparison with the recommendation in Japan that patients aged >70 years be treated with lower intensity, at a PT-INR of 1.60–2.60,⁷ whereas a PT-INR of 2.0–3.0 is recommended in Western countries.

For the analysis of neurological outcomes, we excluded patients with a modified Rankin Scale (mRS) score ≥2 before stroke onset (n=26). Neurological severity on admission was determined using the National Institute of Health Stroke Scale (NIHSS score). Severe neurological deficit was defined as a NIHSS score ≥10. Poor functional outcome was defined as a mRS score of 4–6 at discharge (mean 40 days after stroke onset).

Clinical Variables

Clinical, radiographic, and clinical course data were retrospectively collected from the medical records. Blood samples obtained on admission were adopted in this study. Admission blood pressure (BP) was defined as the first recorded BP at the time of the initial emergency department or in-hospital evaluation for acute infarction. Diagnosis of AF was based on prehospital medical records, ECG taken on admission, 24-h Holter ECG recording, and 24-h ECG monitoring during hospitalization. Hypertension was defined as BP ≥140/90 mmHg on at least 2 occasions, or use of antihypertensive medication. Diabetes was defined as fasting plasma glucose level ≥126 mg/dL, HbA1c level ≥6.5%, or use of antidiabetic therapy. Hyperlipidemia was defined as low-density lipoprotein cholesterol level ≥140 mg/dL, total cholesterol level ≥220 mg/dL, triglycerides level ≥150 mg/dL, high-density lipoprotein cholesterol level <40 mg/dL, or use of cholesterol-lowering therapy. Smoking status was classified as “current” or “quit”. Habitual alcohol intake was defined as intake >20 g/day. The CHADS₂ score was calculated by adding 1 point each for a history of congestive heart failure, hypertension, age ≥75 years, or diabetes mellitus, and 2 points for a history of cerebral infarction or transient ischemic attack.¹³ We used the CHADS₂ score as a confounder because it has a known the correlation with onset severity and functional outcome.¹⁴

Imaging Data Collection

Brain CT examination was performed using a LightSpeed VCT, a Discovery CT 750HD (General Electric Medical Systems, Milwaukee, WI, USA), and an Aquilion ONE (Toshiba Medical Systems, Otawara, Japan) machine in Osaka University Hospital. The Aquilion 16 (Toshiba Medical Systems, Otawara, Japan) machine was used in Osaka National Hospital, and the Aquilion 64 (Toshiba Medical Systems, Otawara, Japan) machine was used in Hoshigaoka Medical Center. The section thickness was 4 mm in the posterior fossa and 8 mm in the superior brain regions (120 kV, 240 mAS). We analyzed CT scans obtained 3±1 days after stroke onset and evaluated infarction volume.¹⁵ All CT scans were retrospectively evaluated by 2 stroke neurologists (M.M. and S.O.) blinded to the patients’ clinical information. We used Image J v. 1.43 software (National Institute of Health, Bethesda, MD, USA) on a desktop computer at a window level of 35 Hounsfield units (HU) and a width of 60 HU for the tracing; we manually traced each region of interest, and calculated the ischemic lesion area in each slice (Figure 2). We multiplied the thickness of each slice and used integration to calculate the total infarction volume. We had previously determined that the interexaminer reliability of this technique was high (intraclass correlation coefficient=0.95).¹¹ Differences in analysis were resolved by consensus.

Figure 2.

Method used to scale the area of infarction in ischemic stroke patients with nonvalvular atrial fibrillation.

Statistical Analysis

Distribution of infarct size was left-skewed, so relationships between log infarction volume and baseline characteristics were compared using ANOVA and categorical variables, including the rate of poor neurological outcome at discharge, were compared using the χ² test. Log infarct size among groups was compared first with univariate analysis and then with multivariate analysis after adjustment for CHADS₂ score 0–2 or 3–6. The threshold of significance was set at P<0.05. All statistical analyses were performed using JMP version 11.0 (SAS Institute Inc., Cary, NC, USA).

Results

The characteristics of all 180 patients upon admission and the relationships with log-transformed infarct volume are shown in Table 1. Log infarct volume correlated with serum glucose level, diabetes mellitus and D-dimer levels (Table 1). The distribution of infarct volume and PT-INR are shown in Figure 3. The infarct volumes in all patients at a PT-INR >2.0 were very small. In fact, there was a relationship between infarct volume and PT-INR (r=−0.1484, P=0.0493). The clinical backgrounds and parameters among the 4 groups are shown in Table 2. There was a significant difference among the 4 groups in D-dimer level (P=0.01). In the non-parametric analysis, the infarct volume in the HC group (median, 11 mL; IQR 0–39 mL) was significantly smaller than in the NW (55 mL; IQR 14–175 mL) and PC (42 mL; IQR 27–170 mL) groups (P=0.02 for both). However, the infarct volume was similar in the LC (36 mL; IQR 6–130 mL) and NW groups.

