Interventional Heart Failure

Medical device investors who have avoided heart failure, because of the long and uncertain development course of ventricular assist devices, should take another look. The minimally invasive revolution in heart failure, to some extent a logical extension of interventional cardiology's migration into other areas of structural heart disease like heart valves and PFOs, is providing new device opportunities, which have the potential to get to market sooner and at the same address an even larger patient population than heart failure devices that came before.

Less might be more in heart failure, as new alternatives to left ventricular assist devices--less invasive, partial assist circulatory devices and percutaneous devices--promise to reach heart failure patients in earlier stages, when they might still have a chance to recover.

Mary Stuart

The dismal tale about chronic heart failure has often been told: five million people in the US have a progressive disease that will kill 70 to 80% of them within eight years of diagnosis, and there is no cure, apart from heart transplantation, in sight. Therapy consists of drugs for early-stage patients, to manage the symptoms but not the progression of disease. Cardiac resynchronization therapy devices provide some benefit, but only to about a third of the 15% of all heart failure patients eligible for them; and finally, at the end stages of the disease, certain patients well enough to undergo major invasive surgery get left ventricular assist devices (LVADs), implantable pumps that replace the functioning of the heart by keeping end-organs perfused, gaining them perhaps two or three additional years of life. Millions of chronic heart failure patients have essentially had no beneficial therapies available to them.

Well, there’s a new chapter in heart failure, and it looks like it’s going to have a happier ending. New therapeutic devices are already entering into clinical trials, and they’ve been purposely designed to avoid the complexity of LVADs and invasive implantation procedures. These new devices may not have the firepower of LVADs, but as simpler, less invasive or otherwise safer alternatives, they have the potential to treat disease in earlier stages, when patients might still have a chance to recover, for there is evidence to suggest that ventricular remodeling can be reversed and that given the opportunity for a little R&R, the congested heart can heal.

Many of the up and coming heart failure products, which are implantable through percutaneous techniques, are the logical extension of an ongoing movement by interventional cardiology into structural heart disease. Cardiologists have already joined cardiovascular surgeons in the transcatheter treatment of congenital heart defects, as well as the percutaneous repair and replacement of heart valves. At the upcoming 2007 Transcatheter Cardiovascular Therapeutics meeting in Washington, DC, in October, a course entitled "Percutaneous Intervention for the Surgeon" officially recognizes the convergence of these two specialties. It was only a matter of time before interventional cardiology began to wrap its arms around chronic heart failure (HF) as well.

Several new companies are offering minimally invasive devices aimed specifically at the earlier-stage heart failure patients; CircuLite Inc., Orqis Medical Corp. , and HeartWare Ltd. are all developing small implantable rotary pumps for partial assist to help the heart keep end-organs perfused. A number of companies are developing implantable extra-aortic counterpulsation devices that help reduce the workload of the heart, including Cardiak Ltd., SCR Inc., Sunshine Heart Co. Pty. Ltd., and CardioPlus Inc. Atria Medical Inc. has taken lessons learned from devices for the percutaneous closure of a congenital heart defect known as a PFO (patent foramen ovale) to do just the opposite; it plans to actually create an opening in the inter-atrial septum with a one-way valve to avoid volume overload and reduce the number of HF hospitalizations. Finally, a number of companies aim to reverse the effects of heart remodeling via transcatheter approaches, for example, Paracor Medical Inc., with a heart wall restraint device, and MiCardia Corp. , with a dynamic approach to treating the type of mitral valve deformation that results from HF. Extensia Medical Inc., an early-stage start-up that isn’t saying much yet, says that with a single minimally invasive device it hopes to address both ventricular remodeling and valvular dysfunction. (See Exhibit 1.) These companies hope that by intervening in heart failure in good time, they’ll stave off today what is an inevitable descent to the point of no return.

