Tilburg University
Treatment outcomes in elderly patients with chronic limb-threatening ischemia
Peters, C.M.L.
Publication date:
2020
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Link to publication in Tilburg University Research Portal
Citation for published version (APA):
Peters, C. M. L. (2020). Treatment outcomes in elderly patients with chronic limb-threatening ischemia: Towards
shared-decision making medicine. GVO Drukkers en vormgevers.
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Treatment outcomes in
elderly patients with
chronic
limb-threatening ischemia
Towards shared-decision making medicine
Treatment outcomes in elderly patients with
chr
onic limb-thr
eatening ischemia
Chloé M.L. Peters
Treatment outcomes in
elderly patients with
chronic
limb-threatening ischemia
Towards shared-decision making medicine
Publication of this thesis was financially supported by:
ABN AMRO, Amphia Ziekenhuis Breda, A. van der Linden Centrum voor Voetklachten, Chipsoft, Fides Bouw & Advies B.V. & Tilburg University.
Financial support by the Dutch Heart Foundation for publication of this thesis is gratefully acknowledged.
Cover design, illustration & lay-out: Esther Beekman (www.estherontwerpt.nl) Printed by: GVO drukkers B.V., Ede
ISBN: 978-94-6332-686-5
Treatment outcomes in elderly patients
with chronic limb-threatening ischemia
Towards shared-decision making medicine
Proefschrift ter verkrijging van de graad van doctor
aan Tilburg University
op gezag van de rector magnificus, prof. dr. W.B.H.J. van de Donk,
in het openbaar te verdedigen ten overstaan van een
door het college voor promoties aangewezen commissie in
de Aula van de Universiteit op vrijdag 20 november 2020
om 13.30 uur
door
Promotor:
Prof. dr. J. de Vries
Promotor:
Prof. dr. L. van der Laan
Promotiecommissie:
Prof. dr. J.F. Hamming
Prof. dr. F.U.S Mattace Raso
Prof. dr. I. Fourneau
9
23
43
73
83
99
117
135
147
154
160
162
Chapter 1 IntroductionChapter 2 Cost-effectiveness of the treatments for chronic limb-threatening ischemia in the elderly population
J Vasc Surg. 2019 Aug;70(2):530-538.e1.
Chapter 3 Long-term quality of life and health status of treatment for the elderly with chronic limb-threatening ischemia
Submitted.
Chapter 4 Is a good quality of life and health status possible in elderly patients dying from chronic limb-threatening ischemia: a prospective clinical study
Ann Vasc Surg. 2020 Apr;64:198-201.
Chapter 5 Quality of life and not health status improves after major amputation in the elderly chronic limb-threatening ischemia patient, a prospective study.
Eur J Vasc Endovasc Surg. 2019 Apr;57(4):547-553.
Chapter 6 Is there an important role for anxiety and depression in the elderly patient with chronic limb-threatening ischemia, especially after major amputation?
Ann Vasc Surg. 2019 Jul;58:142-150.
Chapter 7 Is amputation in the elderly patient with chronic limb-threatening ischemia acceptable in the long term?
Clin Interv Aging. 2019 Jul 2;14:1177-1185.
Chapter 8 Summary, general discussion and future perspectives Chapter 9 Summary in Dutch
Chapter 1
10
GENERAL INTRODUCTION
Chronic limb-threatening ischemia (CLTI) is the end-stage of peripheral arterial disease (PAD), as classified by the Fontaine and Rutherford classifications (Table 1). This disease is caused by atherosclerosis. Therefore, the development of CLTI depends on the cardiovascular risk factors: age, male gender, diabetes mellitus, smoking, hypertension, hyperlipidaemia, genetic abnormalities and family history. (1–4) The yearly incidence of CLTI is between 50 and 100 new cases per 100,000 in a Western population. (1) Approximately 1% to 3% of PAD patients with an age of 50 or older progress to CLTI. (1) The incidence of CLTI is expected to grow due to the increasing elderly population (Figure 1). (1,5,6) Therefore, this thesis focuses on CLTI patients older than 70 years.
Table 1. Fontaine or Rutherford classifi cation systems of peripheral arterial disease Fontaine
Classifi cation Rutherford Classifi cation
Stage Clinical Grade Category Clinical
I Asymptomatic 0 0 Asymptomatic
IIa Mild claudication I 1 Mild claudication
IIb Moderate to severe claudication II 2 Moderate claudication III 3 Severe claudication
III Ischemic rest pain IV 4 Ischemic rest pain
IV Ulceration or
gangrene
V 5 Minor tissue loss:
nonhealing ulcer, focal gangrene with diffuse pedal ischemia
VI 6 Major tissue loss:
11
1
Figure 1. CBS age distribution
Patients with CLTI experience chronic ischemic rest pain (Fontaine III or Rutherford 4) and/or tissue necrosis, ulceration or gangrene (Fontaine IV or Rutherford 5-6) in the lower extremity. (1,7–9) The diagnosis of CLTI is based on the patient’s medical history, physical examination (e.g. discoloration and dependant hyperemia), and ankle-brachial index. Diagnostic tools that support the diagnosis are duplex ultrasound, computed tomographic angiography, and/or magnetic resonance angiography. In the case of ischemic rest pain, the ankle pressure is typically below 50 mmHg. (1,10) Chronic limb-threatening ischemia is also suspected in patients with tissue necrosis and an ankle pressure less than 70 mmHg. (1) In CLTI patients suitable for revascularisation, non-invasive anatomic imaging (computed tomographic angiography, or magnetic resonance angiography) is mandatory to evaluate the arterial anatomy in the affected lower extremity before committing to invasive angiography. (1) Based on the characteristics of the arterial lesions, a decision regarding revascularisation can be made.
