- Email: [email protected]
Frailty in patients with abdominal aortic aneurysm predicts prognosis after elective endovascular aneurysm repair
Frailty in patients with abdominal aortic aneurysm predicts prognosis after elective endovascular aneurysm repair Koichi Morisaki, MD, PhD,a Tadashi Furuyama, MD, PhD,a Keiji Yoshiya, MD,b Shun Kurose, MD,a Shinichiro Yoshino, MD,a Ken Nakayama, MD,a Sho Yamashita, MD,c Eisuke Kawakubo, MD,a Takuya Matsumoto, MD, PhD,c and Masaki Mori, MD,a Fukuoka and Tochigi, Japan
ABSTRACT Objective: The diagnostic criteria for frailty in patients with abdominal aortic aneurysm (AAA) are undefined. Our purpose was to examine the influence of new diagnostic criteria for frailty on overall survival after endovascular aneurysm repair (EVAR). Methods: We retrospectively analyzed data for patients undergoing EVAR between 2007 and 2015. Isolated common iliac artery aneurysm and ruptured AAA were excluded. Patients were defined as having frailty when they had at least two of low Geriatric Nutritional Risk Index, sarcopenia, or nonambulatory status. We examined whether frailty affected overall survival, postoperative complications, and reintervention. Results: Over the study period, 349 patients underwent EVAR. Thirty-three patients were excluded. The 5-year overall survival after EVAR was 76.7% for the frailty-negative group vs 43.1% for the frailty-positive group (P < .01). Age, frailtypositive status, and current cancer therapy were risk factors for overall survival. Positive frailty was the only risk factor for postoperative complications. Forty-two patients underwent reintervention. Outside instructions for use was a risk factor for reintervention after EVAR. Conclusions: Assessing frailty in patients with AAA is useful for determining risk factors for 5-year overall survival and postoperative complications. (J Vasc Surg 2019;-:1-6.) Keywords: Abdominal aortic aneurysm; Endovascular aneurysm repair; Frailty; Reintervention
Commercially available stent grafts have been available for treating abdominal aortic aneurysms (AAA) since 2006, in Japan. Since then, endovascular aneurysm repair (EVAR) has become widespread as an alternative and less invasive treatment compared with open surgical repair.1-3 The prognosis of patients with AAA who are considered unsuitable for open surgery is not improved with EVAR.4,5 Treating AAA is performed to prevent rupture and aneurysm-related death; therefore, it is important to consider not only patients’ operative risk and aneurysm
rupture risk, but also life expectancy, when choosing AAA treatment. Frailty is a clinical syndrome defined by physiological decline that leads to adverse outcomes,6,7 and several diagnostic criteria have been reported previously.8-10 The author previously proposed a new diagnostic criteria of frailty in patients with critical limb ischemia (CLI frailty).10 CLI frailty was a useful prognostic factor for amputation-free survival. The useful diagnostic criteria of frailty in patients with AAA has been unclear; therefore, we examined whether this CLI frailty affects overall survival after EVAR in patients with AAA.
METHODS From the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University,a and the Department of Vascular Surgery, Fukuoka City Hosipital,b Fukuoka; and the Department of Vascular Surgery, International University of Health and Welfare Hospital, Tochigi.c Author conflict of interest: none. Presented at the One hundred eighteenth Annual Congress of Japan Surgical Society, Japan, April 5-7, 2018. Correspondence: Koichi Morisaki, MD, PhD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (e-mail: [email protected]. ac.jp). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvs.2019.09.052
Patients. This study was approved by the Institutional Review Board of Kyushu University (No. 2019-074). Between 2007 and 2015, 349 patients underwent EVAR. Thirty-three patients were excluded owing to isolated iliac artery aneurysm or ruptured aneurysm; thus, 316 patients were analyzed retrospectively. The need for informed consent was waived because of our study’s retrospective design; instead, we disclosed all information about the study protocol to patients in a patient bulletin and we excluded patients at their request. Diagnosis for AAA frailty. According to the CLI Frailty Index,10 we defined patients as frailty positive if more than two following factors were present: low Geriatric Nutritional Risk Index (#89.8), low skeletal muscle mass 1
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Table I. Patients’ baseline characteristics Variable Age, years Male Female HT
AAA frailty (þ) (n ¼ 30)
AAA frailty () (n ¼ 286)
ARTICLE HIGHLIGHTS P value
79.1 6 8.7
74.7 6 8.1
<.01
21 (70.0)
253 (88.5)
<.01
9 (30.0) 23 (76.7)
.81 <.01
DM
1 (3.3)
73 (25.5)
8 (26.7)
89 (31.1)
.68
CHF
4 (13.3)
38 (13.3)
1.00
CVD
13 (43.3)
72 (25.2)
.05
mFI > 0.25
14 (46.7)
134 (46.9)
1.00
4 (13.3)
35 (12.2)
.77
51.6 6 10.4
50.4 6 9.1
.46
12 (40.0)
57 (19.9)
.02
5 (16.7)
86 (30.1)
Excluder
18 (60.0)
87 (30.4)
Powerlink
0 (0)
25 (8.7)
Endurant
7 (23.3)
81 (28.3)
Aorfix
0 (0)
Aneurysm size, mm Outside of IFU
d
Type of Research: Retrospective comparative cohort study Key Findings: Using a new diagnostic criteria for frailty, consisting of low Geriatric Nutritional Risk Index, sarcopenia, and nonambulatory status, the authors found a 5-year overall survival rate of 43.1% among those with more than two risk factors who underwent endovascular aneurysm repair compared with 76.7% of those who had one or no risk factors. Age, frailty-positive status, and current cancer therapy were risk factors for overall survival. Take Home Message: Assessing frailty in patients with abdominal aortic aneurysm is useful predictor for 5-year overall survival and could be useful for decision making in treatment selection of open repair vs endovascular aneurysm repair.
