Prognostic Impact of Reduced Left Ventricular Ejection Fraction After Endovascular Therapy for Lower Extremities

Abstract

Background: The mechanism underlying a poor prognosis in patients with lower-extremity artery disease (LEAD) with heart failure is unknown. We examined the prognostic impact of the left ventricular ejection fraction (LVEF) in patients with LEAD who underwent endovascular therapy (EVT).

Methods and Results: From August 2014 to August 2016, 2,180 patients with LEAD (mean age, 73.2 years; male, 71.9%) underwent EVT and were stratified into low-LVEF (LVEF <40%; n=234, 10.7%) and not-low LVEF groups. In the low- vs. not-low LVEF groups, there was a higher prevalence of heart failure (i.e., history of heart failure hospitalization or New York Heart Association functional class III or IV symptoms) (44.0% vs. 8.3%, respectively), diabetes mellitus, chronic kidney disease, below-the-knee lesion, critical limb ischemia, and incidence of major cardiovascular and cerebrovascular events (MACCEs) and major adverse limb events (MALEs) (P<0.001, all). Low LVEF independently predicted MACCEs (hazard ratio: 2.23, 95% confidence interval: 1.63–3.03; P<0.001) and MALEs (hazard ratio: 1.85, 95% confidence interval: 1.15–2.96; P=0.011), regardless of heart failure (P value for interaction: MACCEs: 0.27; MALEs: 0.52).

Conclusions: Low LVEF, but not symptomatic heart failure, increased the incidence of MACCEs and MALEs. Intensive cardiac dysfunction management may improve LEAD prognosis after EVT.

The incidence of heart failure, as a major cause of death and progressive functional limitation, is increasing worldwide.^1–5 Heart failure is a complex clinical syndrome caused by structural and functional impairment of ventricular filling or ejection, and can manifest as dyspnea, malaise, swelling, and/or decreased exercise capacity.^6,7 The incidence of lower-extremity artery disease (LEAD) is also increasing,⁸ and it often manifests as polyvascular disease with an associated elevated risk of both functional deterioration and cardiovascular death,^9–13 usually attributable to atherosclerosis. LEAD shares risk factors and pathophysiological features with cardiovascular disease, including heart failure,^14–16 and these 2 conditions often coexist.¹⁷ Heart failure is recognized only when it becomes symptomatic, by definition; however, asymptomatic stages of structural heart disease exist, corresponding to Stage B (pre-heart failure: structural and functional abnormalities without symptoms) under the staging system of current major guidelines. Heart failure prevalence and mortality rates are high in patients with LEAD,^16,18–20 and decreased patency after endovascular therapy (EVT)²¹ occurs in patients with both conditions. In most studies, patients with symptomatic heart failure (Stages C and D) are considered to have heart failure; however, whether heart failure itself contributes to the poor prognosis or whether other factors that promote heart failure development affect clinical outcomes is undetermined. Among the factors contributing to heart failure development, left ventricular dysfunction is the leading cause and the most important factor in determining the heart failure monitoring and treatment strategy.^6,7,22–24 Current guidelines describe 3 heart failure categories: heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF) based on the left ventricular ejection fraction (LVEF).^6,7,22–24 Early intervention for asymptomatic heart failure is recommended, especially if patients have structural heart disease with reduced LVEF.^6,7 Therefore, in the present study, we evaluated LVEF and investigated its prognostic impact and the independent predictors of clinical outcomes in Japanese patients with LEAD undergoing EVT using data from an all-comer prospective registry cohort of Japanese patients with LEAD.

Methods

Study Design and Population

The design and primary results of the TOkyo taMA peripheral vascular intervention research COmraDE (Toma-Code) study, a Japanese prospective cohort study of consecutive patients with LEAD who underwent EVT for all indications from August 2014 to August 2016, have been published.²⁵ From it we identified 2,180 patients who were eligible for inclusion in the present analysis (Figure 1). The mean age was 73.2 years (1,568 men [71.9%]). We divided the patients into 2 groups by LVEF on admission. Low LVEF was defined as LVEF <40%,^13,14,22 and not-low LVEF was defined as LVEF ≥40% on echocardiography. The method of measuring LVEF was at the attending physician’s discretion. Data were collected as categorical data, not exact LVEF values, to categorize patients into the low-LVEF or not-low-LVEF group at registry enrollment.

