A patient with intermittent claudication experiences pain in the leg muscles while exercising

Intermittent Claudication

IC is a clinical syndrome characterized by reproducible leg pain brought on by exercise and relieved by rest. Other causes of leg pain that must be considered in the differential diagnosis include neurogenic (e.g., spine disease), venous, joint, and other musculoskeletal disorders. Instruments such as the Rose and San Diego Claudication questionnaires have been used in clinical and epidemiologic studies to distinguish IC from other conditions.46,47 In clinical practice a careful history, combined with a physical exam and simple noninvasive studies, readily establishes the diagnosis in the majority of patients. However, it is well recognized that atypical leg symptoms are common in PAD patients, including pain that may also occur while standing still or sitting and discomfort or fatigability with exercise that does not cause the individual to stop walking.

IC may affect proximal (buttock, hip, thigh) or distal (calf) muscles, although calf pain is by far the most common presentation. Symptom location reflects arterial disease proximal to that level. Thus AI disease frequently presents with proximal muscle symptoms (buttock, hip, or thigh), with or without associated calf pain, whereas FP disease will manifest as calf pain with exercise. An important corollary is that individuals with isolated infrapopliteal (TBP) disease frequently do not have claudication symptoms, although foot claudication in plantar muscles has been described.

Severity of IC is generally described in terms of the initial claudication distance, based on walking in daily life or on a treadmill test. Patients with severe IC are generally unable to complete a standard 5-minute treadmill protocol (2 mph, 12% incline). These individuals often describe symptom onset within minutes of walking that forces them to stop, producing significant disability and impaired QoL. Functional testing of patients with IC demonstrates a broad range of impairment in lower limb strength, balance, and associated loss of mobility. Moreover, functional decline over time in IC is significant and is associated with the severity of PAD (e.g., ABI), as well as other factors such as age, race, and socioeconomic status.42,43,48

Numerous studies have associated IC with long-term risk for cardiovascular events and mortality, highlighting the importance of diagnosis, medical therapy, and surveillance in these patients.39,49,50 Over 5 years, approximately 20% of patients with IC experience a major CV event and mortality ranges between 10% and 15%, (seeFig. 104.5). Data from large registries have demonstrated that symptomatic PAD is strongly associated with CV events and mortality, even more strongly than isolated CAD or CVD.51-53 Despite this natural history, undertreatment of patients with symptomatic PAD has been a consistent finding across studies comparing the use of antithrombotic and lipid-lowering medications across PAD, CAD, and CVD populations.9,54 These studies and others indicate that the delivery of guideline-based medical care remains suboptimal for patients with all stages of PAD.

Intermittent Claudication Prevalence

Intermittent claudication is the classic symptom of PAD, defined as ambulatory calf pain that is not present at, and is relieved by, rest. By definition, this criterion excludes asymptomatic and presumably less severe PAD. However, studies on the relationship between HTN and IC have produced conflicting results, with some studies showing a positive association, whereas others failed to demonstrate a relationship. Typically, this relationship has been stronger for systolic than for diastolic BP.

Cross-sectional studies on IC could be biased by a number of factors. First, IC is an imprecise endpoint for PAD. Although IC reflects symptomatic, and thus usually significant, obstruction, surprisingly nearly half the patients reporting IC in a population study had no demonstrable reduction in arterial flow on extensive noninvasive testing.5 Such misclassification would result in a reduced correlation between HTN and PAD. Second, a similarly reduced HTN-PAD correlation could also be introduced by diet, lifestyle, or pharmaceutical interventions after the diagnosis of IC. In addition, it seems possible that cross-sectional studies could produce a spuriously high correlation by an increase in peripheral resistance secondary to PAD. In this instance, PAD might cause HTN rather than vice versa (see Chapter 8 for a discussion of PAD in the renal arterial bed).

Intermittent Claudication

Based upon a thorough analysis of the available published evidence, the quality of which was rigorously assessed using GRADE (http://www.gradeworkinggroup.org/), in 2012, NICE made a number of recommendations regarding the management of people with IC (Table 110.1). Although these recommendations have no direct legal force in the UK, clinicians and payers (public and private) are expected to follow them and to have good reason for not doing so. As a result of its robust and transparent processes, and strict conflict of interest policies, NICE recommendations have very considerable international reach and affect clinical practice and public and private payer reimbursement in many countries. Within the UK, from a medicolegal viewpoint, a decision not to follow NICE guidance without explaining to the patient why an alternative course of action is being recommended, and without documenting that in the case records, leaves the physician vulnerable to criticism. Despite this, it is still probably the case that many patients in the UK are being offered ET, and even bypass surgery, for IC without having been offered a (supervised) exercise program, without having been given appropriate support to stop smoking, and without having been medically optimized. The reasons for this are complex but unfortunately probably reflect practice in many other countries.24 The important question at time of writing is whether there has been any change in the evidence base since 2012 that would lead NICE, or indeed any other independent guideline body elsewhere in the world,25 to now make materially different recommendations regarding infra-inguinal ET for IC.26

