Prognostic Value of Prothrombin Time International ...

Circulation Journal Vol.80, April 2016

Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

coagulation cascade.Decreased concentrations of plasma coagulation factors have

been previously reported in patients with severe chronic heart failure,5–7 and patients with lower plasma coagulation factors are known to be at increased risk of adverse events.24 Interest-ingly, activated coagulation and fibrinolysis, decreased coagu-lation factors, and inflammatory markers are known to be ameliorated by hemodynamic modification by heart transplan-tation,5 left ventricular (LV) assist devices,6,7 or cardiac resyn-chronization therapy,25 suggesting a reversible relationship between hemostatic derangement and heart failure severity.

mong various observed physiological abnormalities, it has been known for decades that patients with heart failure are in a prothrombotic or hypercoagulable state,

and are at increased risk of stroke and venous thromboembo-lism.1,2 Previous studies have shown that heart failure leads to activation of coagulation, with increased levels of thrombin formation markers such as thrombin-antithrombin complexes (TAT) and fibrinopeptide A,3–9 as well as activation of fibrino-lysis with significant elevation of D-dimer.3,5,7 Recent studies suggest that inflammatory processes and neuroendocrine acti-vation3–5,10–23 are strongly correlated with activation of the

A

Received December 13, 2015; revised manuscript received January 25, 2016; accepted January 26, 2016; released online February 26, 2016 Time for primary review: 22 days

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, JapanMailing address: Toshihisa Anzai, MD, PhD, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1

Fujishiro-dai, Suita 565-8565, Japan. E-mail: [email protected] doi: 10.1253/circj.CJ-15-1326All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Prognostic Value of Prothrombin Time International Normalized Ratio in Acute Decompensated Heart Failure

– A Combined Marker of Hepatic Insufficiency and Hemostatic Abnormality –

Atsushi Okada, MD; Yasuo Sugano, MD, PhD; Toshiyuki Nagai, MD, PhD; Seiji Takashio, MD, PhD; Satoshi Honda, MD; Yasuhide Asaumi, MD, PhD;

Takeshi Aiba, MD, PhD; Teruo Noguchi, MD, PhD; Kengo F. Kusano, MD, PhD; Hisao Ogawa, MD, PhD; Satoshi Yasuda, MD, PhD; Toshihisa Anzai, MD, PhD

on behalf of the NaDEF Investigators

Background: There are limited studies regarding the prognostic value of coagulation abnormalities in heart failure patients. The clinical significance of prothrombin time international normalized ratio (INR), a widely accepted marker assessing coagulation abnormalities, in acute decompensated heart failure (ADHF) remains unclear.

Methods and Results: Among 561 consecutive patients admitted for ADHF, INR was assessed in 294 patients without prior anticoagulation therapy, acute coronary syndrome, liver disease, or overt disseminated intravascular coagulation. Increased INR on admission was positively associated with increased levels of thrombin-antithrombin complex, C-reactive protein, total bilirubin, γ-glutamyl transpeptidase, inferior vena cava diameter, tricuspid regurgi-tation severity, markers of neurohormonal activation, and also negatively associated with decreased albumin, cho-linesterase, and total cholesterol. In contrast, there was no significant association with left ventricular ejection fraction, serum sodium or blood urea nitrogen. Multivariate analysis showed that increased INR was independently associated with increased all-cause mortality (hazard ratio 1.89 per 0.1 increase, 95% confidence interval 1.14–3.13, P=0.013) during the median follow up of 284 days. Increased INR also had a higher prognostic value compared to risk score models including the Model for End-Stage Liver Disease (MELD) score or the MELD excluding INR (MELD-XI) score.

Conclusions: Increased INR is an independent predictor of all-cause mortality in ADHF patients without antico-agulation, reflecting coagulation abnormalities and hepatic insufficiency, possibly through systemic inflammation, neurohormonal activation and venous congestion. (Circ J 2016; 80: 913 – 923)

Key Words: Acute decompensated heart failure; Coagulation; Inflammation; Liver; Prognosis

ORIGINAL ARTICLEHeart Failure


914 OKADA A et al.

failure (ADHF) are uncertain. Our study was conducted to assess the clinical significance and prognostic value of INR in a prospective cohort of ADHF patients.