Table 1. Admission Characteristics of Ischemic Stroke Patients With Nonvalvular Atrial Fibrillation and Relationship With Log-Transformed Infarct Volume (n=180)

			P value
Age, years, mean±SD	76±10	r=0.145	0.052
Male, n (%), M/F	95 (53)	1.52±0.73/1.64±0.77	0.288
Body temperature, median (IQR), ℃	36.5 (36.2–36.8)	r=0.119	0.137
Serum glucose, mg/dL, mean±SD	137±47	r=0.231	0.004
Risk factors
Hypertension, n (%), (yes/no)	137 (76)	1.57±0.76/1.59±0.72	0.893
Diabetes mellitus, n (%), (yes/no)	46 (26)	1.75±0.59/1.49±0.80	0.046
Dyslipidemia, n (%), (yes/no)	65 (37)	1.45±0.87/1.62±0.66	0.133
Smoking, n (%), (yes/no)	40 (25)	1.46±0.74/1.63±0.77	0.178
Alcohol, n (%), (yes/no)	47 (31)	1.59±0.72/1.59±0.77	0.376
Previous ischemic stroke or TIA, n (%), (yes/no)	54 (30)	1.62±0.73/1.56±0.76	0.624
Preadmission CHADS2 score, mean±SD	2.9±1.4	r=0.132	0.078
D-dimer, μg/mL, median (IQR)	1.34 (0.73–3.40)	r=0.199	0.006
Onset-to-admission time, h, mean±SD	10.3±12.0	r=−0.006	0.932
Onset to CT time, days, mean±SD	2.69±0.80	r=0.142	0.058
Infarction volume, mL, median (IQR)	41.6 (14.0–150.4)	–	–

IQR, interquartile range; PT-INR, prothrombin time-international normalized ratio; TIA, transient ischemic attack.

Figure 3.

Relationship between infarct volume and prothrombin time-international normalized ratio (PT-INR).

Table 2. Comparison of the Characteristics of 4 Treatment Groups Based on Admission PT-INR Values

	No warfarin (n=129)	Poor control (n=29)	Low-intensity control (n=14)	High-intensity control (n=8)	P value
Age, years, mean±SD	76±10	76±9	74±7	76±5	0.70
Male, n (%)	66 (51)	16 (55)	9 (64)	4 (50)	0.81
Body temperature, median (IQR), ℃	36.5 (36.2–36.8)	36.6 (35.4–36.8)	35.9 (35.5–36.9)	36.4 (35.8–36.8)	0.22
Serum glucose, mg/dL, mean±SD	138±49	137±39	145±39	108±41	0.13
Risk factors, n (%)
Hypertension	95 (73)	25 (86)	9 (64)	8 (50)	0.05
Diabetes mellitus	33 (27)	7 (24)	4 (14)	2 (25)	0.98
Dyslipidemia	44 (35)	12 (41)	5 (35)	4 (50)	0.79
Smoking	33 (30)	5 (22)	1 (8)	1 (13)	0.59
Alcohol	35 (31)	7 (30)	3 (23)	2 (25)	0.99
Previous ischemic stroke or TIA	33 (26)	10 (34)	8 (57)	3 (38)	0.11
Preadmission CHADS2 score, mean±SD	2.8±1.4	3.1±1.5	3.1±1.4	3.4±1.1	0.47
D-dimer, μg/mL, median (IQR)	1.64 (0.82–3.63)*	1.10 (0.59–3.86)	0.90 (0.23–1.44)	0.73 (0.40–1.06)	0.01
Onset-to-admission time, h, mean±SD	9.7±11.5	12.1±13.0	10.9±14.4	11.5±13.0	0.69
Infarction volume, mL, median (IQR)	55 (14–175)*	42 (27–170)*	35 (6–130)	11 (0–39)	0.07
Onset to CT time, days, mean±SD	2.7±0.8	2.6±0.9	2.6±0.8	2.4±0.7	0.36

*P<0.05 vs. High-intensity control group. Abbreviations as in Table 1.

Table 3 shows the log infarct volumes of the 4 groups. The log infarct volumes was significantly smaller in the HC group compared with the other groups (vs. NW group P=0.007, vs. PC group P=0.003, vs. LC group P=0.027). There was no significant difference between the NW and PC groups (P=0.83), the NW and LC groups (P=0.34), or the PC and LC groups (P=0.49). After adjustment with CHADS₂ score, the difference between the HC group and the other 3 groups remained significant.

Table 3. Comparison of Log10 Infarct Size Among 4 Treatment Groups Based on Admission PT-INR Values

	Model 1 (unadjusted)	Model 2 (adjusted with CHADS2 score)
No warfarin (n=129)	1.64±0.06*	1.63±0.15*
Poor control (n=29)	1.61±0.14*	1.59±0.19*
Low-intensity control (n=14)	1.44±0.20*	1.39±0.24*
High-intensity control (n=8)	0.72±0.26	0.66±0.29
P value	0.007	0.003

Values show mean and standard error. *P<0.05 vs. High-intensity control group. PT-INR, prothrombin time-international normalized ratio.

To investigate the effect of PT-INR on neurological outcome, we analyzed 156 patients with a preadmission mRS score of 0 or 1. Among this group, infarct volume was statistically different between each mRS group (Figure 4). The proportion of patients with severe neurological deficits on admission and poor functional outcome at discharge tended to be low in the HC group; however, this trend was not statistically significant (Table 4).

