Exercise improves the treatment of peripheral arterial disease in extremely old patients

doi:10.21203/rs.3.rs-2960508/v1

Background

This study aimed to investigate the effect of supervised exercise on the walking abilities of patients with peripheral arterial disease(PAD) who are extremely old and in no condition to undergo surgical treatment.

Methods

Forty-four patients aged 78–92 years were recruited and randomly assigned to the control group or the exercise training group. After a 6-minite walking testing(6 MWT), cardiopulmonary exercise test(CPET), and ankle-brachial index(ABI )measurements were performed, personalized exercise training plans were established for the exercise intervention group according to the CPET results. After three months of exercise training, the 6 MWT, CPET, and ABI measurements were repeated.

Results

Compared to the control group, the walking distance in the exercise group significantly increased by 78.27ms (p<0.05), and the claudication distance increased by 72.5ms. Similar results were also observed for other indicators, including the consumption of VO2peak, anaerobic threshold(AT), and metabolic equivalents(METs), which increased by 159.00 ml/min, 2.17 ml/kg. min^-1 and 0.55, respectively. All results were statistically significant.

Conclusion

Personalized aerobic exercise training effectively improved walking ability and physical stamina in patients aged ≥ 75 years.

PAD is a common circulatory disease in the elderly population and is caused by arterial sclerosis obliterans (ASO) in the limbs. Inadequacy to meet the energy needs of the lower extremities results in exercise-induced pain in the lower limbs and ambulatory dysfunction. This study was approved by the American Heart Association Council on Epidemiology and Prevention Statistics Committee and the Stroke Statistics Subcommittee. Heart disease and stroke statistics—2018 update,PAD affects 12–20% of Americans aged 60 years and older, increasing to nearly 50% in those 85 years and older.1 the Prevalence increases dramatically with age, and PAD disproportionately affects black people. [1] .The odds of having PAD increase with each additional risk factor, from a 1.5-fold increase with one risk factor to a 10-fold increase with three or more risk factors.3 ^[2]. In 2015,a total of 236.62 million people aged 25 years and older were suffering from peripheral artery disease in the world, among whom 72–91% were in low-income and middle-income countries. The Eastern Mediterranean Region had the lowest number (14·67 million),whereas the Western Pacific Region had the most peripheral artery disease cases (74·08 million)^[3].

The most common clinical syndrome of PAD is intermittent claudication, which involves leg pain while walking, but resolves when resting. Other symptoms include cold skin, leg numbness, poor nail quality, and ischemia. Atherosclerotic occlusion is a narrowing of the arteries that supply the lower extremity, leading to an inadequate supply of nutrients and oxygen in the legs, resulting in pain when walking and substantially affecting mobility and quality of life. Even though it is a chronic disease, it usually correlates with widespread adverse cardiovascular events and results in cardiovascular disorders within five years^[4]. In addition, many people with PAD have mild or no symptoms, which increases the difficulty of diagnosis and underestimates the prevalence of this disease, subsequently attenuating the therapeutic effect. Patients with PAD were reported to have a 15-fold increased risk of death from cardiovascular disease^[5], with 41,000 deaths in 2013^[6].

The common medical treatment for PAD is medicine and surgical or interventional angiography, but approximately 30% of patients who undergo angioplasty surgery have been reported to develop restenosis within one year^[7]. Over the past decades, exercise training has been considered as an effective auxiliary therapy for PAD, and the benefits of exercise training for patients with PAD have been recognized^[8]. Many recent studies have demonstrated that endovascular treatment combined with exercise training is much more effective than endovascular treatment alone and would significantly improve walking ability over a long time period^[9]. Moreover, supervised treadmill exercise has been recommended as the first-line therapy in the USA, as it has been demonstrated to be more effective than medications in some cases^[10]. The typical 12-week exercise training program showed a great benefit for patients with symptomatic PAD and could significantly improve their quality of life^[10]. Mechanistically, exercise training can improve various pathophysiological mechanisms, such as endothelial function, skeletal muscle metabolism, and gait biomechanics^[11]. However, opinions on the recommendation of exercise training programs in clinical application for PAD are controversial because of both subjective and objective reasons including the problems of persistence, the long-term period but slow effect, and so on^[12]. In the present study, we assessed the effect of exercise training on the walking abilities of middle- and oldest-old patients with PAD aged 78–92 years, providing supporting evidence for evaluating the benefits of exercise training in improving the morbidity of patients with advanced PAD.