Device Zenith
d
33 (11.5) 227 (79.4)
CAD
Current cancer therapy
d
7 (2.5)
AAA, Abdominal aortic aneurysm; CAD, coronary artery disease; CHF, congestive heart failure; CVD, cerebrovascular disease; DM, diabetes mellitus; HT, hypertension; IFU, instructions for use; mFI, modified Frailty Index. Values are mean 6 standard deviation or number (%).
area, or dependent functional status.10 Geriatric Nutritional Risk Index, muscle mass area, and functional status were evaluated as previously described.11-15 Modified Frailty Index. The Modified Frailty Index (mFI) was evaluated as previously described.9 The cut-off for mFI was defined as greater than 0.25.16,17 Definition of instructions for use. Outside the instructions for use (IFU) was defined as a (1) proximal aneurysmal neck length of less than 10 mm and/or a proximal neck angle of greater than 60 or (2) bilateral external iliac artery landing. Follow-up and reintervention. Early and delayed phase contrast-enhanced computed tomography (CT) scans were performed at 1, 6, and 12 months after EVAR and every 12 months thereafter. Patients with renal insufficiency or contrast media allergy underwent a plain CT and duplex ultrasound imaging study. Aneurysmal sac expansion was defined as increasing the maximum transverse diameter of 5 mm or greater compared with the preoperative measurement. Indication for reintervention was significant aneurysmal sac expansion.
End points. The primary outcomes were risk factors for prognosis after EVAR. Secondary outcomes were any postoperative complications (Clavien-Dindo class II-V) and reintervention after EVAR. Statistical analysis. The data was analyzed using the JMP 13 software program (SAS Institute Inc, Cary, NC). The Student t-test or the Mann-Whitney U test was used to compare continuous variables. Comparisons of categorical variables between groups were performed with Fisher’s exact test. The overall survival and reintervention free survival were analyzed by Kaplan-Meier life table method and log-rank test. The risk factor for overall survival and reintervention-free survival were analyzed using univariate and multivariate (backward elimination procedure) Cox proportional hazards models. A P value of less than .05 was considered significant.
RESULTS Patient characteristics. Thirty patients (9.5%) were diagnosed with frailty. The average age and the percentage of outside IFU were higher in frailty group. No difference was found between groups in the percentage of patients with an mFI of greater than 0.25 (Table I). Overall survival. Fig 1, A, shows the Kaplan-Meier curves of overall survival for patients with AAA of the frailty negative and the frailty positive groups. The 5-year overall survival rates after EVAR were 76.7% in the frailty negative group, compared with 43.1% in the frailty-positive groups (P < .01). Fig 1, B, shows that no difference was observed in overall survival between the group with an mFI of greater than 0.25 and the group with an mFI of less than 0.25 (P ¼ .06).
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Fig 2. Causes of death within 5 years after endovascular aneurysm repair (EVAR). Malignancy was the most frequent cause of death after EVAR, followed by respiratory, cardiac and brain-related deaths. AAA, Abdominal aortic aneurysm.
group (P ¼ .02). Table III shows the details of patients’ postoperative complications. On multivariate analysis, frailty (HR, 2.98; 95% CI, 1.27-7.00; P ¼ .01) was the only risk factor for postoperative complications after EVAR (Table IV). Fig 1. A, Kaplan-Meier curves for overall survival after endovascular aneurysm repair (EVAR). The 5-years overall survival after EVAR was 76.7% in the frailty-negative group vs 43.1% in the frailty-positive group (P < .01). B, KaplanMeier curves for overall survival after EVAR. The 5-year overall survival after EVAR was 79.1% in patients with a modified Frailty Index (mFI) of less than 0.25 vs 67.5% in patients with an mFI of greater than 0.25 (P ¼ .06). AAA, Abdominal aortic aneurysm; SE, standard error.
