Background:
Abdominal aortic aneurysm (AAA) is a multifactorial vascular disease associated with high morbidity and mortality. Currently, surgical intervention is the only treatment option, and there is no drug therapy available for AAA. Hence, surveillance of AAA until indication for surgery may impact patient quality of life (QoL). There is a paucity of high-quality observational data on health status and QoL, particularly among AAA patients participating in randomized controlled trials. The objective of this study was to compare the QoL scores of AAA patients on surveillance to those of AAA patients enrolled in the MetAAA trial.
Material and methods:
Overall, 54 MetAAA trial patients and 23 AAA patients under regular surveillance for small AAA (part of a longitudinal monitoring study) were asked to complete three established and validated (in total 561 longitudinally collected) QoL questionnaires: the 36-Item Short Form Health Survey (SF-36), the Aneurysm Symptom Rating Questionnaire (ASRQ), and the Aneurysm-Dependent Quality of Life questionnaire (ADQoL).
Results:
A superior health status and QoL was found in AAA patients participating in the MetAAA trial compared to AAA patients under regular surveillance. In detail, MetAAA trial patients showed superior general health perception (P=0.012), higher energy level (P=0.036) as well as enhanced emotional well-being (P=0.044) and fewer limitations due to general malaise (P=0.021), which was subsequently reflected in an overall superior current QoL score (P=0.039) compared to AAA patients under regular surveillance.
Conclusion:
AAA patients enrolled in the MetAAA trial showed superior health status and QoL compared to AAA patients under regular surveillance.
Keywords: abdominal aortic aneurysm, Aneurysm-Dependent Quality of Life questionnaire (ADQoL), Aneurysm Symptom Rating Questionnaire (ASRQ), metaaa trial, quality of life, 36-Item Short Form Health Survey (SF-36)
Introduction
Highlights
Quality of life (QoL) scores from the world’s first study of metformin prescription to abdominal aortic aneurysm (AAA) patients.
MetAAA trial patients showed a superior health status and QoL compared to control.
The need for a medical treatment option to limit AAA is highlighted by this study.
New therapeutic approaches, such as metformin for AAA may contribute to superior QoL.
AAA patients show a high willingness to participate in clinical trials.
An abdominal aortic aneurysm (AAA) is a frequent condition that can lead to increased morbidity or life-threatening vessel wall rupture with high mortality rates1,2. In developed countries, it is still a leading cause of mortality3. It is often diagnosed incidentally and altered hemodynamic factors, atherosclerosis as well as chronic aortic inflammation are known to drive AAA development and pathogenesis4–6. Since AAA progress indefinitely, the current clinical practice guidelines recommend periodic AAA surveillance imaging, but to date, the maximal aortic diameter is the only clinically applied predictor of AAA progression, rupture risk, and surgical indication7,8. At present, there is no established pharmacological treatment option to significantly reduce aneurysm growth prior to AAA surgery9. The current clinical practice guidelines state three parameters as an indication for surgery: maximal AAA diameter greater than 50 mm in women and 55 mm in men; AAA expansion rate more than 10 mm per year; or symptomatic AAA7,8. When an indication for elective surgery is given, two surgical treatment options are available, open surgical repair (OSR) and endovascular aneurysm repair (EVAR)10. After aortic clamping, open surgical repair aims to replace the diseased arterial segment by a synthetic vascular graft, whereas endovascular aneurysm repair, as a comparable minimally invasive surgical modality, excludes the aneurysmal sac from circulation via the implantation of a stent graft11. The surveillance and treatment of AAA may impact patient quality of life (QoL), especially since there is currently no drug therapy available for AAA and previous clinical trials of pharmacological therapies have yielded negative results9. Ongoing clinical studies such as the Swedish Metformin for Abdominal Aortic Aneurysm Growth Inhibition (MAAAGI) trial (open-label randomized controlled trial) and the Vienna Metformin Therapy in Non-diabetic Patients with Abdominal Aortic Aneurysm (MetAAA) trial (a prospective, double-blind, randomized, and placebo-controlled safety and efficacy study), which aim to demonstrate the efficacy of oral metformin therapy for disease control of AAA, are expected to contribute supporting evidence12,13. Of note, morbidity and mortality are the common parameters to evaluate the outcome of medical or surgical procedures. However, more subjective indicators such as QoL scores and patient satisfaction are of considerable importance to assess the patients’ health condition14. Possible delays in treatment, insufficient coping strategies, essential lifestyle changes, and chronic or preoperative emotional stress can potentially lead to long-term behavioral changes of AAA patients and may negatively alter their QoL15,16. However, a recent systematic review and meta-analysis did not detect a negative impact on QoL from being under surveillance for an AAA17. How participation in clinical trials (such as MetAAA) affects QoL in AAA patients is unclear; the participation itself with increased attention could influence QoL as well as the expectations of a possible effect of the study intervention. Applying established and validated questionnaires, we hypothesized that MetAAA trial patients would show superior QoL compared to AAA patients under longitudinal surveillance without participating in a clinical trial of a novel pharmacological AAA intervention.
