BBI Contributing Editor

Often referred to as a "brain attack," stroke is a heterogeneous collection of disorders that affect the vasculature of the brain. It is defined as a sudden and often severe impairment of the body, caused by a disruption in the flow of blood to the brain. According to the American Heart Association (AHA; Dallas, Texas), there are about 750,000 strokes a year in the U.S. In addition, the AHA estimates that there are about 500,000 "mini-strokes" or transient ischemic attacks (TIAs) annually in the U.S. The two major types of stroke — hemorrhagic and ischemic — are diametrically opposite. The former, which accounts for about 20% of strokes, results in too much blood in the head, while the latter is characterized by too little blood. Hemorrhagic stroke usually is the result of a burst vessel in the brain, typically due to an intracranial aneurysm.

An ischemic stroke is far more common, accounting for about 80% of the total. It is typically caused by the blockage of an artery supplying the brain by a plug of material formed downstream in the heart or proximal vascular system, decreased local perfusion due to formation of a clot within the vessel of the brain or neck; or a severe narrowing in an artery in the brain, typically due to atherosclerotic plaque. In recent years the severity and enormity of the health care and economic costs of stroke have been increasingly recognized. Some of these facts and statistics are outlined in Table 1. It is interesting to note that this rising tide of awareness and concern has reached the political level in Washington, where Senate Bill 1274, sponsored by Sen. Edward Kennedy (D-Massachusetts), is now in Congress.

Kennedy's bill, first introduced about a year ago, is called "The Stroke Treatment and Ongoing Prevention Act of 2002." It directs the Secretary of Health and Human Services to carry out a national educational and information campaign to promote stroke prevention and increase the number of stroke patients who seek immediate treatment and to make available, support and evaluate a grant program to enable a state to develop statewide stroke care systems, foster the development of modern systems of stroke care and provide technical assistance to state and local agencies. Initial funding for this bill is estimated at $40 million annually.

The emergent management or intervention of stroke patients was severely limited until the mid-1990s, when thrombolytic drug therapy such as recombinant t-PA, marketed by Genentech (South San Francisco, California) for ischemic stroke, and embolic agents such as the Guglielmi Detachable Coil, sold by the Target Therapeutics division of Boston Scientific (Natick, Massachusetts), for hemorrhagic stroke were FDA-approved and became widely accepted. Conversely, stroke prevention measures basically have continued to be directed toward lifestyle changes (regular physical exercise, improved diet, blood pressure management) aimed at mitigating modifiable risk factors such as hypertension, high levels of blood lipids, diabetes, smoking, excessive alcohol consumption and obesity.

In recent years, epidemiological evidence has begun to accumulate suggesting that cardiac structural abnormalities of the heart may be a significant cause of stroke. It has been widely known that a percentage of adults suffer from a congenital heart defect, often known as a septal defect. The three principal types of defects are patent foramen ovale (PFO), atrial septal defect (ASD) and a ventricular septal defect (VSD). Of note, only the PFO is routinely implicated as an embolic stroke "enabler." ASD and VSD typically produce hemodynamic changes and, while they need closure, do not appear to play a role in causing stroke.

According to NMT Medical (Boston, Massachusetts), the market leader in the treatment of what it terms "cardiac sources of stroke," the worldwide market potential for septal defect repair is about 500,000 procedures annually, with PFOs accounting for at least 90% of the total.

A patent foramen ovale is a persistent, usually flap-like opening between the atrial septum. In utero, the foramen ovale serves as a physiologic conduit for right-to-left blood shunting. After birth, with the establishment of pulmonary circulation, the increased left atrial blood flow and pressure results in functional closure of the foramen ovale. This functional closure is subsequently followed by anatomical closure. However, incomplete closure or a patent foramen ovale has been shown to persist in 5% to 35% of the adult population, depending on the study and how the PFO is defined.

By itself, a PFO does not cause a stroke, but its presence may be a pathway for a stroke to occur by allowing blood to flow from the venous system to the arterial system without going through the lungs first. One of the important functions of the lungs, in addition to oxygen exchange, is to filter debris from the venous blood returning to the heart. If this debris goes to the arterial circulation, it can lodge in an artery serving the brain, heart or other major organ causing an arterial embolization. When it lodges in the brain, a stroke occurs. If the effects of the stroke last less than 24 hours, the stroke is called a transient ischemic attack. If the symptoms persist longer than 24 hours, it is termed a stroke.

There is believed to be a strong association between the presence of a PFO and the risk of stroke. Specifically, the relative risk of suffering a first-time thromboembolic event is four times as high in patients with PFO and is a whopping 33 times as high in patients with both a PFO and atrial septal aneurysm through the closure of septal defects.

It has been estimated that from 25% to 30% of all ischemic strokes (or about 200,000 strokes annually in the U.S.) are "cryptogenic," i.e., no other identifiable cause of an embolic episode to the brain is apparent. This type of stroke, which is especially common in younger patients, (i.e., less than 60 years old) is viewed as a "paradoxical embolic" event. The paradox is that normal blood flow in the heart goes from right atrium to right ventricle into the lungs, but with this type of event, blood flow has shunted directly from the right atrium to the left atrium through the PFO, allowing embolic material to leave the heart and go "north" into the brain. The shunt can occur when the patient performs daily life activities, such as lifting or defecating, that creates a "valsalva" effect on the right atrium. Simply put, they increase right atrial pressure higher than left atrial pressure, facilitating the paradoxical shunting.