Revascularisation is considered the treatment of choice for CLTI patients to prevent lower limb amputation. (1,7) Revascularisation options include open vascular surgery, endovascular procedures, and hybrid procedures. The main surgical techniques to improve limb perfusion include lower extremity bypass and endarterectomy. Bypass surgery is preferred for multilevel lesions. (1) In bypass surgery options are an
Figure 1. CBS age distribution
5.000.000 10.000.000 15.000.000 20.000.000 25.000.000 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 2060 Year Num be r of pe opl e
Chapter 1
12
autologous or synthetic bypass. Due to superior patency rates, autologous bypasses are favoured. (11) Nowadays, endovascular interventions, such as balloon angioplasty or percutaneous atherectomy, are more commonly performed, due to advances in endovascular techniques. (12) Largely based on the BASIL trial, current guidelines recommend surgical revascularisation in patients with a life expectancy ≥ 2 years. (1,13,14)
Still, the management of CLTI in elderly patients remains a challenge. Elderly patients are often frail, lack autonomy, and have a shorter life expectancy. (15) The main goal in treating the elderly is to do no further harm. (16,17) In patients aged 80 years and older, surgical revascularisation is not always possible due to their frailty and existing comorbidities. Endovascular revascularisation has shown to achieve better limb salvage and survival rates and autonomy levels than surgical revascularisation. (15,18– 20) Therefore, an endovascular revascularisation approach is preferred in elderly CLTI patients. (15,18–22) However, as presented in Figure 2, invasive treatment is often not achievable because of severe comorbidities and/or the characterization of the arterial lesions. (7,16,17,23–25) Consequently, these ‘no-option’ CLTI patients can be managed with conservative treatment (analgesics and optimal wound care) or with lower limb amputation. (16,17,26–28) Treatment selection depends on the arterial lesion and the comorbidities of patients. Unfortunately, there are no selection criteria that distinguish between patients who would benefit from lower limb amputation versus all other treatment options.
13
1
Patient-reported outcome measures
Based on these high mortality and amputation rates, objective outcome measures, such as limb salvage and bypass patency, cannot sufficiently evaluate the effectiveness of treatments for CLTI. (40) Moreover, objective outcome measures do not assess treatment success in an optimal way, due to the multifactorial aspect of the disease in the elderly. (41–43) After lower limb amputation, other objective measures, such as functional outcome and mobility, are considered important. These measures have been described in elderly PAD patients after lower limb amputation. (44,45) Still, it remains a challenge to assess mobility outcomes in elderly CLTI patients who already have mobility impairments. (44) In fact, there is a lower chance of successful rehabilitation and functional improvement in elderly patients with limited preoperative functional abilities. (46,47) In these patients, lower limb amputation may be an optional treatment. However, this also raises the question of how ‘successful outcome’ is defined after lower limb amputation in the elderly. (44) Therefore, primary end points of treatment for CLTI have changed from clinical outcome to patient-reported outcome measures (PROMS).
Figure 2. Percentage of patients who did not qualify for revascularisationFigure 2. Percentage of patients who did not qualify for revascularisation
35% 23% 28% 48% 0% 10% 20% 30% 40% 50% 60% Engelhardt et al. Armstrong et al. Thomas et al. The BASIL Trial
Percentage of Patients
Chapter 1
14
Patient-reported outcome measures may be a supplementary measurement to assess treatment success. Therefore, this thesis focused on PROMS, which have become very important in establishing the best possible treatment in CLTI patients. Quality of life and health status (HS) are examples of PROMS. Both measures are believed to be impaired in CLTI. (1,13,48,49) Thus, a similarity or an increase in QoL and HS is considered a valuable outcome after treatment. There are few studies concerning PROMS, such as HS and QoL in elderly CLTI patients.
Health status questionnaires assess perceived physical, psychological, and social functioning. They measure patients’ daily activities and only provide an objective assessment of functioning, provided by the patients’ themselves. (42,47,48,50–52) Quality of life questionnaires are a subjective appraisal of physical, psychological, and social functioning. In other words, QoL concerns patients’ satisfaction with functioning. (53) Examples of HS instruments are the 12-Item and 36-Item Short Form Health Survey, the European Quality of Life 5D, and the disease-specific VascuQol questionnaire. Unfortunately, these questionnaires are often mistakenly interpreted as QoL questionnaires. (48,52) But, these HS questionnaires do not incorporate the individual’s evaluation or expectations. (48) Therefore, the interpretation of their results may influence treatment decisions wrongly. (48,52,54) In contrast with these HS questionnaires, the World Health Organization has developed a questionnaire that evaluates a complete subjective evaluation of physical, psychological, and social functioning: the World Health Organization Quality Of Life-100 (WHOQOL-100) and the abbreviated version, the WHOQOL-BREF. (55) In this thesis, QoL and HS are investigated in CLTI patients and, more specifically, CLTI patients with a lower-limb amputation. Because guidelines are lacking regarding the use of disease specific QoL questionnaires for CLTI patients, it will also make a reasonable argument for the use of distinctive and subjective QoL questionnaires in future research on CLTI. (30,56) Depression and anxiety
15
1
an association is assumed between depression and worse outcome, such as lower limb amputation. (61,62) Cherr et al. demonstrated that in PAD patients, depression was associated with worse patency rates and recurrent leg symptoms. (63) However, they could not find an association between depression and lower limb amputation. (63) McDermott at al. also evaluated depression in PAD patients. (61) They indicated an association between depression and increased mortality. (61) However in CLTI patients particularly, who are considered the end-stage population of PAD, little is known about the association of anxiety and depression with adverse outcomes. (62) Recently, Zahner et al. evaluated adverse outcomes for specifically CLTI patients with comorbid depression in a retrospective national study. (64) This study demonstrates that depression is associated with a 39% increased odds of lower limb amputation in CLTI patients. (64)
Cost-effectiveness
Given the rise of health care costs, cost-effective care is a huge priority for the general public. (65) The treatment of CLTI is very laborious and costly and despite all efforts to salvage the affected limb, limb amputation cannot always be averted. (66–69) Still, revascularisation is believed to be a cost-effective alternative to wound care and primary amputation, even in patients with a minimal functional status or octogenerians. (68) In CLTI patients, primary amputation provided fewer health benefits and increased costs due to the need for long-term care institutionalisation. (67,68) So, limb preservation needs to be achieved even if only costs are considered. However, not all patients are candidates for surgical revascularisation. In these patients, the question remains whether endovascular revascularisation is a cost-effective alternative to wound care alone. In this thesis, cost-effectiveness is plotted against the willingness-to-pay threshold for these two treatments, endovascular revascularisation and conservative treatment, in frail CLTI patients. The aim of this analysis is to examine whether aggressive revascularisation in patients not suitable for surgery is cost-effective.
