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Peripheral artery disease is associated with poor clinical outcome in patients with abdominal aortic aneurysm after endovascular aneurysm repair
International Journal of Cardiology 268 (2018) 208–213
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Peripheral artery disease is associated with poor clinical outcome in patients with abdominal aortic aneurysm after endovascular aneurysm repair☆ Oh-Hyun Lee a, Young-Guk Ko b,⁎, Chul-Min Ahn b, Dong-Ho Shin b, Jung-Sun Kim b, Byeong-Keuk Kim b, Donghoon Choi b, Do Yun Lee c, Myeong-Ki Hong b,d, Yangsoo Jang b,d a
Division of Cardiology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Gyeonggi-do, Republic of Korea Division of Cardiology, Department of Internal Medicine, & Cardiovascular Research Institute, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea c Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea d Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 30 April 2017 Received in revised form 19 February 2018 Accepted 21 March 2018
Keywords: Aneurysm Endovascular therapy Peripheral artery disease
a b s t r a c t Background: We investigated the effects of coronary artery disease (CAD) or peripheral artery disease (PAD) on clinical outcomes of patients with abdominal aortic aneurysm (AAA) treated with endovascular aortic aneurysm repair (EVAR). Methods: We retrospectively evaluated a total of 475 patients with AAA treated with EVAR at a single center. Patients were divided into three groups: group A (n = 166), patients without CAD or PAD; group B (n = 196), patients with CAD but without PAD; and group C (n = 113), patients with PAD regardless of CAD. The primary endpoint was the accumulated rate of major adverse cardiovascular and cerebrovascular event (MACCE), a composite of all-cause death, myocardial infarction (MI), or stroke. Results: The prevalence of CAD and PAD in patients with AAA was 55.8 and 23.8%, respectively. Patients were followed for 40.2 ± 35.3 months. Baseline characteristics were similar among the groups except for current smoking (A, 27.4%; B, 20.8%; C, 50.5%; p = 0.001). Three years after EVAR, the incidences of MACCE (A, 5.6%; B, 9.5%; C, 16.7%; p = 0.021) and stroke (A, 0%; B, 2.2%; C, 5.2%; p = 0.025) were highest in group C. All-cause death and aneurysm death did not differ among the groups. PAD [hazard ratio (HR) 2.88, 95% confidence interval (CI) 1.32–6.29, p = 0.008] and previous stroke (HR 4.39, 95% CI 1.94–9.93, p b 0.001) were independent predictors of MACCE. Conclusions: PAD was an independent risk factor of increased MACCE and stroke for patients with AAA undergoing EVAR. More intensive secondary prevention may be needed to reduce adverse cardiovascular events in AAA patients with PAD. © 2017 Elsevier B.V. All rights reserved.
1. Introduction The mechanisms that initiate and stimulate the progression of abdominal aortic aneurysm (AAA) are poorly understood. Previous studies suggest that atherosclerosis may play an important role in AAA pathogenesis. AAA and atherosclerosis share multiple risk factors such as smoking, hypertension, obesity, and family history [1]. However, it is unclear whether the association between atherosclerosis and AAA is
☆ The authors take responsibility for all aspects of the reliability and freedom from bias of the presented data and the discussed interpretation. ⁎ Corresponding author at: Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, 50 Yonsei-ro, Seodaemun-gu, 03722 Seoul, Republic of Korea. E-mail address: [email protected] (Y.-G. Ko).
https://doi.org/10.1016/j.ijcard.2018.03.109 0167-5273/© 2017 Elsevier B.V. All rights reserved.
causal or due to common risk factors. Registry studies report a high prevalence of atherosclerotic disease in patients with AAA, including coronary artery disease (CAD, 34.2–43%) and peripheral artery disease (PAD, 19–43.6%) [2–5]. Current guidelines recommended both open and endovascular repair as standard treatments for infrarenal AAA with suitable anatomy [6,7]. However, treatment of AAA has largely shifted to endovascular repair due to shorter hospital length stay, faster recovery to daily life activity, lower short-term morbidity and mortality rates compared to open surgery [8,9]. Several large randomized control trials reported favorable longterm mortality and low aneurysm-related mortality (0–2.3%) after endovascular aortic aneurysm repair (EVAR) [10–12]. Gooney et al. [13] reported that cardiovascular disease was the leading cause of late mortality after endovascular and open surgical repair of infra-renal AAA. However, there is paucity of data regarding clinical outcomes after
O.-H. Lee et al. / International Journal of Cardiology 268 (2018) 208–213
endovascular repair of AAA when the patient also has atherosclerotic diseases. This study investigates clinical outcomes for patients with AAA treated with EVAR who also have CAD or PAD.
2. Materials and methods 2.1. Study population This retrospective study included all 475 consecutive patients treated with EVAR in Severance Cardiovascular Hospital from January 2005 to May 2016, without specific exclusion criteria. Patients were divided into three groups according to the presence of concomitant CAD or PAD: group A (n = 166, 34.9%), group B (n = 196, 41.3%), and group C (n = 113, 23.8%). Group A included patients without CAD or PAD, group B included patients with CAD but without PAD, and group C included patients with PAD regardless of the presence of CAD. The study protocol conformed to the 1975 Declaration of Helsinki. The Institutional Review Board of Severance Hospital approved this study and waived the requirement for informed consent for this retrospective analysis.
2.2. Data collection Baseline clinical information was collected for the patients, including age, gender, risk factors, past medical history, and clinical presentation. We obtained the anatomical parameters of AAA using pre- and post-procedural computed tomography (CT), angiographic data, and procedural and outcome data. Follow-up involved outpatient clinic examinations at 30 days and 3 months after the procedure, and then every 6 to 12 months thereafter. Patients lost from regular clinical follow-up were contacted by telephone and asked about their clinical status. CAD was defined as at least one major epicardial artery with at least 50% stenosis, or a previous history of myocardial infarction (MI), coronary artery bypass surgery, or percutaneous coronary intervention. CAD was routinely screened before EVAR or at the same session using coronary angiography. However, in patients with moderate to severe renal failure independent of dialysis, we primarily performed non-invasive assessment of CAD such as echocardiography, an exercise stress test, or nuclear myocardial perfusion imaging. In those patients, CAD was considered present if a regional myocardial wall abnormality or thinning corresponding to a specific coronary artery territory was found on echocardiography, or a positive finding suggestive of myocardial ischemia was detected on a stress testing. PAD was defined as the presence of any one of the following parameters: ankle-brachial index (ABI) ≤ 0.90 in either leg, significant stenosis of ≥50% in the upper or lower extremity arteries, or history of previous vascular bypass or angioplasty. PAD was evaluated using CT angiography, which routinely included subclavian, iliac, and proximal femoral arteries. ABI measurements and additional imaging studies were performed for cases of suspicious symptomatic PAD. We utilized the following definitions: hostile neck, the presence of a short neck (distance between the lower renal artery and the aneurysm sac b 15 mm); angle neck, the angle between the longitudinal axis of the proximal neck and the longitudinal axis of the aneurysm sac N 60°; and diameter of the aneurysmal neck N28 mm. Obesity is defined as body mass index (BMI) ≥ 25 kg/m2 in Korea [14].