While imperfect, the evidence that, preferably supervised, exercise therapy continues to be the most clinically and cost-effective first-line treatment for most patients with IC remains extremely convincing. A recent meta-analysis of seven RCTs concluded that an ET-only strategy for IC was not associated with any improvement in functional capacity or clinical outcomes, whereas exercise and exercise combined with ET was associated with a significant increase in total walking distance, ankle brachial index (ABI), and a reduced risk of future revascularization or amputation.27

Furthermore, the evidence that lifestyle modification and so-called “best medical therapy” (BMT) aimed at reducing overall cardiovascular risk significantly improves outcomes in patients with PAD, whether they undergo ET or not, grows ever stronger.28 By contrast, unfortunately, hard evidence that advanced endovascular technologies and techniques, such as DCB and DES, durably improve important clinical outcomes in patients with IC remains lacking.29 As discussed later in further detail, most of the literature on ET for infra-inguinal PAD comprises industry-funded trials aimed primarily at obtaining marketing approvals from various regulatory authorities. While one understands why such studies are done, one cannot help reflecting that they often represent a significant “missed opportunity” to gather clinically important data that would help physicians and their patients make truly informed, evidence-based decisions regarding ET. Arguably, the largest industry-sponsored trial with the longest follow-up is that evaluating the Zilver PTX DES.30 Although 5-year anatomic outcomes were favorable, due to the limited and unusual method of reporting the clinical outcomes, the trial design, and the large numbers of patients in whom complete follow-up data were unavailable, it is difficult to draw any firm conclusions regarding the clinical and cost-effectiveness of this device and thus its role in current practice.31,32 One respectfully wonders why sponsors would embark upon large and expensive RCTs of ET for (predominantly) IC without reporting treadmill walking distances (or another validated objective quantifiable measure of individual patient improvement), which, while imperfect, has been for many years and still remains the most widely accepted primary outcome in IC trials. Such reporting of symptomatic improvement would probably be mandatory in a phase III trial of a new medical or physical therapy for IC. It is also worth noting that although more than 90% of the patients in the Zilver PTX trial had IC, they also enrolled CLTI patients, and these two very different conditions and patient groups were largely conflated in the analysis. Methodologically, this is very difficult, many would argue impossible, to justify; and yet such conflation occurs repeatedly in the literature. So the thorny question is why should patients and payers be expected to accept a far inferior level of reporting in trials of ET (and open surgery for that matter) for PAD compared to that which would be expected of new medical and physical therapies? Although there have been setbacks, such as the negative results from EUCLID,33,34 overall, the gap in terms of both quantity and quality between the evidence base for medical and interventional (ET and surgical) treatment of PAD appears to be widening in favor of the former.35

1 Describe claudication and its physiology

Intermittent claudication consists of reproducible lower extremity muscular pain induced by exercise and relieved by short periods of rest. It is caused by arterial obstruction to affected muscular beds, which restricts the normal exercise-induced increase in blood flow, producing transient muscle ischemia. Studies have shown that more than half of patients with intermittent claudication have never complained of this symptom to their physicians, assuming that difficulty with walking is a normal consequence of aging. Finally, only one third or less of patients with peripheral arterial disease (PAD) have typical claudication; others have atypical leg pain or are asymptomatic because medical comorbidities limit ambulation.

Tests for Intermittent Claudication

Intermittent claudication implies arterial insufficiency to the tissues. It is most commonly evident when activity occurs because of the increased vascular demand of the tissues. There are two types of intermittent claudication—vascular and neurogenic. The vascular type is most commonly the result of arteriosclerosis, arterial embolism, or thrombo-angiitis obliterans and commonly manifests itself with symptoms in the legs. The neurogenic type is sometimes calledpseudoclaudication orcauda equina syndrome and is commonly associated with spinal stenosis and its effect on circulation to the spinal cord and cauda equina.263–268 The symptoms in this case may be manifested in the back or sciatic nerve distribution.

1 Describe claudication and its physiology

Intermittent claudication consists of reproducible lower extremity muscular pain induced by exercise and relieved by short periods of rest. It is caused by arterial obstruction, which restricts the normal exercise-induced increase in blood flow, producing transient muscle ischemia. Studies have shown that more than half of patients with intermittent claudication have never complained of this symptom to their physicians, assuming that difficulty with walking is a normal consequence of aging. Finally, only one-third or less of patients with peripheral arterial disease (PAD) have typical claudication; others have atypical leg pain or are asymptomatic because medical comorbidities limit ambulation. Claudication is a marker of systemic atherosclerotic disease, with associated cardiovascular mortality rates at 5 and 10 years of roughly 42% and 65%, respectively.

Clinical Manifestations

Intermittent claudication (IC), as a typical and classic symptom of PAD, was originally described by Dr. Rose for the purposes of epidemiologic study. Nearly 50% of patients with PAD are asymptomatic, and only 10% to 30% complain of IC. The remaining patients may have atypical leg pain on exertion or at rest or other symptoms such as reduced leg strength, impaired balance, slow walking speed, ischemic peripheral neuropathy, and functional decline.6,7 These symptoms are in differential diagnosis with other causes of limb pain, including spinal stenosis, statin-induced myalgia, and orthopedic disorders.8 Patients with atypical symptoms, compared with patients with classical IC, have poorer nerve sensation and a higher prevalence of diabetes and spinal stenosis with more comorbid conditions.6 It is important to know that the greater functional decline means more advanced disease and increased cardiovascular events.

