PART II – TOWARDS NEW OUTCOME MEASURES IN INTERMITTENT CLAUDICATION
Diagnosing IC, are there any alternatives around?
Noninvasive diagnostic vascular examinations are often used as adjunctive tools to confirm the clinical diagnosis IC or to screen patients who have risk factors for PAD. Calculation of the ankle-brachial index (ABI) is a relatively simple and inexpensive method to confirm a suspicion of peripheral arterial disease.26 A resting ABI measurement with additional exercise testing using a standard treadmill test is a simple, inexpensive and effective noninvasive diagnostic method for IC with a high sensitivity (79-95%) and specificity (95-100%).39 A walking test may seem an obvious choice for eliciting symptoms of IC, because an IC patient typically presents with impaired walking rather than for example impaired cycling. However, some patients are not able to adequately perform treadmill
testing, occasionally due to fear (of falling) or due to orthopedic or neurological causes precluding walking on a treadmill. Moreover, orthopedic/neurological diseases may mimic a clear IC diagnosis as a similar pattern of symptoms may present with these disorders during walking.
Cycling is a non-weight bearing form of exercise, relatively non-moving and possibly better tolerated and more discriminating in some of these IC patients. In chapter 6, the correlation in ABI values obtained after treadmill testing and bicycle testing in IC patients was determined. In a validation study, newly diagnosed IC patients (Rutherford 1-3) underwent a standard treadmill test and two bicycle protocols, one with a continuous resistance submaximal character and a second with an incremental ramp form, having a maximal character. ABI of both legs were obtained prior to and twice after each of these three different exercise tests.
It was concluded that bicycle exercise testing is a valid alternative tool in diagnosing patients with IC. Bicycle testing confers additional advantages. The tool is a non-weight bearing and non-moving exercise object whereas a cardiovascular screening program can also be incorporated. Patients suspected of IC who have contraindications for treadmill testing can be accurately diagnosed using a bicycle-test. Submaximal testing is preferred to maximal testing because of optimal sensitivity and specificity characteristics whereas the risk on (cardiovascular) complications is lowest.
Contemporary determination of IC treatment effectiveness
Current IC treatment strategies, described in international guidelines3-5, are mainly based on trials using the limitation in walking distance as primary outcome value. However, the value of various walking distance assessments is disputed. For instance, a patient's estimation of walking distance does not properly reflect objectively measured daily life walking distances.40-43 A disease specific questionnaire such as the Walking Impairment Questionnaire (WIQ) may quantify walking impairments in IC patients better although correlations with walking distances appeared weak.41 Standardized treadmill tests are widely used as an objective assessment of walking distances.3-5 However, there is a substantial variability in treadmill protocols (chapter 2) whereas a relatively artificial measure of walking capacity is tested.44 In chapter 7, results of walking distances in a group of IC patients using four different tools (a graded and a non-graded treadmill protocol, patient estimations and outside walking) that are frequently used by physical therapists in the assessment of IC severity are compared in a single model.
In chapter 7 it is illustrated that walking speed is of importance in the determination of walking capacity in an IC population. But above all an important piece of evidence is added to the discussion whether treadmill testing should be used as primary outcome measurement to determine treatment effects in future PAD trials. Researchers should realize that the frequently used MWD as primary outcome measurement demonstrates a substantial variability. A single MWD assessment may not be a proper reflection of walking impairment in IC patients and may certainly not correspond with (daily life) outside walking.
Furthermore, self-reported walking capacity appeared a poor reflection of objectively measured MWD.40-42,45 Moreover, the value of both assessments is debatable as these parameters merely provide insight into walking capacity, a parameter that not necessarily corresponds with patient-perceived disability.41,46 Future research should therefore focus on patient-reported outcomes of perceived disability and burden of disease, as both can be of more importance than a determination of walking capacity. If walking (exercise) capacity is monitored, it should be measured over prolonged periods of time to provide a more reliable reflection of a patients' walking impairment. A 6-minute walking test, a shuttle walking-test or GPS-based accelerometers (physical activity monitors) may be better alternatives to treadmill testing.
Physical activity as an alternative outcome measure in IC
The fact that treadmill test results and ambulatory functions do show inconsistencies implies that an increased walking capacity does not automatically change a patients' exercise behaviour.41,44 Others have previously suggested that changes in treadmill test results do not properly reflect symptom relief after revascularization interventions for claudication.47 A call was made for future studies to focus on quality of life parameters or other disease-specific functional outcomes to determine the effect of IC treatment modalities (chapter 2&7).20,43 Moreover, in line with the upcoming interest in studying potential associations between daily physical activity (PA) and impact on cardiovascular risk reduction and mortality48-54, it may be more relevant to include PA as outcome measure in future IC research. IC is closely associated with cardiovascular and cerebrovascular disease,3,55,56 and improved levels of PA might result in cardiovascular event risk reduction on the long term.57,58
Nowadays , PA levels can be obtained with activity monitors. Tri-axial accelerometers measure accelerations in three dimensions that can be converted into intensities and metabolic equivalents (METs) enabling a quantification of overall PA. A MET is an estimate of oxygen consumption at rest. A three-MET activity would be an activity that utilizes roughly three times the amount of resting energy expenditure. When combining the recommendations on moderate- and vigorous-intensity physical activity, the daily minimum goal of PA should be in the range of 64-107 METs?min.59
The Dynaport MoveMonitor is an activity monitor that measures PA in METs, is easily applicable in a daily life setting and is optimized for clinical research assessments. The MoveMonitor was previously validated in an elderly population60 as well as for Parkinsons disease61,62 and COPD63-65. In chapter 8, the MoveMonitor is validated in an IC population in a near real-life setting. It was concluded that the MoveMonitor provides accurate information on a diverse set of postures, daily activities and number of steps in IC patients. This tool is useful to assess the role of physical activity as a novel clinically relevant outcome parameter in IC.