AIM AND THESIS OUTLINE
Chapter 1
16
Long-term outcome after treatment for chronic limb-threatening ischemia in the elderly
Currently, there is a paucity of the best treatment choice in elderly CLTI patients. The cornerstone in treating CLTI remains limb salvage, which is often attempted by revascularisation. The treatment of CLTI patients is intensive, difficult and costly. The survival rates remain limited even with treatment. Along with the increase of the elderly age population, health care costs keep rising. Unfortunately, in 35-67% of patients, limb salvage cannot be achieved despite all efforts made to save the affected limb. (7,32,33) Moreover, not all patients are candidates for surgical revascularisation. For these patients, the question rises, which treatment is worthwhile from the patient’s and effective point of view. (65) Chapter 2 will elaborate on this topic and the cost-effectiveness of the two main treatment strategies in frail CLTI patients: endovascular revascularisation and conservative therapy.
Chronic limb-threatening ischemia is associated with a systemic atherosclerotic burden and has a massive impact on daily life. (70) Historically, treatment success has been measured by objective outcomes, such as bypass patency, mortality, and limb salvage. (56) The effects of treatment on the patients themselves can be substantial. Consequently, PROMS have become of great importance. As already mentioned, HS and QoL are frequently used PROMS. Both measurements are considered to be impaired in CLTI patients. Although they have been extensively assessed, long-term outcome results in elderly CLTI patients are scarce. In Chapter 3, QoL and HS, along with objective outcomes, are evaluated after two-years of follow-up. A latent class analysis will be used to determine if there are certain patient characteristics present that can help us recognize which patients are prone to have better or worse QoL and HS outcomes.
Unfortunately, nearly 50% of CLTI patients are expected to die within 2 years after diagnosis. Mortality rates are even worse in CLTI patients with tissue loss. (29) The question remains if QoL and HS are preserved when treating these patients. Chapter 4 elaborates on the QoL and HS outcome of patients who expired during the two-year follow-up period.
The effect of lower limb amputation in the elderly patient
17
1
amputation. (1,71) Moreover, the four-year amputation rate increases to 35-67%. (7,32) Despite high amputation rates, research on PROMS is limited. (73) Though the surgical outcome of lower limb amputation in CLTI patients is undesirable, an adequate QoL is still possible for patients with a lower limb amputation. (30) Unfortunately, many studies claim to assess QoL but their findings are based on HS instruments. (52,73,74) In Chapter 5, the changes on questionnaires assessing QoL or HS, in elderly CLTI patients who underwent lower limb amputation, are discussed and compared with CLTI patients who did not undergo amputation during follow-up.
In patients with coronary artery disease, depressive disorders adversely affect outcome. (75,76) For PAD, in general, an association is assumed between depression and adverse outcomes, such as lower limb amputation. (61,62) The prevalence of symptoms of depression is as high as 48% in patients with PAD. For CLTI, little is known about the association between depressive disorders and poor outcome. (62) Furthermore, lower limb amputation can alter a person’s social situation, which can also be associated with depression and anxiety, another psychiatric manifestation. (77) Anxiety is also known to rise after lower limb amputation in the long-term. In patients with coronary artery disease, anxiety is associated with an increased risk of mortality and also an adverse cardiac outcome. (58) However, the risks associated with anxiety are lower than the risks associated with depression. (58,78) In Chapter 6, the role of anxiety and symptoms of depression will be addressed in elderly patients with CLTI. Results will be compared between patients who underwent an amputation and patients who did not. In Chapter 7, special focus is on the long-term changes of QoL, HS and symptoms of depression exclusively in patients after lower limb amputation.
Chapter 1
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64. Zahner GJ, Cortez A, Duralde E, Ramirez JL, Wang S, Hiramoto J, et al. Association of comorbid depression with inpatient outcomes in critical limb ischemia. Vasc Med. 2020;25(1):25–32. 65. Barshes NR, Chambers JD, Cohen J, Belkin M. Cost-effectiveness in the contemporary
management of critical limb ischemia with tissue loss. J Vasc Surg. 2012;56(4):1015–24. 66. Sachs T, Pomposelli F, Hamdan A, Wyers M, Schermerhorn M. Trends in the national outcomes
and costs for claudication and limb threatening ischemia: Angioplasty vs bypass graft. J Vasc Surg. 2011;54(4):1021–31.
67. Barshes NR, Belkin M. A Framework for the Evaluation of “ Value ” and Cost-Effectiveness in the Management of Critical Limb Ischemia. J Am Coll Surg. 2011;213(4):552–66.
68. Barshes NR, Kougias P, Ozaki CK, Pisimisis G, Bechara CF, Henson HK, et al. Cost-effectiveness of Revascularization for Limb Preservation in Patients with Marginal Functional Status. Ann Vasc Surg. 2014;28(1):10–7.
69. Barshes NR, Kougias P, Ozaki CK, Goodney PP, Belkin M. Cost-effectiveness of revascularization for limb preservation in patients with end-stage renal disease. J Vasc Surg. 2014;60(2):369–74. 70. Teraa M, Conte MS, Moll FL, Verhaar MC. Critical Limb Ischemia: Current Trends and Future
Directions. J Am Heart Assoc. 2016;5(2):1–9.
71. Becker F, Robert-Ebadi H, Ricco J-B, Setacci C, Cao P, de Donato G, et al. Chapter I: Definitions , Epidemiology , Clinical Presentation and Prognosis. Eur J Vasc Endovasc Surg. 2011;42(S3):S4–12.