Study design and setting

This study was a parallel treatment, single-factor, randomized trial with two groups: control (cilostazol treatment) and exercise-interventional (cilostazol treatment combined with individualized exercise training). This study set up blind on the statisticians.After recruitment, both of the two groups received twice assessments of 6-MWT,CPET and ABI testing. CPET was conducted with a submaximal graded exercise protocol, which was conducted with Quark PFT Ergo from Italy; the first was at the beginning of the exercise training and the second at the end of the exercise training. After the first test, the participants were randomly arranged into two groups, and a personalized exercise training schedule was established by rehabilitation therapists for the experimental group according to the 6 MWT and CPET results. After 3-month of exercise training, the second test was performed again, and the differences in walking abilities and physical stamina between the control and experimental groups were assessed. T-test was used to analyze the change in the parameters between the control and interventional groups after exercise training. This study was approved by the ethics committee of Zhejiang Hospital(20156K). Written informed consent was obtained from each patient prior to the study procedure.

Patient recruitment and randomization

All subjects have been given written informed consent. The study was approved by the Human Ethics Committee of Zhejiang Hospital, and complied with the Declaration of Helsinki.This study was carried out from January 2014 to January 2018.Both inpatients and outpatients aged ≥ 78 years were recruited from the database of Zhejiang Hospital according to the following inclusion criteria: (1) diagnosed with arterial sclerosis obliterans, (2) 0.5 < ankle brachial index < 0.9, (3) no interventional treatment, and (4) intermittent claudication in one or both legs. Patients were excluded if they displayed any of the following symptoms: (1) secondary hypertension, (2) aortic incompetence, (3) arteriovenous fistula, (4) acute myocardial infarction, (5) patent ductus arteriosus, (6) moderate or severe anemia, (7) hyperthyroidism, (8) renal dysfunction, (9) valvular heart disease, (10) rest pain, and (11) lower limb gangrene. After screening, eligible patients were randomly assigned to control and experimental groups according to a computer-generated randomization list.

Medical evaluation

All patients underwent a comprehensive medical evaluation, including physical examination, medical history, fasting plasma glucose and lipid concentrations, liver and renal function tests, and a screening maximal effort treadmill test.

The exercise training program consisted of three months of supervised intermittent on-site walking until nearly maximal claudication pain of 3–5 days per week. The patients performed a progressively graded protocol until maximal claudication pain was achieved, while the control group did not receive any exercise training.

Assessments

All patients underwent the 6-MWT, CPET, and ABI tests before and after 3 months of exercise training. For the 6 MWT testing, the subjects were asked to walk as fast as possible for 6 min in a hospital aisle with a length of 30 m and marked every 5 m. Both total and claudication distances were recorded. For CPET, an ergometer was used to record the peak VO2, KgVO2, AT, and metabolic equivalent values. ABI examination was performed using an arteriosclerosis detector. All parameters were measured at least three times in each test.

Study intervention

Individualized exercise strategies were determined according to the CPET and ABI testing results and comprised 3-month,3–5 days per week, 2-h exercise training. The exercise was walking in the hallway of the hospital which was 30ms in length, and exercise intensities of 50–80% VO_2peak were employed. Two sets of 15 lower extremity muscle resistance training with an intensity of 60% of the 1-repetition maximum strength were perceived as exertion ratings between 11–13 on the Borg scale. Upon intolerance, the training intensity was increased to approximately 90–95% of the maximal claudication walking pain. The exercise time was approximately 30–45 min, with an additional 5–10 mins’ warm-up and recovery. The frequency was 3–5 days per week. The blood pressure would was measured before and after each training session. Exercise training was terminated immediately if the subjects presented with disorders of important organs, such as respiratory infection and angina pectoris.

All patients had received oral cilostazol treatment for 3 months after the baseline date.

Statistical analysis

All results are presented as ‾x ± s and analyzed by Software SPSS18.0. T-test was used to analyze the pairwise comparison of the change in morbidity and O₂ consumption after exercise training between the intervention and control groups. two-sided significance test was performed with 95% confidence interval. P values < .05 were considered to indicate statistically significant differences.

44 subjects including 15 females and 29 males were recruited in this study, with 6 female and 16 male in the control group and 9 female and 13 males in the exercise group.As shown in Table 1, the 6-MWT and CPET assessments at the onset of the intervention indicated no significant differences in primary walking abilities and metabolic indicators between the control and exercise groups. Three months later, however, exercise training resulted in a significant improvement in 6-MWD in the exercise-interventional group with 78ms, while it was only 7ms in the control group. Moreover, functional ability assessment showed that the walking distance in the supervised exercise group was much longer than that in the control group (416ms vs 367ms). Similar results were observed for claudication walking distance (329.77ms vs 283.82ms, p < 0.05). Furthermore, the increase in claudication walking distance after three months was more significant (72.50 vs 10.05, p < 0.05) in the interventional group than in the control group. Although the baseline peak oxygen consumption was higher in the exercise group, the increase in peak oxygen consumption was much higher after exercise training (159 vs. 37.18, p < 0.05), with a final assessment of 961.82 vs 809.59 (p<0.05). Similarly, KgVO2 was also highly improved after exercise training, whereas the change in the control group was much less significant (1.85 vs 0.56). Besides, exercise resulted in greater increase in AT (2.17 vs -0.20) and METs (0.55 vs 0.21), although there were no significant changes between these two groups after 3 months. Notably, ABI was significantly decreased in the exercise group (0.69 vs 0.76) compared with the control group, with a much smaller increase (0.03 vs 0.96) after exercise training, suggesting that exercise training slowed the increase in ABI.