MethodsStudy DesignData from the NaDEF (National cerebral and cardiovascular center acute DEcompensated heart Failure) registry, which were obtained between January 2013 and March 2015, were retro-spectively analyzed. The NaDEF Registry is a single-center, observational, on-going, prospective cohort that includes all

However, the mechanism that contributes to decreased coagu-lation factors in heart failure is still uncertain.

Prothrombin time international normalized ratio (INR) has been accepted as a sensitive and reliable marker of coagula-tion abnormalities. It is regulated by multiple coagulation factors synthesized in the liver and is widely used to monitor anticoagulation, to assess hepatic function, and to evaluate coagulation abnormalities such as disseminated intravascular coagulation (DIC). Increased INR is associated with poor clinical outcomes in critically ill patients with hypoxic hepa-titis;26,27 however, the prevalence and prognostic value of increased INR in patients with acute decompensated heart

Figure 1. Distribution of the prothrombin time international normalized ratio (INR) of 294 study patients on admission (A) and 192 at discharge in patients discharged without anticoagulation (B). The median INR on admission and at discharge was 1.03 (inter-quartile range 0.97–1.12) and 1.00 (interquartile range 0.95–1.07), respectively.


915Prognostic Value of INR in ADHF

Study PopulationThe INR values were measured on admission in 651 consecu-tive ADHF patients enrolled in the NaDEF registry. Three hundred and seventeen patients who were on prior oral antico-agulation (vitamin K antagonists, direct thrombin inhibitors, or direct factor Xa inhibitors), 34 patients with acute coronary syndrome, and 7 patients with a history of liver cirrhosis (includ-ing 4 who were on vitamin K antagonists) were excluded from the analysis. To avoid effects of non-cardiac coagulation abnormalities, patients with overt coagulopathy defined as a Japanese Ministry of Health and Welfare DIC score29 of 7 points or more were excluded. Consequently, the final study population consisted of 294 patients.

Blood Sampling and INR MeasurementVenous blood samples were drawn from all ADHF patients on admission for routine laboratory measurements and INR, and were analyzed immediately in the core laboratory of our insti-tution. Blood samples for INR measurement were collected in blood collection tubes containing 3.2% sodium citrate, and were immediately centrifuged at 3,430 g for 5 min at room temperature. INR was measured using the reagent, HemosIL RecombiPlasTin 2G (Instrumentation Laboratory, Bedford, MA, USA) on a STA-R EVOLUTION automated coagulation ana-

patients requiring hospitalization for the first time with a diag-nosis of ADHF by at least 2 experienced cardiologists accord-ing to the Framingham ADHF criteria,28 and follow up was performed at 3, 6, 12, and 24 months after discharge by direct contact with patients or patients’ physicians at a hospital or outpatient clinic, via telephone interview with patients or, if deceased, with family members, and mail, by dedicated coor-dinators and investigators. In this study, because patient infor-mation was anonymized and de-identified prior to analyses, written informed consent was not obtained from each patient. However, we publicized the study by posting a summary of the protocol (with an easily understood description) on the website of the National Cerebral and Cardiovascular Center; the notice clearly informed patients of their right to refuse enrollment. These procedures for informed consent and enroll-ment were in accordance with the detailed regulations regard-ing informed consent described in the guideline (ethical guidelines for epidemiological research), and this study, including the procedure for enrollment, has been approved by the Institu-tional Review Board of the National Cerebral and Cardiovas-cular Center (M22-025), and registered under the Japanese University hospital Medical Information Network (UMIN) Clinical Trials Registration (UMIN000017024).

