Impact of Guideline-Directed Medical Therapy on 2-Year Mortality in Japanese Patients Undergoing Endovascular Therapy for Femoropopliteal Lesions　― Results of the Multicenter GEMINI-FP Study ―

Tatsuro Takei; Takahiro Tokuda; Naoki Yoshioka; Kenji Ogata; Akiko Tanaka; Shunsuke Kojima; Kohei Yamaguchi; Takashi Yanagiuchi; Tatsuya Nakama; on behalf of the LEADers PAD Investigators

doi:10.1253/circj.CJ-25-0086

Abstract

Background: The effect of guideline-directed medical therapy (GDMT) on mid-term mortality in Asian patients, including Japanese patients, who have undergone endovascular therapy (EVT) for lower extremity artery disease remains still unclear. This study evaluated the effects of GDMT, defined as the combined prescription of antiplatelet agents, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, on 2-year mortality in Japanese patients undergoing EVT for femoropopliteal (FP) lesions.

Methods and Results: In this multicenter retrospective study, 1,756 registered patients were divided into 2 groups: those who received all 3 medications that comprised GDMT (full GDMT group) and those who received ≤2 medications (non-GDMT group). After propensity score matching, the baseline characteristics did not differ significantly between the 413 pairs of participants in the full GDMT and non-GDMT groups. All-cause mortality within 2 years was significantly lower in the full GDMT than non-GDMT group (14.3% vs. 20.8%; log-rank P=0.030). Mortalities from cardiovascular and cardiocerebrovascular diseases within 2 years were also significantly lower in the GDMT group (4.2% vs. 9.5% [log-rank P=0.021] and 4.2% vs. 10.5% [log-rank P=0.007], respectively).

Conclusions: In Japanese patients undergoing EVT for FP lesions, GDMT may improve all-cause, cardiovascular, and cardiocerebrovascular mortality within 2 years.

With >200 million patients worldwide affected by lower extremity artery disease (LEAD), this disease is of critical importance in healthcare management.¹ Providing patients with options such as exercise, medication, and revascularization for symptom relief is important. Patients with LEAD are also more prone to cardiovascular diseases and stroke events, which should be the focus for improving their prognosis.² To reduce the risks of these diseases, the primary Class I recommendation is to treat patients with LEAD using statin therapy, antiplatelet therapy, and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs);²^–⁴ such treatment is defined as guideline-directed medical therapy (GDMT) and contributes to improved outcomes in patients with LEAD.⁵ In 2023, a large US database reported that GDMT reduced all-cause mortality in patients with LEAD who underwent endovascular therapy (EVT).⁶ However, only approximately 1% of this database is Asian; thus, the effect of GDMT on this population is unknown. Therefore, further interracial studies are needed, because Japanese patients with LEAD reportedly have a lower mortality rate than their Western counterparts.⁷ To the best of our knowledge, only 2 studies have investigated Asian patients with LEAD and GDMT. Hata et al. reported the long-term effects of GDMT in Japanese patients with chronic limb-threatening ischemia (CLTI).⁸ That study included patients who underwent bypass surgery and EVT, and the clinical phenotype was limited to CLTI. The study reported on long-term follow-up (10 years), but did not perform 2-arm comparisons (GDMT vs. non-GDMT) after propensity score matching, which may have been influenced by differences in patient backgrounds. Thus, Hata et al.’s evaluation of the effect of GDMT itself may be insufficient. A Korean study also reported the effectiveness of GDMT in patients newly diagnosed with LEAD.⁹ However, that report did not provide information on the symptoms of limb ischemia or treatment details, including revascularization procedures, and because their patient population was selected from the National Health Insurance System database, it was likely to differ from the real-world patient population being seen by interventional cardiologists, vascular surgeons, and interventional radiologists for the treatment of LEAD. In the present study, we evaluated the efficacy of GDMT after propensity score matching using a real-world database of Japanese patients who underwent EVT for femoropopliteal artery (FP) lesions for intermittent claudication (IC) or CLTI (LEADers-Femoropopliteal Registry).