In addition, there is good evidence that patients with PFO and paradoxical embolism are at increased risk for future, recurrent cerebrovascular events. A retrospective French multicenter study reported a yearly risk of 1.2% to sustain a recurrent TIA, and of 3.4% to suffer a recurrent stroke or TIA; despite medical treatment with oral anti-coagulants or anti-platelet drugs in patients with PFO and cryptogenic stroke. Similarly, another European study showed that the stroke recurrence rate among 140 patients with PFO and stroke amounted to 1.9% per year, whereas the combined stroke and TIA recurrence rate was 3.8% per year.

The presence of a PFO can be detected non-invasively with either transthoracic echocardiography or transesophageal echocardiography. Patients also can be screened for the presence of right-to-left intracardiac shunting using power M-mode transcranial doppler (TCD) with agitated saline contrast injections. The latter has been gaining in popularity recently, spurred by improved accuracy and the fact that it is far more patient-friendly. The accuracy of these modalities is considered by clinicians to be quite high. Leading manufacturers of TCD equipment include the Nicolet Vascular (Madison, Wisconsin) division of publicly owned Viasys Healthcare (Conshohocken, Pennsylvania) and privately owned Spencer Technologies (Seattle, Washington).

At this year's Summer in Seattle interventional cardiology conference, sponsored by the Swedish Medical Center (Seattle, Washington), several live cases and lectures by experts presented impressive data on septal closure devices. Secondary stroke prevention for patients who have already suffered a stroke prior to the availability of minimally invasive catheter devices traditionally has relied on one of two alternatives — medical management or open-heart surgery. The former approach subjects patients, who often are young and physically active, to a lifelong regimen of anti-coagulation medication, typically Coumadin (generically warfarin). This medication acts as a blood thinner, which means that engaging in certain forms of physical activities that could lead to bleeding is discouraged lest an accident or trauma cause severe bleeding.

An article in the April 7, 1998, issue of Circulation, titled "Recent National Patterns of Warfarin Use in Atrial Fibrillation," authored by Drs. Randall Stafford and Daniel Singer of Massachusetts General Hospital and the Harvard Medical School (both Boston, Massachusetts), discussed the issues and challenges with the use of warfarin. The authors found that in nursing home populations, just 20% to 31% of the eligible patients were taking their warfarin, while in populations in the hospital setting, only 38% to 44% were taking their warfarin at hospital discharge.

Another study, authored by D.C. McCrory et al., reported in the Archives of Internal Medicine 1995;155:277-281, reported that only 26% of outpatients with AFib were treated with warfarin. In addition, the Agency for Health Care Policy and Research (Rockville, Maryland) in its 1995 publication, "Post-Stroke Rehabilitation Guideline Panel" (AHCPR publication 95-0662), states that warfarin is widely underused, with less than half of the eligible AFib patients receiving it.

Perhaps most importantly, the efficacy of warfarin for stroke prevention was challenged in the widely touted Warfarin-Aspirin Recurrent Stroke Study (WARSS), reported in the Nov. 15, 2001, issue of the New England Journal of Medicine in an article titled "A Comparison of Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke." The authors noted that warfarin had a disturbingly high recurrent stroke rate every two years of 17.8%, and was statistically equivalent to aspirin, which checked in at a 16.8% biennial rate. In commenting on the WARSS study, Dr. Robert Feldberg, director of the stroke program at the Ochsner Clinic (New Orleans, Louisiana), noted that "there is no benefit of anti-coagulation and ... neither drug is very good at prevention."

The lack of compliance and efficacy in anti-coagulation therapy, combined with the invasive aspect of open-heart surgery, has created a major market opportunity for new, innovative therapies.

The first percutaneous device for septal defect closure debuted in the mid-1970s, with further refinements and introductions outside the U.S. in the 1980s. In the 1990s, some of these devices were further refined and adapted specifically for the closure of PFOs. Minimally invasive catheter technology has been growing rapidly in interest in recent years, especially in the area of secondary prevention of stroke as the medical community's recognition of a cardiac source of stroke has surged.

At the Summer in Seattle symposium, Dr. Paul Kramer of the Mid-America Heart Institute (Kansas City, Missouri), who has performed the most PFO procedures (nearly 200) in the U.S., described his experience with this brief cath lab procedure as "the most gratifying thing I do for my patients today." His talk centered on the CardioSEAL device, which is marketed worldwide by NMT Medical. He indicated that he has achieved a 100% implant success rate and there have been no recurrent strokes in the patients he has treated.