Cause of death. Fig 2 shows the causes of death. Malignancy was the most common cause of death after EVAR, followed by respiratory, cardiac, and brain-related deaths. Two patients died owing to aneurysm-related complications; one patient in the frailty-positive group and outside IFU, and the other in the frailty negative group and inside IFU. Risk factor for overall survival. On multivariate analysis, frailty (hazard ratio [HR], 3.02; 95% confidence interval [CI], 1.44-5.82; P < .01), age (HR, 1.06; 95% CI, 1.02-1.10; P < .01), and current cancer therapy (HR, 3.45; 95% CI, 1.81-6.22; P < .01) were risk factors for 5-year overall survival after EVAR (Table II). Postoperative complications. The percentage of postoperative complications was 30.0% in the frailty-positive group, compared with 12.6% in the frailty-negative
Reintervention-free survival. The 5-year reinterventionfree survival after EVAR was 84.1% for the inside IFU group vs 59.9% for the outside IFU group (P < .01) (Fig 3, A). Fig 3, B and C, shows the reintervention-free survival of the frailty-negative and -positive groups. In the frailty-negative group, reintervention-free survival was higher in the outside IFU compared with the inside IFU (P < .01), with no differences in the frailty-positive group. Risk factor for reintervention. Table V lists the causes of reintervention between inside and outside IFU. The percentage of reintervention was higher in outside IFU group. On multivariate analysis, outside IFU (HR, 2.98; 95% CI, 1.53-5.58; P < .01) and an mFI of greater than 0.25 (HR, 2.21; 95% CI, 1.19-4.20; P ¼ .01) were risk factors for reintervention (Table VI).
DISCUSSION This study examined whether frailty affects treatment outcomes after EVAR in patients with AAA. Frailty was found to affect overall survival and postoperative complications. We established this new frailty diagnostic criteria for patients with AAA by referring to the CLI frailty. Skeletal muscle mass was evaluated using prediction equations in the previous study. Sarcopenia was diagnosed more accurately using CT measurement compared with
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Table II. Univariate and multivariate analyses of the risk factors for 5-year overall survival Univariate analysis
Multivariate analysis
HR (95% CI)
P value
HR (95% CI)
P value
Age, per 1-year increment
1.06 (1.03-1.10)
<.01
1.06 (1.02-1.10)
<.01
Male sex
1.03 (0.50-2.47)
Outside of IFU
2.13 (1.22-3.59)
Reintervention
0.95 (0.45-1.79)
.87
Current cancer therapy
2.82 (1.49-5.00)
<.01
Variable
.95
e
e
<.01
e
e
mFI > 0.25
1.63 (0.99-2.73)
.06
AAA frailty (þ)
3.65 (1.79-6.76)
<.01
e
e
3.45 (1.81-6.22)
<.01
e
e
3.02 (1.44-5.82)
<.01
AAA, Abdominal aortic aneurysm; CI, confidence interval; HR, hazard ratio; IFU, instructions for use; mFI, modified Frailty Index.
Table III. Postoperative complications Variable
Number
Table IV. Univariate and multivariate analyses of postoperative complications Univariate analysis
Procedure-related complications (n¼20) Type Ia endoleak
2
Type Ib endoleak
1
Limb stenosis/occlusion
5
Brain infarction
2
Blue toe syndrome
2
Renal artery occlusion
1
Spinal cord ischemia
2
Aortic type B dissection
1
Buttock claudication
3
Systemic and local complications (n ¼ 27) Blood transfusion for anemia
7
Surgical site infection
5
Cardiac
3
Delirium
3
Respiratory
2
Brain
1
Renal
1
Ischemic colitis
1
Others
4
prediction equations.18 In the present study, skeletal muscle mass was calculated using CT, because all patients with AAA underwent preoperative CT examination. Previous reports examined the influence of several frailty factors on treatment outcomes after EVAR, namely, hypoalbuminemia, sarcopenia, and functional status. Inagaki et al19 stated that preoperative hypoalbuminemia was a risk factor for poor overall survival after open surgery and EVAR. Harris et al15 found that decline of activities of daily living predicted major complications or death after EVAR. Regarding sarcopenia, Newton et al20 showed that low psoas muscle area predicted poor long-term survival; however, Indrakusuma et al21 showed that sarcopenia was not associated with poor survival. A previous
Variable
HR (95% CI)
Age, per 1-year 1.05 (1.01-1.10) increment
Multivariate analysis
P value
HR (95% CI)
P value
.02
e
e
Male sex
0.47 (0.21-1.04)
.06
e
e
Outside of IFU
1.56 (0.77-3.17)
.22
e
e
mFI > 0.25
1.86 (0.98-3.54)
.06
e
e
AAA frailty (þ) 2.98 (1.27-7.00)
.01
2.98 (1.27-7.00)
.01
AAA, Abdominal aortic aneurysm; CI, confidence interval; HR, hazard ratio; IFU, instructions for use; mFI, modified Frailty Index.
study discussed the cycle of frailty, stating that frailty develops secondary to interactions between several factor.22 Therefore, it is important to consider all inter-related factors when evaluating frailty. Arya et al23 reported that mFI was associated with higher mortality and morbidity after EVAR or open surgery for AAA. In contrast, the present study showed that mFI was not a risk factor for morbidity or overall survival. Most preoperative risk stratification for patients with AAA focuses on disease frailty markers such as mFI, but does not specially consider physical frailty. Our results suggest that it is important to consider both diseaserelated frailty (mFI) and physical frailty (AAA frailty) when determining the treatment strategy in patients with AAA. EVAR is less invasive compared with open repair; however, reinterventions can be necessary because of endoleaks.24 Outside IFU is a reported risk factor for reintervention after EVAR.25 In the present study, outside IFU was a risk factor for reintervention overall. In the subgroup analysis, outside IFU was a risk factor for reintervention in the frailty-negative patients; however, we found no difference in reintervention free survival rates when comparing inside and outside IFU in the frailty
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Table V. Reasons for reintervention Variable
Inside of IFU (n ¼ 247)
Outside of IFU (n ¼ 69)
P value
Reintervention
27 (10.9)
15 (21.7)
.03
Type Ia endoleak
4 (1.6)
3 (4.3)
Type Ib endoleak
4 (1.6)
4 (5.8)
Type II endoleak
13 (5.3)
4 (5.8)
Type III endoleak
1 (0.4)
0 (0)
Limb stenosis/ occlusion
6 (2.4)
5 (7.2)
IFU, Instructions for use. Values are number (%).