2.3. Study outcomes The primary outcome was the absence of major adverse cardiovascular and cerebrovascular events (MACCEs) at 3 years after the procedure, which was defined as a composite of all-cause death, myocardial infarction (MI), and stroke. Aneurysm-related mortality was defined as death from any cause within 30 days after the primary EVAR procedure, death within 30 days after any secondary intervention or surgical conversion, or any death involving aneurysm rupture or device complication. Secondary interventions included all surgical or endovascular interventions performed after the index procedure to resolve graft-related complications. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3 or type 5 [15].
2.4. Statistical analysis Continuous variables were expressed as mean ± SD and were compared using ANOVA. Categorical variables were expressed as percentages and were compared using chi-squared statistics or Fisher's exact test as indicated. Kaplan-Meier curves and estimates were computed using log-rank tests, and were used to compare clinical outcomes between groups for death, stroke, MI, systemic embolization, and major bleeding. Predictors were analyzed as follows. Each predictor was evaluated by univariate analysis using logistic regression models. Then, predictors with a p value b0.10 in the univariate analysis were included in a multivariate analysis to assess the independent effect of each predictor. Multicolinearity was assessed using linear regression analysis, where a variance inflation factor N 4.0 indicated potential intercorrelation among variables. A two-sided p value b0.05 was considered as statistically significant. Statistical analyses were performed with SPSS version 23.0 (SPSS Inc., Chicago, IL, USA).
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3. Results 3.1. Baseline characteristics The baseline demographic and clinical characteristics of the study population are presented in Table 1. Mean patient age was 76.3 ± 9.7 years (range, 45–97 years), and 89.5% (425/475) of patients were male. The prevalence of CAD and PAD among all 475 participants was 55.8% (265/475) and 23.8% (113/475), respectively, whereas 34.9% (166/475) of patients did not have concurrent CAD or PAD (group A). A total of 41.3% (196/475) of patients were diagnosed with only CAD (group B), and 23.8% (113/475) of patients were diagnosed with PAD regardless of concurrent CAD (group C). The baseline characteristics did not differ significantly among the three groups. No differences were observed among groups A, B, and C with respect to the prevalence of symptoms (22.9, 15.8, and 16.8%, respectively; p = 0.195); ruptured AAA (3.6, 3.1, and 2.7%, respectively; p = 0.898); maximal AAA diameter (60.1 ± 15.6, 60.1 ± 11.0, and 57.1 ± 9.8 mm, respectively; p = 0.365); hostile neck (35.5, 43.4, and 38.9%, respectively; p = 0.316); and medication at hospital discharge including antiplatelet agents (p = 0.700), statin (p = 0.826), angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blocker (ARB) (p = 0.590), beta-blocker (p = 0.117), calcium channel blocker (p = 0.107), and diuretics (p = 0.889). 3.2. Clinical outcomes The 3-year clinical outcomes of patients with AAA treated with EVAR and evaluated according to the presence/absence of concurrent CAD or PAD are presented in Table 2. Mean follow-up period was 40.2 ± 35.3 months for all patients, and there were no differences in mean follow-up times among the three groups. Of the 475 patients, 363 patients were available for 1-year follow-up and 240 patients for 3-year follow-up. Overall, there were 36 MACCEs (28 all-cause deaths, 7 aneurysm-related deaths, and 1 MI) and 8 strokes, which represented an event rate of 10.0% during 3 years after EVAR. Aneurysm-related mortality was reported in 1.7% of patients, whereas non-aneurysmrelated mortality was reported in 6.4% of patients. The non-aneurysmrelated deaths were caused by cardiovascular disease (38.1%, 8/21); malignant disease (23.8%, 5/21); and infectious disease (33.3%, 7/21). The event rates of MACCE (A, 5.6%; B, 9.5%; and C, 16.7%, p = 0.021) and stroke (A, 0%; B, 2.2%; and C, 5.2%, p = 0.025) significantly differed among the groups, and were highest in group C. Group C had significantly higher MACCE (p = 0.008) than group A, and a trend toward higher MACCE (p = 0.070) compared with that of group B (Fig. 1A–D). However, the MACCE rate was similar in groups A and B. The stroke rate (p = 0.008) also was higher in group C than in group A. However, stroke rate did not significantly differ between groups A and B and between groups B and C. The rates of all-cause mortality (A, 5.6%; B, 7.4%; C, 12.0%; p = 0.791), aneurysm-related mortality (A, 2.3%; B, 1.1%; C, 1.8%; p = 0.791), cardiovascular death (A, 0.9%; B, 2.6%; C, 5.0%; p = 0.263), and major bleeding (A, 0.7%; B, 0.6%; C, 0%; p = 0.723) did not significantly differ among the three groups. 3.3. Risk factors for MACCE and all-cause death Univariate analyses indicated that the following parameters were associated with MACCE: old age ≥ 80 years (HR 2.06, 95% CI 1.07–3.98), obesity defined as BMI ≥ 25 kg/m2 (HR 0.43, 95% CI 0.18–1.41), concurrent PAD (HR 2.36, 95% CI 1.22–4.55), congestive heart failure (CHF) (HR 3.09, 95% CI 0.95–10.08), previous stroke (HR 3.45, 95% CI 1.66–7.15), maximal AAA diameter ≥ 60 mm (HR 2.10, 95% CI 1.02–4.34), hostile neck (HR 1.95, 95% CI 1.01–3.76), and no use of antiplatelet agents (HR 4.78, 95% CI 1.98–11.51). Multivariate analyses identified the following parameters as independent risk factors for MACCE: concurrent PAD (HR 3.17, 95% CI
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Table 1 Baseline patient characteristics.