Figure 1.

Flowchart of patient inclusion. In total, 2,180 patients were included in the analysis after excluding 75 patients with no follow-up and/or baseline LVEF data and 66 patients who underwent endovascular therapy (EVT) for acute limb ischemia (ALI). LVEF, left ventricular ejection fraction.

Data Collection, Follow-up, and Comorbidity Definitions

Clinical data were collected from the patients’ medical records or from the database by independent researchers using predetermined definitions. The study office collectively managed all data. The follow-up data were obtained from hospital charts or by contacting the patients or their family members via telephone at 1, 6, 12, 18, and 24 months after EVT.

Outcome Measures

The major outcome measures were major adverse cardiovascular and cerebrovascular events (MACCEs: composite of all-cause death, cardiovascular death, myocardial infarction, and stroke), and major adverse limb events (MALEs: composite of major amputation, acute limb ischemia, surgical intervention, and unscheduled EVT), based on the registry’s prespecified definitions.²⁵ The rates of each component of MACCEs and MALEs were also analyzed.

Definitions

Heart failure was defined as a history of heart failure hospitalization or New York Heart Association (NYHA) functional class III or IV symptoms. Cardiovascular death was a composite of sudden death and death caused by myocardial infarction, stroke, vascular disease, aortic disease, arrhythmia, heart failure, and valvular disease. Heart failure death as part of cardiovascular death was recorded when the attending physician reported the cause of death as heart failure. Myocardial infarction was defined as significantly elevated serum biomarkers (troponin T >0.1 μg/L or creatinine kinase twice normal) or new Q waves on ECG. “Stroke” was a cerebral stroke persisting ≥24 h with neurological deficits. Major amputation was amputation above the ankle. Acute limb ischemia was a sudden decrease in limb perfusion that threatened limb viability and presented within 2 weeks after symptom onset. Surgical intervention was a composite of bypass grafting, thrombectomy, and endarterectomy. Unscheduled EVT comprised all unplanned EVT required on the basis of the patient’s condition, regardless of the treatment procedure. Definitions of other comorbidities are shown in Supplementary Table 1. Critical limb ischemia (CLI) was defined as the presence of ischemic rest pain and ischemic lesions or gangrene objectively attributable to arterial occlusive disease.²⁶ Current guidelines use the term chronic limb-threatening ischemia (CLTI) to better reflect the natural history of lower-extremity disease. CLTI indicates a wider spectrum of the most severe LEAD, including CLI; however, we used the term CLI because the data were collected as CLI.

Statistical Analysis

Continuous data are presented as mean±standard deviation when normally distributed or as median (interquartile range) when non-normally distributed, unless otherwise stated. The normality of continuous variables was analyzed using the Kolmogorov-Smirnov test. The low-LVEF and not-low-LVEF groups were compared using an unpaired Student’s t-test. Categorical data are expressed as percentages and absolute values and were compared using Pearson’s chi-square test or Fisher’s exact test, as appropriate. MACCEs and MALEs probabilities during follow-up were estimated using the Kaplan-Meier method. Differences between groups were assessed using the log-rank test. Cox multivariate analysis was used to determine the independent predictors of MACCEs and MALEs. Predictive factors that were statistically significant in the univariate analysis were included in the multivariate analysis. All statistical analyses were performed using R software (version 4.1.2; “tableone” and “RcmdrPlugin. EZR” packages).²⁷ All tests were two-tailed, and P<0.05 was considered statistically significant.

Ethical Considerations

The Toma-Code registry study was approved by the institutional review board of Sakakibara Heart Institute, the core center of this multicenter study (reference no. 14-023), and the committees of each participating facility. The study is registered in the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR No. 000015100). All patients provided written informed consent for participation.