Table VI. Univariate and multivariate analyses of the risk factors for reintervention free survival Univariate analysis Variable
HR (95% CI)
P value
Multivariate analysis HR (95% CI)
P value
Age (per 1 year 1.02 (0.99-1.06) increments)
.25
e
e
Sex (male)
0.37 (0.19-0.80)
.01
e
e
diameter
1.03 (1.01-1.07)
.02
e
e
Outside of IFU
2.66 (1.38-4.95)
<.01
mFI > 0.25
1.97 (1.07-3.71)
.03
2.21 (1.19-4.20)
AAA frailty (þ) 0.77 (0.12-2.51)
.71
e
2.98 (1.53-5.58) <.01 .01 e
AAA, Abdominal aortic aneurysm; CI, confidence interval; HR, hazard ratio; IFU, instructions for use; mFI, modified Frailty Index.
Fig 3. A, Kaplan-Meier curves for reintervention-free survival after endovascular aneurysm repair (EVAR). The 5-year reintervention-free survival rate after EVAR was 83.4% in the inside instruction for use (IFU) group vs 65.5% for the outside IFU group (P < .01). B, Kaplan-Meier curves for reintervention-free survival after EVAR in the frailtynegative group. The 5-year reintervention-free survival rate after EVAR was 84.1% for the inside IFU group vs 59.9% for the outside IFU group (P < .01). C, Kaplan-Meier curves for reintervention-free survival after EVAR in frailty-positive patients with abdominal aortic aneurysm (AAA). There was no difference in reintervention-free survival rates in these patients regarding the inside of IFU vs outside IFU (P ¼ .15).
positive patients. These results may be reflected the poor prognosis in the frailty positive patients. Our study has some limitations. First, this study was a single-center, retrospective study. Second, all patients were not followed for 5 years after EVAR. Third, the number in the frailty-positive group was small. Despite these limitations, frailty was a useful predictive risk factor for 5year overall survival. Considering the poor prognosis in the frailty-positive patients and outside IFU as a risk factor for reintervention after EVAR, open repair may also be appropriate in the frailty-negative patients outside the IFU.
CONCLUSIONS Assessing frailty in patients with AAA is useful for determining risk factors for 5-year overall survival and postoperative complications. This diagnostic criteria for frailty could be useful for decision making when choosing open repair or EVAR for patients with AAA. We thank Jane Charbonneau, DVM, from Edanz Group (https://jp.edanzgroup.com/) for editing a draft of the manuscript.
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AUTHOR CONTRIBUTIONS Conception and design: KM, TF Analysis and interpretation: KM, TF, MM Data collection: KM, TF, KY, SK, SYo, KN, SYa, EK, TM Writing the article: KM Critical revision of the article: KM, TF, KY, SK, SYo, KN, SYa, EK, TM, MM Final approval of the article: KM, TF, KY, SK, SYo, KN, SYa, EK, TM, MM Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: KM
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new index for evaluating at-risk elderly medical patients. Am J Clin Nutr 2005;82:777-83. Matsubara Y, Matsumoto T, Aoyagi Y, Tanaka S, Okadome J, Morisaki K, et al. Sarcopenia is a prognostic factor for overall survival in patients with critical limb ischemia. J Vasc Surg 2015;61:945-50. Yoshizumi T, Shirabe K, Nakagawara H, Ikegami T, Harimoto N, Toshima T, et al. Skeletal muscle area correlates with body surface area in healthy adults. Hepatol Res 2014;44:313-8. Masuda T, Shirabe K, Ikegami T, Harimoto N, Yoshizumi T, Soejima Y, et al. Sarcopenia is a prognostic factor in living donor liver transplantation. Liver Transpl 2014;20:401-7. Harris DG, Bulatao I, Oates CP, Kalsi R, Drucker CB, Menon N, et al. Functional status predicts major complications and death after endovascular repair of abdominal aortic aneurysms. J Vasc Surg 2017;66:743-50. Pandit V, Khan M, Martinez C, Jehan F, Zeeshan M, Koblinski J, et al. A modified frailty index predicts adverse outcomes among patients with colon cancer undergoing surgical intervention. Am J Surg 2018;216:1090-4. Vermillion SA, Hsu FC, Dorrell RD, Shen P, Clark CJ. Modified frailty index predicts postoperative outcomes in older gastrointestinal cancer patients. J Surg Oncol 2017;115: 997-1003. Morisaki K, Furuyama T, Matsubara Y, Inoue K, Kurose S, Yoshino S, et al. External validation of CLI Frailty Index and assessment of predictive value of modified CLI Frailty Index for patients with