72. Van Eijk MS, van der Linde H, Buijck B, Geurts A, Zuidema S, Koopmans R. Predicting prosthetic use in elderly patients after major lower limb amputation. Prosthet Orthot Int. 2012;36(1):45–52.
73. Hawkins AT, Henry AJ, Crandell DM, Nguyen LL. A Systematic Review of Functional and Quality of Life Assessment after Major Lower Extremity Amputation. Ann Vasc Surg. 2014;28(3):763–80. 74. Bradley C. Importance of differentiating health status from quality of life. Lancet. 2001;357:7–8. 75. Musselman DL, Evans DL, Nemeroff CB. The Relationship of Depression to Cardiovascular
Disease. Arch Gen Psychiatry. 1998;55:580–92.
76. Mcmanus D, Pipkin SS, Whooley MA. Screening for Depression in Patients With Coronary Heart Disease (Data from the Heart and Soul Study). Am J Cardiol. 2005;96:1076–81. 77. Deans SA, Fadyen AKMC, Rowe PJ. Physical activity and quality of life: A study of a lower-limb
amputee population. Prosthet Orthot Int. 2008;32(2):186–200.
Cost-effectiveness
of the treatments for
chronic limb-threatening
ischemia in the
elderly population
C.M.L. Peters, J. de Vries, S. Redeker, R. Timman, G.J. van Eijck,
S.L. Steunenberg, N. Verbogt, G.H. Ho, J.J. van Busschbach, L. van der Laan
Chapter 2
24
ABSTRACT
Objective: The treatment of chronic limb-threatening ischemia (CLTI), with the intention to prevent limb loss, is often an intensive and expensive therapy. The aim of this study was to examine the cost-effectiveness of endovascular and conservative treatment of elderly CLTI patients unsuitable for surgery.
Methods: In this prospective observational cohort study, data were gathered in two Dutch peripheral hospitals. CLTI patients aged 70 years or older were included in the outpatient clinic. Exclusion criteria were malignant disease, lack of language skills, and cognitive impairment; 195 patients were included and 192 patients were excluded. After a multidisciplinary vascular conference, patients were divided into three treatment groups (endovascular revascularization, surgical revascularization, or conservative therapy). Subanalyses based on age were made (70-79 years and ≥80 years). The follow-up period was 2 years. Cost-effectiveness of endovascular and conservative treatment was quantified using incremental cost-effectiveness ratios (ICERs) in euros per quality-adjusted life-years (QALYs).
Results: At baseline, patients allocated to surgical revascularization had better health states, but the health states of endovascular revascularization and conservative therapy patients were comparable. With an ICER of €38,247.41/QALY (~$50,869/QALY), endovascular revascularization was cost-effective compared with conservative therapy. This is favourable compared with the Dutch applicable threshold of €80,000/QALY (~$106,400/QALY). The subanalyses also established that endovascular revascularization is a cost-effective alternative for conservative treatment both in patients aged 70 to 79 years (ICER €29,898.36/QALY; ~$39,765/QALY) and in octogenarians (ICER €56,810.14/ QALY; ~$75,557/QALY).
25
2
INTRODUCTION
The treatment of chronic limb-threatening ischemia (CLTI), with the intention to prevent limb loss, is often an intensive and expensive therapy. (1) Chronic limb-threatening ischemia is the end stage of peripheral arterial disease. It is characterized by ischemic pain and/or tissue loss (ulcers or gangrene) and causes impaired quality of life (QoL); in addition, it has a high morbidity and mortality rate. (2,3) Treatment choices are conservative treatment, endovascular revascularization and surgical revascularization. Because of a lack of evidence in randomized controlled trials, there is still continuing international debate over which treatment is preferred, especially for elderly patients. (4–7)
So far, the only randomized controlled trial on this topic is the Bypass vs Angioplasty in Severe Ischaemia of the Leg (BASIL) trial. (7) This trial compared a bypass surgery-first with a balloon angioplasty-first revascularization strategy for CLTI. It was concluded that surgical revascularization was beneficial to the clinical outcome in CLTI patients with a life expectancy of at least two years. (7) The BASIL trial also examined the cost-effectiveness of both treatments, as an individual outcome. According to the BASIL trial, surgery may lead to an increase of costs with little effects on health in the short to medium term. (7,8) In line with the BASIL trial, Barshes et al. recommended that only ambulatory and patients living independently should be treated with surgical revascularization, when only taking costs into consideration.
For elderly patients not suitable for surgery, there is a lack of studies examining the cost-effectiveness of other CLTI treatment, notably conservative treatment. It could well be that surgical or endovascular revascularization is too invasive for fragile patients, leading to a loss of QoL and high costs. Such concern is particularly relevant in view of the increase in patients’ age and the rise of health care costs.
Chapter 2
26
METHODS
The methods of this prospective observational cohort study have been previously published. (9) In summary, data were gathered between January 2012 and February 2016 in two Dutch hospitals. Patients were included if they were aged 70 years or older and suffering from CLTI classified as Rutherford 4 to 6. (10) Exclusion criteria were malignant disease, lack of Dutch language skills, and cognitive impairment. The follow-up period was 2 years. In line with the findings of Arvela et al, Dosluoglu et al, Lejay et al, and Brosi et al, we distinguished between patients aged 80 years and older and patients 70 to 79 years of age. (8,11-13)
According to the criteria of the Central Committee on Research Involving Human Subjects, this prospective observational cohort study did not require a formal written consent for ethical approval. The Institutional Review Board (AMOA) endorsed this. All patients included signed an informed consent.