Material and methods
MetAAA trial
The MetAAA trial is a prospective, randomized, double-blind, placebo-controlled, safety and efficacy phase IIa study, active since September 2018. Based on compelling preclinical and clinical observational data, this prospective trial testing metformin therapy versus placebo for non-diabetic AAA patients was initiated at the Medical University of Vienna18–22. The main objective of the MetAAA trial is to evaluate the efficacy of oral metformin therapy for disease control of AAA. Thus, the MetAAA trial aims to establish the first medical treatment to inhibit AAA progression, and thereby reduce the need for major surgery or the risk of rupture with its associated mortality, morbidity, and cost. The study design of the MetAAA trial is depicted in Figure 1.
Figure 1.
MetAAA trial study design. The tolerability and efficacy of metformin is currently investigated in the MetAAA trial as a prospective, double-blind, randomized and placebo-controlled safety, and efficacy study. After a screening phase, patients with an infrarenal AAA between 30 and 49 mm aneurysm diameter in computed tomography angiographies are included in the study and treated either with metformin or placebo. Quarterly monitoring visits during the 12 months of treatment and subsequent half-yearly follow-up visits are additionally used to allocate and collect established and validated questionnaires for the assessment of quality of life in AAA patients. AAA, abdominal aortic aneurysm; GFR, glomerular filtration rate; IMP, investigational medicinal product, NETs, neutrophil extracellular traps; QoL, quality of life.
Study population
All studies involving human subjects were conducted according to the Code of Ethics of the World Medical Association (Declaration of Helsinki) as well as in line with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and Strengthening the Reporting of Cohort, Cross-Sectional and Case–Control Studies in Surgery (STROCSS) 2021 Guidelines, Supplemental Digital Content 1, http://links.lww.com/JS9/A199, and approved by the institutional ethics committee (license nos. 1729/2014 and 1479/2017)23–25. In total, 54 MetAAA trial patients (44 men and 10 women) and 23 AAA patients (22 men and one woman) under regular surveillance of a small AAA in a longitudinal monitoring study were included. These studies are registered with the Research Registry (unique identifying number researchregistry7647) and the Clinical Trials Registry (ClinicalTrials.gov Identifier: NCT03507413). All AAA patients gave their written informed consent and were treated and followed-up at the outpatient clinic of a tertiary university hospital (Department of General Surgery, Division of Vascular Surgery, Medical University of Vienna, University Hospital Vienna, Vienna, Austria). Independent recruitment of study participants was conducted; the exclusion criteria for patients of the standard surveillance study were recent (<12 months) cancer or chemotherapy, systemic autoimmune or hematological disease, and organ transplantation. The exclusion criteria for patients of the MetAAA trial were diabetes mellitus, indication for surgical AAA repair, pregnancy, and contraindications for metformin. Demographic patient data were recorded by a structured questionnaire (between 12 June 2019 until 18 March 2021) and all study participants underwent serial monitoring visits with collection of the validated QoL questionnaires (every six months for AAA patients under regular surveillance of the observational study and every three months for MetAAA trial patients for the first 12 months, thereafter every six months).
Questionnaires and quality assessment
Three established and validated questionnaires were administered to all patients during their AAA monitoring visits. At the first visit, all patients (of both AAA cohorts) underwent a one-to-one instruction and received assistance by the same attendant study doctor and study nurse for the correct and complete answering of the validated questionnaires. Subsequently, to ensure that the AAA patients answered the following questionnaires in an undisturbed and considerate manner, they were advised to complete them at home and then to return them to the study center. Upon return, an evaluation interview for possible open questions was conducted. Included were the 36-Item Short Form Health Survey (SF-36), the Aneurysm Symptom Rating Questionnaire (ASRQ), and the Aneurysm-Dependent Quality of Life questionnaire (ADQoL)26–30. All questionnaires rely upon patient self-reporting and self-completion. The SF-36 is a set of generic and coherent QoL measures, that are easily administrable and summarize the patient’s state of health based on eight health concepts: general health perceptions, physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, and energy/fatigue. The ASRQ assesses symptoms associated with an AAA combined with their degree of distressing patients and also reflecting their treatment during the surveillance period. The ASRQ has a total of 44 items in six subscales, including general malaise, weight, emotional, lower limb, cognitive, and gastrointestinal symptoms. The ADQoL assesses the individualized QoL in patients diagnosed with an AAA. It is a 24-item questionnaire which measures the present QoL and AAA specific impact on QoL. Since the ADQoL is designed to be an individualized measure, the patients can weight the ratings of the impact of AAA on each aspect of life to reflect a highly personalized assessment of the QoL impact of AAA. For the ADQoL, four subscales are implemented: physical function, psychological health, social life, and a subscale with nonassignable items.
