Abstract
Aims: The HELT-E2S2 score is a newly developed risk stratification tool for stroke in patients with atrial fibrillation. We investigated the prognostic value of the HELT-E2S2 score in patients with lower extremity artery disease (LEAD) and compared it with other risk scores for atrial fibrillation (AF) and LEAD.
Methods: Patients undergoing endovascular therapy (EVT) for symptomatic LEAD between August 2015 and August 2016 were enrolled in the I-PAD NAGANO registry, a prospective, multicenter, observational registry. The primary endpoint was major adverse cardiovascular events (MACEs), defined as a composite of all-cause death, nonfatal myocardial infarction, and stroke at 5 years.
Results: A total of 366 patients were divided into low-risk (HELT-E2S2 score ＜2, n = 146) and high-risk (HELT-E2S2 score ≥ 2, n = 218) groups. The major criteria of the HELT-E2S2 score were hypertension (81.9%) and elderly age (75-84 years old) (34.1%). The incidence of MACEs at 5 years was significantly higher in the high-risk group than in the low-risk group (43.7% vs. 22.8%, P＜0.001). In the COX multivariate analysis, the high-risk group emerged as a significant predictor of MACEs at 5 years (hazard ratio 1.87, 95% confidence interval 1.22-2.89, P = 0.004). The C-statistics for MACEs were comparable among the HELT-E2S2 and other AF and LEAD risk scores.
Conclusions: The HELT-E2S2 score was associated with an increased risk of cardiovascular events in patients with LEAD undergoing EVT.
Yoshiteru Okina and Tatsuya Saigusa contributed equally to the study.
Introduction
The number of patients with lower extremity artery disease (LEAD) has been increasing owing to the aging of the population with an increase in the prevalence of lifestyle-related cardiovascular risk factors1). Patients with LEAD have an elevated risk of cardiovascular and limb events, particularly when comorbid with coronary or cerebrovascular disease (i.e. polyvascular disease). However, the optimal management strategy for patients with LEAD to mitigate ischemic risk is poorly defined.
The CHADS2 and CHA2DS2-VASc scores are well-established risk scores for assessing thromboembolic risk in patients with atrial fibrillation (AF) and thus guide anticoagulation treatment decisions. Furthermore, previous studies have reported the prognostic utility of these scores for long-term cardiovascular events in various patient subsets, including patients undergoing coronary revascularization, heart failure, and LEAD1-4). The predictive value of these scores for ischemic stroke has also been demonstrated in patients with LEAD irrespective of the presence of AF5).
The HELT-E2S2 score is a newly developed risk stratification score for ischemic stroke in Japanese patients with AF6). The score incorporates readily available clinical factors, including a history of hypertension, elderly age (75–84 years old), low body mass index (BMI; ＜18.5 kg/m2), type of AF (persistent or permanent), extreme elderly age (≥ 85 years old), and a history of stroke. The prognostic ability of the HELT-E2S2 score for ischemic stroke was reportedly comparable with CHADS2 and CHA2DS2-VASc scores7, 8). At present, however, the prognostic impact of the HELT-E2S2 score in patients with LEAD compared with other AF and LEAD scores remains unknown.
Although an accurate risk assessment is clinically relevant to optimize subsequent treatment options and improve patient outcomes, risk prediction systems have been poorly utilized in LEAD patients and are not endorsed by the current guidelines. The use of AF scores for risk stratification in LEAD patients may be advantageous in this regard, given its high adoption rate in daily practice. In addition, as extreme elderly age and a low BMI are common characteristics of patients with LEAD, in particular chronic limb threatening ischemia (CLTI), the validation of the prognostic ability of the HELT-E2S2 score incorporating such factors in LEAD patients appears clinically relevant. Therefore, we investigated the prognostic value of the HELT-E2S2 score for long-term cardiovascular events in patients with LEAD undergoing endovascular treatment (EVT).
Materials and Methods
Patient Population
Consecutive patients undergoing EVT for symptomatic LEAD between August 2015 and August 2016 were enrolled in the I-PAD NAGANO registry, a prospective, multicenter observational registry (11 hospitals in Nagano, Japan). EVT was performed according to the guidelines at the discretion of operators at each center9). For the current study, patients in whom the HELT-E2S2 score could not be completely ascertained were excluded. The registry was approved by the Institutional Ethics Committee. Written informed consent was obtained from all patients. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000018297).