27
2
The mortality and QoL results of this study were recently published. (9) In that publication, mortality and QoL were presented as separate items. It could be that mortality and QoL have a complicated interaction, as patients with a low QoL die earlier, leaving the study arm filled with patients with a high QoL. When QoL and mortality are combined in quality-adjusted life-years (QALYs), such complication in the interpretation of the results can be avoided. Moreover, QALYs allow an interpretation of the results in terms of costs per QALY, which is a preferred outcome in health economics. (15) In relation to the calculation of the cost-effectiveness ratio, in-hospital and out-of-hospital costs were obtained retrospectively according to the payer’s perspective, in which all inpatient and outpatient health care costs and effects were incorporated. (16) The actual costs of all services provided in the hospital were retrieved from the financial department. The outpatient costs included wound care and rehabilitation stays in nursing facilities and were provided by the nursing facilities’ financial departments. Missing cost data were estimated according to the Dutch manual for estimating costs. (15) Wound care costs were estimated using the same method. Rehabilitation costs of patients entering the hospital from nursing facilities were excluded because these patients already received nursing care before inclusion. These costs were not considered extra costs due to CLTI after inclusion.
Chapter 2
28
The 12-Item Short Form Health Survey (SF-12) was used to estimate EuroQol-5 Dimension 3-Level (EQ-5D-3L) “utilities” or “values” by mapping Dutch EQ-5D-3L values onto the SF-12 scores. (20-23) An EQ-5D-3L score of 1.00 represents the value of perfect health; a score of 0.00 represents the value of death. The SF-12 questionnaire was measured at baseline (ie, the moment of inclusion in this study), after 5 to 7 days (mostly conducted during hospitalization), and at 6 weeks, 6 months, 12 months, and 24 months after intervention. It consists of 12 questions that provide information about mental and physical functioning. QALYs were calculated per patient during 2 years using the mapped EQ-5D-3L values. QALYs were calculated using a standard multiplicative model that estimated the area under linear interpolation of the EQ-5D-3L trajectory for each individual. The area under the curve was calculated by adding up the areas between the successive measurements (ie, trapezoid or, in case of death, a triangle). If the first measurement was missing, it was imputed with the second measure (first observation carried forward). If the second measure was also missing, it was imputed with the third measure, in which case the first measure was also imputed with the third measure. In case of death, zero was administered at the death date and at the follow-ups thereafter. If the last observations were missing, the last valid observation was carried forward. In general, the 24-month measure was not taken at exactly 24 months. Therefore, the 24-month measure was interpolated or extrapolated to exactly 24 months.
Statistical analysis was done using SPSS software (version 23; IBM Corp, Armonk, NY). Shapiro-Wilks test was used to assess normality of continuous data for the univariate comparisons. Gaussian-shaped distributions were analyzed using the Student t-test, expressed as mean and standard deviation. Non-normally distributed data were analyzed using the Mann-Whitney U test. A P value of <.05 was considered significant.
RESULTS
29
2
Baseline characteristics
Table I presents an overview of the baseline characteristics of the three subgroups, as published earlier by Steunenberg et al. (9) Patients undergoing surgical treatment were significantly younger than the other treatment groups for all patients concerning median age (76 [73,81], p<.001) and had a Rutherford 4 classification (p<.001) more frequently. (9,24) There were no major statistically significant differences in the patients who received endovascular and conservative treatment. Therefore, this study focused on patients who received endovascular or conservative treatment because their characteristics were homogeneous, which allows for a meaningful comparison.
Follow-up
The follow-up characteristics during the first year are summarized in Table II. Hospita-lization rates were significantly lower for conservative treatment when compared with both treatments for the total cohort and in considering both age groups. For stay in intensive care unit, readmission, reinterventions and rehabilitation, no statistically significant difference was reached. Compared with patients aged between 70 and 79 years old, there is a tendency towards fewer reinterventions after initial conservative treatment for patients aged 80 years and older, but no statistically significant difference between all groups was evident.
Costs and health utilities
Costs are presented in Table III. Costs were divided into four categories: hospital costs, rehabilitation or nursing costs, home health nursing costs, and total costs. For the total cohort and the octogenarian group, hospital costs were significantly higher in the endovascularly revascularized patients compared with the conservatively treated patients (p=.008). In the total cohort group, the mean total cost of endovascular revascularization was €21,041.93 during a period of 2 years. Endovascular revascularization produced a mean of 0.946 QALY per patient. Conservative treatment had a mean total cost of €17,103.04 in the same period. Conservative therapy produced a mean of 0.846 QALY per patient.
Cost-utility analysis
Chapter 2
30
Table I Baseline characteristics (n=195)