Methods

Patient Population

The Impact of Guideline-Directed Medical Therapy on 2-Year Mortality in Japanese Patients Treated With Endovascular Therapy for Femoropopliteal Lesions (GEMINI-FP) study was a multicenter retrospective analysis of a database of patients who underwent EVT for FP lesions at 8 Japanese cardiovascular centers (Tenyoukai Central Hospital, Sendai Kosei Hospital, Tokyo Bay Medical Center, Saiseikai Yokohama Eastern Hospital, Nagoya Heart Center, Ogaki Municipal Hospital, Rakuwakai Otowa Hospital, and Miyazaki Medical Association Hospital). We enrolled patients who underwent EVT for de novo FP lesions between January 2018 and December 2020. From this registry, 1,756 patients treated for IC (Rutherford classification 1–3) and CLTI (Rutherford classification 4–6) were selected. The GDMT and non-GDMT groups included patients who did (n=498) and did not (n=1,258) receive all 3 drugs (antiplatelet agents, statins, and ACEi/ARBs). These patients underwent propensity score matching based on patient and lesion background. After matching, 413 pairs of patients from the GDMT and non-GDMT groups were included in the analysis. We then compared 2-year all-cause, cardiovascular, cardiocerebrovascular, and non-cardiocerebrovascular mortalities between the 2 groups. We also evaluated 2-year all-cause mortality based on the number of medications that comprised the GDMT in the matched population. Moreover, we analyzed interactions between subgroups. Patient information and examination, imaging, procedural, and follow-up data were obtained from individual institutional databases by independent investigators, and follow-up after the peripheral intervention was performed according to individual hospital protocols. The prognostic investigations included telephone surveys.

Interventional Procedures

The interventional procedure was performed via a 5- to 7-Fr sheath inserted into the common femoral artery by either the ipsilateral approach or crossover. Patients received 5,000 units of heparin at the start of the procedure. The target lesions were assessed using 0.014-, 0.018-, and 0.035-inch guidewires. Decisions regarding final device and treatment strategy were left to the discretion of the surgeon. Each physician determined the need for oral medications after EVT.

Definitions

Patients who were taking all 3 medications (an antiplatelet agent, statin, and ACEi/ARB) were classified as the full GDMT group, and those who were not taking all 3 medications were classified as the non-GDMT group. Medication details were confirmed at the time of discharge. Antiplatelet agents were defined as aspirin and P2Y₁₂ inhibitors. To eliminate ambiguity, the Clinical Frailty Scale was used to assess a patient’s activity. Coronary artery disease was defined as a history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass. Chronic kidney disease was defined as renal function with an estimated glomerular filtration rate of <60 mL/min/1.73 m². Cardiovascular deaths included myocardial infarction, heart failure, fatal arrhythmia, aortic disease, and sudden death. Stroke was defined as cerebral infarction or hemorrhage. Cardiocerebrovascular death was defined as death due to cardiovascular disease or stroke. The EVT date was defined as the index day, from which the survival and follow-up periods were calculated.

Outcomes

The primary outcome was all-cause mortality within 2 years in the matched population. Cardiovascular, cardiocerebrovascular, and non-cardiocerebrovascular deaths were included as secondary outcomes. We also evaluated the 2-year mortality for each cause based on the number of drugs that constituted the GDMT.

Ethical Considerations

This study was approved by the Ethics Committee of Tenyoukai Central Hospital (Approval no. R5-05) and was conducted in accordance with the Declaration of Helsinki. The study as also approved by the ethics committee of each participating hospital. The requirement for informed consent for registration was waived because this was a retrospective observational study. Patients were able to refuse to participate or withdraw from the study. Information about the study has been made publicly available in accordance with ethical guidelines for medical and health research involving human subjects.