Statistical methods
All patient reported outcome measure questionnaire sets were analyzed according to their formal and recommended evaluation strategy. To analyze the SF-36 sets, graded answers were transformed and normalized, depending on the presence or absence of limitations (Supplemental Table 1, Supplemental Digital Content 2, http://links.lww.com/JS9/A210). The mean values were calculated for the eight health concepts. Furthermore, for the ASRQ and ADQoL sets, recorded values were transformed as shown in Supplemental Table 1, Supplemental Digital Content 2, http://links.lww.com/JS9/A210 and patient reported outcome measures, if relevant, were pooled according to Supplemental Table 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A210. The demographic data are presented as median and interquartile range for continuous variables and counts with percent sample group for nominal variables. Results regarding the validated questionnaires are given as mean values and standard deviation (SD) for continuous variables as well as absolute and relative frequencies for nominal variables. Additionally, results of the ADQoL are stated as dimensionless weighted factors. For assessment of statistical significance, nonparametric tests were employed (Mann–Whitney U test and χ2-test).
Global analysis was chosen to account for differences between the MetAAA trial and the observational study group, such as missing baseline data, and to avoid the need for sensitivity analysis or multiple measurement correction. Global analysis is known to be less sensitive to confounding system bias and reflects the clinical relevance in an abundance of mismatch of the clinical significance of the differences.
Results
Patient collectives
Fifty-four MetAAA trial patients and 23 AAA patients under regular surveillance (longitudinal monitoring study) were included. Patient demographics of both cohorts are listed in Table 1. Overall, the AAA patient cohorts were comparable in terms of age, body mass index, smoking behavior, and characteristic comorbidities such as hypertension, hyperlipidemia, coronary heart disease, and peripheral artery disease. Chronic obstructive pulmonary disease was found to be significantly more prevalent in patients of the longitudinal monitoring study cohort (P=0.014). Since diabetes mellitus type II was an exclusion criterium for the MetAAA trial, no diabetic AAA patients with linked antidiabetic medication, including metformin were enrolled. Consequently, the longitudinal monitoring study cohort included significantly more diabetic AAA patients (P<0.001), antidiabetic medication (P<0.001), and metformin intake (not as an investigational medicinal product) (P<0.001) compared to the MetAAA trial cohort. There were no significant differences in the frequencies of antihypertensive, antiplatelet, anticoagulative, and lipid-lowering therapies between MetAAA trial and observational study patients. Furthermore, no significant differences in AAA maximal diameter, aortic segment volume, and associated intraluminal thrombus morphology as well as in positive AAA family history were found between patients of the two AAA cohorts. In addition, we assessed the educational level and background of the MetAAA trial patients and AAA patients under regular surveillance of the longitudinal monitoring study. There was no significant difference between the compared study groups regarding the educational level.
Table 1.
Demographics of AAA patients enrolled in the MetAAA trial and longitudinal monitoring study
| Parameter | MetAAA trial cohort (n=54) | AAA monitoring cohort (n=23) | P | ||
|---|---|---|---|---|---|
| Continuous variables | n/n ♂/ ♀ | Median (IQR) | n/n ♂/ ♀ | Median (IQR) | |
| Age [years] | 44/10 | 71.00 (11.00) | 22/1 | 67.00 (14.00) | 0.218 |
| Body mass index [kg/m²] | 44/10 | 27.50 (4.84) | 22/1 | 26.78 (4.87) | 0.991 |