From End-Stage Palliation to Timely Intervention

HF is a degenerative disease with a large number of possible triggers; underlying heart valve disease, chronic high blood pressure, long-standing heart arrhythmias, and myocardial infarction, all of which can kick off the process of cardiac deterioration. The hallmark of HF is the progressive enlargement of the heart’s left ventricle, a compensatory mechanism that actually does more harm than good. This structural remodeling further reduces the heart’s pumping efficiency to the point where patients experience shortness of breath, low blood pressure, and fluid retention, all contributing to a poor quality of life and a shortened life span.

Heart failure is classified by the New York Heart Association in four stages according to its severity, and HF patients will inevitably progress over the years from Class I, the early stages of the disease, to Class IV, the end stage, at which point not much can be done for them. Patients in Class IV have a one-year mortality rate of greater than 50%. Indeed, there are approximately two million patients in Class III and Class IV heart failure that no therapies can help. The question has always been: why can’t we use devices in Class III patients to keep them from progressing to the point where they have no options?

The answer lies in two camps, says Mark Slaughter, MD, a cardiovascular surgeon and director of the Mechanical Assist Device program as well as director of cardiac surgery research at the Advocate Christ Medical Center in Chicago. Slaughter is one of the leading surgeons in treating end-stage heart failure with mechanical circulatory assist devices. In one camp, Slaughter says, are those that believe that LVADs, particularly the newer, smaller, and more durable continuous flow pumps in development, should move beyond the very sick, end-stage patients for whom LVADs are currently approved, to patients in Class III, in whom offloading the heart may prevent future deterioration and even perhaps encourage recovery. (For a comprehensive discussion of particular LVADs in development, see "Heart Failure, Strength in Devices," Medtech Insight, August 2007 (Also see "Heart Failure: Strength in Devices" - Medtech Insight, 1 Aug, 2007.).) Members of the other camp are waiting for less invasive and safer devices before they’ll consider treating patients in earlier stages of heart failure. In either case the risk-benefit equation for LVADs will need to change before referring physicians will feel comfortable sending their Class III heart patients to surgery.

Today, ventricular assist devices, which are essentially replacement pumps that do most of the work normally done by the heart, are reserved for the sickest patients. The surgeries to implant them are just too invasive, and the devices too risky--in terms of potential failure, the risk of blood clots, and the need for anti-coagulants, or the occasional suction event, for example--to justify their implantation in Class III patients. The FDA never cleared implantation for this group. Most devices require a sternotomy (cracking the chest open), and patients are put through four-hour procedures during which they are on cardiopulmonary bypass with its attendant risks of neurocognitive deficits.

It’s a catch-22; the benefits of LVADs for these end-stage patients aren’t dramatic, and in light of their risks and uncertain benefits, many physicians are reluctant to recommend them to more patients. Slaughter says, "The bottom line is, in late-stage heart failure, there is no question that devices are better than medical therapy. But many of those people are very sick. So even if you put in a device that works, that restores flow and blood pressure, patients still have many ongoing problems. One of them is renal failure, which still may limit the overall benefit and long-term survival from this long-term device."

A greater understanding of the kinds of patients that can truly benefit from LVADs may help expand the market, which today is only worth $154. 5 million, despite the fact that the leading manufacturers have been working on the technologies for more than 20 years. (See Exhibit 2.) "If we use our current devices in less ill patients with the idea that the pumps work, we would most likely see fewer complications, a better quality of life, and the data would look better than what are currently published," Slaughter believes.

Indeed, anticipating the successful long-term support of patients receiving devices as a destination therapy (rather than as a bridge to heart transplantation), much research into ventricular assist devices has focused on designs that will theoretically last for a patient’s lifetime—hopefully a long one, at that--and that’s what has driven development of the new small, continuous flow pumps, some with magnetically levitated impellers that eliminate bearings subject to wear and tear.