In summary, supervised exercise training significantly improved the walking ability, O2 consumption, and metabolic rate in patients with PAD.

Table 1. Comparison of the 6-MWT, CPET test in the two groups (n=44).

Groups	Num. Time Patients		WD ( m)	CD (m)	VO2peak (ml/min)	KgVO2 (ml/kg.min- 1)	AT (ml/kg.min- 1)	MET	ABI
Pre-training Exercise 22 training			338 ± 77	257 ± 71	803 ± 299	13.2 ± 6.7	10.4 ± 4.5	3.8 ± 1.9	0.7 ± 0.1
Post-training			416 ± 69	330 ± 69	961.82 ± 282.3	15.1 ± 3.9	12.5 ± 5.5	4.3 ± 1.1	0.7 ± 0.1
Difference between Pre- and Post-training			78	72	159.0	1.9	2.2	0.6	0.03
Pre-therapy Control 22			360 ± 75	274 ± 69.	772.4 ± 197.4	13.8 ± 4.7	11.6 ± 4.1	4.0 ± 1.3	0.7 ± 0.9
Post-therapy			367 ± 70	284 ± 69	809.6 ± 216.2	14.4 ± 4.0	11.4 ± 3.8	4.2 ± 1.3	0.8 ± 0.1
Difference between Pre- and Post-therapy			7	10	37.2	0.6	-0.2	0.2	0.1
P value between Control and		Pre-training	0.135	0.15	0.51	0.63	0.25	0.63	0.20
interventional groups Post-training			1.60E-03	9.48E-0E4	1.25E-03	1. 18E-01	3.24E-01	1.89E-01	1.59E-02

6-MWT:6-minite walking test;CPET:cardiopulmonary exercise test;WD:walk distance ;CD:claudication distance;VO2peak: peak oxygen consumption;KgVO2:Oxygen consumption in kilograms;AT:anaerobic threshold ; MET:metabolic equivalent;ABI:ankle-brachial index.

PAD is a common atherosclerotic occlusive disease in patients aged 55 years. Although not lethal, PAD significantly affected lower extremity functioning and led to mobility loss, resulting in poor quality of life of patients, especially those in middle and oldest old ages. As most of these patients were not candidates for revascularization surgery, exercise training has been considered a major management strategy for PAD in this advanced age population.

Exercise therapy for the treatment of intermittent claudication has been extensively studied for over 50 years, and many studies have shown that it is effective in improving the physiological conditions of patients with PAD and may even yield greater benefits than medication^{[13, 14]}. Several trials have shown that exercise training significantly improves the 6-minute walk test, which is closely related to physical function, mobility, and even mortality^[15]. It has been reported to improve endothelial cell function and ameliorate arteriogenesis by increasing plasma nitrite flux^[16]. Moreover, suboptimal exercise training has been shown to improve fibrinolysis in patients^[17].

This pilot study aimed to determine whether on-site exercise training is effective in improving ambulatory function and peripheral circulation in middle-aged and older elderly patients with PAD. As shown by our results, supervised exercise training greatly improved the physical function of patients with PAD, especially the 6 MWT, peak VO2 consumption, and AT. Additionally, the increase in ABI, the typical prognostic factor of PAD, was moderately attenuated, suggesting that exercise efficiently slowed the progression of PAD. However, this study has several limitations this study:1) we did not analyze all the variables related to physical function, such as the claudication onset time (COT) and peak walking time (PWT). 2) The follow-up period was short, 2) the sample size was not large enough, and 3) the gender proportion was distinct.

Since all these factors could lead to different outcomes, it is important to determine the exercise prescription, and the exercise training types and intensity should be well evaluated. However, it is still reasonable that exercise training could alter the balance between vasoconstrictors and vasodilators in favor of vasodilators.

Individualized exercise treatment was helpful for older patients with PAD who were unsuitable for surgical treatment, such as revascularization. We found that it could significantly improve walking ability, O₂ consumption, and metabolic equivalents. No safety or tolerability signals were observed in this study.

PAD=peripheral arterial disease， 6-MWT=6-minite walking testing，

CPET =cardiopulmonary exercise test，ABI=ankle-brachial index

AT=anaerobic threshold， METs=metabolic equivalents.