Results

Patient and Lesion Characteristics and Differences Between the Low- and Not-Low-LVEF Groups

The patients’ baseline characteristics and the differences between the low- and not-low-LVEF groups are shown in Table 1. Among the 2,180 patients who underwent EVT, 234 (10.7%) were allocated to the low-LVEF group (LVEF <40%). The mean age was higher in the not-low vs. low-LVEF groups (73.3±9.2 vs. 71.8±9.1 years, respectively; P=0.03). The proportion of patients with difficulty walking was significantly higher in the low- vs. not-low-LVEF groups (P<0.001). Comparatively, the prevalence of diabetes mellitus (P<0.001), chronic kidney disease (P<0.001), dialysis (P<0.001), chronic obstructive pulmonary disease (P=0.01), and heart failure (P<0.001) was significantly higher in the low-LVEF group; hypertension was more frequent in the not-low-LVEF group (P=0.001). Coronary artery disease (P<0.001) and aortic valve stenosis (P=0.001) were also more prevalent in the low- vs. not-low-LVEF groups. Below-the-knee lesion intervention and CLI were significantly more frequent in the low- vs. not-low-LVEF groups, respectively (below-the-knee lesions: 36.3% vs. 22.3%, P<0.001; CLI: 61.5% vs. 44.1%, P<0.001). The prevalence of chronic total occlusion and lesion length did not differ significantly between the groups. The serum albumin concentration was significantly lower (P<0.001), and inflammatory markers, such as white blood cell count and C-reactive protein concentrations, were significantly higher in the low- vs. not-low-LVEF groups (white blood cell count: P=0.02; C-reactive protein concentration: P<0.001). Regarding the nutritional risk status evaluated by the geriatric nutritional risk index (GNRI), the prevalence of those at major nutritional risk was significantly higher in the low- vs. not-low-LVEF groups, respectively (GNRI: 95.2±13.6 vs. 99.6±12.6, P<0.001; prevalence: 15.0% vs. 7.0%, P<0.001).

Table 1.

