Best medical treatment in patients with PAD
A single-center pilot study and protocol considerations for a multi-aspect intervention trial
Abstract
Summary:Background: Guidelines recommend comprehensive lifestyle change in patients with peripheral arterial disease (PAD) to prevent cardiovascular events and death. When compared with other populations, patients with PAD are less likely to receive best medical therapies (BMT). The aim of this pilot study was to integrate all aspects of BMT in an intervention program and to determine the feasibility of such an approach by highlighting strengths and obstacles of a multi-aspect intervention. Patients and methods: Patients consecutively hospitalized due to symptomatic PAD between 01 December 2021 and 28 February 2022 were included and followed for ten weeks. We randomized into a lifestyle intervention (education on BMT, a list of regional contact data for supervised exercise, weekly counselling by phone for ten times) vs. standard of care (one contact to talk about BMT). Vascular Quality of Life Questionnaire – 6 (VascuQoL-6) was used to collect patient reported outcomes. Results: Of 50 eligible patients 40 agreed to participate (32.5% female, 72.5 years in mean). During follow-up nine patients dropped out (4 in intervention group vs. 5). As for risk factor modification one patient was able to reach a normal weight body-mass-index (BMI) and nine reduced weight. Two patients stopped smoking, three reduced their consumption. The reported adherence to medication was a hundred percent. No patient attended supervised exercise therapy but eight trained at a home-based setting according to guidelines. The mean score of VascuQoL-6 at follow-up was higher in the intervention group compared to the control group (17.4 vs. 13.8 points) at last contact with both groups increasing from baseline. Conclusions: This pilot study followed 40 patients for up to 10 weeks after inpatient treatment while we randomized a multi-aspect lifestyle intervention versus standard of care. Thereby, the current study illustrated the numerous obstacles and provided pragmatic solutions for the planning of studies on BMT in this target population.
Introduction
With a development from 202 million affected patients in 2010 [1] to more than 236 million in 2015 [2], peripheral arterial disease (PAD) is an increasing global health burden. Although prevalence has increased in all age groups [3] the incidence is highest in the elderly with one out of ten people being affected at the age of 70 and one out of six people over the age of 80 years [1, 2]. In the population-based Hamburg City Health Study almost 25% of the inhabitants were affected by PAD with a median age of 63 years [4].
PAD besides coronary artery disease (CAD) and stroke is a common clinical manifestation of atherosclerosis [1, 4]. A considerable number of patients have atherosclerotic vascular lesions in more than one region (a.k.a. polyvascular disease) [5], often without experiencing symptoms [6]. However, the risk for an ischemic heart event or stroke is higher in PAD patients as well as the mortality rate. Death from cardiovascular cause is six to eight times more likely in comparison to an aged-matched person without PAD within ten years. Interestingly, causes of death are only in 20–30% non-cardiovascular for PAD patients [5].
To reduce the inherent risk of cardiovascular events and the need of interventions in PAD patients it is indicated to improve underlying risk factors [3]. This modification was summarized under the expression ‘best medical treatment’ [7] or ‘best medical therapy’ [8] (BMT). Important modifiable risk factors for PAD are smoking, hypertension, hyperlipidemia, diabetes [1, 4], unhealthy diet, physical inactivity [9] and overweight [6, 10, 11]. In addition, a pharmacological treatment for symptomatic patients is part of BMT [7, 10]. The optimal pharmacological treatment (OPT) consists of statins, antihypertensives and antithrombotics [12, 13]. BMT is indicated as fundamental part of prevention [7] and recommended by PAD guidelines [10]. Regardless to the high-level recommendations, patients with PAD have a smaller chance to receive treatment for their risk factor management than patients with CAD, although having the same relative risk of dying as a result to cardiovascular events as patients with CAD [9]. The explanation for this disparity appears to be multifactorial, including a lack of knowledge about the importance of risk factor modification among physicians treating patients with PAD, differences in prescription rates between vascular specialists vs. other medical specialties, and also an underestimation of cardiovascular risks by the patients themselves [14]. Due to this lack of guideline-directed medical care [15], a stronger focus on conservative therapy in patients with PAD appears important. Many papers and interventions have focused on single aspects of BMT such as exercise therapy, diet, or pharmacological treatment. However, there are few papers addressing all aspects together as a comprehensive guideline-directed lifestyle intervention. The aim of this pilot study was to include all aspects of BMT in an intervention program in secondary prevention to determine the feasibility of a multi-aspect approach. Thereby, our focus was not to determine safety or effectiveness differences between both groups, yet we aimed to identify barriers to a randomized, multicenter trial that would include all aspects of BMT.