Steven Koenig, PhD, associate professor of bioengineering and surgery at the Cardiovascular Innovation Institute of the University of Louisville studies the long-term effects of VADs. His research includes monitoring the cardiac function of patients at the time of device implant and explant with pressure catheters and flow probes; his team also collects blood and tissue samples and looks at how devices may help promote myocardial recovery. Koenig says, "A lot of people in the device industry think that in heart failure, the wave of the future is to make devices that last forever. But as a scientist, I’m not convinced that long-term this is the best strategy for treating heart failure. One of our research foci is to study and learn from current LVAD patients and leverage advances in LVAD technology to develop less invasive, partial support devices and effective treatment strategies to recover heart function in early stage heart failure patients." Koenig says that according to research done by the Cardiovascular Innovation Institute, there is no question that there are significant hemodynamic differences (vascular pulsatility and ventricular volume unloading) between patients with pulsatile and continuous flow devices, which may lead to adverse physiologic responses. The clinical significance of these differences isn’t completely understood and continues to be heavily debated among the scientific community and the device industry.

Thus, there is a second camp that is waiting for less invasive, safer devices to arrive on the market; in addressing Class III patients, these need not totally take over the heart’s job of supplying end-organs with their requirements for blood; a partial assist may be just what the heart needs to rest and recover, or at least to avoid further deterioration. It was to fulfill this need that CircuLite was founded.

A Little Bit of Support Goes a Long Way

CircuLite was founded in 2004 by cardiovascular surgeon Paul Spence, MD, a clinical professor at the University of Louisville School of Medicine, and Accelerated Technologies Inc., the physician-run incubator that focuses heavily on interventional cardiology. CircuLite is in an entirely different category from ventricular assist devices, says CEO Paul Southworth, as the first company aiming to provide long-term support to the chronic heart failure patient. Its goal of providing only partial support (two to three liters per minute as compared with LVADs, which are designed to provide four to eight liters per minute) enabled it to create the smallest device that’s in development today, according to the company.

CircuLite’s Synergy is as small as a double-A battery, and, because of its tiny size, it can be implanted, like a pacemaker, subcutaneously under the skin with a three-inch incision under the collarbone. The subcutaneous placement means that the Synergy device can be placed without a sternotomy and there’s also no need for the patient to be placed on cardiopulmonary bypass. The device’s inflow cannula will be placed trans-septally into the left atrium.

Because CircuLite reduces implantation risks, it believes it will be able to treat heart failure patients on the border of Class IIIb and early Class IV in an elective procedure to reduce the symptoms of heart failure and improve quality of life. Since the Synergy device is designed to work in conjunction with the patient’s native heart, there is a "fail-soft" mechanism in case of accidental power loss to the device, Southworth says, because the patient will simply be supported by his or her native cardiac output until power can be restored. In contrast, the interruption of power to a full support LVAD can be catastrophic.

CircuLite’s initial clinical trial strategy involves studying Class IV patients waiting for heart transplant with a surgical version of the device, placed via a mini-thoracotomy. The first patient, who underwent device implantation in June 2007, has been on the device for more than 8 weeks now, without any problems, Southworth reports. A second patient received a device in August. CircuLite is also working on a Class IIIb long-term support trial protocol in which it plans to begin enrollment in the fourth quarter of 2007.

Southworth sees CircuLite’s market as the two million patients in Class IIIb and early Class IV heart failure who are refractory to current therapy. "They have no other option but to wait until the disease progresses and then to wait for a heart transplant or a ventricular assist device. Many of these patients are comfortable at rest, but they can’t do the things they used to, like play with their grandchildren or garden."

CircuLite hopes that its Synergy device will address this quality of life issue. To fund the ongoing and future Synergy clinical trials in Europe and the US, the company has raised approximately $36 million from investors including Forbion Capital Partners, Giza Venture Capital, Oxford Bioscience Partners, Credit Agricole Private Equity, Foundation Medical Partners and SB Life Science Ventures. CircuLite plans to report its first clinical results at the end of 2007.

Counterpulsation Devices

There is a new class of heart failure devices in development, which is building on an understanding of the benefits of intra-aortic balloon pumps, used for the past 40 years or so for acute heart failure or to help the heart recover following surgery. (Acute failure is a different market from chronic heart failure. For more on acute heart failure, see "Abiomed: Heart Recovery, not Replacement," IN VIVO, June 2006 (Also see "Abiomed: Heart Recovery, Not Replacement" - In Vivo, 1 Jun, 2006.).) Intra-aortic balloon pumps (IABPs) themselves can’t do the job—they require a line into the femoral artery, so patients on IABP support are confined to hospital beds. These devices are also subject to infection, as is always the case when a catheter protrudes from an open wound.