HELT-E2S2 Score
The HELT-E2S2 score is a risk prediction tool for ischemic stroke in patients with AF. The components of the HELT-E2S2 score were hypertension, an elderly age (75-84 years old), BMI ＜18.5 kg/m2, persistent AF, extreme elderly age (≥ 85 years old), and a history of stroke6). Because the type of AF was not available in the current study, the presence of AF was applied instead of AF type for the current study. The HELT-E2S2 score was calculated by adding 1 point for hypertension, an elderly age, a low BMI, and AF and 2 points for an extreme elderly age and a history of stroke.
Clinical Endpoints
The primary endpoint was major adverse cardiovascular events (MACEs), defined as a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke at five years. The secondary endpoints were major adverse cardiovascular and limb events (MACLEs), defined as a composite of all-cause death, myocardial infarction, stroke, major amputation, and unplanned target vessel revascularization, each component of the MACLEs, and bleeding. Myocardial infarction was defined according to the 3rd universal definition of MI10). Stroke was defined as rapid development of clinical signs of focal or global disturbance of cerebral function lasting ＞24 h with imaging evidence of acute, clinically relevant ischemic brain lesion. Major amputation was defined as amputation at the level of the ankle or above11). Target vessel revascularization was defined as any unplanned revascularization of the target vessel, respectivley11). Bleeding was defined as Bleeding Academic Research Consortium (BARC) 3 bleeding12).
Statistical Analyses
Continuous variables are summarized as mean±standard deviation (SD) or median (interquartile range [IQR]) and compared using Student’s t-test or Wilcoxon-Mann-Whitney U tests, as appropriate. Binary and categorical variables were calculated as frequencies (percentages) and compared using the chi-square test or Fisher’s exact test. A multivariable Cox regression analysis was performed to determine the predictors of the endpoints. Clinically important variables including sex, history of heart failure, clinical frailty scale, hemodialysis, hemoglobin, albumin, and CLTI reported by previous studies were entered into the model13-15). Discrimination of the risk score was assessed by the C statistic. The C-statistics for MACEs and all-cause death were compared among the HELT-E2S2 score, CHADS2 score, CHA2DS2-VASc score, risk score for LEAD patients developed by Li et al.16), and high ischemic criteria defined by the 2024 European Society of Cardiology (ESC) guidelines for peripheral arterial disease (PAD)17). Poisson models were used to estimate the incidence rates. Kaplan-Meier cumulative event curves were constructed for time-to-event variables and compared using the log-rank test.
All statistical analyses were performed using SPSS 28.0; SPSS Inc., Chicago, IL, USA) and STATA version 18.0 (Stata Corp, College Station, TX, USA).
Results
Patients
Among the 366 patients undergoing EVT for symptomatic LEAD, after excluding 2 patients with no BMI data available, 364 patients were analyzed in the current study (Supplementary Fig.1). Complete follow-up at 5 years was available for 350 (95.6%) patients, and the median follow-up period was 1792 (797, 1954) days. Patients were divided into high-(HELT-E2S2 score ≥ 2 points; n = 218) and low (0-1 point: n = 146) groups according to the median HELT-E2S2 score.
Baseline Characteristics
The patient and lesion characteristics are summarized in Table 1. Patients in the high-risk group were older, more commonly female, and had lower BMI, hemoglobin, albumin, and LDL-cholesterol values and more comorbidities than those in the low-risk group. The distribution and prevalence of these scores are summarized in Fig.1. The major criteria of the HELT-E2S2 score were hypertension (81.9%) and elderly age (75-84 years old) (34.1%). An extreme elderly age (≥ 85 years old) and a history of stroke frequently overlapped with other criteria (Supplementary Fig.2).