Age, years Male BMI, kg/m2 Ex-/Current smoker Hypertension Diabetes mellitus Dyslipidemia COPD CKD Permanent dialysis Previous stroke Malignancy CAD PAD Symptomatic AAA Ruptured AAA Maximal AAA diameter, mm Neck diameter over 60 mm Hostile neck Medication at hospital discharge Aspirin/Clopidogrel Statin ACEi/ARB Beta-blocker Calcium channel blocker Diuretics
Total patients (N = 475)
Group A (N = 166)
Group B (N = 196)
Group C (N = 113)
p value⁎
76.3 ± 9.7 425 (89.5) 23.7 ± 4.7 262 (58.2) 339 (71.4) 106 (22.3) 142 (29.9) 23 (4.8) 46 (9.7) 7 (1.5) 47 (9.9) 68 (14.3) 265 (55.8) 113 (23.8) 88 (18.5) 15 (3.2) 59.4 ± 12.6 134 (28.2) 188 (39.5)
76.3 ± 11.5 148 (89.2) 23.5 ± 3.3 93 (59.2) 113 (68.1) 26 (15.7) 45 (27.1) 9 (5.4) 12 (7.2) 1 (0.6) 12 (7.2) 30 (18.1)
76.1 ± 7.7 174 (88.8) 24.2 ± 6.0 98 (53.8) 147 (75) 54 (27.6) 61 (31.1) 8 (4.1) 19 (9.7) 4 (2.0) 22 (11.2) 25 (12.8)
76.6 ± 9.9 103 (91.2) 23.0 ± 3.9 71 (64.0) 79 (69.9) 26 (23.0) 36 (31.9) 6 (5.3) 15 (13.3) 2 (1.8) 13 (11.5) 13 (11.5)
0.876 0.754 0.082 0.223 0.322 0.067 0.628 0.810 0.375 0.507 0.318 0.247
38 (22.9) 6 (3.6) 60.1 ± 15.6 46 (27.7) 59 (35.5)
31 (15.8) 6 (3.1) 60.1 ± 11.0 59 (30.1) 85 (43.4)
19 (16.8) 3 (2.7) 57.1 ± 9.8 29 (25.7) 44 (38.9)
0.195 0.898 0.365 0.695 0.316
445 (93.7) 344 (72.4) 257 (54.1) 244 (51.4) 142 (29.9) 58 (12.2)
154 (92.8) 118 (71.1) 85 (51.2) 79 (47.6) 40 (24.1) 19 (11.4)
186 (94.9) 145 (74.0) 108 (55.1) 112 (57.1) 67 (34.2) 24 (12.2)
105 (92.9) 81 (71.7) 64 (56.6) 53 (46.9) 35 (31.0) 15 (13.3)
0.700 0.826 0.590 0.117 0.107 0.889
Data are presented as mean ± SD or percentage (%). BMI: body mass index; COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease; CAD: coronary artery disease; PAD: peripheral artery disease; AAA: abdominal aortic aneurysm; ACEi: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blocker; SD: standard variation. ⁎ p value comparison among the three patient groups.
1.47–6.84) and previous stroke (HR 4.24, 95% CI 1.88–9.53) (Table 3). PAD was not a predictor for all-cause mortality at 3 years after the EVAR procedure. Obesity (BMI ≥ 25 kg/m2, HR 0.16, 95% CI 0.04–0.71, p = 0.016) was identified as independent predictors for all-cause mortality (Supplementary Table 1). 4. Discussion The main result of this study is that CAD (55.8%) and PAD (23.8%) are diseases that frequently occur in combination with AAA. All-cause and aneurysm-related deaths did not significantly differ among patients grouped with respect to the co-occurrence of CAD and/or PAD. By contrast, the incidences of MACCE (A, 5.6%; B, 9.5%; C 16.7%; p = 0.021) and stroke (A, 0%; B, 2.2%; C, 5.2%; p = 0.025) were highest in patients with PAD. The co-occurrences of PAD or previous stroke with AAA were identified as independent predictors of MACCE. To the best of our
knowledge, this is the first clinical study evaluating the long-term prognosis of patients with AAA after EVAR according to presence or absence of concurrent CAD or PAD. The early (1.1% at 30 days) and intermediate (8.0% at 3 years) rates of all-cause mortality in the present study were comparable (0.2–1.7% at 30 days and 8–15% at 2 years) with those reported in previous trials (DREAM, OVER, and EVAR-1 trials) [10,11,16,17]. Our observed aneurysm-related mortality rate was low (1.7%) at 3 years, which was comparable (1.4–2.1%) with the 2-year results of OVER and DREAM trials. The prevalence of CAD (55.8%) and PAD (23.8%) in our study was similar to that of previous studies, which ranged from 34.2 to 43% and 19 to 43.6%, respectively [2,4,5]. PAD is an advanced atherosclerotic disease with poor long-term outcome, with 30% all-cause mortality at 5 years after the diagnosis of lower extremity artery disease [18]. Patients with PAD have a greater incidence of MI, stroke, and cardiovascular death, resulting in higher rates of all-cause mortality compared
Table 2 Three-year clinical outcomes after EVAR.
Follow-up duration, months MACCEa All-cause mortality Aneurysm-related mortality Non-aneurysm-related mortality Cardiovascular Malignancy Other 30-day mortality MI Stroke Systemic embolization Major bleeding
Total patients (N = 475)
Group A (N = 166)
Group B (N = 196)
Group C (N = 113)
p value
40.2 ± 35.3 36 (10.0) 28 (8.0) 7 (1.7) 21 (6.4) 8 (2.7) 5 (1.7) 8 (2.2) 5 (1.1) 1 (0.3) 8 (2.2) 3 (0.8) 2 (0.5)
40.1 ± 35.8 7 (5.6) 7 (5.6) 3 (2.3) 4 (3.3) 1 (0.9) 1 (0.9) 2 (1.6) 1 (0.6) 0 (0) 0 (0) 1 (0.7) 1 (0.7)
37.2 ± 34.1 13 (9.5) 10 (7.4) 2 (1.1) 8 (6.4) 3 (2.6) 1 (1.3) 4 (2.6) 2 (1.0) 1 (0.7) 3 (2.2) 1 (1.0) 1 (0.6)
45.9 ± 36.2 16 (16.7) 11 (12.0) 2 (1.8) 9 (10.4) 4 (5.0) 3 (3.6) 2 (2.1) 2 (1.8) 0 (0) 5 (5.2) 1 (0.9) 0 (0)
0.114 0.021 0.240 0.791 0.164 0.263 0.246 0.840 0.647 0.474 0.025 0.947 0.723
Data are presented as mean ± SD or percentage (%). Percentages were computed using Kaplan-Meier estimates and p values were computed with log-rank test. MACCE: major adverse cardiovascular and cerebrovascular events; MI: myocardial infarction; SD: standard variation. a MACCE including all-cause death, myocardial infarction, and stroke.