critical limb ischemia undergoing infrainguinal revascularization. Vascular 2019;27:405-10. Inagaki E, Farber A, Eslami MH, Kalish J, Rybin DV, Doros G, et al. Preoperative hypoalbuminemia is associated with poor clinical outcomes after open and endovascular abdominal aortic aneurysm repair. J Vasc Surg 2017;66:53-63. Newton DH, Kim C, Lee N, Wolfe L, Pfeifer J, Amendola M. Sarcopenia predicts poor long-term survival in patients undergoing endovascular aortic aneurysm repair. J Vasc Surg 2018;67:453-9. Indrakusuma R, Zijlmans JL, Jalalzadeh H, Planken RN, Balm R, Koelemay MJW. Psoas muscle area as a prognostic factor for survival in patients with an asymptomatic infrarenal abdominal aortic aneurysm: a retrospective cohort study. Eur J Vasc Endovasc Surg 2018;55:83-91. Xue QL, Bandeen-Roche K, Varadhan R, Zhou J, Fried LP. Initial manifestations of frailty criteria and the development of frailty phenotype in the Women’s Health and Aging Study II. J Gerontol A Biol Sci Med Sci 2008;63:984-90. Arya S, Kim SI, Duwayri Y, Brewster LP, Veeraswamy R, Salam A, et al. Frailty increases the risk of 30-day mortality, morbidity, and failure to rescue after elective abdominal aortic aneurysm repair independent of age and comorbidities. J Vasc Surg 2015;61:324-31. Qadura M, Pervaiz F, Harlock JA, Al-Azzoni A, Farrokhyar F, Kahnamoui K, et al. Mortality and reintervention following elective abdominal aortic aneurysm repair. J Vasc Surg 2013;57:1676-83. Hwang D, Park S, Kim HK, Lee JM, Huh S. Reintervention rate after open surgery and endovascular repair for nonruptured abdominal aortic aneurysms. Ann Vasc Surg 2017;43:134-43.
Submitted Jul 12, 2019; accepted Sep 23, 2019.
ABSTRACT Objective: The diagnostic criteria for frailty in patients with abdominal aortic aneurysm (AAA) are undefined. Our purpose was to examine the influence of new diagnostic criteria for frailty on overall survival after endovascular aneurysm repair (EVAR). Methods: We retrospectively analyzed data for patients undergoing EVAR between 2007 and 2015. Isolated common iliac artery aneurysm and ruptured AAA were excluded. Patients were defined as having frailty when they had at least two of low Geriatric Nutritional Risk Index, sarcopenia, or nonambulatory status. We examined whether frailty affected overall survival, postoperative complications, and reintervention. Results: Over the study period, 349 patients underwent EVAR. Thirty-three patients were excluded. The 5-year overall survival after EVAR was 76.7% for the frailty-negative group vs 43.1% for the frailty-positive group (P < .01). Age, frailtypositive status, and current cancer therapy were risk factors for overall survival. Positive frailty was the only risk factor for postoperative complications. Forty-two patients underwent reintervention. Outside instructions for use was a risk factor for reintervention after EVAR. Conclusions: Assessing frailty in patients with AAA is useful for determining risk factors for 5-year overall survival and postoperative complications. (J Vasc Surg 2019;-:1-6.) Keywords: Abdominal aortic aneurysm; Endovascular aneurysm repair; Frailty; Reintervention
Commercially available stent grafts have been available for treating abdominal aortic aneurysms (AAA) since 2006, in Japan. Since then, endovascular aneurysm repair (EVAR) has become widespread as an alternative and less invasive treatment compared with open surgical repair.1-3 The prognosis of patients with AAA who are considered unsuitable for open surgery is not improved with EVAR.4,5 Treating AAA is performed to prevent rupture and aneurysm-related death; therefore, it is important to consider not only patients’ operative risk and aneurysm
rupture risk, but also life expectancy, when choosing AAA treatment. Frailty is a clinical syndrome defined by physiological decline that leads to adverse outcomes,6,7 and several diagnostic criteria have been reported previously.8-10 The author previously proposed a new diagnostic criteria of frailty in patients with critical limb ischemia (CLI frailty).10 CLI frailty was a useful prognostic factor for amputation-free survival. The useful diagnostic criteria of frailty in patients with AAA has been unclear; therefore, we examined whether this CLI frailty affects overall survival after EVAR in patients with AAA.
