H.J.P Fokkenrood

Innovative strategies for
intermittent claudication

towards a stepped care approach and new outcome measures



"I swear by Apollo, the healer, Asclepius, Hygieia, and Panacea, and I take to witness all the gods, all the goddesses, to keep according to my ability and my judgment, the following Oath and agreement..."


Each medical student likely remembers the very moment he or she took the Hippocratic Oath. By doing so, the world embraced another certified physician. The oath can be broken down into twelve different precepts. One of the most essential ones is the promise of 'abstaining from doing harm'. This portion was later reformulated by the English physician Thomas Sydenham (1624–1689, figure 2) into a popular aphorism 'Primum non nocere' ('First do no harm').1 This approach originates from an era when physicians were paternalistic and abstained from shared decision making with their patients. This paradigm derives from an era with very limited alternative treatment options and served well as a touchstone of medical ethical practice. Despite its restrictions, this original thought remains a potent reminder of the fact that each medical and pharmacological decision inherently carries a potential for harm. The implications of this maxim are still up-to-date. Improved medical technologies are becoming of more importance in current health care and may offer physicians generous options, possibly without overseeing any future impact. A perfect example of the slippery slope between 'primum non nocere' and the growing set of treatment possibilities is the management of peripheral arterial disease.


Peripheral arterial disease

Peripheral arterial disease (PAD) commonly results from progressive narrowing or occlusion of arteries feeding or residing in the lower extremities and is mostly due to atherosclerosis2. The atherosclerotic process of progressive narrowing and hardening of arteries can occur in each human artery. However, it mainly affects coronary, cerebral and peripheral arteries, especially those in the lower extremities3. The spectral manifestations of PAD range from 'no symptoms' to 'tissue loss that may eventually require amputation of an affected limb'.


Total disease prevalence based on objective testing was found to range from 3-10% in adults, increasing to 15-20% in persons over 70 years.3 PAD increases progressively with age, beginning after the age of 40. Globally, 202 million people were having PAD in 2010, 70% in low-income or middle-income countries.4 During the preceding decade, the number of individuals with PAD increased by almost 30% in low-income or middle-income countries, and by 13% in high income countries.4


Intermittent claudication

 Up to half of the symptomatic PAD patients will demonstrate typical symptoms of intermittent claudication (IC, which means 'to limp').(3) IC is defined as muscle discomfort in the lower limb that is reproducibly elicited by exercise and relieved within a 10 minutes rest.(3) Patients with IC have sufficient blood flow at rest and therefore do not experience limb symptoms while standing, when seated or while resting in bed. Conversely, during exercise, obstruction of the arterial supply of the leg muscles limit a required increase in blood flow resulting in a mismatch of oxygen supply and muscle metabolic demand, leading to IC. This mismatch causes cramping or aching pain in the buttock, hip, thigh, calf or in rare occasions the foot, forcing the patient to pause. In rest, the oxygen debt can be redeemed and symptoms are relieved.


The presence of IC is associated with serious health risks. A 19% 5-year mortality rate is found of which 70% is due to cardiovascular causes. Non-fatal cardiovascular events (e.g. myocardial infarction, stroke) in patients with IC are found in 29% of the population at 5 years of follow-up.(5) An overall strategy is well described in several international guidelines including the American College of Cardiology/American Heart Association (ACC/AHA), Trans-Atlantic Inter-Society Consensus on Management of Peripheral Arterial Disease (TASC II) and the national institute for health and care excellence (NICE).(3,6,7)

Treatment of PAD should consist of a multicomponent therapy of cardiovascular risk reduction including lifestyle coaching and symptomatic treatment. The first two components aim to prevent cardio- and neurovascular events (myocardial infarction, stroke) and related morbidity and mortality. The most important modifiable risk factors for atherosclerosis are smoking, hypertension, diabetes mellitus, hyperlipidaemia and obesity.(8) The third component is to improve the overall quality of life (QoL). This regimen is currently mainly focussed on increasing walking capacity that is realized with conservative treatment (daily exercise) or invasive techniques such as vascular surgery or percutaneous transluminal angioplasty (PTA). The latter is a method of mechanically widening of narrowed or obstructed arteries. An empty and collapsed balloon on a guide wire is passed percutaneously into the narrowed artery portion and then inflated to a fixed size. The balloon forces expansion of the atherosclerotic plaque, opening up the artery. The balloon is then deflated and withdrawn, allowing an improved flow. A stent may or may not be inserted to ensure the vessel's patency.
Pharmacological therapy for IC has been subject of numerous studies.