Table 1. (A) Patient Characteristics Stratified by Admission Prothrombin Time INR Value Tertiles, (B) Patient Characteristics Stratified by Vital Status

(A) 1st tertile INR<0.99 (n=95)

2nd tertile 0.99≤INR<1.10 (n=103)

3rd tertile INR≥1.10 (n=96) P value

Age, years 78 (67–84)　　　 79 (71–84)　　　 75 (63–83)　　　 0.06

Male, n (%) 45 (47) 66 (64) 72 (75) <0.001

Body mass index, kg/m2 22.3 (20.0–26.2) 23.3 (21.0–26.2) 23.3 (20.5–26.4) 0.53

NYHA III or IV, n (%) 77 (88) 90 (91) 77 (89) 0.74

Past history

Atrial fibrillation, n (%) 14 (15) 23 (23) 21 (22) 0.31

Stroke, n (%) 15 (16) 18 (18) 19 (20) 0.77

Chronic kidney disease, n (%) 50 (53) 46 (45) 34 (36) 0.07

Hypertension, n (%) 78 (82) 80 (78) 62 (65) 0.014

Diabetes, n (%) 39 (41) 32 (31) 37 (38) 0.33

Etiology 0.22

ICM, n (%) 28 (29) 22 (21) 21 (22)

NICM, n (%) 32 (34) 33 (32) 42 (44)

Valvular heart disease, n (%) 18 (19) 22 (21) 21 (22)

Others, n (%) 17 (18) 26 (25) 12 (13)

Previous HF hospitalization, n (%) 29 (31) 28 (27) 33 (34) 0.57

LV ejection fraction, % 31 (25–60)　　 40 (25–51)　　 38 (20–50)　　 0.53

Systolic blood pressure, mmHg 145 (129–170) 144 (132–166) 135 (114–159) 0.006

Heart rate, bpm 89 (77–117) 92 (77–113) 102 (77–116)　　 0.37

Medication on admission

Loop diuretic, n (%) 38 (40) 44 (43) 37 (39) 0.83

Aldosterone antagonist, n (%) 10 (11) 15 (15) 13 (14) 0.68

β-blocker, n (%) 42 (44) 47 (46) 38 (40) 0.65

ACE-I/ARB, n (%) 59 (62) 55 (53) 37 (39) 0.004

Medication at discharge

Loop diuretic, n (%) 62 (65) 80 (78) 71 (77) 0.08

Aldosterone antagonist, n (%) 26 (27) 32 (31) 54 (59) <0.001

β-blocker, n (%) 66 (69) 75 (74) 66 (73) 0.80

ACE-I/ARB, n (%) 73 (77) 74 (73) 58 (63) 0.11

(Table 1 continued the next page.)


916 OKADA A et al.

eterization on admission. Hemodynamic parameters including cardiac index and mean right atrial pressure were collected from the study patients. Cardiac index was measured by using the thermodilution method or the Fick method if there was more than moderate tricuspid regurgitation.

Prognostic EndpointsFor our analysis, the patients were followed from admission and we analyzed all-cause death and cardiovascular death as the study endpoints. Cardiovascular death was defined as death attributable to a cardiovascular origin.

Statistical AnalysisAll continuous variables are shown as mean ± standard devia-tion (SD) if the variable was normally distributed, and median (interquartile range (IQR)) if it was not. Categorical data and frequency of events were compared between groups using the Chi-squared test or Fisher’s exact test, and continuous values were compared by using the Student’s t-test or Mann-Whitney U-test, as appropriate. All tests were 2-sided, and a P value under 0.05 was considered statistically significant. The Kaplan-Meier life table, estimating all-cause death and cardiovascular death from admission, was used to summarize the follow-up experience of the patient population. For this analysis, patients were stratified by INR cut-off value determined by receiver operating characteristic (ROC) analysis for study endpoints.

lyzer (Diagnostica Stago, Asnières, France) at an international sensitivity index (ISI) of approximately 1.0.