Baseline Characteristics of the Patients

Variables	Not-low LVEF (n=1,946)	Low LVEF (n=234)	P value
Age	73.3±9.2	71.8±9.1	0.03
Male sex	1,379 (70.9)	189 (80.8)	0.002
Body mass index (kg/m2)	22.6±3.6	21.8±3.4	0.001
Ankle-brachial index	0.68±0.18	0.69±0.20	0.44
Ambulation difficulty	163 (8.4)	42 (17.9)	<0.001
Lower-extremity symptoms (Rutherford category)			<0.001
Claudication (I–III)	1,088 (55.9)	90 (38.5)
Ischemic pain at rest (IV)	317 (16.3)	34 (14.5)
Minor tissue loss (V)	445 (22.9)	79 (33.8)
Major tissue loss (VI)	94 (4.8)	31 (13.2)
Smoking habit	1,133 (58.2)	146 (62.4)	0.25
Comorbidity
Diabetes mellitus	1,085 (55.8)	159 (67.9)	<0.001
Hypertension	1,637 (84.2)	177 (75.6)	0.001
Dyslipidemia	1,134 (58.3)	135 (57.7)	0.92
Chronic kidney disease	827 (42.5)	151 (64.5)	<0.001
Dialysis	491 (25.2)	107 (45.7)	<0.001
Chronic obstructive pulmonary disease	71 (3.6)	17 (7.3)	0.01
Heart failure	161 (8.3)	103 (44.0)	<0.001
Aortic valve stenosis	36 (1.8)	13 (5.6)	0.001
Coronary artery disease	867 (44.6)	185 (79.1)	<0.001
Cerebrovascular disease	284 (14.6)	37 (15.9)	0.67
Atrial fibrillation	185 (9.5)	34 (14.5)	0.02
Spinal canal stenosis	102 (5.2)	10 (4.3)	0.63
Inflammatory disease	60 (3.1)	3 (1.3)	0.18
History of lower-extremity intervention
History of major amputation	59 (3.0)	11 (4.7)	0.24
History of lower-extremity bypass surgery	68 (3.5)	13 (5.6)	0.16
History of lower-extremity EVT	424 (21.8)	59 (25.2)	0.27
Medication and treatment
Aspirin	1,344 (69.3)	185 (79.7)	0.001
Thienopyridine	1,326 (68.4)	165 (71.1)	0.44
Cilostazol	773 (39.9)	66 (28.4)	0.001
Eicosapentaenoic acid	177 (9.1)	15 (6.5)	0.22
Oral anticoagulants	309 (15.9)	43 (18.5)	0.36
ACEI or ARB	1,063 (54.6)	109 (46.6)	0.02
β-blocker	535 (27.6)	132 (56.9)	<0.001
Calcium-channel blocker	1,037 (53.5)	66 (28.4)	<0.001
Statin	996 (51.4)	132 (56.9)	0.13
Insulin	357 (18.4)	66 (28.2)	<0.001
Procedure-related variables
Stent implantation	1,218 (62.6)	123 (52.6)	0.004
Treated lesion
Bilateral lesion	220 (11.3)	23 (9.8)	0.57
Iliac	716 (36.8)	73 (31.2)	0.11
Femoropopliteal	1,259 (64.7)	142 (60.7)	0.25
Below-the-knee	433 (22.3)	85 (36.3)	<0.001
Graft	6 (0.3)	1 (0.4)	1.00
Disease and lesion characteristics
Critical limb ischemia	858 (44.1)	144 (61.5)	<0.001
Chronic total occlusion	881 (45.3)	111 (47.4)	0.58
Lesion length (mm)	100 [40, 230]	100 [45, 260]	0.09
Laboratory data
White blood cell count (109/L)	7.07±2.69	7.54±3.92	0.02
Hemoglobin (g/L)	127±103	119±21	0.25
Platelet count (109/L)	22.6±11.0	20.2±6.8	0.001
Albumin (g/L)	39.0±6.0	37.0±7.0	<0.001
Total cholesterol (mmol/L)	4.47±1.01	4.22±1.19	<0.001
Triglyceride (mmol/L)	1.54±1.02	1.45±1.25	0.20
Aspartate aminotransferase (IU/L)	19 [15, 24]	18 [14, 24]	0.29
Alanine aminotransferase (IU/L)	14 [10, 20]	12 [9, 20]	0.03
Lactate dehydrogenase (IU/L)	200±53	204±71	0.33
Creatine phosphokinase (IU/L)	74 [50, 111]	62.50 [40, 100]	<0.001
C-reactive protein (mg/L)	2.5 [0.8, 8.7]	6.9 [1.7, 21.7]	<0.001
Nutritional status and risk category
GNRI	99.6±12.6	95.2±13.6	<0.001
Nutritional risk category			<0.001
Major risk (GNRI <82)	136 (7.0)	35 (15.0)
Moderate risk (GNRI ≥82 to <92)	274 (14.1)	52 (22.2)
Low risk (GNRI ≥92 to <98)	306 (15.7)	35 (15.0)
No risk (GNRI ≥98)	1,230 (63.2)	112 (47.9)

Data are presented as the mean±standard deviation (normally distributed continuous data), or the median [interquartile range] (non-normally distributed data), or n (%). Groups were compared using an unpaired Student’s t-test. Categorical data are expressed as percentages and absolute values and were compared using Pearson’s chi-square test or Fisher’s exact test, as appropriate. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; EVT, endovascular therapy; GNRI, Geriatric Nutritional Risk Index; LVEF, left ventricular ejection fraction.

Clinical Outcomes

Incidence of Major Outcome Measures and Survival Analysis The 2-year cumulative incidences of MACCEs and MALEs were significantly higher in the low- vs. not-low-LVEF groups, respectively (MACCEs: 23.9% vs. 9.9%, P<0.001; MALEs: 9.8% vs. 4.8%, P<0.001). The freedom from MACCEs and MALEs survival rates are shown in Figure 2. The MACCEs- and MALEs-free survival rates were significantly lower in the low- vs. not-low-LVEF groups (P<0.001 for both). For both MACCEs and MALEs, the survival curves were significantly stratified by LVEF status throughout the observation period.

Figure 2.

MACCEs- and MALEs-free survival rates stratified by LVEF group. The low-LVEF group had a significantly lower event-free survival rate for both MACCEs and MALEs. (Left) Freedom from MACCEs (all-cause death, cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). (Right) Freedom from MALEs (major amputation, acute limb ischemia, surgical intervention, unscheduled EVT, and clinically driven TLR). EVT, endovascular therapy; LVEF, left ventricular ejection fraction; MACCEs, major cardiovascular and cerebrovascular events; MALEs, major limb events; TLR, target lesion revascularization.