Figure 1: illustration of publication by Larsen and Lassen. Lancet. 1966 Nov 19;2(7473):1093-6.


However, only beneficial effects of cilostazol and naftidrofuryl were described.(9,10) Interestingly, approval of this type of medicine is limited to a few countries. Other therapies such as Gingko Biloba, vitamin E, chelation therapy, omega- 3 fatty acids and oestrogen therapies were not effective.(3,11) Most pharmacologic treatment regimens for IC typically involve drugs that are used for cardiovascular risk reduction.

Conservative treatment for IC: Exercise therapy

 In 1898 the German neurologist Wilhelm Erb was the first to describe success following exercise therapy in a patient with IC.(12) The first randomized clinical trial (RCT) was performed by Larsen and Lassen in 1966 (figure 1).(13) In this study, 7 patients treated with exercise therapy were compared with a control group of 7 patients who were given a placebo medical treatment using lactose tablets. In contrast to the control patients, the exercise group demonstrated a significant increase in maximum walking time.


 Nowadays, exercise therapy for patients with IC is extensively studied.(14-17) Apart from a significantly improved maximum walking distance/time, exercise therapy also reduced levels of hypercholesterolemia, hypertension and diabetes mellitus.(16) Thereby reducing cardiovascular mortality and morbidity as collateral beneficial side effects.(18) The most commonly used exercise therapy prescription consisted of a single oral advice, usually without supervision or follow-up. However, patient adherence to orally administered exercise advices is low. Comorbidity, confusion about (specific) advice, fear, lack of discipline and incomplete supervision are barriers precluding regular walking exercise.(19) The importance of supervision for IC treatment was gradually recognised over the past decades.


Supervised exercise therapy for IC

 Supervised exercise therapy (SET) entails adequate coaching by a physical therapist or another exercise specialist (e.g. exercise physiologist, exercise therapist, specialised cardiovascular nurse). SET aims to increase maximum walking distance (capacity), physical activity and Health-related Quality of Life (QoL). Effective programs employ treadmill walking of a sufficient intensity causing symptoms, although other modes of exercises were also studied.(20) Exercise sessions are typically conducted three times a week for a period of 3-12 months.(3,7) A 2006 Cochrane review compared SET with non-supervised exercise programmes in patients with IC.(14) SET showed statistically significant and clinically relevant differences in improvement of maximum walking distance compared to non-supervised exercise therapy regimens, with an overall effect size of 0.58 (95% confidence interval 0.31 to 0.85) at three months. These results translate into an improvement of approximately 150 meters of maximum walking distance in favour of the supervised group. 

 Another systematic review compared supervised and unsupervised ET with PTA in patients with IC in an effort to obtain the best estimates of their relative effectiveness.(21) Eleven studies (reporting data on eight RCTs) met inclusion criteria. One trial included patients with isolated aortoiliac artery obstruction(22), three trials studied SET and PTA in femoropopliteal artery obstructions and five trials studied combined lesions. In summary, no obvious preferential strategy could be defined as both SET and PTA showed inconsistent results. Another large multicenter RCT in aortoiliac PAD randomly assigned patients to receive optimal medical care (OMC), OMC plus SET, or OMC plus PTA. The authors concluded that SET resulted in superior treadmill walking performance compared to PTA.(23) The most recent guideline therefore advocates a multimodal approach including medication, lifestyle changes and symptomatic treatment, mentioning SET as the primary treatment option independent of the anatomical location of the compromising lesion.(7)

 Few studies have focussed on the long-term (>12 months) effects of SET. Gardner et al. tried to determine whether improvements in physical function after 6 months of SET were sustained over a subsequent 12-months in older patients with IC.(24) They concluded that improvements in maximum walking distance and physical activity level, after 6 months of exercise training, were sustained for an additional 12 months period using a less intense exercise maintenance program. Ratliff et al. reported a 3-year follow-up of 212 patients with IC who initially were treated with SET with an exercise programme of two sessions a week for 10 weeks.(25) Their results showed that the maximum walking distance observed at 12 weeks was still present at three years. Based on this limited experience, it appears that SET may have long term benefits for patients with IC.


SET in hospital or community based setting?

