Critical limb ischemia (CLI) is a disease manifested by sharply diminished blood flow to the legs.  More than 750,000 people in the United States suffer from the disease, and CLI leads to amputation for 200,000 people per year in the Untied States.  Up to 10 million people in the United States suffer from severe leg pain (claudication) and non-healing ulcers (peripheral vascular disease), both of which may ultimately lead to CLI.  Peripheral vascular disease (PVD) is linked to cardiovascular disease in general, and is often associated with diabetes, lifestyle and aging.

There are no drugs currently approved for the treatment of CLI.  United Therapeutics is currently conducting two clinical studies of Remodulin; for the treatment of CLI.  A Phase II study completed by United Therapeutics in 1998 showed that Remodulin administered acutely opens blood flow to limbs in critical limb ischemia patients.  The results of this study were presented at the 1999 meeting of the American College of Cardiology.  Based on this “proof of concept”, United Therapeutics commenced two pre-pivotal trials in late 2002:

• Trial 1: 30 patients with no planned revascularization procedure treated with subcutaneous Remodulin continuously or daily (several hours/day), or placebo.  Study duration is 12 weeks.  Dose starting at 5 ng/kg/min, increasing to target dose of 15 ng/kg/min by week 6.  Endpoints include safety, wound healing and treadmill walk distance; secondary endpoints include limb salvage, mortality, quality of life, and patient living status.
   
• Trial 2: 20 patients with CLI who have just had a revascularization procedure.  Endpoints and design similar to Trial 1, but also include graft patency at 30 days and 12 weeks as endpoints.

Both trials are double-blind, randomized, placebo-controlled studies.  A pivotal trial is expected to commence in late 2003.
For more information about critical limb ischemia, click here.

The following text describes critical limb ischemia in detail and how this disease is treated.  This text was written by Dr. John Cooke, Associate Professor and Director, Program in Vascular Medicine and Biology at Stanford University.

What Do We Know About Critical Limb Ischemia and How Do We Treat It?

Introduction

Atherosclerosis is the major cause of death in the United States and Europe, and will soon become the major cause of death and disability in Asia.  When atherosclerosis causes narrowing of the coronary arteries, the individual may have angina or a heart attack; when atherosclerosis affects the carotid arteries that supply the brain with blood, a stroke may ensue.  Atherosclerosis may also obstruct the leg arteries, a condition known as peripheral arterial disease (PAD).  PAD is much more common than is recognized by laypeople or physicians, afflicting about 25% of people over the age of 70, and about 25% of smokers or diabetics over the age of 55.  Indeed, about 10 million people in the United States have PAD.  In its earliest stages, it is silent.  As the blockages in the leg arteries progress, the individual may notice fatigue or cramping in the calf, thigh or buttocks with walking, a discomfort that is relieved by standing still for a few moments before walking on.

As the obstructions in the leg arteries become more severe, the leg discomfort may occur with very little exertion.  The individual becomes very limited, and walking a city block  becomes a painful and tedious process.   With more progression, pain may occur at rest, typically at night, and almost always in the foot.  Relief is obtained by sitting up and dangling the foot over the bed.  The blood flow is now so poor that the limb is in jeopardy of developing ulceration and gangrene.  At this point, the disease has advanced to the stage of Critical Limb Ischemia (CLI).  About 750,000 people in the US have critical limb ischemia.  Unfortunately many of these individuals will end up with amputations.  Indeed, CLI results in about 200,000 amputations annually in this country.

Other diseases that can cause CLI

Atherosclerosis is the most common cause of severe vascular obstructions.  However, there are some other diseases that can narrow the leg vessels.  Buerger’s disease commonly affects young men that are heavy smokers.  This disease causes a severe inflammation of the blood vessels in the toes and fingers, associated with blood clots that obstruct the vessels.  In severe cases, individuals may lose digits or even the limb.  Another cause of CLI is embolization (eg. clot that has been ejected from a failing heart, or from an aneurysm in the aorta, into the leg).  Embolization can cause a dramatic and severe reduction in blood flow to the limb that is manifested by a severely painful, cold and pale foot.  Making the Diagnosis of CLIOften the individual is a diabetic, or a smoker.  They may have had poorly controlled hypertension and/or high levels of cholesterol for many years.  Typically they will have had a gradual progression of symptoms over the years; increasing severity of exertional leg pain, then foot pain occurring at night, then ulceration of a heel or gangrene of a toe.  Often they will have had multiple vascular surgeries or angioplasties in an attempt to relieve the symptoms. 