Table 2 shows the contribution of each component to the major outcome measures. Both all-cause death and cardiovascular death were significantly more frequent in the low- vs. not-low-LVEF groups (hazard ratio [HR]: 3.29, 95% confidence interval [CI]: 2.40–4.52, P<0.001; HR: 5.03, 95% CI: 2.98–8.50, P<0.001, respectively). Regarding cardiovascular death, the risk of heart failure death was significantly higher in the low- vs. not-low-LVEF groups (HR: 9.15, 95% CI: 4.34–19.3; P<0.001). Regarding MALEs, major amputation was significantly more frequent in the low- vs. not-low-LVEF groups (HR: 2.90, 95% CI: 1.63–5.17; P<0.001). The incidence of clinically driven target lesion revascularization was not significantly different between the groups; however, the risk of unscheduled EVT was almost 1.6-fold higher in the low- vs. not-low-LVEF groups (HR: 1.59, 95% CI: 1.10–2.29; P=0.014).

Table 2.

Contribution of Each Component to MACCEs and MALEs

Population	No. of patients (%)		Not-low LVEF vs. low LVEF HR (95% CI)	P value
	Not-low LVEF (n=1,946)	Low LVEF (n=234)
MACCEs	193 (9.9)	56 (23.9)	2.98 (2.21–4.02)	<0.001
All-cause death	161 (8.3)	51 (21.8)	3.29 (2.40–4.52)	<0.001
Bleeding death	5 (0.3)	1 (0.4)	1.81 (0.21–15.5)	0.588
Cardiovascular death	43 (2.2)	21 (9.0)	5.03 (2.98–8.50)	<0.001
Heart failure death	15 (0.8)	13 (5.6)	9.15 (4.34–19.3)	<0.001
Non-fatal MI	17 (0.9)	3 (1.3)	1.80 (0.53–6.15)	0.349
Non-fatal stroke	31 (1.6)	4 (1.7)	1.29 (0.46–3.66)	0.631
MALEs	93 (4.8)	23 (9.8)	2.38 (1.51–3.76)	<0.001
Major amputation	50 (2.6)	15 (6.4)	2.90 (1.63–5.17)	<0.001
Acute limb ischemia	16 (0.8)	1 (0.4)	0.61 (0.08–4.60)	0.631
Clinically driven TLR	349 (17.9)	43 (18.4)	1.30 (0.94–1.78)	0.108
Surgical reintervention	38 (2.0)	8 (3.4)	2.03 (0.94–4.35)	0.070
Unscheduled EVT	216 (11.1)	33 (14.1)	1.59 (1.10–2.29)	0.014

CI, confidence interval; EVT, endovascular therapy; HR, hazard ratio; LVEF, left ventricular ejection fraction; MACCEs, major adverse cardiovascular and cerebrovascular events; MALEs, major adverse limb events; MI, myocardial infarction; TLR, target lesion revascularization.

Predictors of MACCEs and MALEs

Table 3 shows the results of the multivariate Cox proportional hazards analysis of MACCEs and MALEs. Low LVEF was an independent predictor of both MACCEs and MALEs, even after covariate adjustment (MACCEs: HR: 2.23, 95% CI: 1.63–3.03, P<0.001; MALEs: HR: 1.85, 95% CI: 1.15–2.96, P=0.011). CLI was also significantly associated with both MACCEs and MALEs. Diabetes mellitus, atrial fibrillation, and chronic kidney disease were significantly associated with MACCEs, but not with MALEs.

Table 3.