Model for End-Stage Liver Disease (MELD) and MELD Excluding INR (MELD-XI) ScoresWe also analyzed the MELD score and the MELD-XI score in our analysis. Both the MELD and MELD-XI scores are combined scoring systems that evaluate both renal and hepatic organ damage. As previously reported, the MELD score was calculated as: (3.78×log (total bilirubin)+11.2×log (INR)+ 9.57×log (creatinine)+6.43), and the MELD-XI score was calculated as: (5.11×log (total bilirubin)+11.76×log (creati-nine)+9.44); variables with a value of <1 were given the value of 1.30

Echocardiographic AnalysisEchocardiographic examinations were performed by at least 2 experienced technicians for all patients in a blinded manner on admission. LV volume and LV ejection fraction were mea-sured by using the modified biplane Simpson’s method, and valvular regurgitation was assessed in accordance with the guidelines of the American Society of Echocardiography.31,32

Hemodynamic AssessmentTwenty-nine patients (10%) who were clinically judged to require hemodynamic assessment underwent right heart cath-

(B) Events (n=19)

No events (n=275) P value

Age, years 79 (71–89) 77 (65–84) 0.09

Male, n (%) 14 (74) 169 (61)　　 0.28

Body mass index, kg/m2 21.7 (19.0–24.0) 23.2 (20.6–26.4) 0.06

NYHA III or IV, n (%) 19 (100) 227 (88)　　 0.04

Past history

Atrial fibrillation, n (%) 7 (37) 51 (19) 0.07

Stroke, n (%) 7 (37) 45 (16) 0.04

Chronic kidney disease, n (%) 13 (68) 117 (43)　　 0.03

Hypertension, n (%) 15 (79) 205 (75)　　 0.68

Diabetes, n (%) 7 (37) 100 (36)　　 0.99

Etiology 0.13

ICM, n (%) 8 (42) 63 (23)

NICM, n (%) 4 (21) 103 (37)　　 Valvular heart disease, n (%) 2 (11) 59 (21)

Others, n (%) 5 (26) 50 (18)

Previous HF hospitalization, n (%) 10 (53) 80 (29) 0.04

LV ejection fraction, % 30 (24–49)　　 37 (25–52)　　 0.59

Systolic blood pressure, mmHg 137 (111–166) 144 (126–162) 0.40

Heart rate, bpm 99 (73–113) 93 (77–117) 0.96

Medication on admission

Loop diuretic, n (%) 10 (53) 109 (40)　　 0.27

Aldosterone antagonist, n (%) 0 (0) 38 (14) 0.02

β-blocker, n (%) 9 (47) 118 (43)　　 0.71

ACE-I/ARB, n (%) 13 (68) 138 (50)　　 0.12

Medication at discharge

Loop diuretic, n (%) 10 (67) 203 (74)　　 0.53

Aldosterone antagonist, n (%) 7 (47) 105 (38)　　 0.52

β-blocker, n (%) 10 (67) 197 (72)　　 0.65

ACE-I/ARB, n (%) 10 (67) 195 (71)　　 0.71

Data are expressed as median (interquartile range 25–75%) or n (%). ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HF, heart failure; ICM, ischemic cardiomyopathy; INR, international normalized ratio; LV, left ventricle; NICM, non-ischemic cardiomyopathy; NYHA, New York Heart Association.



bution of discharge INR values of 192 patients who were discharged without anticoagulation is shown in Figure 1B. The clinical characteristics of the study patients are summa-rized in Tables 1 and 2. Patients in the highest INR tertile

Differences in survival curves were tested with a log-rank test (Mantel-Cox). Univariate and multivariate analysis were per-formed with a Cox proportional hazards model. Selection of variables for univariate Cox proportional hazards analysis was based on clinical relevance and data from the existing litera-tures. Continuous variables and dichotomized variables were entered into the model with their individual values and accord-ing to the presence or absence of the variable, respectively. Only variables that proved to have a P value under 0.10 in the univariate analysis were candidates for the final multivariate model, which was determined using a forward stepwise vari-able selection procedure. We developed each risk score model including age and gender based on the regression coefficients, as previously described.33 Age and sex were forced into the model to adjust for age and gender effects. The area under the ROC curves (AUC) was used to compare the predictive value of INR, MELD score, and MELD-XI score for all-cause mor-tality. Correlation coefficients between INR and hemodynamic parameters were determined by using Spearman’s rank cor-relation test. Statistical analyses were performed by using JMP 12 statistical software package (SAS Institute, Inc, Cary, NC, USA) and SPSS version 22 (SPSS Inc, Chicago, IL, USA).