Total gr oup Aged 70-79 Aged 80+ Tr eatment Endovascular n = 82 Sur gical n = 67 Conservative n = 46 Endovascular n = 34 Sur gical n = 47 Conservative n = 12 Endovascular n = 48 Sur gical n = 20 Conservative n = 34 Gender Male 45 (55) 44 (66) 21 (46) 22 (65) 34 (72 )8 (67) 23 (48) 10 (50) 13 (38)
Age Median age [IQR]
81 [76,86] 76* [73,81] 83 [79,87] 75 [72,77] 75* [72,77] 75 [73,76] 84 [82,88] 83 [81,86] 86 [83,88] Rutherfor d-class Category 42 2 (27) 36* (54) 6 (13) 9 (26) 28 (60 )2 (17) 13 (27 )8 (40) 4 (12% Category 5/6 60 (73) 31* (46) 40 (87) 25 (74) 19 (40) 10 (83) 35 (73) 12 (60) 30 (88% Co-morbidity Pulmonary 54 (68) 28* (42) 26 (58) 22 (65) 19 (40 )7 (58) 32 (70 )9 (45) 19 (58) Car diac 62 (76) 36* (54) 36 (78) 25 (74) 27 (57 )9 (75) 37 (77) 9* (45) 27 (79) Neur ological 23 (28) 19 (28) 21 (46) 11 (32) 13 (28 )6 (50) 12 (25 )6 (30) 15 (44) Arthritis 21 (26) 17 (25) 20 (44) 8 (24) 10 (21) 9* (75) 13 (28 )7 (35) 11 (33)
Vascular risk factors Hypertension
62 (76) 39 (58) 29 (64) 31* (91) 27 (57 )8 (67) 31 (65) 12 (60) 21 (64) Diabetes mellitus 49 (60) 22* (33) 23 (50) 19 (56) 18 (38 )8 (67) 30 (63 )4 (20) 15 (44) Renal impairment 55 (67) 23* (34) 33 (72) 20 (59) 14* (30 )9 (75) 35 (73) 9* (45) 24 (71) Curr ently smoking 15 (19) 23* (34) 7 (16) 10 (29) 17 (36 )4 (33 )5 (11 )6 (30) 3 (9) Pr
eoperative risk scor
es ASA scor e 22 6 (32) 19 (28) 8 (17) 14 (41) 13 (28 )2 (17) 12 (25 )6 (30 )6 (18) ASA scor e 35 0 (61) 46 (69) 28 (61) 17 (50) 32 (68 )7 (58) 33 (69) 14 (70) 21 (62) ASA scor e 46 (7 )2 (3) 10 (21)* 3 (9 )2 (4) 3 (25) 3 (6) --7 (21) V-POSSUM scor e 26 Median morbidity[IQR] 55 [37] 53 [47] 53 [41] 59 [41] 50 [44] 61 [58] 55 [31] 61 [54] 49 [41]
Median mortality [IQR]
19 [16] 9* [12] 17 [19] 21 [27] 9 [11] 16 [27] 18 [17] 11 [16] 17 [19]
ASA = American Society of Anesthesiologists; IQR = inter
quartile range; V
-POSSUM = V
ascular
-Physiological and Operative Severit
y Scor
e for the Enumeration of Mortality and Morbidity
Date ar
e pr
esented as number (%), unless otherwise specifi
ed, as published pr eviously by Steunenber g et al. (9) * Signifi cant dif fer ence compar
ed with the other tr
eatment gr
31
2
Table II Follow-up characteristics
Total gr oup Aged 70-79 Aged 80+ Endovascular n = 82 Sur gical n =67 Conservative n =46 Endovascular n = 34 Sur gical n = 47 Conservative n = 12 Endovascular n = 48 Sur gical n = 20 Conservative n = 34
Admission Admission, days ICU ICU, days Readmision Readmision, days Reinterventions:
No r
einterventions
Conservative Endovascular Sur
gical
Major Amputation Rehabilitation Rehabilitation, days 82 (100) 8 (9) 7 (9) 3 (10) 29 (35) 9 (17) 46 (56) 23 (28) 9 (11) 10 (12) 21 (26) 25 (31) 88 (100) 67 (100) 9 (8) 6 (9) 2 (2) 27 (30) 9 (14) 34 (51) 16 (24) 15 (22) 9 (13) 10 (15) 17 (25) 155 (185) 20 (44)* 8 (7)* 0 (0) -19 (41) 10 (14) 23 (50) 11 (24) 5 (11) 6 (13) 10 (22) 12 (26) 171 (279) 34 (100) 8 (10) 3 (9%) 2 (.) 16 (47) 9 (13) 18 (53) 8 (24) 6 (15) 5 (15) 7 (21) 12 (35) 104 (112) 47 (100) 8 (6) 4 (9) 2 (1) 19 (40) 6 (8) 25 (53) 10 (21) 10 (21) 6 (13) 5 (11) 9 (19) 155 (226) 7 (58)* 5 (6)* 0% - 7 (58) 9 (.) 3 (25) 6 (50) 1 (8) 2 (17) 3 (25) 4 (33) 166 (.) 48 (100) 8 (10) 4 (8) 4 (8) 13 (17) 17 (31) 28 (58) 15 (31) 3 (6) 5 (10) 14 (29) 13 (27) 86 (164) 20 (100) 13 (10) 2 (10) 4 (.) 8 (40) 16 (15) 9 (45) 6 (30) 5 (25) 3 (15) 5 (25) 8 (40) 161 (243) 13 (38)* 9 (6)* 0 (0) -12 (35) 10 (24) 20 (59) 5 (15) 4 (12) 4 (12) 7 (21) 8 (24) 175 (288)
ICU = intensive car
e unit
Data ar
e pr
esented as number (%) or median (inter
quartile range)
Admission and days of admission wer
e r
eported pr
eviously by Steunenber
g et al. (9)
Only admitted patients wer
e included in the calculation of median days of admission, ICU, r
eadmission and r ehabilitation * Signifi cant dif fer ence compar
ed with the other tr
eatment gr
Chapter 2
32
Table III Hospital costs, rehabilitation costs, and home health nursing costs
Endovascular Conservative
Mean Range Mean Range p-value*
Total group
Hospital costs 13,878.49 (2,378.95 – 64,797.68) 9,770.35 (100.06 – 36,273.49) 0.008
Rehabilitation or
nursing home costs 6,239.70 (0 – 66,110.43) 6,467.95 (0 – 40,460.50) 0.960
Home health nursing
costs 923.74 (0 – 26,787.93) 864.74 (0 – 15,398.33) 0.807
Total cost 21,041.93 (2,378.95 – 130,908.11) 17,103.04 (100.06 – 76,016.75) 0.041
Aged 70-79
Hospital costs 14,152.12 (2,378.95 – 48,437.60) 10,643.75 (558.46 – 23,959.41) 0.484
Rehabilitation or
nursing home costs 6,474.79 (0 – 30,192.80) 8,814.24 (0 – 30,010.33) 0.652
Home health nursing
costs 1,171.73 (0 – 26,783.94) 177,37 (0 – 1,132.23) 0.806
Total cost 21,798.64 (2,378.95 – 79,899.51) 19,635.36 (548 – 52,501.15) 0.484
Aged 80+
Hospital costs 13,684.68 (2,797.50 – 64,797.68) 9,462.09 (100.06 – 36,273.49) 0.008
Rehabilitation or
nursing home costs 6,073.17 (0 – 66,110.43) 5,639.84 (0 – 40,460.50) 0.835
Home health nursing
costs 748.08 (0 – 11,171.34) 1,107.35 (0 – 15,398.33) 0.696
Total cost 20,505.93 (2,797.5 – 130,908.11) 16,209.28 (100.06 – 76,016.75) 0.060
Costs are presented in euros * Mann-Whitney U test
Table IV Cost-utility analysis Total cost
€ Incremental cost€ Benefi t QALY Incremental benefi t €/QALYICER
Total group Conservative 17,162.14 0.84588 Endovascular 20,988.12 3,825.99 0.94591 0.10003 38,247.41 Aged 70-79 Conservative 19,602.06 0.93669 Endovascular 21,823.51 2,221.45 1.01099 0.0743 29,898.36 Aged 80+ Conservative 16,236.61 0.82064 Endovascular 20,540.01 4,303.40 0.89640 0.07576 56,810.14
33
2
Figure 1. The incremental costs and incremental benefits (quality-adjusted life-years [QALYs]) are demonstrated for endovascular revascularization and conservative treatment. ICERs, Incremental cost-effectiveness ratios
Chapter 2
34
Figure 2. The cost-effectiveness acceptability curve for endovascular revascularization compared with conservative treatment. The critical 50% level is surpassed at €37,350.00 in the total cohort group. ICER, Incremental costeffectiveness ratio.