METHODS From the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University,a and the Department of Vascular Surgery, Fukuoka City Hosipital,b Fukuoka; and the Department of Vascular Surgery, International University of Health and Welfare Hospital, Tochigi.c Author conflict of interest: none. Presented at the One hundred eighteenth Annual Congress of Japan Surgical Society, Japan, April 5-7, 2018. Correspondence: Koichi Morisaki, MD, PhD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (e-mail: [email protected]. ac.jp). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvs.2019.09.052
Patients. This study was approved by the Institutional Review Board of Kyushu University (No. 2019-074). Between 2007 and 2015, 349 patients underwent EVAR. Thirty-three patients were excluded owing to isolated iliac artery aneurysm or ruptured aneurysm; thus, 316 patients were analyzed retrospectively. The need for informed consent was waived because of our study’s retrospective design; instead, we disclosed all information about the study protocol to patients in a patient bulletin and we excluded patients at their request. Diagnosis for AAA frailty. According to the CLI Frailty Index,10 we defined patients as frailty positive if more than two following factors were present: low Geriatric Nutritional Risk Index (#89.8), low skeletal muscle mass 1
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Table I. Patients’ baseline characteristics Variable Age, years Male Female HT
AAA frailty (þ) (n ¼ 30)
AAA frailty () (n ¼ 286)
ARTICLE HIGHLIGHTS P value
79.1 6 8.7
74.7 6 8.1
<.01
21 (70.0)
253 (88.5)
<.01
9 (30.0) 23 (76.7)
.81 <.01
DM
1 (3.3)
73 (25.5)
8 (26.7)
89 (31.1)
.68
CHF
4 (13.3)
38 (13.3)
1.00
CVD
13 (43.3)
72 (25.2)
.05
mFI > 0.25
14 (46.7)
134 (46.9)
1.00
4 (13.3)
35 (12.2)
.77
51.6 6 10.4
50.4 6 9.1
.46
12 (40.0)
57 (19.9)
.02
5 (16.7)
86 (30.1)
Excluder
18 (60.0)
87 (30.4)
Powerlink
0 (0)
25 (8.7)
Endurant
7 (23.3)
81 (28.3)
Aorfix
0 (0)
Aneurysm size, mm Outside of IFU
d
Type of Research: Retrospective comparative cohort study Key Findings: Using a new diagnostic criteria for frailty, consisting of low Geriatric Nutritional Risk Index, sarcopenia, and nonambulatory status, the authors found a 5-year overall survival rate of 43.1% among those with more than two risk factors who underwent endovascular aneurysm repair compared with 76.7% of those who had one or no risk factors. Age, frailty-positive status, and current cancer therapy were risk factors for overall survival. Take Home Message: Assessing frailty in patients with abdominal aortic aneurysm is useful predictor for 5-year overall survival and could be useful for decision making in treatment selection of open repair vs endovascular aneurysm repair.
Device Zenith
d
33 (11.5) 227 (79.4)
CAD
Current cancer therapy
d
7 (2.5)
AAA, Abdominal aortic aneurysm; CAD, coronary artery disease; CHF, congestive heart failure; CVD, cerebrovascular disease; DM, diabetes mellitus; HT, hypertension; IFU, instructions for use; mFI, modified Frailty Index. Values are mean 6 standard deviation or number (%).
area, or dependent functional status.10 Geriatric Nutritional Risk Index, muscle mass area, and functional status were evaluated as previously described.11-15 Modified Frailty Index. The Modified Frailty Index (mFI) was evaluated as previously described.9 The cut-off for mFI was defined as greater than 0.25.16,17 Definition of instructions for use. Outside the instructions for use (IFU) was defined as a (1) proximal aneurysmal neck length of less than 10 mm and/or a proximal neck angle of greater than 60 or (2) bilateral external iliac artery landing. Follow-up and reintervention. Early and delayed phase contrast-enhanced computed tomography (CT) scans were performed at 1, 6, and 12 months after EVAR and every 12 months thereafter. Patients with renal insufficiency or contrast media allergy underwent a plain CT and duplex ultrasound imaging study. Aneurysmal sac expansion was defined as increasing the maximum transverse diameter of 5 mm or greater compared with the preoperative measurement. Indication for reintervention was significant aneurysmal sac expansion.
End points. The primary outcomes were risk factors for prognosis after EVAR. Secondary outcomes were any postoperative complications (Clavien-Dindo class II-V) and reintervention after EVAR. Statistical analysis. The data was analyzed using the JMP 13 software program (SAS Institute Inc, Cary, NC). The Student t-test or the Mann-Whitney U test was used to compare continuous variables. Comparisons of categorical variables between groups were performed with Fisher’s exact test. The overall survival and reintervention free survival were analyzed by Kaplan-Meier life table method and log-rank test. The risk factor for overall survival and reintervention-free survival were analyzed using univariate and multivariate (backward elimination procedure) Cox proportional hazards models. A P value of less than .05 was considered significant.
RESULTS Patient characteristics. Thirty patients (9.5%) were diagnosed with frailty. The average age and the percentage of outside IFU were higher in frailty group. No difference was found between groups in the percentage of patients with an mFI of greater than 0.25 (Table I). Overall survival. Fig 1, A, shows the Kaplan-Meier curves of overall survival for patients with AAA of the frailty negative and the frailty positive groups. The 5-year overall survival rates after EVAR were 76.7% in the frailty negative group, compared with 43.1% in the frailty-positive groups (P < .01). Fig 1, B, shows that no difference was observed in overall survival between the group with an mFI of greater than 0.25 and the group with an mFI of less than 0.25 (P ¼ .06).