ResultsPatient CharacteristicsThe distribution of admission INR values is shown in Figure 1A. The median INR value was 1.03 (IQR 0.97–1.12). The distri-

Table 2. Laboratory Data on Admission

1st tertile INR<0.99 (n=95)

2nd tertile 0.99≤INR<1.10 (n=103)

3rd tertile INR≥1.10 (n=96) P value

Albumin, g/dl 3.9 (3.7–4.1)　 3.8 (3.5–4.1)　 3.6 (3.4–3.9)　 <0.001

Total bilirubin, mg/dl 0.4 (0.3–0.7)　 0.7 (0.5–0.9)　 0.9 (0.6–1.2)　 <0.001

AST, U/L 30 (21–49)　　 29 (21–46)　　 35 (23–53)　　 0.43

ALT, U/L 22 (14–36)　　 21 (12–34)　　 24 (14–49)　　 0.33

ALP, U/L 259 (203–320) 243 (190–311) 269 (206–351) 0.10

GGT, U/L 40 (22–74)　　 36 (21–76)　　 48 (29–113) 0.012

Cholinesterase, U/L 244 (199–307) 218 (179–260) 210 (176–247) 0.003

Total cholesterol, mg/dl 180 (149–210) 157 (135–177) 147 (127–168) <0.001

Sodium, mEq/L 141 (138–143) 141 (138–142) 140 (138–143) 0.50

Blood urea nitrogen, mg/dl 23 (17–36)　　 21 (17–28)　　 22 (17–31)　　 0.27

eGFR, ml/min/1.73 m2 47.6 (24.1–61.7) 47.7 (34.8–60.2) 49.6 (36.3–64.2) 0.36

Troponin T, ng/ml 0.040 (0.026–0.114) 0.038 (0.020–0.070) 0.039 (0.022–0.060) 0.30

C-reactive protein, mg/dl 0.20 (0.07–0.47) 0.41 (0.10–1.38) 0.93 (0.27–3.49) <0.001

BNP, pg/ml 571 (332–1,082) 694 (401–1,092) 683 (369–1,224) 0.45

Hemoglobin, g/dl 12.2±2.3 12.1±2.1 12.3±2.2 0.59

Platelet, ×103/μl 173 (144–205) 172 (132–214) 169 (136–218) 0.75

Fibrinogen, mg/dl 356 (295–405) 341 (297–409) 349 (292–418) 0.90

FDP, μg/dl 7 (5–9)　　　　 7 (5–11)　　 8 (5–12)　　 0.25

D-dimer, μg/dl 2.3 (1.7–4.0)　 2.4 (1.3–5.5)　 3.4 (1.5–6.4)　 0.17

TAT, ng/ml 2.61 (1.48–4.62) 2.89 (1.60–5.98) 3.67 (1.82–7.49) 0.04

Renin activity, ng · ml−1 · h−1 1.8 (0.7–4.0)　 1.1 (0.4–3.2)　 1.3 (0.5–4.7)　 0.11

Aldosterone, ng/dl 7.7 (5.5–15.8) 8.5 (5.5–18.1) 10.2 (6.3–46.0)　 0.07

Norepinephrine, pg/ml 599 (424–816) 620 (385–871) 717 (430–992) 0.18

MELD score 7.0 (6.4–11.7) 7.8 (7.0–10.5) 10.1 (8.5–12.3)　 <0.001

MELD-XI score 10.1 (9.4–15.9)　 10.5 (9.4–14.4)　 11.2 (9.8–14.2)　 0.39

Data are expressed as median (interquartile range 25–75%) or mean ± SD. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; FDP, fibrin/fibrinogen degradation products; GGT, γ-glutamyl transpeptidase; MELD, model for end-stage liver disease; MELD-XI, MELD excluding INR; TAT, thrombin-antithrombin complex. Other abbreviation as in Table 1.

Figure 2. In-hospital change of the prothrombin time interna-tional normalized ratio (INR) in 192 patients admitted and discharged without anticoagulation. Differences were com-pared using the Mann-Whitney U-test.