Table 1.Patient characteristics
|
Low risk
(HELT-E2S2 score 0-1 point)
(n = 146)
|
High risk
(HELT-E2S2 score ≥ 2 points)
(n = 218)
|
P value
|
| Age (years) |
68 [64, 72] |
79 [75, 84] |
＜0.001 |
| Elderly, n (%)
|
9 (6.2) |
115 (52.8) |
|
| Extreme elderly, n (%)
|
0 |
51 (23.4) |
|
| Female, n (%)
|
31 (21.2) |
68 (31.2) |
0.04 |
| BMI (kg/m2)
|
22.8 [20.8, 25.2] |
21.9 [19.4, 24.1] |
0.002 |
| BMI ＜18.5 kg/m2, n (%)
|
5 (3.4) |
41 (18.8) |
＜0.001 |
| Hypertension, n (%)
|
101 (69.2) |
197 (90.4) |
＜0.001 |
| Dyslipidemia, n (%)
|
93 (63.7) |
126 (57.8) |
0.26 |
| Atrial fibrillation, n (%)
|
3 (2.1) |
61 (28.0) |
＜0.001 |
| Diabetes, n (%)
|
73 (50.0) |
112 (51.6) |
0.76 |
| Hemodialysis, n (%)
|
41 (28.1) |
50 (22.9) |
0.27 |
| History of heart failure, n (%)
|
12 (8.2) |
36 (16.6) |
0.02 |
| Stroke, n (%)
|
0 |
70 (32.1) |
＜0.001 |
| Current smoker, n (%)
|
32 (22.9) |
18 (8.5) |
＜0.001 |
| Clinical frailty scale ≥ 7, n (%)
|
10 (6.8) |
42 (19.3) |
＜0.001 |
| CLTI, n (%)
|
31 (21.2) |
93 (42.7) |
＜0.001 |
| Rutherford classification, n (%)
|
|
|
＜0.001 |
| 0 |
1 (0.7) |
5 (2.3) |
|
| I |
2 (1.4) |
4 (1.8) |
|
| II |
33 (22.6) |
30 (13.8) |
|
| III |
79 (54.1) |
86 (39.4) |
|
| IV |
8 (5.5) |
36 (16.5) |
|
| V |
19 (13.0) |
51 (23.4) |
|
| VI |
4 (2.7) |
6 (2.8) |
|
| TASC II classification, n (%)
|
|
|
0.29 |
| A |
38 (26.0) |
52 (23.9) |
|
| B |
47 (32.2) |
54 (24.8) |
|
| C |
14 (9.6) |
31 (14.2) |
|
| D |
43 (29.5) |
67 (30.7) |
|
| Target lesion location, n (%)
|
|
|
0.07 |
| Aortoiliac |
60 (41.1) |
76 (34.9) |
|
| Femoropopliteal |
79 (54.1) |
117 (53.7) |
|
| Below the knee |
7 (4.8) |
25 (11.5) |
|
| Laboratory data
|
|
|
|
| Hemoglobin (g/dL) |
13.3±2.0 |
12.6±2.0 |
0.001 |
| Albumin (g/dL) |
4.0 [3.6, 4.3] |
3.8 [3.4, 4.1] |
0.002 |
| eGFR (mL/min/1.73m2)
|
54.4 [10.0, 68.0] |
47.0 [22.5, 61.0] |
0.37 |
| LDL cholesterol (mg/dL) |
103.0±34.4 |
93.9±27.3 |
0.01 |
| Hemoglobin A1c (%) |
6.2 [5.7, 7.0] |
6.2 [5.7, 6.9] |
0.93 |
| BNP (pg/mL) |
60.3 [17.1, 201.9] |
122.6 [50.3, 363.7] |
＜0.001 |
| C-reactive protein (mg/dL) |
0.1 [0.05, 0.5] |
0.2 [0.1, 0.8] |
0.11 |
| Medication
|
|
|
|
| Aspirin, n (%)
|
120 (82.2) |
174 (80.2) |
0.63 |
| P2Y12 inhibitor, n (%)
|
112 (76.7) |
143 (65.6) |
0.23 |
| Cilostazol, n (%)
|
39 (26.7) |
69 (31.7) |
0.31 |
| Statin, n (%)
|
83 (56.8) |
104 (47.7) |
0.09 |
| ACE-i/ARB, n (%)
|
67 (45.9) |
123 (56.4) |
0.05 |
| β-blocker, n (%)
|
40 (27.4) |
62 (28.4) |
0.83 |
| Warfarin, n (%)
|
8 (5.5) |
27 (12.4) |
0.03 |
| DOAC, n (%)
|
6 (4.1) |
25 (11.5) |
0.01 |
Values are means (±standard deviation), median [interquartile range], or n (%).
ACE-i: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, BMI: body mass index, BNP: B-type natriuretic peptide, CLTI: chronic limb threatening ischemia, DOAC: direct oral anticoagulant, eGFR: estimated glomerular filtration rate, LDL: low density lipoprotein.