On examination of the leg, the skin appears shiny and hairless.  These changes are due to the poor skin blood flow, which causes hair loss, and thinning of the skin.  There may be an ulcer on the foot, typically in a weight-bearing part of the foot, eg. the heel, or in a part of the foot that is exposed to pressure by poorly fitting shoes.  The ulcer is typically round, well-demarcated, painful, and covered with a thick black scab.  With the person supine, and the leg raised in the air, the foot becomes very pale, due to poor blood flow.  With the person sitting and dangling the leg, the foot becomes very red, because the small blood vessels in the foot are maximally dilated all the time, in a desperate attempt to recruit more blood flow to the foot (thus blood tends to pool in these small vessels, causing the reddish appearance).   In a healthy individual, a strong pulse can be felt in the foot, much as one can palpate a pulse in the wrist.  But in the individual with CLI, pulses are no longer palpable in the foot.

In some cases, the onset of CLI can be rapid.  This may be due to embolization as mentioned above.  Or it can be due to a sudden worsening of an obstruction, due to clot forming rapidly over a pre-existing narrowing.  In these cases, the pace of diagnosis and treatment must be quickened, and a more interventional approach is generally followed.  Therefore, the management of these cases (Figure 1) must be individualized.

Laboratory studies to assist in the diagnosis

There are a number of vascular studies that can help to refine the diagnosis of CLI.  There are physiological studies that can detect the strength of the pulse (eg. photoplethysmography);  measure the blood pressure at various levels in the leg (Doppler-derived segmental pressure measurements); measure limb blood flow (strain gauge plethysmography or magnetic resonance imaging); and image the blood vessels noninvasively (eg. with Duplex ultrasound, which can image the vessel by sonography, and can provide information on the velocity of blood flow).

However, when the clinical picture is clear, these intermediate steps are generally bypassed and the patient is sent for an angiogram, in preparation for interventional procedures.

Typically an individual who has symptoms consistent with a diagnosis of CLI needs an angiogram, with a view toward getting more specific information about where the blockages are so that an interventional procedure can be performed.  Interventional procedures include thrombolysis (dissolving clot with medication infused into the leg artery), thrombectomy (extraction of a clot from the leg artery using a balloon catheter), angioplasty (using a balloon catheter to expand the vessel), stenting (using a catheter to place a metal coil inside the artery, so as to expand it), and surgery (using a segment of vein, or a synthetic conduit, to surgically bypass the obstruction, allowing blood to flow around the obstruction and into the native vessel below the obstruction.

Before any of these procedures can be performed, it is necessary to know where are the obstructions.  In an individual with CLI, there are often multiple obstructions in the leg artery.  Typically, the catheter is placed in the femoral artery (in the groin region) in the opposite leg.  The catheter is pushed up the femoral artery, through the iliac artery, into the aorta, and then is directed downward into the iliac artery of the affected leg.  Contrast agent is administered, and Xrays are taken.  The contrast agent (a radio-opaque iodinated dye that can be seen on the Xray) flows through the iliac artery and into the affected leg, outlining the obstructions.  Once this is done, it may be possible to use the catheter to perform angioplasty and or stenting of the plaque that is obstructing the vessel.  If the problem is a large blood clot, then clot-busting medicine can be infused through the catheter into the leg artery.  If the obstructions are severe or multiple, it may be better to send the individual to the surgeon for a bypass. 

Medical approaches

Unfortunately, about 30% of these procedures fail within a year in these patients.  Another 25% of patients are inoperable due to severe and diffuse disease.  And even in the patients where the procedure has been successful, 40% of these patients have died within 4 years, usually due to stroke or heart attack.  To improve on these figures, we need to use the medical therapy that we have more effectively, and we also need to develop new medical approaches.

Current medical therapy for the patient with critical limb ischemia involves aggressive risk factor modification to improve longevity; antiplatelet therapy or anticoagulation to prevent clot from forming and causing rapid deterioration; aggressive treatment of any infection; narcotics for severe foot pain; and foot care, with proper foot wear. The latter seems obvious for someone with poor blood flow to the foot, but these are simple measures that are woefully overlooked.  About 75% of amputations in diabetics are due to avoidable trauma to the foot (as with poorly fitting shoes).  The skin should be well hydrated by an emollient cream, which will make it more supple and less likely to fissure (cracks in the skin which represent portals of entry for infectious agents).

Aggressive risk factor modification saves more lives than any surgical or catheter-based intervention.  Patients with critical limb ischemia need to be treated intensively with medications (preferably statins) to reduce their LDL cholesterol; anti-hypertensive agents to control their blood pressure; insulin, insulin-releasing or insulin-sensitizing drugs to lower the blood sugar to normal levels; and agents to thin the blood, ie. aspirin or the newer and more effective anti-platelet agent, clopidogrel.   Furthermore, it is critical to get these individuals to stop smoking.  A successful stop-smoking program includes behavioral therapy (eg. group counseling sessions), nicotine patches, gums or sprays, and other agents to reduce cravings such as Zyban or clonidine.  In addition, proper nutrition is paramount; a modified Mediterranean diet has been shown to improve blood vessel function and to reduce death from cardiovascular disease. 

These medical and nutritional interventions are targeted to reduce the probability that the patient with CLI will succumb to a heart attack or stroke.  There is also some evidence that the progression of disease in the leg arteries can be slowed by aggressive treatment of high levels of cholesterol.