Intermittent claudication is defined by exercise-provoked muscular discomfort, primarily in the calf, which is relieved at rest. In PAD, progressive atherosclerosis leads to chronic occlusion of lower extremity arteries, and in contrast with coronary circulation, plaque rupture does not have any role in manifestations.9

Critical limb ischemia is the most severe clinical manifestation of PAD and presents as ischemic rest pain or a lesion with risk of tissue loss. Although only 1% to 2% of patients with PAD develop CLI, the prognosis is very poor, with a 30% amputation rate and a 25% mortality during just 1 year after the index presentation.10

Signs of PAD may include weak pulses, arterial bruits caused by turbulent flow, impaired capillary refill, pallor on elevation (or dependent rubor caused by impaired autoregulation in dermal arterioles), trophic changes, and skin discoloration as a consequence of chronic vasodilation, all of them present in advanced stages of disease. Ulceration or gangrene of the toes occurs in CLI group of patients. Arterial ulcerations have a characteristic well-demarcated “punched-out” appearance (Fig. 23.1).11,12

Acute limb ischemia (ALI) is a vascular emergency caused by sudden disruption of an extremity blood flow. The causes of ALI are acute thrombosis and less commonly, embolic event from a central or proximal source such as cardiac structures. The “six Ps”—pain, pallor, pulselessness, paresthesia, paralysis, and poikilothermia—are the classical presentation of patients with ALI.

Intermittent Claudication

Intermittent claudication (limping) refers to a condition in which a patient experiences difficulty in walking that is brought about by use of the lower extremities. The evolution of concepts of intermittent claudication is of historical interest and is described elsewhere.1 In brief, Charcot initially described this syndrome in 1858 and related it to occlusive peripheral vascular disease in the lower extremities. In 1906, Dejerine distinguished claudication caused by ischemia of the leg muscles from that caused by ischemia of the spinal cord. In the latter condition, the arterial pulses in the legs tend to be preserved, pain tends to be dysesthetic or paresthetic in quality and may not occur, and neurologic signs are frequently present, especially after exercise. In 1961, Blau and Logue identified another form of neurogenic claudication caused by ischemia or compression of the cauda equina and resulting from a narrowed lumbosacral canal (either congenital or due to degenerative disease). This condition is similar to that produced by ischemia of the spinal cord; however, the sensory complaints tend to have a more radicular distribution, and signs of cord involvement (e.g., Babinski signs) are not present.

The clinical distinction between various types of claudication, particularly between the two neurogenic varieties, is sometimes difficult. The cauda equina variety, however, is far more common than the spinal cord form.1,29 Intermittent spinal cord ischemia, when it occurs, can be associated with intrinsic diseases of the aorta, such as coarctation or atherosclerotic occlusive disease although, more commonly, it is due to degenerative disease of the cervical and thoracic spine.30 Bony erosion through vertebral bodies from an abdominal aortic aneurysm with direct compression of the spinal nerve roots has also been reported to produce intermittent neurologic symptoms.1 The clinical details of the single reported case, however, are not sufficient to determine whether the symptoms resemble those of intermittent claudication.

Signs and Symptoms

Intermittent claudication is the most common symptom of arteriosclerosis obliterans. The claudication manifests as pain, numbness, or weakness in certain muscles during exercise. As it worsens, exercise tolerance is reduced and there may be pain at rest. Neurotrophic ulcers, paresthesias in the foot and toes, skin fissuring, ulceration, or necrosis may also be seen with the buttocks, thighs, and calves most often involved Creager and Dzau (1998).

Raynaud's disease is associated with a triphasic response where the fingers, and sometimes the toes, turn white due to vasospasm, then blue due to cyanosis, and finally red when hyperemia returns blood flow to normal. Pain, numbness, and a cold feeling may occur with paresthesias, ulcerations, and necrosis Creager and Dzau (1998).

Ischaemic muscle pain

Intermittent claudication and angina pectoris are two well-known examples of this type of pain that occurs in muscles whose blood supply is unduly compromised. In normal subjects it disappears rapidly after contractions stop, leaving no residual effects. Accumulation of metabolites is responsible although the stimulus, or combination of stimuli, is not clear. Lactic acid is not the prime algesic substance as patients with myophosphorylase deficiency (McArdle's syndrome) experience particularly severe pain during exercise, despite an inability to produce lactic acid (Schmid and Hammaker 1961, Cady et al 1989). Furthermore, clearance of intramuscular lactic acid is slower than the disappearance of pain. Possible agents, acting alone or in combination, are thought to include histamine, acetylcholine, serotonin, and bradykinin. Potassium (Lendinger and Sjogaard 1991) and adenosine (Sylven et al 1988) are currently receiving considerable attention in this respect.