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Fig. 1. Accumulated event rates: (A) major adverse cardiovascular cerebrovascular event (MACCE); (B) all-cause death; (C) aneurysm-related death; (D) stroke.
with those of patients without PAD [11,19–22]. In the present study, the co-occurrence of PAD in AAA patients treated with EVAR was significantly associated with increased risk of MACCE, which was driven primarily by stroke. The stroke rate (2.2%) in our study was comparable with that reported in previous studies. Stroke rates ranged from 1.6–3.8% in randomized clinical trials [23]. In our study, the rates of MI and cardiovascular mortality at 3 years after EVAR were low (0.3 and 2.7%, respectively), and did not significantly differ among the patient groups. These results may be explained by our protocol. CAD was routinely screened before EVAR using coronary angiography, and significant CAD was treated with percutaneous coronary intervention (PCI) or bypass surgery. In addition, prescriptions of antiplatelet drugs and statins may have reduced the incidences of MI or cardiovascular mortality. The leading causes of mortality in AAA patients after EVAR in our study were non-cardiovascular diseases, such as malignancy or infection, rather than cardiovascular disease. Randomized trials reported that cardiovascular death was the most common cause of death. However, cancer was reported as the primary cause of death in a large-scale retrospective study using U.S. Medicare data [24]. A recent meta-analysis evaluated the prognostic factors influencing late survival following open surgical repair or EVAR [25]. This study found that cerebrovascular disease (HR 1.57, 95% CI 1.40–1.77) and peripheral artery disease (HR 1.36, 95% CI 1.18–1.58) were associated
with the increased risk of mortality. Other clinical variables such as age, female gender, heart failure, ischemic heart disease, COPD, chronic kidney disease, and diabetes also were identified as risk factors for late mortality in AAA patients after aortic repair. In our study, PAD was not a predictor for all-cause mortality. Obesity (BMI N 25 kg/m2) was a protective factor for all-cause mortality (HR 0.351, 95% CI 0.14–0.88, p = 0.026). Previous studies reported that lower BMI was associated with reduced late survival after open repair or EVAR [26–29]. On the other hand, overweight and mild obesity have shown to be associated with reduced cardiovascular and total mortality in patients with CAD suggesting an obesity paradox [30]. Higher catabolic reserve and favorable neurohormonal, inflammatory, and hemodynamic responses may confer protective effect against cardiovascular events in obese patients [31,32]. However, disease-related weight loss and higher mortality in patients with advanced cardiovascular disease may lead to a bias. To date, the association between obesity and mortality in patients with cardiovascular disease remains still inconclusive. The different risk factors for mortality identified by different studies may be due to differences in patient demographics and different definitions for risk factors among the studies. This study has several limitations. First, this is a retrospective analysis of data from a single center. Second, detailed anatomical factors of AAA were not included in the analyses because of low rates of
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Table 3 Univariate and multivariate analyses for predictors of 3-year MACCE after EVAR. Variable
Age ≥ 80 years Male BMI N 25 kg/m2 Ex-/Current smoker Anemiaa HTN DM CKD CAD PAD CHF Previous stroke COPD Aneurysm diameter ≥ 60 mm Hostile neck CRP No antiplatelet agents No statin No ACEi/ARB No beta-blocker No CCB No diuretics
Univariate analysis
Multivariate analysis
HR (95% CI)
p value
HR (95% CI)
p value
2.06 (1.07–3.98) 2.02 (0.49–8.41) 0.43 (0.178–1.41) 1.42 (0.70–2.86)
0.031 0.334 0.063 0.332
1.57 (0.72–3.41)
0.254
0.42 (0.16–1.16)
0.094
0.98 (0.51–1.91) 1.44 (0.66–3.17) 0.63 (0.24–1.61) 1.07 (0.33–3.49) 1.06 (0.55–2.06) 2.36 (1.22–4.55) 3.09 (0.95–10.08) 3.45 (1.66–7.15) 1.99 (0.61–6.49) 2.10 (1.02–4.34)
0.962 0.361 0.333 0.911 0.859 0.011 0.061 0.001 0.254 0.044
2.88 (1.32–6.29) 2.60 (0.74–9.14) 4.39 (1.94–9.93)
0.008 0.136 b0.001
2.09 (0.95–4.60)
0.068
1.95 (1.01–3.76) 1.01 (0.99–1.04) 4.78 (1.98–11.51)
0.047 0.317 b0.001
1.88 (0.86–4.09)
0.114
2.25 (0.52–9.79)
0.278
1.64 (0.84–3.21) 1.74 (0.90–3.36) 1.32 (0.69–2.55) 1.33 (0.63–2.83) 0.57 (0.25–1.29)
0.148 0.100 0.402 0.455 0.175
a Anemia: male, b13.5 g/dL; female, b12.0 g/dL; BMI: body mass index; CRP: C-reactive protein; HTN: hypertension; CKD: chronic kidney disease; CAD: coronary artery disease; PAD: peripheral artery disease; CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; EVAR: endovascular aortic aneurysm repair; ACEi: angiotensinconverting enzyme inhibitors; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; HR: hazard ratio; CI: confidence interval.