| Smoking pack-years [py] | 41/9 | 40.00 (32.00) | 20/1 | 40.00 (25.00) | 0.990 |
| Mean systolic blood pressure [mmHg] | 43/10 | 132.00 (15.00) | 21/1 | 130.25 (24.00) | 0.675 |
| Mean diastolic blood pressure [mmHg] | 43/10 | 79.50 (8.00) | 21/1 | 76.75 (16.00) | 0.405 |
| Maximal AAA diameter [mm] | 44/10 | 42.75 (8.90) | 22/1 | 44.60 (12.00) | 0.295 |
| Aortic segment volume [cm³] | 44/10 | 72.29 (60.63) | 22/1 | 61.57 (101.23) | 0.680 |
| Maximal ILT diameter [mm] | 42/9 | 10.80 (11.50) | 22/1 | 10.5 (10.40) | 0.578 |
| ILT volume [cm³] | 42/9 | 24.28 (40.82) | 22/1 | 24.38 (43.65) | 0.479 |
| Nominal variables | Frequency n (%) | Frequency n (%) | |||
| Sex | |||||
| Men | 44 (81.48) | 22 (95.65) | 0.106 | ||
| Women | 10 (18.52) | 1 (4.35) | |||
| Smoking | |||||
| Never | 44/10 | 4 (7.41) | 22/1 | 2 (8.70) | 0.848 |
| Past | 44/10 | 23 (42.59) | 22/1 | 12 (52.17) | 0.203 |
| Current | 44/10 | 27 (50.00) | 22/1 | 9 (39.13) | 0.286 |
| AAA family history | 44/10 | 7 (12.96) | 22/1 | 6 (26.09) | 0.396 |
| Hypertension | 44/10 | 41 (75.93) | 22/1 | 19 (82.61) | 0.751 |
| Hyperlipidemia | 44/10 | 38 (70.37) | 22/1 | 17 (73.91) | 0.977 |
| Coronary heart disease | 44/10 | 14 (25.93) | 22/1 | 8 (34.78) | 0.580 |
| Myocardial infarction | 44/10 | 9 (16.67) | 22/1 | 4 (17.39) | 0.938 |
| Stroke | 44/10 | 3 (5.56) | 22/1 | 4 (17.39) | 0.207 |
| Diabetes mellitus type II | 44/10 | 0 (0) | 22/1 | 6 (26.09) | < 0.001 |
| Peripheral artery disease | 44/10 | 13 (24.07) | 22/1 | 4 (17.39) | 0.520 |
| COPD | 44/10 | 6 (11.11) | 22/1 | 8 (34.78) | 0.014 |
| Antiplatelet therapy | 44/10 | 45 (83.33) | 22/1 | 19 (82.61) | 0.938 |
| Anticoagulation therapy | 44/10 | 13 (24.07) | 22/1 | 5 (21.74) | 0.826 |
| Antihypertensive therapy | 44/10 | 46 (85.19) | 22/1 | 20 (86.96) | 0.840 |
| Lipid-lowering agents | 44/10 | 53 (98.15) | 22/1 | 22 (95.65) | 0.531 |
| Antidiabetic medication | 44/10 | 0 (0) | 22/1 | 6 (26.09) | <0.001 |
| Metformin intake (not as IMP) | 44/10 | 0 (0) | 22/1 | 6 (26.09) | < 0.001 |
| Educational level | |||||
| Primary school | 43/8 | 3 (5.88) | 21/0 | 0 (0) | 0.256 |
| Compulsory secondary or academic secondary school (lower cycle) | 43/8 | 7 (13.73) | 21/0 | 4 (19.05) | 0.568 |
| Vocational school and apprenticeship | 43/8 | 25 (49.02) | 21/0 | 8 (38.10) | 0.398 |
| Secondary technical and higher vocational school | 43/8 | 8 (15.69) | 21/0 | 3 (14.29) | 0.881 |
| Academic secondary school (upper cycle) | 43/8 | 4 (7.84) | 21/0 | 4 (19.05) | 0.169 |
| University or university of applied sciences | 43/8 | 4 (7.84) | 21/0 | 2 (9.52) | 0.815 |
The following statistical analyses were applied: Mann–Whitney U test for continuous variables, χ2-test for nominal variables. Boldface entries indicate statistical significance.
AAA, abdominal aortic aneurysm; COPD, chronic obstructive pulmonary disease; ILT, intraluminal thrombus; IMP, investigational medical product; IQR, interquartile range; n, number of individuals.
Compilation of QoL questionnaires
Due to the study designs with differences in the monitoring intervals (every three months in the MetAAA trial treatment phase versus every six months in the monitoring study), more sets of questionnaires from MetAAA trial patients have been obtained and analyzed (in median 8 questionnaires per MetAAA trial patient and in median 5 per AAA patient in the surveillance study). Details of proportional allocation and the collection of QoL questionnaires concerning monitoring timepoints are listed in Supplemental Table 3, Supplemental Digital Content 2, http://links.lww.com/JS9/A210. The MetAAA trial is currently ongoing and AAA patient treatments are still blinded, which implies that placebo is included in the QoL analysis of the MetAAA trial patients. Questionnaire sets collected from 12 June 2019 until 18 March 2021 were included in this analysis.