35
2
DISCUSSION
In our study, CLTI patients (n=195) aged 70 years and older were included in a prospective observational cohort study to quantify the cost-effectiveness of treatment for elderly CLTI patients, in whom surgical treatment is not preferred. As presented in Table I, patients undergoing surgical treatment had significantly better characteristics than the patients who were treated endovascularly or conservatively, which does not allow a meaningful comparison. On the other hand, patients who received endovascular or conservative treatment had comparable characteristics at inclusion, which thus allows a meaningful comparison. In this comparison, we found that endovascular revascularization is more expensive but still showed a reasonable cost-effectiveness over conservative treatment.
The design and results of the present study are different from results published earlier. (1,7) The BASIL trial stated that surgical revascularization is recommended over endovascular revascularization after a 3-year follow-up, but has an unfavorable ICER of $184,492/QALY (~€138,369/QALY). (13) We could not confirm these results, as our patients allocated to surgical revascularization were in better health than the patients allocated to endovascular revascularization. Barshes’ probabilistic Markov model compared conservative therapy, endovascular revascularization, bypass surgery, and primary amputation in CLTI patients. Barshes et al. concluded that surgical bypass, with endovascular revision, was the most cost-effective treatment after 1-year follow-up for ambulatory and patients living independently, ICER $47,738/QALY (~€35,804/ QALY). (1)
Our assumption at the beginning of the study was that endovascular treatment results in fewer admission days and is less harmful than surgery. However, our data suggest otherwise. Admission days were similar to those of surgically treated patients, with no statistically significant difference between these two groups. Consequently, there was no statistically significant difference in the hospital costs between the endovascularly and surgically treated patients. There was also no statistically significant difference in readmission and rehabilitation rates or the number of reinterventions after initial treatment.
Chapter 2
36
state of the elderly would complicate endovascular revascularization. Nevertheless, our results suggest that despite this assumption, elderly still benefit from endovascular revascularization, although with higher costs. The interpretation of our results must be done in the light of the observation that both the absolute difference in costs and difference in effects are small: €3,825.99 and 0.10003 QALY. Small differences in the execution of endovascular revascularization and conservative treatment, local logistics, and the characteristic of the patients may therefore easily influence the individual outcomes.
Indeed, individual circumstance are often mentioned in the literature in discussing treatment allocation. For instance, Lelay et al. stated that the choice of treatment for the age group 80 years and older depends on life expectancy. (12) Surgical revascularization leads to a longer lasting outcome than endovascular revascularization. However, the outcome of surgery is limited in this age group because of a high rate of morbidity and mortality. (2,4,25) Moreover, initial costs of surgical revascularization are high. (25) All these factors were taken into consideration in choosing a treatment of choice, in the multidisciplinary vascular conference, where this study’s treatment selection took place. The older age category, octogenarians, was more likely to receive conservative or endovascular treatment. Only octogenarians in extremely good health, with a long life expectancy, were treated surgically. The difficulty lies in determining which patient has a life expectancy <2 years. Soga et al. developed a risk score to identify CLTI patients with <50% probability of 2-year survival. (26) However, this risk score was not part of the multidisciplinary vascular conference.
37
2
patients allocated to conservative treatment and endovascular treatment resembles a random allocation. Obviously, randomization cannot be guaranteed, which makes that the interpretation of our results should be done with care.
A second limitation of the present study is that in this relatively small sample size. Primary amputations had to be excluded because of the small number of patients (n = 5).
A third limitation is that we did not conduct the EQ-5D-3L questionnaire to provide us “utility weight” for the calculation of QALYs. Instead we used the SF-12 to estimate EQ-5D-3L by mapping. Mapping is done by regression. Any regression will result in a smaller range and thus in smaller effects sizes. It is unlikely that this hampers our conclusion, as our ICER is already favorable compared to a reasonable willingness-to-pay threshold. (20–22)
A fourth limitation is that we did not include all possible costs items beside the medical costs. For instance, we did not include private costs to the patients or others (e.g. caretakers). Inclusion of these costs items would have given a better cost estimate from a societal perspective, but these costs were not recorded in this study. (28) The last limitation is that we were unable to obtain the cost of limb prosthesis purchased and prosthesis maintenance costs. However, elderly CLTI patients rarely ambulate or use prosthesis after lower limb amputation. (29)
CONCLUSION
Chapter 2
38
SUPPLEMENTARY TABLE
Supplementary table 1 procedure characteristics
Surgical procedures
Aorta-iliac
18
Supraingenual Femoro-popliteal
2
Infraingenual Femoro-popliteal
21
Femoro-distal
14
Hybrid procedures
Aorto-iliac procedure with PTA
4
Femoro-popliteal bypass with iliac PTA
7
Femoro-popliteal bypass with crural PTA
1
Endovascular procedures
Combined PTA
20
Iliac
PTA 8 Stenting 10 SFA PTA 18 Stenting 11 Popliteal arteries PTA 3 Stenting 1 Crural arteriesPTA of one artery 2
PTA of two arteries 4
PTA of three arteries 2
Failed procedures
3
39
2
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Long-term quality of
life and health status
of treatment for the
elderly with chronic
limb-threatening ischemia
C.M.L. Peters, P. Lodder, J. de Vries, S.L. Steunenberg, E.J. Veen,
H.G.W. de Groot, G.H. Ho, L. van der Laan
Chapter 3
44
ABSTRACT
Objective: In elderly patients, chronic limb-threatening ischemia (CLTI) diminishes quality of life (QoL) and health status (HS) considerably prior to treatment. There is also little scientific understanding of the long-term changes of QoL and HS after the treatment of elderly CLTI patients. Therefore, this was examined in this prospective study. The primary therapy was: endovascular revascularization, surgical revascularization, or conservative treatment. Furthermore, this study aimed to identify the distinctive trajectories of QoL and HS in elderly CLTI patients.