Figure 4.

Association between infarct volume and functional outcome at discharge of ischemic stroke patients with nonvalvular atrial fibrillation.

Table 4. Comparison of Neurological Outcomes Among 4 Treatment Groups Based on Admission PT-INR Values

Previous mRS <2	All patients (n=156)	No warfarin (n=112)	Poor control (n=26)	Low-intensity control (n=12)	High-intensity control (n=6)	P value
Length of hospital stay, days, mean±SD	40±40	38±34	52±57	45±51	28±46	<0.001
Admission NIHSS score, median (IQR)	12 (4–19)	12 (4–20)	12 (4–19)	12 (3–17)	3 (2–17)	0.38
mRS at discharge, median (IQR)	2 (1–5)	3 (1–5)	2 (1–4)	3 (1–4)	2 (0–3)	0.50
Severe neurological deficits, n (%)	85 (56)	61 (56)	15 (58)	7 (58)	2 (33)	0.73
Poor functional outcome, n (%)	70 (45)	54 (49)	11 (42)	4 (33)	1 (17)	0.32

Severe neurological deficits defined as baseline NIHSS ≥10. Poor functional outcome was defined as mRS ≥4 at discharge. mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale. Other abbreviations as in Table 1.

Discussion

Warfarin treatment in patients with a PT-INR ≥2.00 has consistently been shown to be associated with better outcome after cardioembolic stroke in NVAF patients.^1–4 Previously, we showed that anticoagulation with a PT-INR >1.60 could reduce the infarct size, but the small sample size (n=68) did not allow us to analyze the effect of PT-INR of 1.60–1.99.¹¹ In this study, the infarct volume in the high-intensity group was much smaller than in all of the other groups, supporting the beneficial outcome of warfarin in patients with a PT-INR ≥2.00.¹⁶ However, the effect of low-intensity anticoagulation (PT-INR, 1.60–1.99) on clinical outcome remains unclear,¹ although a PT-INR of 1.50–1.99 has been shown to be effective in stroke prevention.⁹ As already pointed out, many NVAF patients <70 years old are controlled with PT-INR 1.50–1.99,^10,17 and there were 3 patients <70 years old in the present low-intensity group. In this study, we found that the infarct volume in the low-intensity group was similar to that in the NW group. It remains unclear why low-intensity warfarin control is effective for stroke prevention but not for reduction in infarct volume. This might be explained by the difference in the activity of thrombus formation at low- and high-intensity anticoagulation. This hypothesis could be supported by the finding that the D-dimer levels in the HC group were significantly smaller than in the NW group, but the difference between the LC and NW groups was not significant (Table 2). As has already been shown, the D-dimer level correlates with clot size in intracardiac thrombi.¹⁸ The clot size might be similar in the LC and NW group, and might be smaller in the HC group than in the other groups. In addition, thrombi formed at a PT-INR of 1.60–1.99 would be more resistant to the endogenous fibrinolytic system than those formed at a PT-INR ≥2.00. Our results seem to indicate that the lower limit of PT-INR could be 2.0 when trying to prevent severe ischemic stroke in NVAF patients.

Study Limitations

First, the small number of patients in the LC and HC groups did not allow us to analyze the difference between these groups. The small sample size might be the reason why there was no difference between these 2 groups in our study. Though adjustment with CHADS₂ score is preferable, it was not possible to use each component rather than a categorized CHADS₂ score 0–3 and 4–6 because of the small sample size. Second, the interval from onset to admission (median, 5 h; IQR 2–13 h) might have led to an underestimated PT-INR at the time of stroke onset. There were 22 patients with >24 h before admission. Excluding them, people, log10 infarct volume still showed a difference between the NW and HC groups (P=0.020). There was no statistical difference between other pairs. Third, the neurological outcome was evaluated by using mRS on discharge, although the length of hospital stay might be shorter because the severity was milder. Fourth, the study was retrospective and not all of the patients had a magnetic imaging scan upon admission. Most of the severe infarction patients had CT only, therefore we used CT for calculating infarct volume. Also, with retrospective results, careful interpretation is required. Fifth, as this study was focused on infarct volume, we did not consider the effect of bleeding.

In conclusion, warfarin control at a PT-INR ≥2.00 reduced infarct volume, and warfarin control at a PT-INR of 1.60–1.99 was not effective for reducing infarct volume. This might be the reason why warfarin control at a PT-INR ≥2.00 is beneficial for both stroke prevention and reduction of stroke severity,¹ as previously demonstrated in NVAF patients.

Acknowledgments

The authors thank Dr. Hideki Etani and Dr. Masafumi Tagaya in Osaka National Hospital and Dr. Shouko Amino in Hoshigaoka Medical Center for supporting this work, Ms. Chiharu Ito, Ms. Kumiko Nishiyama and Ms. Yuki Kurano for their assistance with the manuscript.

Sources of Funding

This study was supported in part by the research grant for cardiovascular disease from the Japanese Ministry of Health, Welfare and Labor.

Disclosures

None.

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