918 OKADA A et al.

In-Hospital Change of INRFigure 2 shows the change of INR in 192 patients admitted and discharged without anticoagulation treatment. INR sig-nificantly decreased during hospitalization from a median of 1.04 (IQR 0.96–1.11) to 1.00 (IQR 0.95–1.07).

Echocardiographic Variables and Hemodynamic ParametersAs shown in Figure 3, INR had a significant positive associa-tion with inferior vena cava (IVC) diameter and tricuspid regurgitation severity. In contrast, there was no significant association with LV ejection fraction or LV diastolic dimen-sion. Assessment of hemodynamic parameters revealed a sig-nificant correlation between INR and central venous pressure (R=0.59, P=0.003), but not between INR and cardiac index (R=−0.11, P=0.58).

were predominantly male, had lower prevalence of hyperten-sion, lower systolic blood pressure, less use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists on admission, and had more frequent use of aldo-sterone antagonists at discharge (Table 1A). When analyzed by vital status, patients with adverse events had a more fre-quent history of previous heart failure hospitalization, stroke, chronic kidney disease, and higher New York Heart Associa-tion functional class (Table 1B). On laboratory examination, patients with higher INR had significantly lower albumin, cholinesterase, and total cholesterol levels, as well as signifi-cantly higher total bilirubin, γ-glutamyl transpeptidase (GGT), C-reactive protein and TAT levels, and tended to have higher plasma aldosterone concentration and norepinephrine levels (Table 2).

Figure 3. Log prothrombin time international normalized ratio (INR) compared with echocardiographic parameters. Q1 through Q4 indicate quartile levels of each parameter with actual values. IVC, inferior vena cava; LV, left ventricle; TR, tricuspid regurgita-tion.



Predictive Value of INR in Comparison With MELD and MELD-XI ScoresThe AUC of INR included in the risk score model was sig-nificantly higher compared to that of the MELD or MELD-XI score, indicating that INR had the highest predictive value for predicting mortality (Table 4).

INR and Clinical OutcomesDuring a median follow-up period of 284 days (IQR 85–513 days), Kaplan-Meier analysis revealed that INR>1.05 was significantly associated with increased all-cause mortality and cardiovascular mortality (Figures 4A,B). In the multivariate Cox proportional hazards model, body mass index and INR were independent determinants of all-cause mortality (Table 3).

Figure 4. Kaplan-Meier curves for all-cause mortality (A) and cardiovascular mortality (B). Patients were stratified into 2 groups by prothrombin time international normalized ratio (INR) cut-off value determined by receiver oper-ating characteristic analysis. Differences between the groups were compared by using a log-rank test.


920 OKADA A et al.

hepatic insufficiency may lead to decreased plasma coagula-tion factors. Elevated right-sided pressure, which in turn leads to hepatic congestion, may affect the production of coagula-tion factors. Third, hemodilution has also been reported as a cause of increased INR.34 In the present study, the concomitant increases in IVC diameter and tricuspid regurgitation severity in patients with higher INR may reflect hemodilution.

Previous studies have not shown a relationship between decreased coagulation factors and hepatic insufficiency in patients with heart failure. Alehagen et al studied 450 elderly patients with possible heart failure and reported that decreased coagulation factors II, VII, XI were observed irrespective of alanine transaminase (ALT) level, which is one of the most sensitive enzymes indicating liver disease.24 However, elevated transaminase levels are only observed when hepatocellular necrosis due to organ hypoperfusion occurs, which does not always accompany hepatic congestion in ADHF. Wang et al also examined 19 advanced heart failure patients and reported that amelioration of plasma levels of factor II, V, VII, XI after LV assist device implantation was observed regardless of hepatic dysfunction, defined as total bilirubin>2.0 mg/dl, aspar-tate transaminase (AST) and ALT>60 U/L.6 However, total bilirubin is a non-specific marker of liver damage determined by hepatic congestion, hepatocellular dysfunction, biliary obstruction, or even non-hepatic causes such as hemolysis. In addition, the hepatic functional reserve of protein synthesis was not examined in those previous studies.