The clinical outcomes at five years are summarized in Table 2 and Fig.2. The incidence of MACEs was significantly higher in the high-risk group than in the low-risk group (43.7% vs. 22.8%, P＜0.001). The high-risk group had an increased risk of MACLEs (60.9% vs. 41.4%, P＜0.001), all-cause death (34.0% vs. 17.2%, P＜0.001), myocardial infarction (6.0% vs. 2.1%, P = 0.03), stroke (12.6% vs. 4.9%, P = 0.003), and BARC 3 bleeding (9.7% vs. 4.9%, P = 0.05), whereas there were no significant differences in major amputation (3.9% vs. 2.8%, P = 0.47) and target vessel revascularization (20.6% vs. 19.9%, P = 0.36). A sub-group analysis, including age, sex, diabetes, and hemodialysis, demonstrated that patients with a high HELT-E2S2 score consistently carried an increased risk of MACEs compared with those with low HELT-E2S2 scores (Supplementary Fig.3). Among patients available for LDL-C at 1 year after EVT (n = 209), 136 had optimal control of LDL-C level (＜100 mg/dL). Of those, patients with high HELT-E2S2 scores (n = 78) had an increased risk of MACEs at 5 years compared with those with a low HELT-E2S2 score (n = 58) (33.3% vs. 13.8%, P = 0.003) (Supplementary Fig.4).
Table 2.Clinical outcomes
|
Low risk
(HELT-E2S2 score 0-1 point)
(n = 146)
|
High risk
(HELT-E2S2 score ≥ 2 points)
(n = 218)
|
| MACE
|
33 events |
94 events |
| Event rate (per 100 patient-years), (95% CI) |
5.73 (4.03-8.15) |
13.47 (10.82-16.76) |
| Unadjusted, HR (95% CI) |
Reference |
2.43 (1.63-3.61) |
|
|
P＜0.001
|
| Adjusted, HR (95% CI) |
Reference |
1.87 (1.22-2.89) |
|
|
P = 0.004
|
| MACLE
|
60 events |
131 events |
| Event rate (per 100 patient-years), (95% CI) |
13.14 (10.16-17.00) |
24.43 (20.35-29.33) |
| Unadjusted, HR (95% CI) |
Reference |
1.86 (1.37-2.52) |
|
|
P＜0.001
|
| Adjusted, HR (95% CI) |
Reference |
1.52 (1.09-2.13) |
|
|
P = 0.02
|
| All-cause death
|
25 events |
73 events |
| Event rate (per 100 patient-years), (95% CI) |
4.12 (2.74-6.20) |
10.09 (7.88-12.91) |
| Unadjusted, HR (95% CI) |
Reference |
2.39 (1.52-3.77) |
|
|
P＜0.001
|
| Adjusted, HR (95% CI) |
Reference |
1.71 (1.03-2.81) |
|
|
P = 0.04
|
| Non-fatal MI
|
3 events |
13 events |
| Event rate (per 100 patient-years), (95% CI) |
0.55 (0.18-1.71) |
1.63 (0.88-3.03) |
| Unadjusted, HR (95% CI) |
Reference |
3.67 (1.04-12.90) |
|
|
P = 0.04
|
| Adjusted, HR (95% CI) |
Reference |
2.77 (0.77-10.02) |
|
|
P = 0.12
|
| Non-fatal stroke
|
7 events |
27 events |
| Event rate (per 100 patient-years), (95% CI) |
1.31 (0.62-2.74) |
3.91 (2.60-5.88) |
| Unadjusted, HR (95% CI) |
Reference |
3.78 (1.43-7.54) |
|
|
P = 0.005
|
| Adjusted, HR (95% CI) |
Reference |
2.88 (1.20-6.88) |
|
|
P = 0.02
|
| Major amputation
|
4 events |
8 events |
| Event rate (per 100 patient-years), (95% CI) |
0.70 (0.26-1.87) |
1.25 (0.63-2.51) |
| Unadjusted, HR (95% CI) |
Reference |
1.55 (0.47-5.16) |
|
|
P = 0.48
|
| Adjusted, HR (95% CI) |
Reference |
0.70 (0.17-2.56) |
|
|
P = 0.62
|
| Target vessel revascularization
|
33 events |
43 events |
| Event rate (per 100 patient-years), (95% CI) |
6.68 (4.75-9.39) |
7.64 (5.62-10.37) |
| Unadjusted, HR (95% CI) |
Reference |
1.10 (0.70-1.73) |
|
|
P = 0.68
|
| Adjusted, HR (95% CI) |
Reference |
0.93 (0.56-1.53) |
|
|
P = 0.77
|
| BARC 3 Bleeding
|
7 events |
20 events |
| Event rate (per 100 patient-years), (95% CI) |
1.06 (0.48-2.36) |
2.78 (1.73-4.48) |
| Unadjusted, HR (95% CI) |
Reference |
2.35 (0.99-5.57) |
|
|
P = 0.05
|
| Adjusted, HR (95% CI) |
Reference |
1.78 (0.71-4.48) |
|
|
P = 0.22
|
CI: confidence interval, HR: hazard ratio, MACE: major adverse cardiovascular event, MACLE: major adverse cardiovascular limb event, MI: myocardial infarction.