Multivariate Cox Proportional Hazards Regression Analysis of MACCEs and MALEs

Variables	Univariate			Multivariate
	HR	95% CI	P value	HR	95% CI	P value
MACCEs
Low LVEF	2.98	2.21–4.02	<0.001	2.23	1.63–3.03	<0.001
Male sex	0.74	0.57–0.97	0.026	0.96	0.73–1.26	0.743
Diabetes mellitus	1.42	1.10–1.85	0.008	1.38	1.04–1.82	0.025
Hypertension	0.65	0.48–0.88	0.005	0.83	0.61–1.13	0.233
Body mass index	0.87	0.84–0.90	<0.001	0.90	0.87–0.94	<0.001
Stent implantation	0.59	0.46–0.76	<0.001	0.88	0.68–1.14	0.327
Atrial fibrillation	2.00	1.43–2.78	<0.001	1.56	1.11–2.19	0.011
Age per 5-year age group	1.17	1.09–1.26	<0.001	1.14	1.06–1.23	<0.001
Chronic kidney disease	3.15	2.40–4.12	<0.001	2.15	1.62–2.85	<0.001
Critical limb ischemia	4.53	3.37–6.08	<0.001	2.77	2.02–3.80	<0.001
MALEs
Low LVEF	2.38	1.51–3.76	<0.001	1.85	1.15–2.96	0.011
Male sex	0.59	0.41–0.86	0.006	0.63	0.43–0.93	0.019
Diabetes mellitus	1.57	1.06–2.31	0.023	1.16	0.77–1.75	0.483
Hypertension	0.59	0.39–0.90	0.015	0.89	0.57–1.39	0.609
Body mass index	0.91	0.86–0.96	0.001	0.93	0.88–0.98	0.006
Stent implantation	0.47	0.32–0.67	<0.001	0.72	0.49–1.06	0.099
Atrial fibrillation	1.63	0.98–2.73	0.062
Age per 5-year age group	0.85	0.78–0.93	<0.001	0.84	0.77–0.92	<0.001
Chronic kidney disease	2.27	1.56–3.31	<0.001	1.34	0.90–2.00	0.153
Critical limb ischemia	5.63	3.54–8.96	<0.001	3.92	2.39–6.42	<0.001

Estimated hazard ratios and associated confidence intervals were obtained using a Cox proportional hazards regression model for an interaction between the low LVEF group and the not-low LVEF group. Abbreviations as in Table 2.

To adjust the baseline imbalance between the groups, we used inverse probability of treatment weighting (IPTW). Propensity scores were calculated using factors with significant differences between the groups, excluding factors that correlated with each other and factors that could contain extreme outliers, in accordance with the characteristics of this method. The selected factors are shown in Supplementary Table 2A. Low LVEF was significantly associated with MALEs (HR: 2.29, 95% CI: 1.17–4.49; P=0.016), and the same tendency was observed with MACCEs (HR: 1.51, 95% CI: 0.94–2.39; P=0.082). Supplementary Figure shows the weighted survival estimates for event-free survival and Supplementary Table 2B shows the Cox proportional hazards analysis of each component.

Potential Modification of the Association Between LVEF Status and Outcome Measures by Demographics and Comorbidities

To explore the potential modification by demographics and comorbidities, the associations between low LVEF and MACCEs (Figure 3A) and MALEs (Figure 3B) were analyzed in patient subgroups divided by comorbidities, including heart failure. Only oral anticoagulant intake significantly modified the association between low LVEF and MACCEs. In contrast, the association between low LVEF and MALEs was significantly modified by the presence of diabetes mellitus and chronic kidney disease. Low LVEF was more strongly associated with MALEs in patients with vs. without diabetes mellitus (HR: 3.21, 95% CI: 1.96–5.27 vs. HR: 0.34, 95% CI: 0.05–2.45, respectively; P for interaction=0.03). Patients with vs. without chronic kidney disease tended to have a stronger association between low LVEF and MALEs (HR: 2.72, 95% CI: 1.64–4.53 vs. HR: 0.67, 95% CI: 0.16–2.78, respectively; P for interaction=0.07). However, the presence of heart failure did not affect the association between low LVEF and MALEs (P for interaction=0.52). GNRI status did not modify the association between low LVEF and MACCEs or MALEs (P for interaction, MACCEs: 0.12; MALES: 0.62).

Figure 3.