aneurysm-related event. Third, PAD was not rigorously screened in all patients before EVAR, and its prevalence in our patient cohort may have been underestimated. Our CT protocol included iliac arteries and only proximal segments of femoral arteries. In cases of suspected PAD, ABI and additional imaging studies were performed. Fourth, factors that are known to affect the clinical outcome of EVAR treatment for AAA were not analyzed in this retrospective study, including patient adherence and duration of medications, blood pressure control, and lifestyle habits. Fifth, although stroke is included as an event component of the primary endpoint, MACCE, stroke risk assessment such as carotid artery imaging and holter monitoring for paroxysmal atrial fibrillation were not performed. In conclusion, co-occurrence of PAD in AAA patients treated with EVAR led to poor prognosis in terms of increased MACCE and stroke. More active secondary prevention may be needed to reduce adverse cardiovascular events in AAA patients with PAD. Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2018.03.109. Conflict of interest The authors have no conflicts of interest to declare. Author contributions OHL collected and interpreted data, performed statistical analyses, and wrote the paper. YGK was responsible for the conception and designed the study, wrote the paper, and discussed the paper. CMA, DHS, JSK, BKK, DC, DYL, MKH, YJ collected data, and discussed the paper. Funding This research was supported by grants of the Korea Health Technology R&D Project through the Korea Health Industry Development
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Peripheral artery disease is associated with poor clinical outcome in patients with abdominal aortic aneurysm after endovascular aneurysm repair☆ Oh-Hyun Lee a, Young-Guk Ko b,⁎, Chul-Min Ahn b, Dong-Ho Shin b, Jung-Sun Kim b, Byeong-Keuk Kim b, Donghoon Choi b, Do Yun Lee c, Myeong-Ki Hong b,d, Yangsoo Jang b,d a
Division of Cardiology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Gyeonggi-do, Republic of Korea Division of Cardiology, Department of Internal Medicine, & Cardiovascular Research Institute, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea c Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea d Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 30 April 2017 Received in revised form 19 February 2018 Accepted 21 March 2018
Keywords: Aneurysm Endovascular therapy Peripheral artery disease
a b s t r a c t Background: We investigated the effects of coronary artery disease (CAD) or peripheral artery disease (PAD) on clinical outcomes of patients with abdominal aortic aneurysm (AAA) treated with endovascular aortic aneurysm repair (EVAR). Methods: We retrospectively evaluated a total of 475 patients with AAA treated with EVAR at a single center. Patients were divided into three groups: group A (n = 166), patients without CAD or PAD; group B (n = 196), patients with CAD but without PAD; and group C (n = 113), patients with PAD regardless of CAD. The primary endpoint was the accumulated rate of major adverse cardiovascular and cerebrovascular event (MACCE), a composite of all-cause death, myocardial infarction (MI), or stroke. Results: The prevalence of CAD and PAD in patients with AAA was 55.8 and 23.8%, respectively. Patients were followed for 40.2 ± 35.3 months. Baseline characteristics were similar among the groups except for current smoking (A, 27.4%; B, 20.8%; C, 50.5%; p = 0.001). Three years after EVAR, the incidences of MACCE (A, 5.6%; B, 9.5%; C, 16.7%; p = 0.021) and stroke (A, 0%; B, 2.2%; C, 5.2%; p = 0.025) were highest in group C. All-cause death and aneurysm death did not differ among the groups. PAD [hazard ratio (HR) 2.88, 95% confidence interval (CI) 1.32–6.29, p = 0.008] and previous stroke (HR 4.39, 95% CI 1.94–9.93, p b 0.001) were independent predictors of MACCE. Conclusions: PAD was an independent risk factor of increased MACCE and stroke for patients with AAA undergoing EVAR. More intensive secondary prevention may be needed to reduce adverse cardiovascular events in AAA patients with PAD. © 2017 Elsevier B.V. All rights reserved.
1. Introduction The mechanisms that initiate and stimulate the progression of abdominal aortic aneurysm (AAA) are poorly understood. Previous studies suggest that atherosclerosis may play an important role in AAA pathogenesis. AAA and atherosclerosis share multiple risk factors such as smoking, hypertension, obesity, and family history [1]. However, it is unclear whether the association between atherosclerosis and AAA is
☆ The authors take responsibility for all aspects of the reliability and freedom from bias of the presented data and the discussed interpretation. ⁎ Corresponding author at: Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, 50 Yonsei-ro, Seodaemun-gu, 03722 Seoul, Republic of Korea. E-mail address: [email protected] (Y.-G. Ko).
https://doi.org/10.1016/j.ijcard.2018.03.109 0167-5273/© 2017 Elsevier B.V. All rights reserved.
causal or due to common risk factors. Registry studies report a high prevalence of atherosclerotic disease in patients with AAA, including coronary artery disease (CAD, 34.2–43%) and peripheral artery disease (PAD, 19–43.6%) [2–5]. Current guidelines recommended both open and endovascular repair as standard treatments for infrarenal AAA with suitable anatomy [6,7]. However, treatment of AAA has largely shifted to endovascular repair due to shorter hospital length stay, faster recovery to daily life activity, lower short-term morbidity and mortality rates compared to open surgery [8,9]. Several large randomized control trials reported favorable longterm mortality and low aneurysm-related mortality (0–2.3%) after endovascular aortic aneurysm repair (EVAR) [10–12]. Gooney et al. [13] reported that cardiovascular disease was the leading cause of late mortality after endovascular and open surgical repair of infra-renal AAA. However, there is paucity of data regarding clinical outcomes after
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endovascular repair of AAA when the patient also has atherosclerotic diseases. This study investigates clinical outcomes for patients with AAA treated with EVAR who also have CAD or PAD.
2. Materials and methods 2.1. Study population This retrospective study included all 475 consecutive patients treated with EVAR in Severance Cardiovascular Hospital from January 2005 to May 2016, without specific exclusion criteria. Patients were divided into three groups according to the presence of concomitant CAD or PAD: group A (n = 166, 34.9%), group B (n = 196, 41.3%), and group C (n = 113, 23.8%). Group A included patients without CAD or PAD, group B included patients with CAD but without PAD, and group C included patients with PAD regardless of the presence of CAD. The study protocol conformed to the 1975 Declaration of Helsinki. The Institutional Review Board of Severance Hospital approved this study and waived the requirement for informed consent for this retrospective analysis.
2.2. Data collection Baseline clinical information was collected for the patients, including age, gender, risk factors, past medical history, and clinical presentation. We obtained the anatomical parameters of AAA using pre- and post-procedural computed tomography (CT), angiographic data, and procedural and outcome data. Follow-up involved outpatient clinic examinations at 30 days and 3 months after the procedure, and then every 6 to 12 months thereafter. Patients lost from regular clinical follow-up were contacted by telephone and asked about their clinical status. CAD was defined as at least one major epicardial artery with at least 50% stenosis, or a previous history of myocardial infarction (MI), coronary artery bypass surgery, or percutaneous coronary intervention. CAD was routinely screened before EVAR or at the same session using coronary angiography. However, in patients with moderate to severe renal failure independent of dialysis, we primarily performed non-invasive assessment of CAD such as echocardiography, an exercise stress test, or nuclear myocardial perfusion imaging. In those patients, CAD was considered present if a regional myocardial wall abnormality or thinning corresponding to a specific coronary artery territory was found on echocardiography, or a positive finding suggestive of myocardial ischemia was detected on a stress testing. PAD was defined as the presence of any one of the following parameters: ankle-brachial index (ABI) ≤ 0.90 in either leg, significant stenosis of ≥50% in the upper or lower extremity arteries, or history of previous vascular bypass or angioplasty. PAD was evaluated using CT angiography, which routinely included subclavian, iliac, and proximal femoral arteries. ABI measurements and additional imaging studies were performed for cases of suspicious symptomatic PAD. We utilized the following definitions: hostile neck, the presence of a short neck (distance between the lower renal artery and the aneurysm sac b 15 mm); angle neck, the angle between the longitudinal axis of the proximal neck and the longitudinal axis of the aneurysm sac N 60°; and diameter of the aneurysmal neck N28 mm. Obesity is defined as body mass index (BMI) ≥ 25 kg/m2 in Korea [14].
