Differentiating Lower Extremity Pain: Arteries, Veins and Nerves

products in a highly competitive environment and marketplace. First, for an established manufacturer with specific areas of business development, does the product replace, supplement or create a new product that will increase market share or leadership in the treatment of a specific disease, and if so, how long will it take to get the product to market and what is the prOjected market size. The femoral stent market was projected ro be $18.9 million in 2003 and is projected ro increase at CAGR of 18.8% through 2008. The introduction of a FDA approved and CE mark DES for peripheral indication below the inguinal ligament, will contribute greatly to this growth of market size. There are multiple other factors which industry must also consider including: intellectual property(past, present and future); novelty of device in treatment of disease; position in market place; long term outcomes and durability of established therapy, i.e., operative treatment; and competitive therapies under R&D. Two major hurdles for new product development include firstly, the FDA regulatory pathway required and its associated clinical trials to support labeling claims and secondly, whether the device or combination product will be reimbursed and at the appropriate level. The regulatory pathway, especially for a first to market product, is not always well defined, especially for novel devices or combination products. This often significantly increases the number of patients required in a clinical trial, especially if the manufacturer wants to show superiority to an existing device, combination product or therapy used to treat the same patient population having a given condition. Larger clinical uials obViously increases the time and cost to get the product to market, and risk loss of first to market opportunities. Previous FDA approval of devices using stents, either coated or uncoated, for another indication such as treatment of coronary artelY disease, would not be expected to shorten the regulatory process because of different fatigue issues, sizes of devices, and drug dosing, Add a biologic to a device and the approval pathway becomes even more complicated. Novel technology will also raise reimbursement issues that may require studies to support a new CPT code and the determination by CMS at what level the technology will be reimbursed. The planning for reimbursement should occur early in the process and cost effectiveness data can be collected during the clinical trial. Obviously, the claim of long term freedom from restenosis and durability of the device in a peripheral artery will have to be supported by long term clinical follow-up, resulting in more time and costs. There are also other factors that are unknown at this time that may potentially impact on the return that a manufacturer may project will be gained from the introduction of a new device, combination product or therapy. What factors could Significantly reduce the need for these treatment methods? These include the impact that

early screening for a "vulnerable plaque" in an infrainguinal artery and early u'eatment of these lesions may have on long term outcomes. In addition, with the newly published guidelines for cholesterol, triglyceride, LDL, and HDL levels and the availability and effectiveness of various statin therapies ro achieve these levels, the clinical benefit in the peripheral arterial system is yet to be determined. Thus, the manufacturer must consider all of the costs associated with the factors mentioned plus the costs of manufacturing, marketing, sales and distribution, overhead, royalties, license agreements and ongOing FDA regularory requirements such as post market surveillance, before a return on their investment may be realized. 12:20 p.m. Differentiating Lower Extremity Pain: Arteries, Veins and Nerves Amjad AIMahameed, MD

PAD is one of the 3 major atherosclerotiC syndromes (coronary artery disease, and cerebrovascular disease are the other two) that result from shared risk. While earlier estimates suggested 8-10 million Americans are affected by PAD, the PARTNERS program uncovered a 29% prevalence of the disease in high-risk patients (age> 70 or 50-69 with a histolY of cigarette smoking or cUabetes) presenting to primalY care clinics across the United States. According to US census population projections, older adults are the most rapidly expanding segment of the population and PAD incidence appears to be increasing making it an evolving public health problem. Additionally, recent data suggest that PAD dispropoltion-ately affects Blacks and Hispanics, and the amputation rates in these minorities are higher than that for whites. PAD also affects slightly more males than females but females appear to have worse outcomes. These racial and gender disparities were not explained by known risk factors for PAD. Symptomatic PAD and its impact on the quality of life: While it is appropriate ro refer to intermittent claudication (IC) as the "classic" symptom, evolving knowledge suggest that (IC) is not the most common Symptom of lower extremity PAD (present in 8.7-33% of patients). The majority of PAD patients are either asymptomatic (subclinical) or have atypical leg symptoms, such as "impaired leg function" or "atypical leg pain". It seems the wide range of exertionalleg symptoms (beyond that of classic IC) in persons with PAD may contribute to the gross under- recognition of the disease. Since the prompt diagnosis of PAD and timely institution of proper therapies necessitate that physicians should not restrict their evaluation to be based on patients' complaint of IC alone, it is imponant ro avoid using PAD and IC interchangeably. The previously reported lack of worsening in IC symptoms over time in patients with PAD is poten-