Physical activity levels of claudicants versus healthy individuals
Compared to healthy adults, IC patients are burdened with a low health-related quality of life and functional impairment during daily activities.66,67 Individuals who are regularly physically active report better overall health, lower health care expenditures and fewer mobility limitations than their sedentary counterparts.68,69 The American Heart Association (AHA) and the American College of Sports Medicine (ACSM) provide specific recommendations of various types of activity to stimulate the elderly. Tailored recommendations are suggested that apply to adults with clinically-significant chronic conditions or functional limitations that affect mobility and activity.59 In chapter 9, we quantified daily PA level and energy expenditure of newly diagnosed patients with IC and healthy controls. In conclusion, more than half of the patients with IC do not meet recommended standards of PA. Considering the serious health risks associated with low PA levels, these findings underscore the need for more awareness to improve physical exercise in patients with IC.
The impact of SET on physical activity level in IC patients.
Since SET is the first choice option in the treatment of IC3-5 and as it is the cornerstone of a SCM, it may be relevant to study the potential beneficial effects of SET on PA level and exercise behaviour in IC patients. Moreover, SET offers patients at least 25 full hours of counseling with a specialized physiotherapist trained in motivation interviewing and life-style change. We do know that SET significantly improves the maximal and pain-free walking distance in IC (chapter 2), SET possibly leads to significant savings in our healthcare system (chapter 3) and that SET is proven to be cost-effective based on the change in walking distance.14-19 However, the question arises whether effectiveness of IC treatment modalities should be evaluated on the basis of changes in walking capacity only (chapter 2&7&8). In chapter 9 it was demonstrated that free-living daily PA levels in IC patients are lower compared to healthy controls.70-73 Despite these findings, PA is scantly used as an outcome parameter in trials concerning IC treatment, a fact that was previously reported by other researchers in this field.9,72,74-77 If PA levels improve following SET, cardiovascular risk reduction and improved Health related Quality of Life (HrQoL) may follow on the long term.57,58 Therefore, the effect of a SET program on PA, HrQoL and walking behavior in an IC population was assessed in chapter 10. We hypothesized that a SET induced increased walking distance would also improve PA levels in IC patients. A total of 41 newly diagnosed IC patients were requested to wear an activity monitor one week prior to and one week immediately following 3 months of SET.
A 3-month SET program was found to increase the number of patients achieving the ACSM/AHA public health minimum recommendations for physical activity (baseline: 43%; 3 months: 63%, p= .003). However, firm conclusions could not be drawn, since some patients did show a decline in PA level or mean values for ambulatory activities after a period of SET. Probably large variations in activities per patient (duration as well as intensity) as well as between patients could have caused this contradiction. Moreover, a relatively small population was studied. Further research with larger populations is necessary to study PA levels in patients suffering from IC.
It seems that solely focusing on exercise capacity such as maximal walking distance or time in the determination of effectiveness of IC treatment strategies seems insufficient. In chapter 8&9 it was demonstrated that PA is correctly measured with an activity monitor whereas IC patients show less activity levels as advised in the international guidelines compared to healthy adults. Increasing PA levels in an IC population may have beneficial effects. SET seems promising in achieving to do so (chapter 10). Surprisingly, no significant correlation between the change in PA levels and the increase in walking distance was found (chapter 10). Therefore one may argue that components of a SET program other than an increased walking capacity do influence daily PA. It appears that patients who are able to walk further (because of a decrease in IC symptoms), will not use this capacity to walk more often, longer or with probably more intensity in daily life. In addition, no significant correlation between the increase in walking capacity and the change of SF-36 values was found (chapter 10). This finding was recently confirmed by others.78 They reported that the improvement in self-efficacy, satisfaction with functioning, pain acceptance and social functioning after six months of home-based walking exercise compared to a non-exercising control group was independent of walking performance. In combination with our finding that walking capacity might be of diminished value, a shift in both SET treatment and primary research outcomes seems necessary. Nordanstig et al. were one of the first to use HrQoL as primary outcome in the recently published IRONIC (Invasive Revascularization or Not in IntermittentClaudication) trial.79 Apparently the call for and use of patient-centered outcomes is beginning to proliferate in medicine.80 A patient's assessment of how quality of life is affected by both the disease and its treatment is very important. Future research should therefore primarily focus on the change in HrQol and the reliable assessment of (disease-specific) HrQoL.
What other directions should future research take? SET programs require optimization. Factors such as intrinsic motivation, life-style change, patient satisfaction and expectations and social functioning should be subject of research other than the optimization of increasing walking capacity alone. We should concentrate on changing a patients' exercise behavior in daily life (life-style change) by tailoring SET to a patients needs (shared-decision making). Expectations of an IC patient should be leading in treatment. Moreover, a SET physiotherapist should address the change of a patients' walking pattern and combine different modes of exercise.81 One may also consider the effect of initiating exercise programs in a home-based environment, thereby diminishing the amount of labour-intensive supervision.82,83 Two recent published trials and a meta-analysis revealed promising results regarding the effect of such an approach.75,77,78,84 Future research should also be aimed at the optimal mixture of supervised and home-based programs in combination with evolving eHealth and mHealth technologies (activity monitors, smartphones, apps; chapter 5). This endeavor is likely to result in an optimal treatment strategy, both from a patient's perspective as well as from a cost-effectiveness perspective.