2.3. Study outcomes The primary outcome was the absence of major adverse cardiovascular and cerebrovascular events (MACCEs) at 3 years after the procedure, which was defined as a composite of all-cause death, myocardial infarction (MI), and stroke. Aneurysm-related mortality was defined as death from any cause within 30 days after the primary EVAR procedure, death within 30 days after any secondary intervention or surgical conversion, or any death involving aneurysm rupture or device complication. Secondary interventions included all surgical or endovascular interventions performed after the index procedure to resolve graft-related complications. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3 or type 5 [15].
2.4. Statistical analysis Continuous variables were expressed as mean ± SD and were compared using ANOVA. Categorical variables were expressed as percentages and were compared using chi-squared statistics or Fisher's exact test as indicated. Kaplan-Meier curves and estimates were computed using log-rank tests, and were used to compare clinical outcomes between groups for death, stroke, MI, systemic embolization, and major bleeding. Predictors were analyzed as follows. Each predictor was evaluated by univariate analysis using logistic regression models. Then, predictors with a p value b0.10 in the univariate analysis were included in a multivariate analysis to assess the independent effect of each predictor. Multicolinearity was assessed using linear regression analysis, where a variance inflation factor N 4.0 indicated potential intercorrelation among variables. A two-sided p value b0.05 was considered as statistically significant. Statistical analyses were performed with SPSS version 23.0 (SPSS Inc., Chicago, IL, USA).
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3. Results 3.1. Baseline characteristics The baseline demographic and clinical characteristics of the study population are presented in Table 1. Mean patient age was 76.3 ± 9.7 years (range, 45–97 years), and 89.5% (425/475) of patients were male. The prevalence of CAD and PAD among all 475 participants was 55.8% (265/475) and 23.8% (113/475), respectively, whereas 34.9% (166/475) of patients did not have concurrent CAD or PAD (group A). A total of 41.3% (196/475) of patients were diagnosed with only CAD (group B), and 23.8% (113/475) of patients were diagnosed with PAD regardless of concurrent CAD (group C). The baseline characteristics did not differ significantly among the three groups. No differences were observed among groups A, B, and C with respect to the prevalence of symptoms (22.9, 15.8, and 16.8%, respectively; p = 0.195); ruptured AAA (3.6, 3.1, and 2.7%, respectively; p = 0.898); maximal AAA diameter (60.1 ± 15.6, 60.1 ± 11.0, and 57.1 ± 9.8 mm, respectively; p = 0.365); hostile neck (35.5, 43.4, and 38.9%, respectively; p = 0.316); and medication at hospital discharge including antiplatelet agents (p = 0.700), statin (p = 0.826), angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blocker (ARB) (p = 0.590), beta-blocker (p = 0.117), calcium channel blocker (p = 0.107), and diuretics (p = 0.889). 3.2. Clinical outcomes The 3-year clinical outcomes of patients with AAA treated with EVAR and evaluated according to the presence/absence of concurrent CAD or PAD are presented in Table 2. Mean follow-up period was 40.2 ± 35.3 months for all patients, and there were no differences in mean follow-up times among the three groups. Of the 475 patients, 363 patients were available for 1-year follow-up and 240 patients for 3-year follow-up. Overall, there were 36 MACCEs (28 all-cause deaths, 7 aneurysm-related deaths, and 1 MI) and 8 strokes, which represented an event rate of 10.0% during 3 years after EVAR. Aneurysm-related mortality was reported in 1.7% of patients, whereas non-aneurysmrelated mortality was reported in 6.4% of patients. The non-aneurysmrelated deaths were caused by cardiovascular disease (38.1%, 8/21); malignant disease (23.8%, 5/21); and infectious disease (33.3%, 7/21). The event rates of MACCE (A, 5.6%; B, 9.5%; and C, 16.7%, p = 0.021) and stroke (A, 0%; B, 2.2%; and C, 5.2%, p = 0.025) significantly differed among the groups, and were highest in group C. Group C had significantly higher MACCE (p = 0.008) than group A, and a trend toward higher MACCE (p = 0.070) compared with that of group B (Fig. 1A–D). However, the MACCE rate was similar in groups A and B. The stroke rate (p = 0.008) also was higher in group C than in group A. However, stroke rate did not significantly differ between groups A and B and between groups B and C. The rates of all-cause mortality (A, 5.6%; B, 7.4%; C, 12.0%; p = 0.791), aneurysm-related mortality (A, 2.3%; B, 1.1%; C, 1.8%; p = 0.791), cardiovascular death (A, 0.9%; B, 2.6%; C, 5.0%; p = 0.263), and major bleeding (A, 0.7%; B, 0.6%; C, 0%; p = 0.723) did not significantly differ among the three groups. 3.3. Risk factors for MACCE and all-cause death Univariate analyses indicated that the following parameters were associated with MACCE: old age ≥ 80 years (HR 2.06, 95% CI 1.07–3.98), obesity defined as BMI ≥ 25 kg/m2 (HR 0.43, 95% CI 0.18–1.41), concurrent PAD (HR 2.36, 95% CI 1.22–4.55), congestive heart failure (CHF) (HR 3.09, 95% CI 0.95–10.08), previous stroke (HR 3.45, 95% CI 1.66–7.15), maximal AAA diameter ≥ 60 mm (HR 2.10, 95% CI 1.02–4.34), hostile neck (HR 1.95, 95% CI 1.01–3.76), and no use of antiplatelet agents (HR 4.78, 95% CI 1.98–11.51). Multivariate analyses identified the following parameters as independent risk factors for MACCE: concurrent PAD (HR 3.17, 95% CI
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Table 1 Baseline patient characteristics.