MetAAA trial patients show increased quality of life
In total, we analyzed 561 QoL questionnaires, of which 492 (87.70%) were entirely and 69 (12.30%) were partially completed. Among all questionnaires, 444 (79.14%) and 117 (20.86%) were of AAA patients enrolled in the MetAAA trial and longitudinal monitoring study, respectively. Further details regarding the proportional allocation and collection of QoL questionnaires concerning monitoring timepoints are listed in Supplemental Table 3, Supplemental Digital Content 2, http://links.lww.com/JS9/A210. The analysis revealed superior QoL attributes of MetAAA trial patients compared to AAA patients of the longitudinal monitoring study receiving essentially the best medical care. Among the eight health concepts of the SF-36 set, general health was found to be significantly better rated by MetAAA trial patients compared to longitudinally monitored study patients (60.98 vs. 52.50%, P=0.012), as shown in Table 2. Additionally, energy/fatigue (61.17 vs. 52.94%, P=0.036) and emotional well-being (77.74 vs. 69.37%, P=0.044) were noticed to show a significant difference regarding superior QoL in MetAAA trial patients. The SF-36 set further provides the assessment of perceived change in patient health over the recent twelve months, which was found to be significantly superior in MetAAA trial patients compared to AAA patients of the longitudinal monitoring study (51.63 vs. 42.50%, P=0.002). Regarding the ASRQ (Table 3), in total, a significantly smaller number of negative symptoms was recorded within the MetAAA trial cohort compared to AAA patients of the longitudinal monitoring study (17.17 vs. 26.00%, P<0.001). In detail, there was significantly less occurrence of negative symptoms in the MetAAA trial cohort with respect to the following subscales: emotional (17.31 vs. 26.74%, P<0.001), lower limb (20.52 vs. 28.21%, P=0.002), cognitive (17.76 vs. 29.91%, P<0.001), gastrointestinal symptoms (13.49 vs. 23.08%, P=<0.001) and general malaise (18.04 vs. 26.21%, P=0.001). As a second measure of the ASRQ, the subscale of limitations due to general malaise (49.85 vs. 60.31%, P=0.021) was discovered to be significantly less prevalent in MetAAA trial patients, as indicated in Table 3. In addition, fewer limitations due to emotional distress (45.14 vs. 54.73%, P=0.060) were stated in the MetAAA trial cohort. All detailed answer frequencies of patient reported outcome measures of the ASRQ for the MetAAA trial and observational study cohort are listed in Supplemental Table 4, Supplemental Digital Content 2, http://links.lww.com/JS9/A210. The ADQoL as an individualized measure for present QoL and associated AAA specific impact revealed a significant difference between the MetAAA trial and longitudinal monitoring study (Table 4), for higher current QoL in the MetAAA trial (2.50 vs. 2.82, P=0.039). Supplemental Table 5, Supplemental Digital Content 2, http://links.lww.com/JS9/A210 shows individual evaluation of patient reported outcome measures of the ADQoL set. Supplemental Table 6, Supplemental Digital Content 2, http://links.lww.com/JS9/A210 displays the comparison of the SF-36 health concepts, the ASRQ and AQoL subscales between AAA patients of the MetAAA trial and monitoring study at baseline as a measure of health-related QoL. It is demonstrated that changes with regard to QoL were made as a result of the study’s design and/or treatment because the two groups’ baseline QoL levels were shown to be statistically comparable.
Table 2.
Comparison of the SF-36 health concepts between AAA patients of the MetAAA trial and monitoring study as a measure of health-related quality of life
| MetAAA trial cohort | AAA monitoring cohort | ||||
|---|---|---|---|---|---|
| SF-36 – Health concepts | n | Mean [%] (SD) | n | Mean [%] (SD) | P |
| General health perception | 154 | 60.98 (17.42) | 40 | 52.50 (20.35) | 0.012 |
| Physical functioning | 151 | 66.99 (25.53) | 40 | 67.41 (27.44) | 0.741 |
| Bodily pain | 151 | 76.14 (26.77) | 40 | 71.45 (32.34) | 0.485 |
| Role limitations due to physical health problems | 149 | 60.40 (43.02) | 40 | 61.25 (42.35) | 0.997 |
| Role limitations due to personal or emotional problems | 148 | 73.87 (39.18) | 39 | 76.07 (38.20) | 0.792 |
| Emotional well-being | 147 | 77.74 (17.63) | 38 | 69.37 (22.42) | 0.044 |
| Social functioning | 151 | 84.52 (20.14) | 40 | 76.56 (27.76) | 0.129 |
| Energy/fatigue | 149 | 61.17 (19.42) | 38 | 52.94 (22.42) | 0.036 |
| Health change over recent 12 months | 153 | 51.63 (17.37) | 40 | 42.50 (17.17) | 0.002 |
Scores represent the percentage of total possible score achieved. The following statistical analysis was applied: Mann–Whitney U test. Boldface entries indicate statistical significance.
AAA, abdominal aortic aneurysm; n, number of questionnaires; SD, standard deviation; SF-36, 36-Item Short Form Health Survey.
Table 3.