Among various liver function tests known to be prognostic predictors in heart failure,35–46 total cholesterol,47 albumin,38,39,48 and cholinesterase46 are accepted markers of hepatic protein synthesis related to adverse clinical outcomes in heart failure. MELD and MELD-XI scores, reported to reflect end-organ damage caused by elevated right-sided pressure, are also prog-nostic markers recently studied in ADHF42,49,50 and chronic heart failure.51 However, increased INR could reflect not only hepatic functional reserve but also hemostatic derangement, possibly through systemic inflammation, neurohormonal acti-vation and venous congestion, thereby making INR a stronger prognostic predictor compared to existing variables.

DiscussionThe present study findings indicated that elevation of INR was a significant independent determinant of future adverse events in patients with ADHF. Increased INR on admission was positively associated with activated coagulation (TAT), inflammation (C-reactive protein), neurohormonal activity (aldosterone, norepinephrine), hepatic congestion (total biliru-bin, GGT) and elevated right-sided pressure (IVC diameter, tricuspid regurgitation severity). It was also negatively associ-ated with indicators of hepatic protein synthesis (albumin, cholinesterase, and total cholesterol). Of note, there was no significant relationship between INR and clinical signs of hypoperfusion such as hepatic transaminases, serum sodium, or blood urea nitrogen.

Increased INR and Decreased Coagulation Factors in Heart FailureSeveral mechanisms can be considered for the increased INR in ADHF patients. First, activation of the coagulation system may result in consumption of coagulation factors. Our study demonstrated increased inflammation and activated neurohor-monal activity, which have been previously suggested to cause activated coagulation in patients with increased INR.3–5,10–23 Second, as coagulation factors are synthesized in the liver,

Table 3. Univariate and Multivariate Cox Proportional Hazards Analysis of Mortality

Univariate analysis Multivariate analysis

HR (95% CI) P value HR (95% CI) P value

Age, 5 years 1.26 (1.02–1.59) 0.028 1.22 (0.94–1.61) 0.13

Male 1.56 (0.60–4.82) 0.38

Body mass index, kg/m2 0.85 (0.78–0.95) 0.004 0.88 (0.78–0.99) 0.038

Systolic blood pressure, 10 mmHg 0.94 (0.80–1.09) 0.39

LV ejection fraction, 10% 0.97 (0.73–1.27) 0.81

Hemoglobin, 1 g/dl 0.65 (0.51–0.82) <0.001 0.86 (0.65–1.13) 0.29

INR, 0.1 1.50 (1.07–2.06) 0.02 1.89 (1.14–3.13) 0.013

Sodium, 1 mEq/L 0.93 (0.84–1.04) 0.22

Blood urea nitrogen, 1 mg/dl 1.01 (0.99–1.03) 0.15

eGFR, 10 ml/min/1.73 m2 0.96 (0.78–1.15) 0.69

Log BNP, pg/ml 0.98 (0.90–1.04) 0.60

Albumin, 0.1 g/dl 0.81 (0.73–0.90) <0.001 0.89 (0.79–1.01) 0.08

Total bilirubin, 0.1 g/dl 0.88 (0.75–1.01) 0.07 0.86 (0.68–1.06) 0.19

AST, 10 U/ml 1.04 (0.97–1.08) 0.25

ALT, 10 U/ml 0.97 (0.79–1.07) 0.60

GGT, 10 U/ml 0.96 (0.87–1.03) 0.35

HR, hazard ratio; CI, confidence interval. Other abbreviations as in Tables 1,2.

Table 4. AUC of Risk Score Model for Predicting All-Cause Mortality

AUC P value

Model 1 (age, gender, INR) 0.671 0.009

Model 2 (age, gender, MELD score) 0.588 0.13

Model 3 (age, gender, MELD-XI score) 0.578 0.17

AUC, area under the receiver operating characteristics curve. Other abbreviations as in Tables 1,2. Model 1, 0.071×age+0.253× male (1)/female (0)+0.614×(INR×10). Model 2, 0.057×age+0.356× male (1)/female (0)+0.037×MELD score. Model 3, 0.055×age+ 0.389×male (1)/female (0)+0.008×MELD-XI score.