Statistical Analysis

Statistical analyses were performed using JMP Pro version 16 (SAS Institute, Inc.). Data on baseline patient and lesion characteristics are presented as the mean±SD for continuous variables and as frequencies and percentages for categorical variables, unless noted otherwise. Statistical significance was set at two-tailed P<0.05. The significance of differences in baseline characteristic categories between groups were analyzed using t-tests and Chi-squared tests for continuous and categorical variables, respectively. When comparing clinical outcomes between the full and non-GDMT groups, we used propensity score matching to minimize the effect of group differences in baseline characteristics. We calculated the propensity scores using a logistic regression model. Logistic regression analysis was performed using the following variables: age, sex, symptoms, body mass index, hypertension, dyslipidemia, diabetes, renal failure, dialysis, smoking, chronic obstructive pulmonary disease, coronary artery disease, stroke, atrial fibrillation, left ventricular ejection fraction, ankle-brachial pressure index, cilostazol, warfarin, oral direct coagulation, β-blockers, sodium-glucose cotransporter 2 inhibitors, insulin, ezetimibe, and Transatlantic Inter-Society Consensus II classification. Intergroup differences after matching were analyzed with stratification by pairs. The balance of baseline characteristics between the 2 groups was assessed using P values and standardized differences. Standardized differences ≥0.1 were considered statistically significant. A caliper cut-off of 0.2 was applied for propensity score matching. We used Kaplan-Meier survival analysis to evaluate mortality. The interaction between baseline characteristics and the effect of GDMT was also analyzed using a Cox proportional hazard regression model with propensity score stratification.

Results

Baseline Characteristics

We analyzed the clinical outcomes of 413 pairs (full and non-GDMT groups) after propensity score matching (Figure 1). The baseline characteristics of patients are presented in Table 1. In the overall patient population, there were significant differences between the full and non-GDMT groups in body mass index, clinical frailty, smoking status, diabetes, hypertension, dyslipidemia, coronary artery disease, atrial fibrillation, chronic renal failure, dialysis, CLTI, ankle-brachial index, cilostazol, ezetimibe, β-blockers, chronic total occlusion, severe calcification, and the number of runoff vessels. After propensity score matching, no statistically significant differences in baseline characteristics were observed (P>0.05, standardized difference <0.1).

Figure 1.

Study flowchart. The 2-year mortality rate was analyzed for 413 pairs (full guideline-directed medical therapy [GDMT] and non-full GDMT groups), whose patient and lesion backgrounds were adjusted using propensity matching. FP, femoropopliteal.

Table 1.