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Fig 2. Causes of death within 5 years after endovascular aneurysm repair (EVAR). Malignancy was the most frequent cause of death after EVAR, followed by respiratory, cardiac and brain-related deaths. AAA, Abdominal aortic aneurysm.
group (P ¼ .02). Table III shows the details of patients’ postoperative complications. On multivariate analysis, frailty (HR, 2.98; 95% CI, 1.27-7.00; P ¼ .01) was the only risk factor for postoperative complications after EVAR (Table IV). Fig 1. A, Kaplan-Meier curves for overall survival after endovascular aneurysm repair (EVAR). The 5-years overall survival after EVAR was 76.7% in the frailty-negative group vs 43.1% in the frailty-positive group (P < .01). B, KaplanMeier curves for overall survival after EVAR. The 5-year overall survival after EVAR was 79.1% in patients with a modified Frailty Index (mFI) of less than 0.25 vs 67.5% in patients with an mFI of greater than 0.25 (P ¼ .06). AAA, Abdominal aortic aneurysm; SE, standard error.
Cause of death. Fig 2 shows the causes of death. Malignancy was the most common cause of death after EVAR, followed by respiratory, cardiac, and brain-related deaths. Two patients died owing to aneurysm-related complications; one patient in the frailty-positive group and outside IFU, and the other in the frailty negative group and inside IFU. Risk factor for overall survival. On multivariate analysis, frailty (hazard ratio [HR], 3.02; 95% confidence interval [CI], 1.44-5.82; P < .01), age (HR, 1.06; 95% CI, 1.02-1.10; P < .01), and current cancer therapy (HR, 3.45; 95% CI, 1.81-6.22; P < .01) were risk factors for 5-year overall survival after EVAR (Table II). Postoperative complications. The percentage of postoperative complications was 30.0% in the frailty-positive group, compared with 12.6% in the frailty-negative
Reintervention-free survival. The 5-year reinterventionfree survival after EVAR was 84.1% for the inside IFU group vs 59.9% for the outside IFU group (P < .01) (Fig 3, A). Fig 3, B and C, shows the reintervention-free survival of the frailty-negative and -positive groups. In the frailty-negative group, reintervention-free survival was higher in the outside IFU compared with the inside IFU (P < .01), with no differences in the frailty-positive group. Risk factor for reintervention. Table V lists the causes of reintervention between inside and outside IFU. The percentage of reintervention was higher in outside IFU group. On multivariate analysis, outside IFU (HR, 2.98; 95% CI, 1.53-5.58; P < .01) and an mFI of greater than 0.25 (HR, 2.21; 95% CI, 1.19-4.20; P ¼ .01) were risk factors for reintervention (Table VI).
DISCUSSION This study examined whether frailty affects treatment outcomes after EVAR in patients with AAA. Frailty was found to affect overall survival and postoperative complications. We established this new frailty diagnostic criteria for patients with AAA by referring to the CLI frailty. Skeletal muscle mass was evaluated using prediction equations in the previous study. Sarcopenia was diagnosed more accurately using CT measurement compared with
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Table II. Univariate and multivariate analyses of the risk factors for 5-year overall survival Univariate analysis
Multivariate analysis
HR (95% CI)
P value
HR (95% CI)
P value
Age, per 1-year increment
1.06 (1.03-1.10)
<.01
1.06 (1.02-1.10)
<.01
Male sex
1.03 (0.50-2.47)
Outside of IFU
2.13 (1.22-3.59)
Reintervention
0.95 (0.45-1.79)
.87
Current cancer therapy
2.82 (1.49-5.00)
<.01
Variable
.95
e
e
<.01
e
e
mFI > 0.25
1.63 (0.99-2.73)
.06
AAA frailty (þ)
3.65 (1.79-6.76)
<.01
e
e
3.45 (1.81-6.22)
<.01
e
e
3.02 (1.44-5.82)
<.01
AAA, Abdominal aortic aneurysm; CI, confidence interval; HR, hazard ratio; IFU, instructions for use; mFI, modified Frailty Index.
Table III. Postoperative complications Variable
Number
Table IV. Univariate and multivariate analyses of postoperative complications Univariate analysis
Procedure-related complications (n¼20) Type Ia endoleak
2
Type Ib endoleak
1
Limb stenosis/occlusion
5
Brain infarction
2
Blue toe syndrome
2
Renal artery occlusion
1
Spinal cord ischemia
2
Aortic type B dissection
1
Buttock claudication
3
Systemic and local complications (n ¼ 27) Blood transfusion for anemia
7
Surgical site infection
5
Cardiac
3
Delirium
3
Respiratory
2
Brain
1
Renal
1
Ischemic colitis
1
Others
4
prediction equations.18 In the present study, skeletal muscle mass was calculated using CT, because all patients with AAA underwent preoperative CT examination. Previous reports examined the influence of several frailty factors on treatment outcomes after EVAR, namely, hypoalbuminemia, sarcopenia, and functional status. Inagaki et al19 stated that preoperative hypoalbuminemia was a risk factor for poor overall survival after open surgery and EVAR. Harris et al15 found that decline of activities of daily living predicted major complications or death after EVAR. Regarding sarcopenia, Newton et al20 showed that low psoas muscle area predicted poor long-term survival; however, Indrakusuma et al21 showed that sarcopenia was not associated with poor survival. A previous
Variable
HR (95% CI)
Age, per 1-year 1.05 (1.01-1.10) increment
Multivariate analysis
P value
HR (95% CI)
P value
.02
e
e
Male sex
0.47 (0.21-1.04)
.06
e
e
Outside of IFU
1.56 (0.77-3.17)
.22
e
e
mFI > 0.25
1.86 (0.98-3.54)
.06
e
e
AAA frailty (þ) 2.98 (1.27-7.00)
.01
2.98 (1.27-7.00)
.01
AAA, Abdominal aortic aneurysm; CI, confidence interval; HR, hazard ratio; IFU, instructions for use; mFI, modified Frailty Index.