Age, years Male BMI, kg/m2 Ex-/Current smoker Hypertension Diabetes mellitus Dyslipidemia COPD CKD Permanent dialysis Previous stroke Malignancy CAD PAD Symptomatic AAA Ruptured AAA Maximal AAA diameter, mm Neck diameter over 60 mm Hostile neck Medication at hospital discharge Aspirin/Clopidogrel Statin ACEi/ARB Beta-blocker Calcium channel blocker Diuretics
Total patients (N = 475)
Group A (N = 166)
Group B (N = 196)
Group C (N = 113)
p value⁎
76.3 ± 9.7 425 (89.5) 23.7 ± 4.7 262 (58.2) 339 (71.4) 106 (22.3) 142 (29.9) 23 (4.8) 46 (9.7) 7 (1.5) 47 (9.9) 68 (14.3) 265 (55.8) 113 (23.8) 88 (18.5) 15 (3.2) 59.4 ± 12.6 134 (28.2) 188 (39.5)
76.3 ± 11.5 148 (89.2) 23.5 ± 3.3 93 (59.2) 113 (68.1) 26 (15.7) 45 (27.1) 9 (5.4) 12 (7.2) 1 (0.6) 12 (7.2) 30 (18.1)
76.1 ± 7.7 174 (88.8) 24.2 ± 6.0 98 (53.8) 147 (75) 54 (27.6) 61 (31.1) 8 (4.1) 19 (9.7) 4 (2.0) 22 (11.2) 25 (12.8)
76.6 ± 9.9 103 (91.2) 23.0 ± 3.9 71 (64.0) 79 (69.9) 26 (23.0) 36 (31.9) 6 (5.3) 15 (13.3) 2 (1.8) 13 (11.5) 13 (11.5)
0.876 0.754 0.082 0.223 0.322 0.067 0.628 0.810 0.375 0.507 0.318 0.247
38 (22.9) 6 (3.6) 60.1 ± 15.6 46 (27.7) 59 (35.5)
31 (15.8) 6 (3.1) 60.1 ± 11.0 59 (30.1) 85 (43.4)
19 (16.8) 3 (2.7) 57.1 ± 9.8 29 (25.7) 44 (38.9)
0.195 0.898 0.365 0.695 0.316
445 (93.7) 344 (72.4) 257 (54.1) 244 (51.4) 142 (29.9) 58 (12.2)
154 (92.8) 118 (71.1) 85 (51.2) 79 (47.6) 40 (24.1) 19 (11.4)
186 (94.9) 145 (74.0) 108 (55.1) 112 (57.1) 67 (34.2) 24 (12.2)
105 (92.9) 81 (71.7) 64 (56.6) 53 (46.9) 35 (31.0) 15 (13.3)
0.700 0.826 0.590 0.117 0.107 0.889
Data are presented as mean ± SD or percentage (%). BMI: body mass index; COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease; CAD: coronary artery disease; PAD: peripheral artery disease; AAA: abdominal aortic aneurysm; ACEi: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blocker; SD: standard variation. ⁎ p value comparison among the three patient groups.
1.47–6.84) and previous stroke (HR 4.24, 95% CI 1.88–9.53) (Table 3). PAD was not a predictor for all-cause mortality at 3 years after the EVAR procedure. Obesity (BMI ≥ 25 kg/m2, HR 0.16, 95% CI 0.04–0.71, p = 0.016) was identified as independent predictors for all-cause mortality (Supplementary Table 1). 4. Discussion The main result of this study is that CAD (55.8%) and PAD (23.8%) are diseases that frequently occur in combination with AAA. All-cause and aneurysm-related deaths did not significantly differ among patients grouped with respect to the co-occurrence of CAD and/or PAD. By contrast, the incidences of MACCE (A, 5.6%; B, 9.5%; C 16.7%; p = 0.021) and stroke (A, 0%; B, 2.2%; C, 5.2%; p = 0.025) were highest in patients with PAD. The co-occurrences of PAD or previous stroke with AAA were identified as independent predictors of MACCE. To the best of our
knowledge, this is the first clinical study evaluating the long-term prognosis of patients with AAA after EVAR according to presence or absence of concurrent CAD or PAD. The early (1.1% at 30 days) and intermediate (8.0% at 3 years) rates of all-cause mortality in the present study were comparable (0.2–1.7% at 30 days and 8–15% at 2 years) with those reported in previous trials (DREAM, OVER, and EVAR-1 trials) [10,11,16,17]. Our observed aneurysm-related mortality rate was low (1.7%) at 3 years, which was comparable (1.4–2.1%) with the 2-year results of OVER and DREAM trials. The prevalence of CAD (55.8%) and PAD (23.8%) in our study was similar to that of previous studies, which ranged from 34.2 to 43% and 19 to 43.6%, respectively [2,4,5]. PAD is an advanced atherosclerotic disease with poor long-term outcome, with 30% all-cause mortality at 5 years after the diagnosis of lower extremity artery disease [18]. Patients with PAD have a greater incidence of MI, stroke, and cardiovascular death, resulting in higher rates of all-cause mortality compared
Table 2 Three-year clinical outcomes after EVAR.
Follow-up duration, months MACCEa All-cause mortality Aneurysm-related mortality Non-aneurysm-related mortality Cardiovascular Malignancy Other 30-day mortality MI Stroke Systemic embolization Major bleeding
Total patients (N = 475)
Group A (N = 166)
Group B (N = 196)
Group C (N = 113)
p value
40.2 ± 35.3 36 (10.0) 28 (8.0) 7 (1.7) 21 (6.4) 8 (2.7) 5 (1.7) 8 (2.2) 5 (1.1) 1 (0.3) 8 (2.2) 3 (0.8) 2 (0.5)
40.1 ± 35.8 7 (5.6) 7 (5.6) 3 (2.3) 4 (3.3) 1 (0.9) 1 (0.9) 2 (1.6) 1 (0.6) 0 (0) 0 (0) 1 (0.7) 1 (0.7)
37.2 ± 34.1 13 (9.5) 10 (7.4) 2 (1.1) 8 (6.4) 3 (2.6) 1 (1.3) 4 (2.6) 2 (1.0) 1 (0.7) 3 (2.2) 1 (1.0) 1 (0.6)
45.9 ± 36.2 16 (16.7) 11 (12.0) 2 (1.8) 9 (10.4) 4 (5.0) 3 (3.6) 2 (2.1) 2 (1.8) 0 (0) 5 (5.2) 1 (0.9) 0 (0)
0.114 0.021 0.240 0.791 0.164 0.263 0.246 0.840 0.647 0.474 0.025 0.947 0.723
Data are presented as mean ± SD or percentage (%). Percentages were computed using Kaplan-Meier estimates and p values were computed with log-rank test. MACCE: major adverse cardiovascular and cerebrovascular events; MI: myocardial infarction; SD: standard variation. a MACCE including all-cause death, myocardial infarction, and stroke.
