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Vascular Health: a Business Opportunity?
An Industry Commentary

A number of unmet needs in the vascular market have evaded the attention of many major cardiovascular firms. Consequently, considerable market opportunities exist surrounding these unaddressed needs. In this article, we briefly cover the vascular physiology and associated disorders, and discuss 1) the markets that sell solutions to those problems, 2) the ways in which the current solutions are unsatisfactory, and 3) the opportunities that may be emerging as a consequence of those unmet needs.

Physiology and Disorders

In simplest terms, veins return blood to the heart. If the blood comes from the lungs, those veins comprise the Central Vascular System. If the blood originates from anywhere else in the body, those veins comprise the Peripheral Vascular System. In this article, we primarily focus on the Peripheral Vascular System. Problems within the vascular system generally result in insufficient return of blood to the heart. This is usually caused by either a blockage within the vein (e.g., a blood clot, or "thrombus") or flaws in the valves that manage blood flow in the veins.

If the problem does not occur routinely, which is the case with many thrombi, it is called an "acute" problem; however, if the problem exists on a continuing basis, it is termed a "chronic" problem. Flaws in the valves that manage blood flow are chronic problems, and they lead to a condition known as Chronic Venous Insufficiency (CVI).

Chronic Venous Insufficiency

Chronic Venous Insufficiency, also called Chronic Venous Disease, is a long-term condition. It causes blood pooling and an increase in venous pressure, typically in the legs. Chronic Venous Insufficiency stems from failure of the venous valves. This can be caused by deep vein thrombosis, obesity, genetics, trauma, and standing or sitting for extended periods of time. CVI may also lead to further venous conditions, including varicose veins and venous ulcers.

Chronic Venous Insufficiency is a progressive disorder. It can range in severity from unattractive (although not medically serious) spider veins in the legs to open-wound venous ulcers. CVI affects roughly 5% of the population in the US and Europe. The greatest incidence is observed among women aged 50 and older, with roughly 50% of this population suffering from Chronic Venous Insufficiency. Recent studies have shown that CVI causes the loss of almost 6 million work days per year in the US.

Varicose Veins

Varicose veins are twisted, enlarged superficial veins that bulge above the surface of the skin. Spider veins are a mild and medically insignificant variation of varicose veins. Although all veins have the potential to become varicose, veins in the legs and feet are most at risk, due to increased gravitational pressure in the lower extremities. 13% of the US population suffers from varicose veins; 63% of those are females.

In the typical cycle of care, low severity varicose veins are either ignored or treated with compression therapy. The patient may also be told to make lifestyle changes (e.g., lose weight, modify diet, etc.).

The standard of care for more severe varicose veins has long been invasive surgery: vein stripping/phlebectomy. But post-operative complications (e.g., bruising, skin pigmentation, deep vein thrombosis), expensive hospital operating costs, and a recurrence rate of 20% are making invasive surgery increasingly unpopular.

Another therapeutic approach is sclerotherapy. According to the Cleveland Clinic, "Sclerotherapy involves an injection of a solution ... directly into the varicose vein. The solution irritates the lining of the vessel, causing it to swell and stick together, and the blood to clot. Over time, the vessel turns into scar tissue that fades from view... In general, spider veins respond to sclerotherapy in 3 to 6 weeks, and larger veins respond in 3 to 4 months."

Liquid sclerosants fall into three categories: detergents, hypertonic solutions, and cellular toxins, all of which have drawbacks. For example, hypertonic saline solutions have been associated with significant pain and cramping; furthermore, if the solution extravasates (that is, if it leaks into the surrounding tissue) it causes significant necrosis. Foam sclerotherapy is emerging as a preferred alternative to liquid sclerotherapy, as it associated with greater efficacy and fewer side effects.

However, more convenient minimally invasive therapies have emerged within the past few years. One such method is endovenous ablation, which uses radiofrequency or laser technology to collapse veins from the inside. Two advantages of endovenous ablation over invasive surgery are reduced surgery time and fewer post-surgical complications.

Not surprisingly, endovenous ablation is rapidly growing in popularity as an alternative to surgical methods, such as vein stripping and phlebectomies. In fact, the number of endovenous ablation procedures performed in the US has more than doubled within the last three years, from 80,000 in 2004 to 197,000 in 2007. The procedure is performed by a diverse group of practitioners, including vascular, cardiovascular, and general surgeons, as well as interventional radiologists and phlebologists.

The most important driver of growth for the endovenous ablation market is customer dissatisfaction with the issues and side effects associated with the invasive surgical options. Several companies are now offering competitive products for endovenous surgery, and among those companies, the primary driver of market share growth will be catheter innovation. Large diameter catheters can only ablate larger veins, where thinner diameter catheters offer access to more (and smaller) vessels.

Another opportunity for innovation is in increasing the tip length of the ablation catheters. Ablation occurs at the tip of the catheter, where the radiofrequency or laser emissions are generated. If the tip is small, the ablated area is small, and it takes a longer time to ablate a vein than with a larger tip. Longer ablation time increases the risk of collateral damage.

Emerging companies are currently launching new catheter types with thinner diameters and longer tip lengths.