study discussed the cycle of frailty, stating that frailty develops secondary to interactions between several factor.22 Therefore, it is important to consider all inter-related factors when evaluating frailty. Arya et al23 reported that mFI was associated with higher mortality and morbidity after EVAR or open surgery for AAA. In contrast, the present study showed that mFI was not a risk factor for morbidity or overall survival. Most preoperative risk stratification for patients with AAA focuses on disease frailty markers such as mFI, but does not specially consider physical frailty. Our results suggest that it is important to consider both diseaserelated frailty (mFI) and physical frailty (AAA frailty) when determining the treatment strategy in patients with AAA. EVAR is less invasive compared with open repair; however, reinterventions can be necessary because of endoleaks.24 Outside IFU is a reported risk factor for reintervention after EVAR.25 In the present study, outside IFU was a risk factor for reintervention overall. In the subgroup analysis, outside IFU was a risk factor for reintervention in the frailty-negative patients; however, we found no difference in reintervention free survival rates when comparing inside and outside IFU in the frailty
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Table V. Reasons for reintervention Variable
Inside of IFU (n ¼ 247)
Outside of IFU (n ¼ 69)
P value
Reintervention
27 (10.9)
15 (21.7)
.03
Type Ia endoleak
4 (1.6)
3 (4.3)
Type Ib endoleak
4 (1.6)
4 (5.8)
Type II endoleak
13 (5.3)
4 (5.8)
Type III endoleak
1 (0.4)
0 (0)
Limb stenosis/ occlusion
6 (2.4)
5 (7.2)
IFU, Instructions for use. Values are number (%).
Table VI. Univariate and multivariate analyses of the risk factors for reintervention free survival Univariate analysis Variable
HR (95% CI)
P value
Multivariate analysis HR (95% CI)
P value
Age (per 1 year 1.02 (0.99-1.06) increments)
.25
e
e
Sex (male)
0.37 (0.19-0.80)
.01
e
e
diameter
1.03 (1.01-1.07)
.02
e
e
Outside of IFU
2.66 (1.38-4.95)
<.01
mFI > 0.25
1.97 (1.07-3.71)
.03
2.21 (1.19-4.20)
AAA frailty (þ) 0.77 (0.12-2.51)
.71
e
2.98 (1.53-5.58) <.01 .01 e
AAA, Abdominal aortic aneurysm; CI, confidence interval; HR, hazard ratio; IFU, instructions for use; mFI, modified Frailty Index.
Fig 3. A, Kaplan-Meier curves for reintervention-free survival after endovascular aneurysm repair (EVAR). The 5-year reintervention-free survival rate after EVAR was 83.4% in the inside instruction for use (IFU) group vs 65.5% for the outside IFU group (P < .01). B, Kaplan-Meier curves for reintervention-free survival after EVAR in the frailtynegative group. The 5-year reintervention-free survival rate after EVAR was 84.1% for the inside IFU group vs 59.9% for the outside IFU group (P < .01). C, Kaplan-Meier curves for reintervention-free survival after EVAR in frailty-positive patients with abdominal aortic aneurysm (AAA). There was no difference in reintervention-free survival rates in these patients regarding the inside of IFU vs outside IFU (P ¼ .15).
positive patients. These results may be reflected the poor prognosis in the frailty positive patients. Our study has some limitations. First, this study was a single-center, retrospective study. Second, all patients were not followed for 5 years after EVAR. Third, the number in the frailty-positive group was small. Despite these limitations, frailty was a useful predictive risk factor for 5year overall survival. Considering the poor prognosis in the frailty-positive patients and outside IFU as a risk factor for reintervention after EVAR, open repair may also be appropriate in the frailty-negative patients outside the IFU.
CONCLUSIONS Assessing frailty in patients with AAA is useful for determining risk factors for 5-year overall survival and postoperative complications. This diagnostic criteria for frailty could be useful for decision making when choosing open repair or EVAR for patients with AAA. We thank Jane Charbonneau, DVM, from Edanz Group (https://jp.edanzgroup.com/) for editing a draft of the manuscript.
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AUTHOR CONTRIBUTIONS Conception and design: KM, TF Analysis and interpretation: KM, TF, MM Data collection: KM, TF, KY, SK, SYo, KN, SYa, EK, TM Writing the article: KM Critical revision of the article: KM, TF, KY, SK, SYo, KN, SYa, EK, TM, MM Final approval of the article: KM, TF, KY, SK, SYo, KN, SYa, EK, TM, MM Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: KM
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Submitted Jul 12, 2019; accepted Sep 23, 2019.