Comparison of the ASRQ subscales between AAA patients of the MetAAA trial and monitoring study as a measure of health-related quality of life
| ASRQ subscales | MetAAA trial cohort | AAA monitoring cohort | P | ||
|---|---|---|---|---|---|
| Appearance of negative symptoms | n/N of items | % | n/N of items | % | |
| General malaise | 230/1275 | 18.04 | 92/351 | 26.21 | 0.001 |
| Weight | 54/424 | 12.74 | 19/116 | 16.38 | 0.309 |
| Emotional | 219/1265 | 17.31 | 92/344 | 26.74 | <0.001 |
| Lower limb | 261/1272 | 20.52 | 99/351 | 28.21 | 0.002 |
| Cognitive | 151/850 | 17.76 | 70/234 | 29.91 | <0.001 |
| Gastrointestinal | 152/1127 | 13.49 | 72/312 | 23.08 | <0.001 |
| Total appearance of negative symptoms | 1067/6213 | 17.17 | 444/1708 | 26.00 | <0.001 |
| Other negative symptoms (non-assignable) | 7/142 | 4.90 | 4/39 | 10.26 | 0.217 |
| Limitations due to symptoms | n (of questionnaires) | Mean [%] (SD) | n (of questionnaires) | Mean [%] (SD) | |
| General malaise | 95 | 49.85 (24.07) | 33 | 60.31 (21.64) | 0.021 |
| Weight | 47 | 33.70 (31.90) | 14 | 35.36 (34.77) | 0.873 |
| Emotional | 83 | 45.14 (21.00) | 30 | 54.73 (21.06) | 0.060 |
| Lower limb | 89 | 56.23 (26.84) | 32 | 53.77 (27.66) | 0.969 |
| Cognitive | 75 | 48.80 (24.52) | 30 | 51.15 (26.00) | 0.838 |
| Gastrointestinal | 81 | 56.22 (25.28) | 27 | 57.59 (22.63) | 0.686 |
| Total limitations due to symptoms | 127 | 48.84 (19.21) | 38 | 52.82 (19.64) | 0.182 |
Scores represent the percentage of total possible score achieved. The following statistical analyses were applied: χ²-test and Mann–Whitney U test. Boldface entries indicate statistical significance.
AAA, abdominal aortic aneurysm; ASRQ, Aneurysm Symptom Rating Questionnaire; n, number of applicable items; N, total number of items; SD, standard deviation.
Table 4.
Comparison of the ADQoL subscales between AAA patients of the MetAAA trial and monitoring study as a measure of health-related quality of life
| MetAAA trial cohort | AAA monitoring cohort | ||||
|---|---|---|---|---|---|
| ADQoL subscales | n | WI (SD) | n | WI (SD) | P |
| Physical function | 146 | −1.68 (2.25) | 38 | −2.16 (2.89) | 0.793 |
| Psychological health | 145 | −1.89 (2.30) | 37 | −2.61 (3.21) | 0.545 |
| Social life | 147 | −1.37 (1.97) | 38 | −1.72 (2.30) | 0.590 |
| Individual evaluation | MetAAA trial cohort | AAA monitoring cohort | P | ||
| n | Mean (SD) | n | Mean (SD) | ||
| Current QoL (I) | 147 | 2.50 (0.66) | 38 | 2.82 (0.98) | 0.039 |
| QoL if I would not have an AAA (II) | 147 | 3.03 (0.98) | 37 | 2.78 (1.13) | 0.261 |
| If I had no AAA, my health would be (17) | 145 | −2.52 (2.95) | 37 | −3.00 (3.52) | 0.638 |
For the individual evaluation lower mean values indicate superior quality of life. The following statistical analysis was applied: Mann–Whitney U test. Boldface entries indicate statistical significance.
AAA, abdominal aortic aneurysm; ADQoL, Aneurysm-Dependent Quality of Life questionnaire; n, number of questionnaires; QoL, quality of life; SD, standard deviation; WI, weighted impact.
Discussion
This single-center retrospective cohort study focused on the evaluation of high-quality observational data on the health status and QoL of AAA patients under surveillance compared to AAA patients enrolled in the MetAAA study. In total, we analyzed 561 established and validated, longitudinally collected QoL questionnaires of 54 MetAAA trial patients and 23 AAA patients of an observational monitoring study. We demonstrated that AAA patients participating in the MetAAA trial showed superior health status and QoL with regard to general health perception, higher energy level, and less limitations due to general malaise, which was additionally also reflected in an overall superior current QoL score.