Methods: Chronic limb-threatening ischemia patients aged 70 years or older were included in a prospective observational cohort study with a follow-up period of 2 years. The World Health Organization Quality Of Life-BREF (WHOQOL-BREF) was used to asses QoL. The 12-Item Short Form Health Survey (SF-12) was used to measure HS. These self-report questionnaires were completed six times during follow-up. The QoL and HS scores of the elderly sample in this current study were compared to the normal scores in the general elderly population.
Results: In total, 195 patients were included in this study. The 2-year mortality was 42.1%. After 2 years, in all treatment groups patients showed significantly higher physical QoL score compared to baseline: endovascular treatment (13.7 vs. 10.9, 95% CI -3.63; -1.74, p<.001), surgical treatment (15.0 vs. 10.4, 95% CI -5.28; -3.64, p<.001), and conservative treatment (13.8 vs. 11.6, 95% CI -3.88; -1.14, p<.001). There was no significant difference between the physical QoL 2-year results and the corresponding normal values in the elderly population for all treatment groups. The physical HS (SF-12) significantly improved compared to the baseline measurement in the endovascular (37.4 vs. 28.9, 95% CI -9.46; -2.53, p=.001) and surgical revascularization group (42.5 vs. 28.0, 95% CI -16.58; -10.48, p<.001). After two years, only surgically treated patients had physical HS scores corresponding with the scores of their peers (mean Δ = -1.69, 95% CI -4.854; 1.474, p=.287). In the latent class trajectory analysis, there were no overlapping risk factors for poorer QoL and/or HS in this patient population.
45
3
INTRODUCTION
The end stage of peripheral arterial disease is represented by chronic limb-threatening ischemia (CLTI). This disease is characterized by ischemic rest pain and/or tissue necrosis. (1–3) Chronic limb-threatening ischemia diminishes quality of life (QoL) considerably (4) and is associated with high mortality and morbidity rates. (5–7) Revascularization (surgical or endovascular) is the cornerstone in the treatment of CLTI patients. (1) However, scientific data is scarce to determine the best revascularization management in elderly (aged ≥ 70 years) CLTI patients. (6–8) Moreover, revascularization is not always an option in frail elderly patients. In these patients, conservative treatment is a possible approach. (9–11) However, objective clinical outcome measures of conser-vative treatment are poor.
Lately, primary end points of treatment for CLTI have changed from clinical outcome, such as bypass patency and survival, to patient-reported outcome measures, most prominently QoL and health status (HS). Some research has been carried out on the long-term changes of these patient-reported outcome measures. (12,13) Still, there is little scientific understanding of the long-term changes of QoL and HS after the treatment of elderly CLTI patients. (13,14)
Chapter 3
46
The primary goal of the present study was to provide long-term QoL and HS results for elderly CLTI patients after primary therapy: endovascular revascularization, surgical revascularization, or conservative treatment. The QoL and HS scores of this study’s elderly sample were compared to the normal scores in the general elderly population. The second goal was to identify within the entire CLTI patient group distinctive trajectories of QoL and HS, followed by an assessment of the clinical and sociodemographic variables associated with each trajectory.
METHODS
In this prospective observational cohort study, elderly CLTI patients were included between January 2012 and February 2016 in two hospitals. (11) Inclusion criteria were diagnosis with CLTI and an age of 70 years or older. Because of the use of questionnaires, patients with a lack of Dutch language skills and cognitive impairment were excluded. Patients treated for or with a recent diagnosis of malignancy and patients undergoing primary major lower extremity amputation were also excluded. A formal written consent for ethical approval was not required according to the criteria of the Central Committee on Research Involving Human Subjects. The institutional review board (AMOA) approved this. (11) An written informed consent was obtained from all included patients.
After careful consideration of standard diagnostics (e.g. duplex ultrasound, computed tomographic angiography, and/or magnetic resonance angiography) in the outpatient clinic and The Trans-Atlantic Inter-Society Consensus (TASC II) classification, a panel of experts recommended each patient a particular treatment in a weekly multidisciplinary vascular conference.(11) The recommendation of treatment was based on current clinical practice in addition to the patient’s condition. As reported previously, the treatment options were endovascular revascularization, surgical revascularization, or conservative therapy (local wound care, antibiotics, and analgesics with or without minor amputation). (11)
47
3
mellitus, cardiac disease). During a period of 24 months, follow-up measurements were performed at 5-7 days, 6 weeks, 6 months, 12 months, and 24 months after the initial therapy. At baseline and at each follow-up moment, patients completed the WHOQOL-BREF questionnaire to determine QoL and the 12-Item Short Form Health Survey (SF-12) to measure HS. (16,17) Health status questionnaires evaluate perceived physical, psychological, and social functioning. They assess patients’ daily activities and only provide an objective assessment of functioning, provided by the patients’ themselves. (18–21) Quality of life questionnaires are a subjective appraisal of physical, psychological, and social functioning. Hence, QoL concerns patients’ satisfaction with functioning. (22) The treatment course (e.g. treatment, complications of treatment, time in hospital, time of amputation, time of death, et cetera) was also duly noted during follow-up.
Statistical analysis