 An outpatient hospital setting is routinely offered in the majority of studies on SET. This approach may seem appropriate in trials but is associated with several limitations in daily clinical practise. First, the capacity of an exercise therapy program in an outpatient clinic is limited and possibly not sufficient to accommodate all patients with IC. Second, attending a hospital 3 times a week leads to considerable transportation fees and is rather time-consuming. For this reason, implementation of a community- based SET program was instigated in the Netherlands.(26) The first results of a cohort study of patients treated with community-based SET resulted in a statistically significant improvement in maximum walking distance (as determined using a treadmill) after 3 and 6 months.(27) Others suggested initiating exercise programs in a home-based environment, thereby diminishing the amount of labour-intensive supervision.(28,29) Two recent published trials and a meta-analysis revealed promising results regarding the effect of such an approach.(30-33) Although SET may seem superior compared to other conservative treatment regimens with respect to improvement in walking distances, no significant differences between home-based exercise and SET was found at six months of follow up.(31)


Cost-effectiveness of SET

 Several cost-effectiveness analyses in the treatment of IC have been performed.(34-39) Non-supervised exercise therapy was compared with supervised programs in both a multi-centered trial and in a Markov model.(34,39) For community- based SET, the incremental cost-effectiveness ratio for cost per QALY was estimated between £1,608 to €28,693. Both studies considered SET as cost-effective compared to 'no exercise'. Others compared SET in a randomized cost-effectiveness analysis with endovascular revascularization (PTA).(35-38) There was no significant difference in effectiveness between endovascular revascularization compared to SET. Any gains following PTA appeared non-significant. Moreover, endovascular revascularization was more costly in relation to the generally accepted threshold of 'willingness-to-pay' (£11,777 to € 231,800 per QALY), a result that favors SET.(35,37) Others revealed that QALYs were lost when PTA alone was used as first-line treatment in comparison with SET.(35)

Overall, SET seems to be the most cost-effective first-line treatment for IC.(35-38) If SET fails, it may subsequently be combined with endovascular revascularization, a sequence that is probably more cost-effective than PTA alone.


Also 'Primum non nocere' in IC

 The prevalence of IC is growing as a clinical problem due to the increasingly aged population in developed countries. Recently, governments as well as nongovernmental organizations and the private sector were called to assess the social and economic consequences of PAD and to explore the best strategies for optimum treatment and prevention of this disease.(4) Numerous studies and guidelines have issued clear recommendations for IC treatment. Ideally a 'primum non nocere' strategy, existing of an initial treatment with SET should be followed.(7,40) However, SET programs are largely underutilized in daily practice.(41-44) Some blame the lack of a sufficient number of supervised settings as well as the need for patients to travel to a SET facility.(30,36,40,41,45) Another complicating factor is a failing reimbursement policy issue for SET in most of the Western societies including the Netherlands.(30,40,41,44,46) Despite a claimed 100% Dutch SET availability, reimbursement issues stimulate physicians to direct patients towards a vascular intervention strategy.(44)


Thomas Sydenham


Figure 2: Thomas Sydenham (10 September 1624 – 29 December 1689)


 This reimbursement issue in IC treatment originates from a contradictory policy in the Dutch healthcare system. In the Netherlands, healthcare insurance companies have an obligation to accept everyone for a basic healthcare insurance. The Dutch government determines coverage of the standard insurance. In case of patients suffering from IC, the government decided not to cover the first 20 treatment sessions of a SET program. Therefore, these sessions have to be paid by the patient, either directly or through additional insurance. From the 21st session onwards all additional treatment sessions given in one year are covered by the basic health care insurance. Around 30- 40% of the people aged >50 years who are insured by CZ (one of the largest Dutch insurance companies) do not have an additional insurance package that covers 100% of those first 20 physiotherapy sessions. Therefore, a proven effective, nationwide available SET program with supervision performed by trained physiotherapists, aimed at improving cardiorespiratory health status as well as life style factors and medication compliance is not fully reimbursed in the Netherlands.

On the other hand, a (minimally) invasive intervention, a possibly less effective, less durable, potentially harmful, and single leg focused treatment option is fully reimbursed from the basic healthcare insurance. Most of these interventions are continuously advertised by marketing campaigns. Novel invasive techniques are thus promoted, frequently without solid level of evidence, by multi- billion dollar companies, whereas SET lacks sponsoring promotional activities.

 Another factor contributing to SET under usage is a knowledge gap of physicians using outdated arguments for not offering SET to IC patients. As a consequence, exercise regimens often instituted in the form of a basic "go home and walk" advice or the non-"primum non nocere" interventional approach. Patients may also not enthusiastically embrace SET as some are in need, or at least think they are, of a 'quick fix' of their problem. Changed lifestyles such as reducing nicotine use, adopting a healthier diet and increasing exercise habits are not very popular. Current guideline recommendations are clear: "SET is advised as primary treatment option". So the following question arises: "How to optimize the implementation of our current guidelines and research outcomes?" In this thesis, a nationwide innovative strategy (a so-called 'stepped care approach') for the treatment of IC is introduced.