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Fig. 1. Accumulated event rates: (A) major adverse cardiovascular cerebrovascular event (MACCE); (B) all-cause death; (C) aneurysm-related death; (D) stroke.
with those of patients without PAD [11,19–22]. In the present study, the co-occurrence of PAD in AAA patients treated with EVAR was significantly associated with increased risk of MACCE, which was driven primarily by stroke. The stroke rate (2.2%) in our study was comparable with that reported in previous studies. Stroke rates ranged from 1.6–3.8% in randomized clinical trials [23]. In our study, the rates of MI and cardiovascular mortality at 3 years after EVAR were low (0.3 and 2.7%, respectively), and did not significantly differ among the patient groups. These results may be explained by our protocol. CAD was routinely screened before EVAR using coronary angiography, and significant CAD was treated with percutaneous coronary intervention (PCI) or bypass surgery. In addition, prescriptions of antiplatelet drugs and statins may have reduced the incidences of MI or cardiovascular mortality. The leading causes of mortality in AAA patients after EVAR in our study were non-cardiovascular diseases, such as malignancy or infection, rather than cardiovascular disease. Randomized trials reported that cardiovascular death was the most common cause of death. However, cancer was reported as the primary cause of death in a large-scale retrospective study using U.S. Medicare data [24]. A recent meta-analysis evaluated the prognostic factors influencing late survival following open surgical repair or EVAR [25]. This study found that cerebrovascular disease (HR 1.57, 95% CI 1.40–1.77) and peripheral artery disease (HR 1.36, 95% CI 1.18–1.58) were associated
with the increased risk of mortality. Other clinical variables such as age, female gender, heart failure, ischemic heart disease, COPD, chronic kidney disease, and diabetes also were identified as risk factors for late mortality in AAA patients after aortic repair. In our study, PAD was not a predictor for all-cause mortality. Obesity (BMI N 25 kg/m2) was a protective factor for all-cause mortality (HR 0.351, 95% CI 0.14–0.88, p = 0.026). Previous studies reported that lower BMI was associated with reduced late survival after open repair or EVAR [26–29]. On the other hand, overweight and mild obesity have shown to be associated with reduced cardiovascular and total mortality in patients with CAD suggesting an obesity paradox [30]. Higher catabolic reserve and favorable neurohormonal, inflammatory, and hemodynamic responses may confer protective effect against cardiovascular events in obese patients [31,32]. However, disease-related weight loss and higher mortality in patients with advanced cardiovascular disease may lead to a bias. To date, the association between obesity and mortality in patients with cardiovascular disease remains still inconclusive. The different risk factors for mortality identified by different studies may be due to differences in patient demographics and different definitions for risk factors among the studies. This study has several limitations. First, this is a retrospective analysis of data from a single center. Second, detailed anatomical factors of AAA were not included in the analyses because of low rates of
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Table 3 Univariate and multivariate analyses for predictors of 3-year MACCE after EVAR. Variable
Age ≥ 80 years Male BMI N 25 kg/m2 Ex-/Current smoker Anemiaa HTN DM CKD CAD PAD CHF Previous stroke COPD Aneurysm diameter ≥ 60 mm Hostile neck CRP No antiplatelet agents No statin No ACEi/ARB No beta-blocker No CCB No diuretics
Univariate analysis
Multivariate analysis
HR (95% CI)
p value
HR (95% CI)
p value
2.06 (1.07–3.98) 2.02 (0.49–8.41) 0.43 (0.178–1.41) 1.42 (0.70–2.86)
0.031 0.334 0.063 0.332
1.57 (0.72–3.41)
0.254
0.42 (0.16–1.16)
0.094
0.98 (0.51–1.91) 1.44 (0.66–3.17) 0.63 (0.24–1.61) 1.07 (0.33–3.49) 1.06 (0.55–2.06) 2.36 (1.22–4.55) 3.09 (0.95–10.08) 3.45 (1.66–7.15) 1.99 (0.61–6.49) 2.10 (1.02–4.34)
0.962 0.361 0.333 0.911 0.859 0.011 0.061 0.001 0.254 0.044
2.88 (1.32–6.29) 2.60 (0.74–9.14) 4.39 (1.94–9.93)
0.008 0.136 b0.001
2.09 (0.95–4.60)
0.068
1.95 (1.01–3.76) 1.01 (0.99–1.04) 4.78 (1.98–11.51)
0.047 0.317 b0.001
1.88 (0.86–4.09)
0.114
2.25 (0.52–9.79)
0.278
1.64 (0.84–3.21) 1.74 (0.90–3.36) 1.32 (0.69–2.55) 1.33 (0.63–2.83) 0.57 (0.25–1.29)
0.148 0.100 0.402 0.455 0.175
a Anemia: male, b13.5 g/dL; female, b12.0 g/dL; BMI: body mass index; CRP: C-reactive protein; HTN: hypertension; CKD: chronic kidney disease; CAD: coronary artery disease; PAD: peripheral artery disease; CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; EVAR: endovascular aortic aneurysm repair; ACEi: angiotensinconverting enzyme inhibitors; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; HR: hazard ratio; CI: confidence interval.
aneurysm-related event. Third, PAD was not rigorously screened in all patients before EVAR, and its prevalence in our patient cohort may have been underestimated. Our CT protocol included iliac arteries and only proximal segments of femoral arteries. In cases of suspected PAD, ABI and additional imaging studies were performed. Fourth, factors that are known to affect the clinical outcome of EVAR treatment for AAA were not analyzed in this retrospective study, including patient adherence and duration of medications, blood pressure control, and lifestyle habits. Fifth, although stroke is included as an event component of the primary endpoint, MACCE, stroke risk assessment such as carotid artery imaging and holter monitoring for paroxysmal atrial fibrillation were not performed. In conclusion, co-occurrence of PAD in AAA patients treated with EVAR led to poor prognosis in terms of increased MACCE and stroke. More active secondary prevention may be needed to reduce adverse cardiovascular events in AAA patients with PAD. Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2018.03.109. Conflict of interest The authors have no conflicts of interest to declare. Author contributions OHL collected and interpreted data, performed statistical analyses, and wrote the paper. YGK was responsible for the conception and designed the study, wrote the paper, and discussed the paper. CMA, DHS, JSK, BKK, DC, DYL, MKH, YJ collected data, and discussed the paper. Funding This research was supported by grants of the Korea Health Technology R&D Project through the Korea Health Industry Development
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