Baseline Characteristics in the Overall and Matched Populations

	Overall population			Matched population
	Full GDMT (n=498)	Non-GDMT (n=1,258)	P value	Full GDMT (n=413)	Non-GDMT (n=413)	P value	Standardized difference
Male sex	350 (70.3)	833 (66.2)	0.10	287 (69.5)	283 (68.5)	0.76	0.017
Age (years)	73.8±8.3	75.0±9.5	0.012	73.7±8.2	73.9±9.4	0.79	0.023
BMI (kg/m²)	22.9±3.5	22.2±3.8	<0.001	23.0±3.5	22.8±3.7	0.53	0.044
Clinical Frailty Scale ≥4	129 (25.9)	516 (41.0)	<0.001	100 (24.2)	116 (28.1)	0.21	0.088
Current smoker	154 (30.9)	318 (25.3)	0.017	129 (31.2)	117 (28.3)	0.36	0.063
Diabetes	321 (64.5)	747 (59.4)	0.049	261 (63.2)	257 (62.2)	0.77	0.020
Hypertension	458 (92.0)	976 (77.6)	<0.001	380 (92.0)	379 (91.8)	0.90	0.009
Dyslipidemia	386 (77.5)	568 (45.2)	<0.001	312 (75.4)	316 (76.5)	0.74	0.022
Coronary artery disease	240 (48.2)	513 (40.8)	0.005	195 (47.2)	197 (47.7)	0.89	0.010
Stroke	76 (15.3)	232 (18.4)	0.11	65 (15.7)	70 (17.0)	0.64	0.032
Atrial fibrillation	64 (12.9)	209 (16.6)	0.046	58 (14.0)	56 (13.6)	0.84	0.014
COPD	28 (5.6)	72 (5.7)	0.93	19 (4.6)	21 (5.1)	0.75	0.022
CKD without dialysis	211 (42.4)	378 (30.1)	<0.001	169 (41.0)	169 (41.0)	1.0	0
CKD with dialysis	119 (23.9)	541 (43.0)	<0.001	102 (24.7)	109 (26.4)	0.58	0.039
CLTI	138 (27.7)	587 (46.7)	<0.001	112 (27.1)	118 (28.6)	0.64	0.032
Ejection fraction (%)	59.4±12.0	59.0±12.6	0.54	59.6±12.1	59.6±11.5	0.97	0.003
Missing data	22 (4.4)	111 (8.8)	0.001	0	0	1	0
Previous ABI	0.60±0.22	0.55±0.27	0.002	0.59±0.22	0.59±0.24	0.85	0.014
Missing data	22 (4.4)	90 (7.2)	0.029	0	0	1	0
Cilostazol	57 (11.5)	221 (17.6)	0.001	51 (12.4)	44 (10.7)	0.45	0.053
Warfarin	26 (5.2)	96 (7.6)	0.07	22 (5.3)	21 (5.1)	0.88	0.011
Direct oral anticoagulant	55 (11.0)	125 (9.9)	0.49	48 (11.6)	46 (11.1)	0.83	0.015
Ezetimibe	49 (9.8)	52 (4.1)	<0.001	39 (9.4)	35 (8.5)	0.63	0.034
β-blocker	207 (41.6)	416 (33.1)	<0.001	165 (40.0)	163 (39.5)	0.89	0.010
SGLT2 inhibitor	25 (5.0)	56 (4.5)	0.61	21 (5.1)	15 (3.6)	0.31	0.071
Insulin user	91 (18.3)	186 (14.8)	0.07	70 (17.0)	73 (17.7)	0.78	0.019
TASC II C/D	259 (52.0)	614 (48.8)	0.23	206 (49.9)	202 (48.9)	0.78	0.019
Chronic total occlusion	231 (46.4)	499 (39.7)	0.01	190 (46.0)	181 (43.8)	0.53	0.044
Lesion length (mm)	172±104	172±108	0.93	170±104	171±105	0.97	0.003
Severe calcification	113 (22.7)	355 (28.2)	0.017	92 (22.3)	84 (20.3)	0.50	0.047
Proximal RVD (mm)	5.8±0.8	5.8±0.8	0.76	5.8±0.8	5.8±0.7	0.34	0.066
Distal RVD (mm)	5.4±0.8	5.4±0.9	0.20	5.4±0.8	5.5±0.8	0.27	0.074
No. runoff vessels	1.7±0.8	1.6±0.8	<0.001	1.7±0.8	1.7±0.9	0.19	0.086

Unless indicated otherwise, values are expressed as the mean±SD or n (%). ABI, ankle-brachial index; BMI, body mass index; CKD, chronic kidney disease; CLTI, chronic limb-threatening ischemia; COPD, chronic obstructive pulmonary disease; GDMT, guideline-directed medical therapy; RVD, reference vessel diameter; SGLT2, sodium-glucose cotransporter 2; TASC II, Trans-Atlantic Inter-Society Consensus II.

Outcome Measures

Table 2 presents laboratory findings and procedural characteristics in the matched population. Both total cholesterol and low-density lipoprotein cholesterol levels were significantly lower in the full GDMT than non-GDMT group (165±39 vs. 171±41 mg/dL [P=0.032] and 89±31 vs. 95±33 mg/dL [P<0.001], respectively). There were no significant differences in HbA1c levels between the 2 groups. In EVT procedures, drug-coated balloons were used significantly more often in the non-GDMT group, whereas bare nitinol stents were used more often in the GDMT group.

Table 2.

Laboratory Data and Procedural Characteristics in the Matched Population

	Full GDMT (n=413)	Non-GDMT (n=413)	P value
Total cholesterol (mg/dL)	165±39	171±41	0.032
Missing data	10 (2.4)	8 (1.9)	0.63
LDL-C (mg/dL)	89±31	95±33	<0.001
Missing data	8 (1.9)	8 (1.9)	1.0
HDL-C (mg/dL)	50±15	49±16	0.56
Missing data	8 (1.9)	7 (1.7)	0.63
Triglycerides (mg/dL)	148±97	152±171	0.68
Missing data	7 (1.69)	7 (1.69)	1.0
HbA1c (mg/dL)	6.6±1.6	7.0±6.0	0.26
Missing data	8 (1.9)	5 (1.2)	0.40
Use of DCB	222 (53.8)	259 (62.7)	0.009
Use of DES or DCS	116 (28.1)	94 (22.8)	0.08
Use of BNS	90 (21.8)	66 (16.0)	0.03
Use of stent graft	4 (0.97)	8 (1.94)	0.24
IVUS use	333 (80.6)	342 (82.8)	0.42

Unless indicated otherwise, values are expressed as the mean±SD or n (%). BNS, bare nitinol stent; DCB, drug-coated balloon; DCS, drug-coated stent; DES, drug-eluting stent; HDL-C, low-density lipoprotein cholesterol; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol.