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Differentiating True Claudication from Pseudoclaudication

Intermittent Claudication

Venous Claudication

Pseudoclaudication (Neurogenic)

Character of discomfort Cramping, tightness, tiredness Heaviness and aching Distance to discomfort Exacerbation

Same each time Walking, leg elevation

Relief

Stop walking

tially misleading and may inadvertently lead to downplaying the disease impact on long-term outcomes. Recent data suggest that declining functional performance over time, rather than lack of disease progression, may be the principal dynamic leading to thiS misconception. From a symptomatology stand point; PAD has major detrimental effect on quality of life (slower walking velocity, poorer standing balance score, deceased community ambulation, as well as a taxing economic burden). This is particularly important when considering the demographics of an aging society (> 90% of the elderly in the US, defined as >70 y/o, live independently and almost one fifth of them live alone). These effects of PAD on their mobility would lead them to lose their independence. Differential diagnosis of leg dysfunction (Arteries, Veins, and Nerves) The differential diagnosis of leg dysfunction is broad but could be generally divided into three categories: arterial insufficiency, venous insufficiency, and neuropathic or musculoskeletal in origin. Classically, IC has been differentiated from neurogenic claudication (commonly referred to as pseudoclaudication) [table 1]. Some of the symptomatology seen in chronic venous insufficiency (CVI), such as achy legs and inability to ambulate, may overlap with that seen in PAD. CVI affects 6-7 million individuals in the USA, and similar to PAD, its prevalence increases with age. While some patients may have both PAD and CVI, patients with severe PAD who suffer rest pain tend to develop a moderate degree of pitting edema as a result of keeping their legs in a dependent position in order to alleviate the pain. This, along with the dependent rubor seen in some of these patients, may further confuse the clinical picture. Clues to venous disease include, dilated superficial veins that initially are seen distally and at the medial aspect of the calf, development of pronounced supramalleolar edema at the early stages that later extends to the midcalf with upright posture and resolves with recumbent position, hyperpigmentation secondary to hemosiderin deposition, and lipodermosclerosis with inflammatOIy (stasis) dermatitis. In patients with CVI without PAD, their peripheral pulses are easily palpable. The most common type of leg pain in CVI manifests as heavy achy legs. These may worsen

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Same or tingling, weakness, clwnsiness Variable Variable Standing, walking, leg in Variable but usually dependent position standing with or without walking Leg elevation/compression Often must sit or change garment body positions

with conclitions that lead to increased salt and water retention, such as seen during wann humid weather or during menses for women. Leg pain is typically relieved by leg elevation (as opposed to PAD pain which worsens with leg elevation and improves with dangling the leg) Diagnosing PAD-The Value of ABI Measurement of the ankle-brachial index (ABI) offers a qUick, accurate, office-based, and cost effective noninvasive diagnostic test of PAD. Important aspects of this marker include: ABI value between 0.9-1.4 is deemed normal. Values < 0.90 are diagnostic of PAD and values of < 0.4 usually correlate with severe disease, rest pain, and tissue loss. High ABI (> 1.4) is at least as common as low ABI and recent data suggest its clinical significance similar to that of a low ABI « 0.9) (a U-shaper curve for ABI). ABI measures the systemic atherosclerotic burden, predicts all cause as well as cardiovascular mortality (inversely related to survival), and measures PAD severity. ABI is more closely associated with leg function in patients with PAD than is IC or other leg symptoms. ABI has limited use in patients with non-compressible vessels (usually noted in diabetics, patients with chronic renal failure, and the elderly). In these populations, the ABI may be > 1.4 and it usually loses its value as a post-procedure surveillance test. Severely obese patients may also have noncompressible vessels. Selected References are prOvided at the end of syllabus for 1.35 PM talk. 12:35 p.m.

Current Role of Duplex in the Era of MRA!CfA Kenneth S. Rholl, MD Inova Alexandria Hospital Alexandria, VA 12:50 p.m.

MRA: Should Every Patient Have One? Bany Stein, MD Hartford Hospital and Center for Minimally Invasive Thempy, Jefferson X-Ray Group Hartford, CT