A recent systematic review and meta-analysis of quantitative and qualitative studies concluded that the current evidence does not support a negative impact on QoL from being under surveillance for an AAA17. However, preliminary data from our currently ongoing MetAAA trial with a sample size of 54 MetAAA trial patients and 23 AAA patients under regular surveillance suggest that randomized controlled trial participation with metformin therapy may still improve the QoL of AAA patients. The phenomenon of superior or improved QoL in randomized controlled trials is known from other medical fields, for example, oncology and is an appreciated effect of trial participation31. Oncological studies also highlighted the importance of long-term QoL assessment for patients in randomized controlled trials, not only pre- or postintervention but preferably until patient death to ascertain a lasting treatment benefit on QoL32. In general, changes in all mental and physical aspects of QoL, except bodily pain, were reported to be exercise dose-dependent, therefore more likely to reach an improved QoL by experiencing a higher energy level and less limitations due to symptoms33.
In this study, distinct aspects in patients’ lives and subsequent QoL were shown to be superior in the MetAAA trial versus monitoring patients. Yet, it appears that AAA patients felt safe and had trust in health professionals, regardless of being included in the MetAAA trial or being under longitudinal surveillance. Notably, AAA patients in the MetAAA trial experienced more standardized routine in patient information and education, which may lead to a better patient’s health perception. This is particularly important since a recent study demonstrated that the knowledge of AAA disease is quite poor among patients and the vascular surgeon is the most important source of AAA information to patients34. Additionally, more monitoring visits and more comprehensive medical consultations of AAA patients enrolled in the MetAAA trial may determine several aspects of superior QoL, because the AAA patients’ concerns are better taken care of.
Current research indicates important sex differences, especially in cardiovascular diseases in terms of patient presentation, management and compliance, outcome, and impact on QoL35,36. AAAs are predominantly affecting the elderly male population and recent data states that the prevalence of AAA is up to fourfold higher in men than women7,8. This is well in accordance with our observed study population in the MetAAA trial cohort with 81.48% men. In the longitudinal monitoring study cohort men are slightly overrepresented with 95.65%, most likely due to the smaller sample size. However, the compared AAA cohorts did not significantly differ with regards to sex.
Of note, there are several study limitations, that should be addressed. The data for this study was retrieved while the MetAAA trial was still ongoing, and the sample size of our study has certainly limited the assessment of potential further QoL differences between the AAA patient cohorts. Patient treatment in the MetAAA trial is still blinded, implying that metformin as well as placebo effects are included in the QoL analysis of the MetAAA trial patients and a further distinction between metformin versus placebo impact on QoL of MetAAA patients will have to be conducted upon study unblinding. While only patients of the MetAAA group participated in the randomized controlled trial, the same standards of thorough and detailed patient surveillance and data recording were applied to the regular AAA monitoring group to warrant comparability. Since the analyzed MetAAA cohort comprised both, patients with metformin or placebo administration, it is conceivable that differences of health-related QoL between the study cohorts are an effect of experiencing any treatment per se. Interestingly, a recent study analyzing 142 meta-analyses revealed no evidence for an average difference in estimated treatment effect between trials with and without blinded patients, healthcare providers, or outcome assessors37. Nevertheless, according to current practice guidelines, AAA patients are suggested to participate and potentially benefit in clinical trials since no specific medical therapy has been proven to slow the AAA expansion rate7,8. Likewise, in the AAA guidelines, therapy with metformin is specifically mentioned as a potential candidate drug for imminent clinical trials. It is well known that randomized controlled trials in general often offer beneficial interventions in routine clinical practice, but regarding conservative aneurysm treatment and impact on QoL in AAA patients, there is a lack of evidence38. Four recent retrospective studies and a meta-analysis on metformin prescription to diabetic AAA patients revealed a significant reduction of AAA progression, rupture rate, and incidence of repair when compared to AAA patients treated with other antidiabetic drugs18–22. Thus, the detection of a superior health status and QoL in AAA patients participating in the MetAAA trial may indeed be an effect of metformin treatment, although the present analysis includes the placebo arm. This study involves three validated QoL questionnaires with a clear structure and strong reliability and is based on patient self-reporting and self-completion26–30. Despite comprehensive information and support, intermittently QoL questionnaires were incomplete. Especially questions addressing the work or sex life were often difficult to answer for the elderly AAA patient population. The educational level between the study groups was not significantly different, hence the patients’ levels of cognitive understanding of the questionnaire’s content was expected to be comparable. In addition, comorbidities may have influenced the QoL assessment, although the two AAA cohorts were remarkably comparable, only significantly different in the prevalence of diabetes mellitus type II (due to the study exclusion criteria) and chronic obstructive pulmonary disease. Finally, due to the differences in the study design more sets of QoL questionnaires from MetAAA trial patients have been obtained and analyzed (in median 8 questionnaires per MetAAA trial patient and in median 5 per AAA patient in the surveillance study). However, we showed statistically comparable QoL scores at baseline, indicating that changes and later differences between groups with regard to health and QoL are a result of study design and/or treatment. QoL represents an essential endpoint in patient care and QoL research involves a diversity of target and research designs.