Figure 2 shows the breakdown of causes of death within 2 years in the matched population. During a mean observation period of 16.6±8.6 months, 109 patients died. The causes of death were cardiovascular disease (40 patients; 36.7%), stroke (3 patients; 2.8%), and non-cardiocerebrovascular deaths (66 patients; 60.5%).

Figure 2.

Causes of death in the matched population, The causes of death included cardiovascular events (n=40; 36.7%), stroke (n=3; 2.8%), and non-cardiocerebrovascular deaths (n=66; 60.5%).

Figure 3 shows Kaplan-Meier survival analysis for all-cause mortality within 2 years in the full and non-GDMT groups. All-cause mortality within 2 years was significantly lower in the full GDMT than non-GDMT group (14.3% vs. 20.8%, respectively; log-rank P=0.030).

Figure 3.

All-cause mortality within 2 years after endovascular therapy (EVT) in the full guideline-directed medical therapy (GDMT) and non-GDMT groups. The 2-year overall mortality rate was 14.3% in the full GDMT group and 20.8% in the non-GDMT group (log-rank P=0.03).

The 2-year mortality rate and causes of death are shown in Figure 4. The rates of both cardiovascular and cardiocerebrovascular deaths were significantly lower in the full GDMT than non-GDMT group (4.2% vs. 9.5% [log-rank P=0.021] and 4.2% vs. 10.5% [log-rank P=0.007], respectively). However, the rate of non-cardiocerebrovascular deaths did not differ significantly between the full GDMT and non-GDMT groups (10.6% vs. 11.5%, respectively; log-rank P=0.53).

Figure 4.

(A) Cardiovascular, (B) cardiocerebrovascular, and (C) non-cardiocerebrovascular mortality within 2 years after endovascular therapy (EVT) in the full guideline-directed medical therapy (GDMT) and non-GDMT groups. The 2-year cardiovascular mortality rate was lower in the full GDMT than in the non-GDMT group (4.2% vs. 9.5%; log-rank P=0.021), as was the 2-year cardiocerebrovascular mortality rate (4.2% vs. 10.5%; log-rank P=0.007). However, non-cardiocerebrovascular mortality was similar in the full GDMT and non-GDMT groups (10.6% vs. 11.5%, respectively; log-rank P=0.53).

Figure 5 shows all-cause, cardiovascular, and cerebrovascular mortality rates within 2 years of EVT based on the number of drugs that comprise GDMT. Analysis of the matched group of 826 patients revealed significantly higher all-cause, cardiovascular, and cardiocerebrovascular mortality within 2 years among patients receiving ≤1 drug compared with patients receiving 2–3 drugs. Figure 6 shows the results of the interaction analyses for each subgroup, including the hazard ratios and 95% confidence intervals for all-cause mortality within 2 years for each subgroup. The effect of GDMT on all-cause death within 2 years in the matched population showed no interaction in each subgroup (all subgroups P<0.05).

Figure 5.

Two-year (A) all-cause, (B) cardiovascular, and (C) cardiocerebrovascular mortality after endovascular therapy (EVT) according to the number of components of guideline-directed medical therapy (GDMT; 1–3) in the matched population. The 2-year all-cause, cardiovascular, and cerebrovascular mortality rates were significantly higher in group with ≤1 GDMT components than in the 2- or 3-drug group (all-cause mortality: 38.9% vs. 14.5% and 14.3%, respectively [log-rank P<0.001]; cardiovascular mortality: 23.4% vs. 5.1% and 4.2%, respectively [log-rank P<0.001]; and cerebrovascular mortality: 23.4% vs. 6.5% vs. 4.2%, respectively [log-rank P<0.001]).