Conflicts of interest: ¾The authors certify that there are no conflicts of interest with any financial organization regarding the material discussed in the manuscript.

Funding.¾The authors report no involvement in the research by the sponsor, which could have influenced the outcome of this study.

Authors’ contributions. ¾ Xinwen Liu and Jianan Wang have substantially contributed to the conception and design of the manuscript. Jianmei Zhou,Liyue Zhu,Rongfang Zhou, and Cuicui Yang have contributed to the acquisition,analysis, and interpretation of the data.A ll authors participated in drafting the manuscript,and Jianan Wang revised it critically. All authors have read and approved the final version of the manuscript. All authors have contributed equally to the manuscript and have read and approved the final version of the manuscript.

Acknowledgements¾We would like to thank all the patients for participating in this study and MD Fang Ding for the statistical support of the clinical trial.

Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Benjamin EJ, Virani SS, Callaway CW, et al.; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2018 update: a report from the American Heart Association [published correction appears in Circulation. 2018;137(12):e493]. Circulation. 2018;137(12):e67-e492.
Eraso LH, Fukaya E, Mohler ER, Xie D, Sha D, Berger JS. Peripheral arterial disease, prevalence and cumulative risk factor profile analysis. Eur J Prev Cardiol. 2014;21(6):704-711.
Peige Song, Diana Rudan, Yajie Zhu, Freya J I Fowkes, Kazem Rahimi, F Gerald R Fowkes,etal.Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis.Lancet Glob Health 2019; 7: e1020–30.
Pande RL, Perlstein TS, Beckman JA, Creager MA. Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004. Circulation. 2011; 124(1): 17-23.
M H Criqui , R D Langer, A Fronek, H S Feigelson, M R Klauber, T J McCann, , et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992; 326(6): 381-6.
Mortality GBD, Causes of Death C. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 385(9963): 117-71.
McDermott MM, Polonsky TS. Home-Based Exercise: A Therapeutic Option for Peripheral Artery Disease. Circulation. 2016; 134(16): 1127-9.
Hiatt WR, Regensteiner JG, Hargarten ME. Benefit of exercise conditioning for patients with peripheral arterial disease. Circulation. 1990; 81(2): 602-9.
R M Greenhalgh , J J F Belch, L C Brown, P A Gaines, L Gao, J A Reise,, et al. The adjuvant benefit of angioplasty in patients with mild to moderate intermittent claudication (MIMIC) managed by supervised exercise, smoking cessation advice and best medical therapy: results from two randomised trials for stenotic femoropopliteal and aortoiliac arterial disease. Eur J Vasc Endovasc Surg. 2008; 36(6): 680-8.
Hiatt WR, Wolfel EE, Meier RH, Regensteiner JG. Superiority of treadmill walking exercise versus strength training for patients with peripheral arterial disease. Implications for the mechanism of the training response. Circulation. 1994; 90(4): 1866-74.
Hiatt WR, Regensteiner JG, Wolfel EE, Carry MR, Brass EP. Effect of exercise training on skeletal muscle histology and metabolism in peripheral arterial disease. J Appl Physiol (1985). 1996; 81(2): 780-8.
Popplewell MA, Bradbury AW. Why do health systems not fund supervised exercise programmes for intermittent claudication? Eur J Vasc Endovasc Surg. 2014; 48(6): 608-10.
Schorr E. Review of an article: Gardner AW, Parker DE, Montgomery PS, Scott KJ, Blevins SM. Efficacy of quantified home-based exercise and supervised exercise in patients with intermittent claudication: a randomized controlled trial. Circulation 2011; 123(5) :491-98.
Whayne TF, Mukherjee D. Increased Exercise Favorably Modifies Coronary Artery Disease and Peripheral Arterial Disease Outcomes. Curr Vasc Pharmacol. 2016; 14(5): 458-65.
McDermott MM, Ades PA, Dyer A, Guralnik JM, Kibbe M, Criqui MH. Corridor-based functional performance measures correlate better with physical activity during daily life than treadmill measures in persons with peripheral arterial disease. J Vasc Surg. 2008; 48(5): 1231-1237.
Jason D Allen , Thomas Stabler, Aarti Kenjale, Katherine L Ham, Jennifer L Robbins, Brian D Duscha, et al. Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3months of exercise training. Free Radic Biol Med. 2010; 49(6): 1138-44.
Estelles A, Aznar J, Tormo G, Sapena P, Tormo V, Espana F. Influence of a rehabilitation sports programme on the fibrinolytic activity of patients after myocardial infarction. Thromb Res. 1989; 55(2): 203-12.

No competing interests reported.

Exercise improves the treatment of peripheral arterial disease in extremely old patients

Status:

Version 1

Abstract

Background

Materials and methods

Statistical analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

Data Availability

References

Additional Declarations

Status:

Version 1