Conclusion
Enhanced health-related QoL in AAA patients is increasingly considered a prominent goal of AAA surveillance and treatment. The knowledge about QoL in AAA patients enrolled in randomized clinical trials is important for understanding disease, treatment, and medical decision making. Based on the current preliminary evaluation of QoL research in MetAAA trial patients, we conclude a superior health status and QoL compared to AAA patients under longitudinal surveillance.
Ethical approval
The institutional ethics committee of the Medical University of Vienna approved the study in all details of the study protocol. (license nos. 1729/2014 and 1479/2017).
Sources of funding
This work was primarily supported by the Austrian Science Fund (SFB project F 5409-B21) as well as the Medical Scientific Fund of the Mayor of the City of Vienna (project 15012). Of importance, Merck (Delpharm Brétigny, Brétigny-Sur-Orge, Cedex France) supported the MetAAA trial and established the manufacturing process of metformin at pharmaceutical quality as well as the production of placebo under good medical practice conditions.
Author contribution
J.K.: conceptualization and methodology of the study, data acquisition, data analysis and interpretation, article drafting, statistical analysis, revising the article, final article approval; R.W.: conceptualization and methodology of the study, data acquisition, data analysis and interpretation, article drafting, statistical analysis, revising the article, final article approval; A.S.: conceptualization and methodology of the study, data acquisition, revising the article, final article approval; L.F.: conceptualization and methodology of the study, data acquisition, revising the article, final article approval; A.S.: conceptualization and methodology of the study, data acquisition, revising the article, final article approval; A.W.: conceptualization and methodology of the study, revising the article, final article approval; C.B.: conceptualization and methodology of the study, data acquisition, data analysis and interpretation, article drafting, statistical analysis, revising the article, final article approval, obtained funding; C.N.: conceptualization and methodology of the study, revising the article, final article approval; W.E.: conceptualization and methodology of the study, data acquisition, data analysis and interpretation, article, drafting, statistical analysis, revising the article, final article approval, obtained funding.
Conflicts of interest disclosure
The authors declare that they have no conflict of interest.
Research registration unique identifying number (UIN)
This study is registered with the Research Registry and the unique identifying number is: researchregistry7647. This hyperlink can be used to publicly access our specific registration: These studies are registered with the Research Registry (unique identifying number researchregistry7647) and the clinical trials registry (ClinicalTrials.gov Identifier: NCT03507413). These hyperlinks can be used to publicly access our specific registration: https://www.researchregistry.com/register-now#home/registrationdetails/620cd5f5137159001eeec81c/and https://clinicaltrials.gov/ct2/show/NCT03507413?cond=metformin&cntry=AT&city=vienna&draw=2&rank=1
Guarantor
Assoc. Prof. Wolf Eilenberg, MD, PhD.
Data availability statement
The datasets generated during the study are available from the corresponding author on reasonable request.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Supplementary Material
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.journal-surgery.net.
Published online 31 March 2023
Contributor Information
Johannes Klopf, Email: johannes.klopf@meduniwien.ac.at.
Robin Willixhofer, Email: 61801968@edu.kl.ac.at.
Andreas Scheuba, Email: andreas.scheuba@meduniwien.ac.at.
Lukas Fuchs, Email: n1248453@students.meduniwien.ac.at.
Anna Sotir, Email: anna.sotir@meduniwien.ac.at.
Anders Wanhainen, Email: Anders.Wanhainen@surgsci.uu.se.
Christine Brostjan, Email: christine.brostjan@meduniwien.ac.at.
Christoph Neumayer, Email: christoph.neumayer@meduniwien.ac.at.
Wolf Eilenberg, Email: wolf.eilenberg@meduniwien.ac.at.
Acknowledgments
None.
Article summary
Quality of life (QoL) has received increasing attention as a key outcome in the management of abdominal aortic aneurysm (AAA). The objective of this study was to assess the distinct QoL scores of AAA patients under surveillance (n=23) according to the current clinical practice guidelines compared to AAA patients enrolled in the MetAAA trial (n=54), a double-blinded randomized controlled trial evaluating the aneurysm growth inhibitory effect of metformin in non-diabetic AAA patients. Health-related QoL was found to be superior in MetAAA trial patients with regard to general health perception (P=0.012), higher energy level (P=0.036) as well as enhanced emotional well-being (P=0.044) and fewer limitations due to general malaise (P=0.021), which was additionally reflected in an overall superior current QoL score (P =0.039).
Take home message
We found that the QoL, assessed with three established, validated questionnaires was superior in MetAAA trial patients compared to patients under regular surveillance for small AAA.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during the study are available from the corresponding author on reasonable request.