Patients and methods
As a sub-study of the prospective multicenter GermanVasc cohort study (NCT03098290) [16] this single-center study included patients who were hospitalized due to symptomatic lower extremity PAD in a tertiary care center between 01 December 2021 and 28 February 2022. The study was approved by the ethical committee at the medical association in Hamburg, Germany (PV5691). Every patient agreed specifically to the participation in this study in addition to the GermanVasc study.
Study population
The study population contained adult patients (≥18 years) suffering from symptomatic stages of PAD, including chronic intermittent claudication (IC) and chronic limb-threatening ischemia (CLTI), who underwent inpatient treatment at the study center. Patients undergoing endovascular or surgical procedures as well as amputations and diagnostic angiographies were included. Patients who were not capable of giving consent (e.g. dementia), who were limited in the German language (a total of five patients during our recruitment process) or patients hospitalized in an intensive care unit were excluded. Also, the possession of a phone to be contacted during the pilot study was mandatory.
Study groups
We planned to enroll a total of 40 patients and randomize these patients in a 1:1 fashion into two groups (20 vs. 20). The patients were followed for ten weeks after being discharged with one planned contact per week.
Both groups completed the Vascular Quality of Life Questionnaire – 6 (VascuQoL-6) [17] during recruitment and last contact.
The intervention group additionally received a structured education by a trained last year medical student about BMT for symptomatic PAD patients. This education was given twice during hospitalization. The content of the education sessions was based on a brochure about recommendations of conservative therapy and secondary prevention of PAD as previously published by our study group [18]. In addition to the oral education each patient received a copy of the brochure and a list of contact data for supervised exercise therapy (SET) in Hamburg, Germany. Following discharge from the hospital every patient in the intervention group was supervised by telephone ten times (in general once a week for ten weeks in total), structured by a survey containing the aspects of the given education on BMT (smoking cessation, healthy diet, weight reduction, optimal pharmacological treatment [OPT], walking exercise, diabetes control). In case of any questions, a supervisor was involved in the discussion about preventive medicine.
The control group received the standard of care, no additional education or supervision of guideline-directed recommendations and was only once contacted after approximately ten weeks to talk about their BMT management.
Survey
Smoking cessation
Only patients currently smoking or less than four weeks smoke-free were considered as active smokers. Patients were asked if they were able to reduce their smoking habits. Only a reduction of at least 50% of the number of cigarettes smoked directly before hospitalization was considered as a sufficient reduced consumption.
Nutrition
Food categories were decided to use to investigate the nutrition of the patients [19, 20]. The first category was about the fraction of vegetable products in the diet. The second one focused on fat acids and differentiated between the amount of mono – or polyunsaturated fat acids and the amount of saturated fat acids. The third one addressed the daily salt intake based on the World Health Organization (WHO) recommendations of 5 g or less per day [21].
Weight reduction
Patients with a Body-Mass-Index (BMI) ≥25 kg/m2 (based on WHO recommendations) at hospitalization were considered as overweighted and were asked if they were able to lose weight since the last consultation. A weight loss was considered as 1 kg or more.
Optimal pharmacological treatment
The OPT in symptomatic PAD patients includes the use of lipid-lowering drugs, antihypertensives (in case of an elevated blood pressure) and antithrombotic medication [12].
The prescription for all agents was investigated and additionally if patients took their medication regularly, irregularly, or not at all.
Exercise therapy
As part of conservative treatment of PAD and also in combination with surgical interventions [22, 23] SET is advised in PAD guidelines [10, 24, 25, 26, 27]. The guidelines also suggest a walking-based exercise program for patients with CLTI after revascularization therapy [10, 24]. Alternatively, if SET is not possible to attend, home-based exercise (HBE) should be considered [10].
In the consultations patients were asked if they attended SET or if not possible HBE. Training had to fulfill the recommendations of the German national S3-Guideline (at least 30 minutes, at least three times a week) to be sufficient [27].
Diabetes mellitus
As part of the BMT, glycemic control in PAD patients is recommended in the guidelines [10, 25, 27]. Patients undergoing pharmacological diabetic treatment were checked whether they took their medication as prescribed.
Health-related quality of life
The health-related quality of life (HRQoL) in PAD patients has become an important patient-reported outcome [28, 29]. HRQoL has therefore become a primary treatment goal in PAD guidelines [10, 17, 24, 25]. Hence VascuQoL-6 was used to detect the HRQoL. It consists of six items, including limitations in the ability to walk or in other activities, as well as fatigue in the legs, concerns about the poor circulation in the legs, the ability to participate in social activities, and discomfort from pain in the leg. The six items have a four-point response scale (1 point given for the highest possible impairment for the individual, 4 points meaning no impairment at all) leading to a sum score from 6 to 24. A higher score indicates a better health status [29]. As a shorter version of the 25-item Vascular Quality of Life Questionnaire (VascuQoL-25) the VascuQoL-6 has been validated before [29, 30, 31]. Currently it is being validated for the German language. The translation was offered to our team by the author Mr. Morgan.