Of the study patients, 94.8% (347/366) were entered into the multivariable model. The model was adjusted for sex, history of heart failure, clinical frailty scale, hemodialysis, hemoglobin, albumin, and chronic limb threatening ischemia.
As a sensitivity analysis among 362 patients who were available for the HELT-E2S2 and CHADS2 scores, we divided patients into four groups based on HELT-E2S2 (≥ 2 or ＜2) and CHADS2 (≥ 2 or ＜2) scores and assessed clinical outcomes. The HELT-E2S2 and CHADS2 scores were concordant in 77.3% of patients (HELT-E2S2 score ≥ 2 and CHADS2 score ≥ 2 [n = 199, 55.0%], HELT-E2S2 score ＜2 and CHADS2 score ＜2 [n = 81, 22.4%], HELT-E2S2 score ≥ 2 and CHADS2 score ＜2 [n = 17, 4.7%], HELT-E2S2 score＜2, and CHADS2 score ≥ 2 [n = 65, 18.0%]). A Kaplan-Meier analysis revealed that the high HELT-E2S2 score and high CHADS2 score group and the high HELT-E2S2 score and low CHADS2 score group had a higher incidence of MACEs than the other groups (Supplementary Fig.5). Patients with discordance between the HELT-E2S2 and CHADS2 scores had an increased risk of MACEs compared with those with low HELT-E2S2 and CHADS2 scores.
Cox Regression Analyses
In the multivariable Cox regression analysis, the high-risk group (i.e. HELT-E2S2 score ≥ 2 points) emerged as an independent predictor for MACEs at 5 years (HR 1.87, 95% CI 1.22-2.87, P = 0.004) (Table 2 and Supplementary Table 1). The prognostic value of each component of the HELT-E2S2 score is summarized in Supplementary Table 2. The C-statistics of the HELT-E2S2 score, CHADS2 score, CHA2DS2-VASc score, the risk score for LEAD patients developed by Li et al.16), and the high ischemic criteria defined by the 2024 ESC guidelines for PAD17) for MACEs at 5 years were 0.61, 0.62, 0.62, 0.64, and 0.65, respectively (Fig.3). The c-statistic of the ESC criteria for all-cause death at five years was greater than that of the HELT-E2S2 score (Supplementary Fig.6). The HELT-E2S2 score showed accurate calibration (Supplementary Fig.7).
Supplementary Table 1.COX regression analysis for MACEs and MACLE at 5 years
| Variables |
MACE |
MACLE |
| Univariable |
Multivariable |
Univariable |
Multivariable |
| HR (95% CI) |
P value
|
HR (95% CI) |
P value
|
HR (95% CI) |
P value
|
HR (95% CI) |
P value
|
| HELT-E2S2 score
|
2.43 (1.63-3.61) |
＜0.001 |
1.87 (1.22-2.88) |
0.004 |
1.86 (1.37-2.52) |
＜0.001 |
1.52 (1.09-2.13) |
0.020 |
| Male gender |
0.74 (0.51-1.07) |
0.110 |
0.99 (0.66-1.48) |
0.97 |
0.66 (0.49-0.90) |
0.007 |
0.93 (0.67-1.29) |
0.660 |
| History of heart failure |
2.79 (1.85-4.21) |
＜0.001 |
2.05 (1.32-3.19) |
0.001 |
1.80 (1.24-2.61) |
0.002 |
1.39 (0.93-2.06) |
0.110 |
| Clinical frailty scale ≥ 7 |
1.38 (1.27-1.51) |
＜0.001 |
1.09 (0.97-1.24) |
0.15 |
1.35 (1.26-1.45) |
＜0.001 |
1.14 (1.03-1.27) |
0.010 |
| Hemodialysis |
2.25 (1.57-3.23) |
＜0.001 |
1.45 (0.98-2.14) |
0.07 |
1.80 (1.33-2.44) |
＜0.001 |
1.23 (0.89-1.72) |
0.210 |
| Hemoglobin (g/dL) |
0.76 (0.70-0.83) |
＜0.001 |
0.94 (0.84-1.05) |
0.28 |
0.82 (0.77-0.88) |
＜0.001 |
0.98 (0.89-1.07) |
0.640 |
| Albumin (g/dL) |
0.38 (0.30-0.50) |
＜0.001 |
0.58 (0.40-0.85) |
0.005 |
0.46 (0.37-0.57) |
＜0.001 |
0.62 (0.45-0.84) |
0.002 |
| CLTI |
3.14 (2.21-4.47) |
＜0.001 |
1.66 (1.05-2.64) |
0.03 |
2.76 (2.07-3.69) |
＜0.001 |
1.44 (0.98-2.13) |
0.070 |
CI: confidence interval, CLTI: chronic limb threatening ischemia HR: hazard ratio, MACE: major adverse cardiovascular event, MACLE: major adverse cardiovascular limb event.