NMT Medical has been marketing its PFO device in the U.S. since February 2000, when it received FDA approval to sell under a humanitarian device exemption protocol, which allows patients who have failed medical management and who have had a second ischemic stroke to receive the CardioSEAL device. In December 2001, the company received premarket approval (PMA) for ventricular septal defects, and in April of this year it filed a PMA application for its next-generation STARFlex device to treat high-risk patients who have had an ischemic stroke and are not candidates for conventional therapies. According to NMT Medical, STARFlex offers several advantages over CardioSEAL and other devices, including a non-distorting centering mechanism, an ability to close more anatomically difficult defects, a smaller delivery profile and a smaller profile in the heart.

However, the path to approval for the STARFlex device suffered a setback last month, when the FDA's Circulatory System Devices Panel voted unanimously against recommending approval of NMT's premarket approval application. That vote followed a day of discussion consisting in considerable measure of lambasting the clinical data supporting the PMA application. Panelist John Marler, MD, associate director for clinical trials at the National Institute of Neurological Disorders and Stroke, told NMT: "Your argument for effectiveness is that this device closed a [patent foramen ovale] hole. It's not clear from this data that just stopping up the hole can prevent recurrent strokes." A week after the panel's rejection, NMT Medical CEO John Ahern said the company was working with the FDA to develop "the least-burdensome clinical trial design with the best chance for clinical success and ultimately, PMA approval."

Another catheter device, which attained FDA approval in late 2001, is the Amplatzer ASD Occluder, sold by AGA Medical (Golden Valley, Minnesota). The device is intended for occlusion of ASDs and for patients who have undergone a fenestrated Fontan procedure and require closure of the fenestration. The company has had less clinical experience in the U.S. with its PFO device (trade-named the Amplatzer PFO Occluder) but hopes to begin a pivotal trial in the U.S. shortly, randomizing its device to patients on anti-coagulation therapy. It also recently began marketing this product under an HDE program for patients who have failed medical management and have had a second ischemic stroke.

A third contender in the septal defect market is W. L. Gore & Associates (Flagstaff, Arizona), which has sold its Helex Septal Occluder for both PFOs and atrial septal defects in Europe for several years. The company currently does not market these devices in the U.S. and its plans are unknown.

Another novel interventional approach to stroke prevention was discussed at the Summer in Seattle conference by Dr. Carlo DiMario of the Ospedale San Raffaelle (Milan, Italy). DiMario is one of several European investigators for a new device for primary stroke prevention for patients with atrial fibrillation. Various studies have pegged the increased stroke risk arising from AFib at five- to 18-fold. The American Heart Association estimates that AFib patients suffer about 125,000 strokes annually, representing about 20% of all strokes. Moreover, AFib-related strokes are often severe, since about 70% of the patients die or end up with permanent neurological deficits.

This new percutaneous, catheter-based technique, dubbed PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) was developed by privately owned, venture capital-backed Appriva Medical (Sunnyvale, California). PLAATO is a mechanical means to occluding the left atrial appendage (LAA), an outpouching of the atrium. The LAA is believed to be a localized source of more than 90% of the blood clots that form in the heart during AFib. Prior to the development of PLAATO, the only known method of LAA occlusion was used almost exclusively during open-heart surgery, typically in concert with mitral valve surgery. It is rarely performed as a stand-alone procedure.

DiMario reported the results on the first 50 patients treated in a multicenter trial in Europe and the U.S. The patients included in this initial cohort had either chronic or paroxysmal AFib, had two or more stroke risk factors and were poor candidates for anti-coagulation medication.

The initial results have been impressive, with 100% successful implantation and LAA occlusion. No adverse neurological events have been noted, with an average follow-up of five months. Whereas PFO-related stroke victims are typically younger than 50, the lion's share of the patients treated in this trial were 65 or older, the age when AFib begins to significantly increase in prevalence. DiMario concluded his talk by calling PLAATO "a very promising new technique to treat AFib patients." Appriva received its CE mark in the middle of this year and hopes to begin its pivotal U.S. trial by the end of this year, with possible U.S. market introduction in either the latter part of 2004 or early in 2005.

Another company that plans to enter the LAA occlusion market is Atritech (Plymouth, Minnesota). The company recently successfully completed its first two human cases, which were performed by noted interventional cardiologist Eberhard Grube, MD, of the Heart Center Siegburg (Siegburg, Germany). It is privately owned and has been funded by St. Paul Venture Capital (Minneapolis, Minnesota).

Recently it was reported that a potential competitor may challenge PLAATO. In an unorthodox procedure, Dr. Bernhard Meier of Swiss Cardiovascular Center (Bern, Switzerland) has used the Amplatzer ASD device to block the left atrial appendage in a patient with atrial fibrillation, after Appriva Medical declined to allow him to use its device in that particular patient, deeming the case too high-risk. Meier performed the procedure during live case demonstrations at the annual meeting of the Swiss Society of Cardiology (Bern, Switzerland).

This use of the Amplatzer ASD device, which already has FDA approval for ASD closure in the U.S., may introduce an element of competition for Appriva in this new application, occlusion of LAA to prevent stroke in the setting of AFib, the utility of which itself remains to be substantiated over the long term. If it proves beneficial, however, a potentially vast market awaits.