In addition to these therapies, there are some exciting new medical approaches that are showing some promise. 

When anecdotal reports began to emerge of ulcer healing and pain relief with the use of intermittent pneumatic compression, they were met with skepticism.  Subsequently, small but rigorous clinical trials, including one at Mayo Clinic, have supported the use of this interesting device.  The device consists of a rigid boot that is intermittently pressurized with air.  The increase in pressure is timed to the beat of the heart, such that the increase in pressure occurs in diastole, when the heart is resting.  The mechanisms by which this device improves the condition of the leg may include:  maintaining a higher blood pressure in the leg during diastole, at a time when the heart is resting, and the blood pressure is dropping; increasing the flow of venous blood back from the leg to the heart, which can improve cardiac output, and can increase the pressure gradient across the leg circulation; increasing shear stress in the leg vessels, thereby increasing the release from the vessel of nitric oxide and prostacyclin (see below).  Whatever the mechanism, ulcer healing and pain relief can be observed after a series of treatments over a period of weeks.

Prostanoids

Prostaglandin derivatives have received considerable interest due to a growing body of evidence that suggests that these agents accelerate ulcer healing, circumvent the need for amputation, and reduce pain as well as mortality in patients with critical limb ischemia. (Loosemore 1994, European Working Group 1991).  In addition, prostanoid therapy is recommended in patients who have a viable limb in whom revascularization procedures are impossible, carry a poor chance of success or have previously failed, and particularly in those cases when the alternative is amputation. (TransAtlantic Inter-Society 2000)

During the past two decades, over 2,000 patients with critical limb ischemia have been studied in European trials involving intravenously administered prostacyclin analogues. (Loosemore 1994, European Working Group 1991, Mohler 2000).  Improved ulcer healing and relief of rest pain have been documented.

While promising effects have been observed with intravenous prostanoids, the clinical usefulness of these agents is limited by the fact that an indwelling intravenous line must be used, making the therapy somewhat cumbersome, and increasing the risk of infection.  If the therapy could be delivered subcutaneously, this would be safer and more convenient than intravenous administration.  Recently, the US Food and Drug Administration approved a subcutaneous formulation of treprostinol sodium (Remodulinä, United Therapeutics Corp. Research Triangle Park, NC) for the treatment of patients with pulmonary arterial hypertension.  In clinical trials of patients with pulmonary arterial hypertension, treprostinol, administered subcutaneously, produced significant improvement as compared to placebo in a number of hemodynamic measures, inclucing cardiac index (a measure of pump function of the heart), and pulmonary pressures. 

A recently published study by Mohler and colleagues indicated that intravenous treprostinol can also improve blood flow in the legs of patients with severe vascular disease  (Mohler 2000).   Unlike previous studies evaluating the vasodilatory effects of prostacyclin analogs, this study used state-of-the-art non-invasive ultrasonography to test the hemodynamic effects of treprostinol.  Blood flow in the leg arteries increased 29%  during the infusion.  In two of four patients in whom blood flow was undetectable prior to the infusion, arterial blood flow at the ankle level was detectable during the infusion of the drug.  The treatment was well-tolerated and no serious treatment-related adverse events occurred during the therapy.  This positive result, combined with the positive experience in Europe with prostanoid therapy, has been the stimulus for a formal trial of the therapy to gain approval for treating this condition. 

Angiogenesis

This is an experimental approach not yet proven to be effective, but with exciting animal data, and some preliminary human trials, that suggest proof of concept.  Angiogenesis is the creation of “biological bypasses,” small vessels that can grow around a blocked artery, and thereby provide blood flow to the tissue downstream.  Our bodies have the innate capacity to generate biological bypasses, and to some extent this occurs in everyone that has a blocked vessel.  In some people, the biological bypass formation is so effective, they may never realize that one of their major leg arteries has become blocked over time.  However, in most people, the generation of biological bypasses is insufficient.

The use of growth factors such as VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor) are under investigation.  However, evidence indicates from our laboratory and others suggests that these agents work in part by increasing the release of prostacyclin and nitric oxide from the vessels, which substances play a critical role in vessel growth.  Prostacyclin and nitric oxide have each been shown to enhance the growth of endothelial cells that line the blood vessels. It is the growth of endothelial cells, and their organization into tubules, that is one of the first steps in angiogenesis. 

Nitric oxide and prostacyclin are normally produced in sufficient quantities in the healthy blood vessel to maintain blood flow at normal levels, and to prevent obstructions from forming.  In diseased vessels, the production of these vasoprotective molecules is markedly reduced.  As described above, administration of prostanoids can replace the loss of endogenous prostacyclin.

Ultimately, it may be that combinations of growth factors, with prostacyclin and/or NO-enhancing agents (such as L-arginine), may be required to maximally improve blood flow to the severely diseased leg circulation. 

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