Of the study patients, 94.8% (347/366) were entered into the multivariable model.
Supplementary Table 2.COX multivariable analysis for MACEs at 5 years
| Variables |
HR (95% CI) |
P value
|
| Hypertension |
0.89 (0.56-1.40) |
0.610 |
| Age |
|
|
| Non-elderly |
Reference |
|
| Elderly (75-84 years old) |
2.09 (1.39-3.12) |
＜0.001 |
| Extreme elderly age (85 years or older) |
2.69 (1.62-4.46) |
＜0.001 |
| BMI ＜18.5kg/m2
|
2.56 (1.63-4.02) |
＜0.001 |
| Persistent AF |
1.51 (0.98-2.31) |
0.060 |
| Previous stroke |
1.02 (0.81-1.28) |
0.884 |
AF: atrial fibrillation, BMI: body mass index, CI: confidence interval, HR: hazard ratio, MACE: major adverse cardiovascular event.
Of the study patients, 94.8% (347/366) were entered into the multivariable model.
Discussion
This is the first study to evaluate the prognostic impact of HELT-E2S2 scores on long-term (i.e. 5 years) outcomes in patients with LEAD undergoing EVT. The current study demonstrated that patients with high HELT-E2S2 scores had an increased risk of death, myocardial infarction, and stroke, whereas there was no significant association with amputation or revascularization. Discriminative ability was similar among the HELT-E2S2, CHADS2 and CHA2DS2-VASc scores.
Similar to previous findings of CHADS2 and CHA2DS2-VASc scores, high HELT-E2S2 scores were associated with worse cardiovascular outcomes among LEAD patients undergoing EVT. This increased risk was mainly driven by an elevated risk of MI and stroke, whereas there was no significant association with limb-related events. Indeed, no significant difference was observed in lesion complexity as assessed by the TASC II classification between the groups, despite a higher incidence of CLTI in the high-risk group. The HELT-E2S2 score appears to be more prognostic for patient-oriented endpoints than adverse limb events among patients with LEAD, suggesting the potential utility of the HELT-E2S2 score in a broader range of patients. Indeed, the prognostic value of the HELT-E2S2 score has been demonstrated in other patient subsets such as coronary artery disease18) and heart failure19). In line with our observation, a sub-analysis of the COMPASS trial, a randomized controlled trial investigating the efficacy of a combination treatment of low-dose rivaroxaban and aspirin over aspirin alone among patients with stable atherosclerotic vascular disease, has demonstrated the prognostic value of CHADS2 and CHA2DS2-VASc scores for future cardiovascular events among LEAD patients without AF4). Interestingly, the greatest ischemic risk reduction from combined therapy with rivaroxaban 2.5 mg twice daily plus aspirin was observed in patients with high CHADS2 score. The current guideline on the management of LEAD recommends dual-pathway anti-thrombotic therapy among patients with LEAD (class I)20). In this regard, patients with high HELT-E2S2 scores may be good candidates for enhanced cardiovascular benefit from dual-pathway inhibition.