Figure 6.

Hazard ratios for full guideline-directed medical therapy (GDMT) for all-cause mortality in the matched population. No interaction was observed between the subgroups (P>0.05). ABI, ankle-brachial index; BMI, body mass index; CLTI, chronic limb-threatening ischemia; EF, ejection fraction; IC, intermittent claudication.

Discussion

In the present study, 2-year all-cause mortality rates differed significantly between patients who received and did not receive GDMT (14.3% vs. 20.8%, respectively). Compared with a US report on GDMT in patients undergoing EVT,⁶ the 2-year all-cause mortality rate was relatively low among Japanese patients with LEAD. However, patient background and treated lesions likely differ between the present and previous studies. Moreover, compared to reports from Korea on GDMT in patients with LEAD, the all-cause mortality in our patient population was higher (5-year all-cause mortality rate in Korea 2.8% for GDMT and 4.8% for non-GDMT).⁹ This difference may be because the study from Korea excluded high-risk patients with coronary artery disease or those with a history of treatment. In addition, the authors of that noted that their analyses may have included patients with incidentally discovered atherosclerosis.⁹ Therefore, our results may better reflect the actual status of LEAD in Asian populations.

The results of the present study suggest that GDMT may reduce cardiovascular and cardiocerebrovascular mortality in patients with LEAD undergoing EVT. To the best of our knowledge, this is the only study to demonstrate statistically significant differences in the potential of GDMT to reduce cardiovascular and cerebrovascular deaths in patients with LEAD who have undergone EVT. Although we did not demonstrate that GDMT was effective in preventing deaths other than those due to cardiovascular and cerebrovascular diseases, our results support the effectiveness of GDMT in reducing deaths from cardiovascular and cerebrovascular diseases, after matching was used to remove the effects of patient background. The reduction in deaths from cardiovascular and cerebrovascular diseases may be attributed to the administration of antiplatelet drugs, statins, ACEi, and ARBs. A meta-analysis by the Antithrombotic Trialists’ Collaboration reported a relatively low incidence of serious vascular events among patients with LEAD who received antiplatelet therapy compared with patients who did not receive antiplatelet therapy.¹⁰ Moreover, reports on statin use have demonstrated significant suppression of vascular events over the short and long term.¹¹^–¹⁴ Furthermore, ACEi and ARBs improve the prognosis of patients with LEAD.¹⁵^–¹⁷ The efficacy of these drugs as single agents has been reported previously.¹⁰^,¹¹^,¹⁵ However, few studies have reported the effectiveness of GDMT, which uses a combination of these 3 drugs, for patients with LEAD. Furthermore, to the best of our knowledge, no studies have examined the effectiveness of GDMT for Asian patients with LEAD, including Japanese patients who have undergone EVT. The risk of atherosclerotic vascular disease differs between Asian populations and other ethnic groups.⁷^,¹⁸ In recent years, the American Heart Association has also emphasized the importance of understanding the details of atherosclerotic diseases in Asian populations, to assess and manage the risks in individual patients,¹⁹ because many cases in the available literature do not individually survey Asian patients. Thus, the results of the present study may contribute to the management of risk in Asian patients with LEAD.

Although current Japanese guidelines for LEAD also strongly recommend the administration of an antiplatelet agent, statin, and ACEi/ARB, only 28.4% of patients enrolled in the present study received GDMT. Takahara et al. reported an approximately 3-fold higher mortality among patients with LEAD who underwent revascularization compared with patients with coronary artery disease.²⁰ In the present study, patients who received ≤1 GDMT component had a very poor prognosis. The fact that these patients comprised 14.7% of matched patients (n=122) highlights an important concern. Of the 122 patients who received ≤1 medication, 111 (91.0%) were only administered antiplatelet drugs. This may be explained by preadministration of EVT or a prescription for concomitant coronary artery disease. Our results suggest that the combined administration of the drugs that comprise the GDMT is important. In the US, where guidelines are clearly established, the low rate of prescribing GDMT for patients with LEAD is problematic, and fully understanding its effectiveness is necessary.²¹ In this context, the results of the present study further emphasize the effectiveness of GDMT. Jelani et al. also reported that the prescription rate of GDMT was low in patients with CLTI and in those with renal failure.²² In the prematched cohort in this study, the proportions of patients with CLTI and undergoing dialysis were significantly lower in the full GDMT than non-GDMT group (27.7% vs. 46.7% [P<0.001] and 23.9% vs. 43.0% [P<0.001], respectively). This difference can be explained to some degree by the assumption that patients with advanced disease do not receive GDMT. Our interaction analysis showed no difference in the effect of GDMT according to clinical phenotype or dialysis status. This suggests the need to more widely prescribe GDMT, even in patients with CLTI or those on dialysis. Based on these results, medical professionals specializing in vascular disease need to fully understand the importance of GDMT for LEAD as well as heart disease.²³^,²⁴ The results of the present study, which show the potential of GDMT despite the low prescription rate, suggest the importance of reviewing and improving the medical treatment of Japanese patients who have undergone EVT for FP lesions.