Follow-up questions
At the last contact some additional information were collected. Patients were asked if they had any major adverse cardiovascular event (MACE), defined as acute myocardial infarction, stroke, cardiovascular death, unstable angina, or heart failure. Also, patients stated if they had had any major adverse limb event (MALE), defined as untreated loss of patency, reintervention on the index arterial segment, or amputation of the index limb. Additionally, patients could define which type of potential intervention format they would prefer, double mentioning was possible.
Considerations about necessary statistical power
The importance of appropriate power and sample size calculations is beyond debate. For the most commonly used composite endpoint, MACE, event rates after one year of approximately 30–40% were reported in the literature [32, 33, 34, 35, 36, 37]. Thereby, the event rates vary widely between patients with IC vs. CLTI. Using a common estimation for type I and II errors (β=0.8 and α<0.05), a cohort size of approximately 3700 patients (for MACE) appears necessary to derive valid results after 12 months. This example estimation also acknowledged the unavoidable lost-to-follow-up rate as well as further statistical challenges introduced by likely clustered data.
Statistical analysis
The pilot study was not powered to derive statistically significant group differences. For the merely descriptive statistical analysis Microsoft Excel (Redmond, Washington, USA) was used. Means with standard deviations as well as proportions were calculated.
Results
Of eligible 50 patients a total of 40 patients agreed to participate in the pilot study and were divided into two groups of 20 patients each (Figure 1) Baseline characteristics by group are shown in Table I. A total of 13 patients (32.5%) were female. The mean (SD) age was 72.5 (9.0) years. The mean (SD) hospitalization period was 16.9 (17.6) days. The proportion of patients with IC was 37.5%.
Nearly half of the patients (19 in total) had a BMI ≥25kg/m2 and were therefore obese. The mean BMI of the overweighted patients was 29.1 (3.2) kg/m2.
Almost three quarters of the patients (72.5%) were actively or former smokers with one out of five patients still smoking (20%). Thirty-five patients (87.5%) suffered from hypertension.
In addition, almost one-third (27.5%) of the patients had diabetes, nine of them receiving medical treatment for their condition.
At baseline the mean (SD) score of VascuQoL-6 was 12.2 (4.0) points with a slightly higher score in the intervention group 12.6 (4.6) points in comparison to 11.9 (3.4) points in the control group.
Both groups, intervention and control, had a loss of patients during follow-up (Figure 1). Five patients (two in the intervention and three in the control group) were not reachable, defined as three unanswered calls in one week. In the intervention group two patients requested to drop out. In the control group one patient dropped out due to a lethal heart attack during hospitalization and a second one changed to a palliative condition and was no longer contacted by us. A total of 16 patients completed the follow-up in the intervention and 15 in the control group, leading to 62% patients with a complete follow-up from eligible 50 patients for this study.
Follow-up characteristics are presented in Table II. The mean (SD) duration of participation (recruitment to last contact) was 80.9 (16.1) days. During this timeframe there were zero events of MACEs and five events of MALEs (16.1%).
Only one of the overweighted patients at baseline was able to reach a normal weight BMI. Even so nine patients (29%) reduced weight (four in the intervention and five in the control group) leading to a mean (SD) BMI of 28.9 (3.0) kg/m2 in those with a BMI ≥25 kg/m2.
Two patients (6.5%) quit smoking, five (16.1%) stayed active with three out of them being able to reduce their consumption (one in the intervention and two in the control group).
Approximately 90% of the patients were prescribed an OPT, the other approximately 10% did not receive a prescription for lipid-lowering drugs. A hundred percent of the patients stated to take their prescribed medication regularly even though only 83.9% of the patients were aware of what they took. Also, each diabetic patient with medical treatment (five in total) stated to take their prescribed medication regularly.
No patient attended SET but approximately 50% (16 in total) did HBE, only half of them exercised sufficiently according to current guidelines.
The mean (SD) score of VascuQoL-6 was 15.6 (5.5) points at last contact, with more than 3.5 points difference between both groups: 17.4 (5.2) in the intervention vs. 13.8 (5.3) in the control group. The intervention group was able to increase almost five points during participation time, the control group only increased by almost two points (Figure 2). When asked which type of intervention format patients preferred, (with the possibility of double mentioning) almost three-quarters (74.2%) named phone, 19.4% the internet and the same amount a mobile health app.