Of note, another sub-analysis of the COMPASS trial showed that a combination of rivaroxaban and aspirin significantly reduced the incidence of stroke by 42% in comparison with aspirin alone in patients with stable atherosclerotic disease without AF21). In the current study, although AF was more frequent in the high-risk group than in the low-risk group, patients with high HELT-E2S2 scores had significantly higher incidences of stroke events despite more frequent use of anticoagulant therapy at baseline than those with low HELT-E2S2 scores. Low-dose rivaroxaban plus aspirin may also be a relevant option for stroke prevention in patients with high HELT-E2S2 scores without AF documentation.
In the current study, patients with high HELT-E2S2 scores also showed an increased risk of bleeding events. Major components of the HELT-E2S2 score, such as age, BMI, AF (i.e. oral anticoagulation), and a history of stroke, overlap with those of the bleeding risk score22, 23). A strong association between ischemic and bleeding risk has been reported in previous observational studies24, 25). Further research is required to define the optimal management of this dilemmatic (i.e. high ischemic and bleeding risks) cohort, including optimal antithrombotic regimen and close monitoring to detect new-onset AF, to mitigate the increased ischemic and bleeding risks.
An extreme elderly age and low BMI are common characteristics of patients with LEAD, particularly CLTI26, 27). Although these factors were not included in the CHADS2 and CHA2DS2-VASc scores, the prognostic value of the HELT-E2S2, CHADS2, and CHA2DS2-VASc scores were similar in the current study. This can be explained by the fact that criteria such as hypertension (81.9%), an older age (34.1%), and a history of stroke (19.2%) overlapped across these scores. Furthermore, the current study demonstrated that the prognostic values of AF scores (i.e. HELT-E2S2, CHADS2, and CHA2DS2-VASc scores) were comparable to those of LEAD scores (i.e. scores by Li et al. and ESC guideline for PAD), suggesting the potential utility of AF scores for risk prediction as LEAD scores. Since the AF score is frequently used in daily clinical practice, greater utilization of AF scores for risk prediction in LEAD patients may contribute to improved patient outcomes.
Limitations
Several limitations need to be considered for the current study. First, this study was a post hoc analysis of a prospective registry with a relatively small sample size. The study findings should be considered for hypothesis generation. Second, although persistent/permanent AF (not paroxysmal AF) was included as a component of the original HELT-E2S2 score, the type of AF was not available in the current study, which hindered the accurate calculation of the HELT-E2S2 score. Third, there may be several potentially unmeasured confounding factors inherent to the observational data. Finally, the duration and intensity of antithrombotic treatment were determined at the discretion of the operator. Data on detailed medication status and new occurrence of AF during the follow-up period were not available.
Conclusion
The HELT-E2S2 score was associated with an increased risk of MACEs, all-cause death, and ischemic stroke among patients undergoing EVT. The HELT-E2S2 score appears to be a useful tool for predicting future ischemic events in LEAD patients undergoing EVT.
Funding
This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.
Disclosures
Dr. Ueki reports grants from Astellas Pharma and personal fees from Abbott Vascular, Amgen, Bayer, Daiichi Sankyo, Kowa, NIPRO, and Novartis, outside the submitted work. Dr. Minamisawa has received consulting fees from Alexion Pharma GK, payment or honoraria for lectures from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co. Ltd., Sanofi K.K., AstraZeneca K.K., Toa Eiyo Ltd., Bayer Yakuhin Ltd., Takeda Pharmaceutical Company Limited, Sumitomo Pharma Co. Ltd., Janssen Pharmaceutical, Otsuka Pharmaceutical, Kowa Company Limited, Novartis Pharma, Daiichi Sankyo Company Limited, and Alnylam Japan, and is a member of the Advisory Board for Pfizer Japan Inc. and Alexion Pharma GK.
Dr. Kuwahara has received lecture fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Kowa Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd. (Sumitomo Pharma Co., Ltd.), Mitsubishi Tanabe Pharma Corp., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., and Janssen Pharmaceutical K.K.; funded research or joint research expenses from Kowa Co., Ltd., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., Amgen, Janssen Pharmaceutical K.K., Parexel International Inc., and Astellas Pharma Inc. His affiliated institution (Shinshu University School of Medicine) has received grants from Otsuka Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., and Kyowa Kirin Co., Ltd., and his department has endowed chairs from Medtronic Japan Co. Ltd., Boston Scientific Japan K.K., Abbott Japan LLC, Japan Lifeline Co.,Ltd., Biotronik Japan, Terumo Corporation, Nipro Corporation, and Cordis Japan G.K. Other authors report no conflicts of interest.
IRB Information
The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000018297).
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