Peripheral arterial disease (PAD): A Significant Opportunity for Interventional Therapies

Peripheral arterial disease (PAD), caused by systemic atherosclerosis, is vastly underappreciated despite its abysmal mortality rates. With 5 and 10-year rates of 30% and 50% respectively mortality due to PAD is greater than that caused by coronary artery disease and stroke and is exceeded only by colorectal cancer. Better use of the pharmacological and interventional treatments available would dramatically improve the lives of the millions of PAD patients while at the same time ballooning the revenue for companies marketing these treatments.

In 2003, the Sage Group published a unique report highlighting the lack of awareness of PAD concluding that the high prevalence of this condition (14-18 million Americans, compared to coronary artery disease and diabetes afflicting 12.6 and 17 million Americans respectively) is dramatically under-estimated. Furthermore less then 20% of patients are diagnosed. Despite the availability of pharmacological treatments those patients that are diagnosed are often under-treated explaining the high mortality rates and also underlying a total of $35 billion in unrealized annual US sales of cardiovascular therapeutics.

The Sage Group’s 2003 report discussed pharmacological treatment options and analyzed the impact that improved awareness and treatment of PAD would have on pharmaceutical sales (for more on this report click here).

When disease is too severe to be treated pharmacologically a variety of interventional therapies are indicated and these are the focus of a second report published by The Sage Group in September, 2004 (for further details or to order the report click here). This unique report:

• Describes PAD comparing and contrasting disease in different regions of the extremities
  
• Discusses the treatment of PAD and how it varies according to the anatomical location, including in depth evaluation of clinical data for existing and emerging interventional strategies
  
• Compares successfulness, adverse effects and cost-effectiveness of interventional strategies
  
• Evaluates how improved use of interventional therapies could result in an explosion in revenue for compared involved in PAD
  
• Provides a detailed look at all companies with a significant involvement in the field of PAD describing relevant marketed products as well as ongoing R&D

PAD is most frequently manifested in its early stages by pain in the leg when walking which disappears at rest (intermittent claudication). As the disease progresses in severity, pain is experienced at rest, and in the later stages of PAD (critical limb ischemia) blood flow is so inadequate that ulcerations and gangrene occur. Interventional treatment for PAD depends on how far claudication has progressed. As stressed by the SAGE group in report, PAD is usually not associated with claudication and contrary to popular opinion the 65-95% of PAD patients that do not suffer intermittent claudication are not asymptomatic. These patients experience a loss of mobility and an increased mortality rate. Thus the report authors conclude that PAD patients should be considered candidates for interventional therapy whether or not they suffer intermittent claudication, although the two groups of patient may require different courses of treatment. A further misconception is that PAD is a benign disease characterized by slow progression. This is not true since progression occurs in 30%-50% of patients and when measured in the vascular laboratory, disease progression is as high as 90% at 5 years. This underlines the report’s recommendation to treat PAD patient irrespective of presenting indications and furthermore supports the authors’ conclusion that these patients should be treated early with relatively non-invasive approaches before the disease progresses to a point where appropriate treatments carry a greater risk of morbidity and mortality.

As well as depending on level of ischemia, the choice of interventional treatments for PAD is dictated by the anatomy of disease. Three subtypes of PAD have been defined: type I aortoiliac disease which extends from the aorta at a point below the kidneys to ileac arteries; type II disease which extends into the femoral arteries and accounts for 35% of patients; and the most common type III diffuse disease which includes even more distal sites in the popliteal and tibial arteries lower leg and affects over 55% of PAD sufferers. This report discusses in detail the various interventional therapies, indications for each, their advantages/disadvantages and their complications.

Bypass surgery produces frequent and long-lasting patency and is therefore the gold standard interventional therapy for PAD. Bypass, either with one of a large number of artificial grafts or using an autologous graft is particularly indicated in patients with long and/or diffuse disease or disease associated with aneurisms or atheroemboli. Due to its invasive nature bypass surgery does carry a relatively high incidence of mortality and morbidity. Restenoses and embolisms are relatively common albeit treatable risks.