Subgroup analyses for (A) MACCEs and (B) MALEs stratified by patient demographics and comorbidities. The presence of symptomatic heart failure did not modify the association between low LVEF and clinical outcomes. CI, confidence interval; CKD, chronic kidney disease; CLI, critical limb ischemia; DL, dyslipidemia; DM, diabetes mellitus; GNRI, Geriatric Nutritional Risk Index; HR, hazard ratio; LVEF, left ventricular ejection fraction; MACCEs, major cardiovascular and cerebrovascular events; MALEs, major limb events; OAC, oral anticoagulant.

Discussion

In this study of patients with LEAD who underwent EVT, low LVEF significantly increased the risk of MACCEs and MALEs, regardless of the presence of symptomatic heart failure. Our results indicate that low LVEF affects the clinical outcomes of patients with LEAD after EVT, which suggests a potential role of the hemodynamic changes caused by left ventricular dysfunction, independent of heart failure symptoms, in LEAD development and progression.

LEAD often coexists with heart failure, which increases the risk of death.^28–32 In our study, 10.7% of the patients had low LVEF and were more likely to have coronary artery disease, diabetes mellitus, chronic kidney disease, and atrial fibrillation, which are common and major risk factors for heart failure and atherosclerosis; each condition has a different effect on the incidence of cardiovascular and limb events. Diabetes mellitus, atrial fibrillation, and chronic kidney disease were independent predictors of MACCEs, but not MALEs. However, these findings may suggest that the presence of factors that modify the influence of the atherosclerotic burden on each vascular bed, and more complicated mechanisms other than atherosclerosis should be considered to understand LEAD progression.

Heart failure did not affect the association between low LVEF and MACCEs (P for interaction: 0.27) or MALEs (P for interaction: 0.52). Previous studies have reported an association between heart failure and reduced primary patency or an increased risk of amputation after EVT.^33,34 However, a recent study suggested that heart failure is associated with higher mortality and cardiovascular event rates in the LEAD population, but not with limb event rates, despite the higher prevalence of severe LEAD in patients with vs. without heart failure.²⁰ Furthermore, different types of heart failure may have different effects on limb events.^19,21 Considering our results showing that low LVEF was associated with an increased incidence of MALEs, regardless of the presence of symptomatic heart failure, LVEF, rather than the heart failure itself, may be responsible for limb events after EVT. The definition of heart failure used in our study, which excluded those with NYHA class ≤II symptoms, was more severe than that used in previous reports.^18,20,21 Nonetheless, our study failed to demonstrate an interaction of heart failure with the association between low LVEF and MALEs. This may suggest that limb patency after EVT is determined by the atherosclerotic burden as well as a complex combination of factors possibly resulting from left ventricular dysfunction. A previous report suggested that the association between heart failure and poor EVT durability is complex, and the poor prognosis of patients with heart failure after EVT may reflect the results of the subgroup of patients with systolic dysfunction.²¹ Our results may support this hypothesis, suggesting that the association between heart failure and limb events may be attributable to HFrEF.

In our population, low LVEF independently predicted MALEs, regardless of the presence of symptomatic heart failure. Changes in cardiac output in patients with heart failure provoke hemodynamic changes in the peripheral arteries and affect end-organ function.³⁵ These findings suggest that ventricular dysfunction in heart failure, not heart failure itself, contributes to disease progression and increased limb events in patients with LEAD with heart failure. Our results suggest that hemodynamic changes caused by left ventricular dysfunction play a substantial role in the prognosis of patients with LEAD after EVT. Further studies of patients with LEAD stratified by LVEF with or without heart failure are needed.