Funding SourcesThis study was supported by a grant from the Japan Cardiovascular Research Foundation (T.A., 24-4-2), and a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science (T.N., 15K19402).

DisclosuresAll authors have no conflicts of interest to disclose.

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Role and Choice of Anticoagulants in Heart FailureDespite the recognition that coagulation abnormalities in heart failure lead to increased risk of stroke and venous thromboem-bolism,1,2 no clinical benefit has been achieved regarding the use of anticoagulants or antiplatelet agents in heart failure patients without atrial fibrillation.21,52 A vitamin K antagonist, warfarin, is known to modify elevated markers of hyperco-agulability;53–56 however, recent investigations including the Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial showed no benefit of warfarin in patients with reduced ejection fraction in sinus rhythm compared to aspirin.57 In fact, the use of warfarin led to a significant increase in major hemorrhage. It is well known that plasma factor VII and complexes of tissue factor/factor VIIa are important initiators of the coagulation cascade, and thus sup-pression of factor VII by warfarin may lead to increased hem-orrhage.58,59 We found that a significant number of ADHF patients who were not treated with anticoagulants showed increased INR on admission. Therefore, warfarin should be used carefully during the acute phase of heart failure, although ADHF patients are susceptible to thromboembolism through diuretic use and activated coagulation system.

The safety and efficacy of recently available non-vitamin-K oral anticoagulants (NOACs) for the treatment of heart failure are not well studied, although they are also known to reverse the hypercoagulability in acute coronary syndrome, venous thromboembolism and heart failure.60–62 As NOACs are known for their potential to decrease major hemorrhage compared to warfarin,63,64 they may provide clinical benefits in heart failure patients at risk of thromboembolic events.

In the present study, inflammation was significantly related to hemostatic abnormalities in ADHF patients. This may hold potential as a therapeutic target. In addition to their anticoagu-lation effects, factor Xa inhibitors are proposed to carry anti-inflammatory effects through protease-activated receptors (PARs),65–67 and animal studies have shown factor Xa inhibi-tors to downregulate inflammatory mediators68 and to atten-uate progression or promote stability of atherosclerotic plaques.69,70 NOACs may provide additional clinical benefits through their anti-inflammatory effect, and may be of use in heart failure patients.

Study LimitationsOur study was performed with data from a prospective regis-try in a single institute with a relatively small number of patients. Also, in our study design, data with respect to the medical therapy prior to death were not available, and how these factors influenced the outcome is unknown. The prog-nostic value of INR needs to be evaluated in a large prospec-tive study.

ConclusionIncreased INR is an independent predictor of all-cause mortal-ity in ADHF patients without anticoagulation. An increase in INR was significantly associated with activated coagulation, inflammation, neurohormonal activation and hepatic insuffi-ciency. This mechanism may portend a novel target for future investigations.

AcknowledgmentsWe are grateful for the contributions of all the investigators, clinical research coordinators, data managers and laboratory technicians involved in the NaDEF study.


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AppendixNaDEF Investigators:Shoji Kawakami, Yoshiya Yamamoto, Naotsugu Iwakami, Masahiro Yamamoto, Yasuyuki Honda, Tetsufumi Motokawa and Yasuhiro Hamatani (Department of Cardiovascular Medicine, National Cerebral and Cardio-vascular Center, Suita, Japan).Tatsuhiro Shibata and Takehiro Homma (Department of Internal Medi-cine, Division of Cardiovascular Medicine, Kurume University School of Medicine, Kurume, Japan).Daigo Chinen (Department of Cardiology, Asahi General Hospital, Asahi, Japan).Takafumi Yamane (Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan).

Clinical Research Coordinators and Data Managers:Chinatsu Yoshida, Sachiko Ogura, and Yoko Sumita (Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan).

Laboratory Technical Assistance:Mana Mitsuguro and Akira Okamoto (Laboratory of Clinical Chemistry, National Cerebral and Cardiovascular Center, Suita, Japan).

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