Less invasive endovascular procedures are becoming more popular. Associated with a considerably reduced morbidity compared to bypass, increased cost-effectiveness, but much more frequent restenosis, angioplasty is the most common endovascular procedure. In addition a wide variety of stents are also used as are, much less frequently, atherectomy devices. Over the past 20 years angioplasty and/or stenting has replaced bypass as the initial treatment of choice for aortoiliac disease, in particular in patients with short stenoses devoid of aneurysms or embolisms. This report weighs up the pros and cons of stenting versus angioplasty and also focuses on how stenting can improve the outcome of angioplasty. The report details the various stents employed and makes the important point that although a large number of stents are available for aortoiliac disease, most are used off-label.

In contrast to aortoiliac disease, the much more frequent femoropopliteal lesions are difficult to treat with angioplasty. The high incidence of occlusions versus stenoses is a key complicating factor that limits technical success and long-term patency. Bypass surgery produces much better long-term patency than angioplasty and is less frequency compromised by restenosis. Morbidity is a more significant problem however complicated by the older age of patients with femoropopliteal lesions and the incidence of co-morbities. Furthermore, bypass surgery is considerable more expensive and perhaps more significantly, successful bypass does not necessarily translate into a perceived improvement in quality of life. One of the conclusions of the report is that a combined approach to femoropopliteal disease consisting of initial angioplasty followed by bypass in the event of treatment failure may be the most appropriate strategy.

Poor outcomes in older studies evaluating stenting as an approach to PAD in the femoropopliteal arteries have led to the accepted view that this strategy has only limited use. Another conclusion of the report is that newer studies employing improved stent technologies such as nitinol stents and the development of drug eluting stents should prompt a reevaluation of the treatment of femoropopliteal disease. Although stenting of femoropopliteal lesions is increasing in successfulness, it can be compromised by the mechanical forces exerted during extension and contraction of the leg and fracture appears to be the primary negative aspect of nitinol stents. The authors forecast therefore that the issue of stent fracture will contribute to a slow adoption of drug eluting stents, and overcoming this issue would confer significant market advantage. In addition vascular inflammation is a more significant problem in this region of the vasculature than in more proximal areas and this may have an impact on the eventual uptake of femoropopliteal stenting.

Like patients with femoropopliteal disease, patients with tibioperoneal PAD are generally old and suffer significant co-morbidities however in general their legions are more diffuse, extending up the leg, and are also frequently heavily calcified. Hence angioplasty is rarely an approach for these patients until critical limb ischemia develops. In this instance the authors conclude that endovascular interventions, and in particular laser or cutting balloons, are now preferable to bypass and considerably more beneficial than amputation which is nearly twice as costly as angioplasty with respect to the procedure itself and nearly $12,000 more expensive/patient in terms of medical care during the first year after surgery. Furthermore amputation can result in mortality rates approaching 30% and in patients that survive, annual long-term care is estimated at nearly $50,000 per patient.

Endovascular procedures are more successful and have fewer side-effects when conducted early in the course of disease and the report concludes that intervention should be practiced sooner and more aggressively in patients with PAD in order to prevent progression to critical limb ischemia. A shift in practice is already underway with the number of endovascular procedures almost trebling between 1983 and 2000. The report authors estimated that the number of patients requiring endovascular intervention in 2000 was 3.4 million. Given that patients may require intervention in both limbs and that repeat interventions may be indicated, the total potential market for endovascular procedures currently stands at 5.2 million compared to the 0.6 million procedures actually conducted, thus representing an untapped market. The potential market will continue to grow with population ageing, and greater awareness of PAD as well as improvements in endovascular procedures will allow companies in the medical devices arena to reap considerable rewards. The final section of the report describes these companies and the products that they are developing.

(for further details or to order the report click here)