Major guidelines have recommended treatment with the maximum tolerable dose of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) alongside β-blockers as standard therapy for HFrEF because these agents improve the clinical outcomes of HFrEF.^22–24 However, only 46.6% and 56.9% of the patients in our low-LVEF group were taking renin-angiotensin system inhibitors (ACEIs or ARBs) and β-blockers, respectively (Table 1). Although various issues may hinder the introduction of standard therapy for patients with heart failure, our results show that left ventricular dysfunction may be inadequately managed in patients with LEAD. This may be because LEAD and heart failure can mask the symptoms of each condition because of limited mobility, a common feature in heart failure and LEAD, leading to the under-recognition of both conditions.³⁶ Historically, the management of coronary artery disease in patients with LEAD and concomitant coronary artery disease has been less intensive compared with that in patients with coronary artery disease only.³⁷ Our results suggest that poor clinical outcomes in patients with LEAD with low LVEF may be partly attributable to suboptimal management of cardiovascular risk factors, including left ventricular dysfunction. Recently, there has been a paradigm shift in heart failure treatment based on the results of large-scale clinical trials, and guideline-directed medical therapy (GDMT) for heart failure has also changed.^6,7,38 Evidence has emerged to support the use of new cardioprotective drugs. For example, angiotensin receptor-neprilysin inhibitors (ARNI) have shown survival-improving effects exceeding those of enalapril,³⁹ and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower the risk of cardiovascular death and heart failure hospitalization, regardless of the presence of diabetes mellitus.^40–43 These drugs are included in the current GDMT, with β-blockers, mineralocorticoid receptor antagonists, and renin-angiotensin system inhibitors, traditionally ACEIs or ARBs, and now, ARNI, if tolerated.^6,7,38 If the current GDMT had been introduced during our study, our results would have been different. However, more than half of the patients with reduced LVEF were not undergoing standard HFrEF treatment (Table 1). Insufficient implementation and early discontinuation of GDMT for heart failure have been reported,^37,44–47 which should be overcome clinically.^37,48 Although our data were collected in mid-2010 when ARNI and SGLT2 inhibitors were still not a Class I recommendation in major guidelines, published studies show that under-treatment, as noted in our study, remains a clinical issue. Reflecting the fact that low LVEF is a multifactorial condition, IPTW showed a non-significant P value (0.082) for the association between low LVEF and MACCEs. Therefore, our data may support the implementation of more intensive interventions for concomitant left ventricular dysfunction with multifactorial approaches to comorbidities in patients with LEAD, which may improve survival, cardiovascular outcomes, and limb-related outcomes after EVT.

Study Limitations

This study has several limitations. First, the data were collected between 2014 and 2016. Treatment guidelines for both LEAD and heart failure have since changed. GDMT for heart failure has markedly changed; therefore, if the patients had undergone current GDMT for concomitant heart failure, our results would have been different. Similarly, the concept of severe LEAD has changed from CLI to CLTI; however, our data were collected according to the conventional definition of CLI, which focuses on only lower-limb ischemic status. Therefore, our results may not fully apply to patients with CLTI according to the current definition. Second, this study involved only Japanese patients, and therefore the results may not be applicable to other ethnicities. Third, because of the definition of heart failure, patients with NYHA functional class ≤II symptoms, including asymptomatic patients corresponding to Stage B under current guidelines, were considered not to have heart failure. Fourth, the method of measuring LVEF was at the attending physician’s discretion, and data were collected as categorical data, not as actual LVEF values, to categorize patients into the low- and not-low-LVEF groups (those with an LVEF of 40–50% [HFmrEF] were allocated to the not-low-LVEF group). This might have affected the results. Fifth, this study was a subanalysis of a previously reported registry study, and data for the etiology of low LVEF and time-dependent changes in LVEF were unavailable. Finally, it was difficult to collect treatment strategy information for patients with LEAD, which may have differed among the participating facilities.

Conclusions

The presence of low LVEF (LVEF <40%) significantly increased the risk of MACCEs and MALEs in patients with LEAD who underwent EVT, regardless of the presence of symptomatic heart failure. More intensive and integrated management with GDMT for concomitant cardiac dysfunction, together with multifactorial approaches to comorbidities, may improve the cardiac and limb prognoses of patients with LEAD. Further studies are warranted to evaluate the association between cardiac output and functional prognosis in patients with LEAD.

Acknowledgment

This work was supported by the Vascular Disease Research Project of the Japan Research Promotion Society for Cardiovascular Disease, Tokyo, Japan.

Disclosures

The authors declare they have no conflicts of interest.

IRB Information

This study was approved by the institutional review board of Sakakibara Heart Institute, the core center of this multicenter study (reference no. 14-023), and the committees of each participating facility.

Data Availability

The deidentified participants’ data will not be shared as data sharing was not included in the IRB approval.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0215

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