Study Limitations

This study has several limitations. First, this was a retrospective multicenter study, rather than a prospective or randomized study. Therefore, we performed propensity score matching; however, biases could not be completely ruled out. In addition, because the information analyzed in this study was extracted from an EVT registry for FP lesions, the target of the revascularization therapy was limited to FP lesions. Therefore, no information was available on interventions for lesions outside of the registry survey categories. However, because the lesion site was limited, we were able to match not only patient background but also lesion morphology and severity. FP lesions are the most common lesions in patients with LEAD.²⁵ Various interventional treatment devices have been developed for FP lesions, and the problem of restenosis presents many opportunities to treat patients who have undergone EVT for these lesions.²⁶^–²⁸ Therefore, the present study has high significance.

In addition, although the baseline characteristics after matching were similar, the tendency for higher usage rates of drug-eluting stents, drug-coated stents, and bare nitinol stents in the GDMT group and the significantly lower rate of use of drug-coated balloons are important and may have affected antiplatelet therapy. The Japanese guidelines recommend that the duration of dual antiplatelet therapy should be 1–3 months for patients treated with drug-coated balloons,²⁹ drug-eluting stents, drug-coated stents, or bare nitinol stents. In this study, the administration of antiplatelet drugs was left to the discretion of each operator, based on Japanese guidelines and attached documents. There was no significant difference in the use of stent grafts, which require long-term dual antiplatelet therapy, between the 2 groups. Furthermore, in this study, 95.9% (396/413) of patients in the non-GDMT group were taking antiplatelet drugs. Thus, most patients in the non-GDMT group were taking antiplatelet medications. In addition, the rate of dual antiplatelet therapy use was not significantly different between the full GDMT and non-GDMT groups (74.3% vs. 71.2%; P=0.31). Finally, because this was a retrospective study, we were unable to obtain information on compliance with oral medications. We only evaluated GDMT at the time of hospital discharge and did not have access to data on GDMT prescriptions or adherence after discharge, which could have affected the outcomes. Therefore, insufficient medication compliance may have resulted in underestimation of the effect of GDMT. Despite these limitations, the results of the present study are critical and support future prospective studies of GDMT.

Conclusions

The results of our study suggest that GDMT may improve all-cause, cardiovascular, and cerebrovascular mortality within 2 years after EVT in Japanese patients for FP lesions.

Acknowledgments

The authors thank Editage for English language editing a draft of this paper.

Sources of Funding

This study did not receive any specific funding.

Disclosures

T.N. is a consultant for Asahi Intecc, Becton, Dickinson, Boston Scientific, Cook Medical, Cordis, Kaneka Medix, Nipro, and OrbusNeich. All other authors have no conflicts of interest related to this paper.

IRB Information

This study was approved by the Ethics Committee of Tenyoukai Central Hospital (Approval no. R5-05) and was conducted in accordance with the Declaration of Helsinki. The ethics committee of each participating hospital also approved this study.

Data Availability

The deidentified participant data will be shared upon reasonable request. Requests for data sharing should be directed to the corresponding author. All datasets used are available, including the study protocol. Data will be shared after approval by the ethics committee of Tenyoukai Central Hospital. The data will be available until March 2030. Data will be shared with those wishing to access the data. Data analysis will be approved and data will be shared via email as an Excel file.

References

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