Discussion
This pilot study aimed to identify strengths and obstacles of a multi-aspect lifestyle health intervention approach for secondary prevention of symptomatic PAD. Thereby the purpose was not to demonstrate statistically significant differences between the intervention and control group but to determine the feasibility of this approach including all aspects of BMT. We evaluated pragmatic tools to both educate and follow patients and identified particular challenges in terms of attendance, follow-up completeness and necessary considerations about statistical power for a future trial.
Interestingly in our study every patient stated a complete adherence to the prescribed medication, although only 83.9% were aware of their prescribed substances. In a previous study including patients from twelve university hospitals and one non-university hospital approximately twice as many patients (33.1%) did not know the indication for all their drug prescriptions [38]. Also, our adherence rate is contrarily to the common opinion that PAD patients are non-compliant in their medication use. In 2016 Gandapur et al. mentioned that medication non-adherence was detected in more than 60% of cardiovascular disease patients [39]. The valid measurement of medication adherence counts as distinct challenge of prospective studies while pill-counting and other methods appear impractical. A validated questionnaire such as the 8-item Morisky Medication Adherence Scale (MMAS-8D) may be used in future studies. This score was frequently used in research on chronic disease and is available in different languages [40].
Our prescription rate for OPT was approximately 90%. In another study from 2020 the OPT rate based on data of the second largest insurance fund in Germany (BARMER) was at 37% for women and 43% for men, representing 11% of the German population [12]. Recruiting only at one university hospital may partly explain these gaps in prescription rate, adherence, and knowledge of medication. It appears reasonable to further illuminate differences between treatment reality at academic vs. non-academic institutions while approximately 36 university institutions are accompanied by overall 2000 hospitals in Germany. For following interventions, it will remain challenging to ensure the prescription of OPT in each patient, however adherence rate and prescription knowledge may be higher than expected.
Although patients were advised to attend SET no patient participated in any structured program. In previous studies a low adherence to SET in PAD patients has also been widely reported [41, 42, 43]. A prospective study from 2020 by Saxon et al. including 16 different centers in the United States of America, Australia and the Netherlands examined patients enrolled with new or an exacerbation of PAD symptoms showed that only 23% had been referred to attend SET [44]. In a different study by our team including patients from 16 centers in Germany, 35.6% of the patients were appropriately informed about walking exercise programs. But only 11.4% had attended any walking exercise program before their index treatment [45]. Unfortunately, our results of attendance to SET are even below that (not having one participant) although 50% of our patients (the intervention group) were specifically advised to attend SET.
Even though according to guidelines SETs are more effective than HBEs [10, 26] and patients were informed about it, approximately half of our patients attended HBE. Unfortunately, only half of them (eight in total) did it sufficiently in frequency and duration, leading to only one quarter of patients training accordingly to guideline recommendations in a home-based setting. Implementing attendance to SETs will remain a challenge for further studies and everyday practice, suggesting by our results that only education without a direct integration into a program might not be sufficient. The Netherlands may be a role model as for Saxon et al. could show in a sub analysis that up to 90% of patients in the Netherlands included in his study were prescribed to SET and the referral network is well developed [44]. Maybe leading also to a higher attendance after the prescription.
Also, because of its lower barrier HBEs might sometimes be an alternative for SET. Especially for mobile health applications an integration of HBEs may seem reasonable. Alushi et al. previously showed that already 66.8% of inpatients owned a smartphone and more than 40% used apps. When asked which type of intervention format patients preferred approximately 20% of our patients stated a mobile health app [38]. The same amount was interested in the internet as a tool showing that there is an interest in newer technology for health programs. But nearly three-quarters of patients also stated to be interested in an intervention by phone. These results suggest that it might be beneficial for a multi-approach study to use different formats for intervention programs, staying openminded to newer technology in everyday health care.
Finally, including all topics of secondary prevention in an intervention program remains challenging. We hope that this pilot study may have shown some obstacles but also possibilities making it easier for further studies to use a multi-approach, integrating all aspects of BMT in secondary prevention.
Conclusions
Patients with PAD have a strong requirement to modify their risk profile to prevent cardiovascular and overall mortality. We developed an intervention program based on education and supervision to be evaluated in a future trial. Included were smoking cessation, healthy diet, weight loss, OPT, exercise therapy and diabetes control.
Management of OPT and diabetic medication developed easily due to a complete adherence (hundred percent) to medication prescription. As described in previous studies our results confirm an extremely low adherence to SET. The validated VascuQoL-6 was used to measure patient reported outcomes while it already revealed interesting differences in this small pilot study.
The interesting results will help to design a future trial to evaluate a pragmatic multi-aspect lifestyle intervention that may ultimately help to improve devastating outcomes in this vulnerable target population.
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