Venous ulcers

Venous ulcers are wounds that occur due to Chronic Venous Insufficiency, primarily in the sub-torso region. The exact etiology of this disease is unknown, but the current theory is that the increased venous pressure and blood pooling consequent to CVI triggers a series of events that culminate in an open wound. Some of those causative events are thought to include:

• The release of inflammatory agents and reactive oxygen species from pooled white blood cells
• Stretching of the veins due to increased pressure
• Leakage of blood proteins into the intracellular matrix

Venous ulcers are generally treated with compression bandages and stockings and are characterized by a cyclical pattern of healing and recurrence. The wound is usually treated with dressings, although in severe cases, a skin graft is required. The patient is then prescribed some form of compression therapy, such as bandages or stockings.

It is important to note that although compression therapy is reasonably effective, it merely treats the symptom, rather than the underlying Chronic Venous Insufficiency that is the cause. Not surprisingly, the one-year recurrence rate of venous ulcers ranges from 25%-70%. Although life-long compression therapy does reduce recurrence, it only works if the patients wear the compression stockings. The often bulky, hot, and itchy compression devices have poor patient compliance, which limits the efficacy of the therapy. In the near future, endovenous ablation may become a more viable option for treating the Chronic Venous Insufficiency that causes the venous ulcers.

The Endovenous Ablation Market

Total revenues in this marketplace were slightly over $100 MM in 2007, and are forecast to be nearly $300 MM in 2012. Although the market is modestly sized, it is growing quite rapidly. It is noteworthy that none of the major players in the cardiovascular field are represented as of yet. That is, the field has not yet been entered by the large companies that typically compete in the cardiovascular arena.

Thrombosis

Blood clot formation is the most common and most threatening medical venous condition. "Thrombosis" is the term for the formation or presence of a blood clot in a blood vessel. The blood vessel may be a vein or artery, and the clot itself is termed a "thrombus." A "thromboembolism" occurs when the clot breaks loose, travels through the bloodstream, and clogs another vessel in the body. When a portion of the clot breaks loose, travels to the lungs and lodges within the pulmonary arteries, it is called a "pulmonary embolism," which is frequently fatal. 200,000 patients die each year in the U.S. from a pulmonary embolism, more than the number of deaths from breast cancer and AIDS combined. In fact, pulmonary embolism is the single largest cause of preventable hospital deaths in the U.S.

The most common form of thrombosis is Deep Vein Thrombosis (DVT), which is caused by stasis of the blood in the veins of the limbs, damage to the lining of a vein, or by inflammation of a vein. DVT is a multifactorial disease involving clinical risk factors, genetics, or trauma. It affects 2 million Americans annually, 6% of whom die within one month of diagnosis.

Interestingly, roughly two thirds of the population that has DVT is undiagnosed. This is because thrombi can break up and disperse without ever causing symptoms. As the clot fragments separate and circulate they often damage the interior walls of the veins, but the patients remain unaware of the thrombus and of the consequent vascular damage.

There are shortcomings with the currently accepted diagnostic processes. Angiography is generally undesirable, due to the invasive dye injections. Another approach is the d-Dimer test, which detects the presence of blood clot fragments in the blood stream. A normal d-Dimer level generally means the patient does not have a blood clot that is breaking up. An elevated d-Dimer level, however, does not necessarily confirm that there is a clot, as elevated d-Dimer levels can be caused by a number of other conditions, including recent surgery, trauma, infection, and pregnancy. The remaining diagnostic option, ultra-sonography, is widely used, but many believe that it is neither sensitive nor specific enough.

Following diagnosis, the vast majority of DVT patients are treated with anti-coagulants to break up the clot; however, giving concentrated doses usually causes greater bleeding, especially in older individuals.

Of greater interest is thrombectomy, which is the process of physically breaking up (and frequently removing) the clot. The traditional method has long been the intravenous injection of thrombolytic agents to remove the clot; however, this procedure has resulted in a 15% higher risk of major hemorrhages, which may be intracranial and/or fatal. Additionally, in 66% of patients, this treatment does not fully restore the vein to normalcy.

Consequently, emerging companies are offering novel catheter technologies that allow localized thrombus removal. These technologies garnered their first regulatory approval in 2006. Examples include:

• Aspiration catheter; an example is AngioJet by Possis, which breaks apart the thrombus using saline solution at high speeds, and then aspirates the debris.
• Thrombectomy catheter; an example is Trellis by Bacchus, which isolates and destroys the thrombus using vibrations or thrombolytics
• Thrombolytics catheter; an example is MicroSonic by Ekos, which delivers microsonic energy and a thrombolytic agent that effectively breaks down the clot

The Thrombectomy Market

Much like the market for endovenous ablation, total revenues in the thrombectomy market were slightly over $100 MM in 2006, and will grow to be nearly $300 MM in 2012. This is another market that is not very large, but is growing rapidly. In the thrombectomy market, we see a few major players, but their participation is modest.

Summary

Vascular disorders include varicose veins, venous ulcers, and thrombosis (particularly, Deep Vein Thrombosis). The need for faster and more effective treatment of these disorders is growing, driven by:

• Continuing increase in aging, obese, and diabetic populations
• Increasing patient dissatisfaction with current therapies (including unpleasant side effects and a high disease recurrence rate)

Most of the treatments currently employed are either invasive or sufficiently uncomfortable with poor patient compliance. Additionally, all of the current treatments are plagued by high recurrence rates. This has presented an opportunity for minimally invasive surgical treatments, where several young companies are offering novel, promising solutions for this market.