Several new companies have adopted the mechanisms of benefit of IABPs, which unload the ventricles and also perfuse the heart, in new extra-aortic counterpulsation devices that can be used long term in ambulatory patients. This group includes Sunshine Heart, CardioPlus (formerly L-VAD Technologies), Cardiak, and the newest company, SCR.

Cardiak is in preclinical studies of a new counterpulsation device called the akpulsor, which consists of a cuff that fits around the descending aorta. The cuff inflates to compress the aorta when the aortic valve is closed and the ventricles are filling. Rob Carson, a project director at Cardiak, explains that when the cuff inflates, it pushes blood back toward the heart, and because the aortic valve is closed, it pushes the blood through the coronary arteries. The cuff inflates during diastole, the relaxation phase of the heart, during which 70% of the heart’s blood flow is achieved. When the cuff deflates, a vascular void results, so when the heart goes into systole, it need only eject into an area of low pressure, thereby reducing its workload. Again, the device has safety advantages over LVADs because it does not contact the blood, thus reducing the risk of clotting; there is no requirement for long-term anti-coagulation therapy; and it is fully implanted, with no percutaneous drive connections, minimizing infection risk. The implantation operation is also less invasive than that of an LVAD; a left thoracotomy, not a sternotomy, is required for implantation of the akpulsor.

Still, there are clinicians who feel that even a thoractomy is too invasive to justify treating Class III patients, so brand new counterpulsation company SCR Inc., founded by CircuLite founder Paul Spence, has created a very small 30-ml stroke volume device that doesn’t require a thoracotomy for placement. It will be implanted like a pacemaker with a small incision in the pectoral region with a single anastomosis to the sub-clavian artery.

The Cardiovascular Innovation Institute’s Steven Koenig, who is collaborating on the project, says, "We are envisioning a small, simple, surface procedure surgery that can be completed in less than an hour." The goal of this therapy, he says, is to leave the device in from 30 days to perhaps six months, to provide the same level of counterpulsation support as an IABP but in a closed system that allows the patient to be completely ambulatory and restores their quality of life. "The SCR device is a 30-ml pneumatically driven blood sac that fills when the heart ejects and ejects blood while the heart is resting. The idea is that we can control ventricular workload by partially unloading the ventricle to enable the heart to rest or reload the ventricle to exercise the heart following recovery."

Koenig believes that extra-aortic counterpulsation devices will have a greater role in recovery because they not only reduce ventricular workload, they also improve blood flow to the heart. The SCR counterpulsation device has the additional advantage of offering a less invasive surgical procedure and a much less expensive device than other counterpulsation or LVAD devices.

Long-Arm of Interventional Cardiology

The migration of interventional cardiology into heart failure has resulted in some pretty creative approaches to some of the structural features of the disease. Atria Medical, founded by Israeli cardiologist Gad Keren, MD, the director of the Cardiology Center at Tel Aviv Sourasky Medical Center, has patented a novel one-way valve, designed to be delivered percutaneously to the wall between the left and right atrium, to reduce the problem of fluid overload, the number one cause of hospitalizations from heart failure. Indeed, the story of Atria Medical’s founding is that of a clinician deliberately looking for an answer to a particular question, and coming up with an unusual solution.

CEO Zvika Slovin, PhD, explains that in the US, there are 6.5 million hospitalizations per year due to congestive heart failure resulting in a direct cost to the health care economy of almost $14 billion each year. A large number of these are rehospitalizations. Half of the patients return every six months and spend about a week in the hospital. After analyzing the hospitalization data, the founders of Atria Medical learned that fluid overload was the chief cause of admissions due to heart failure. They decided to try to do something about it.

"This is a significant economic burden, and a quality-of-life issue," says Slovin, "because patients suffering from pulmonary congestive edema are literally gasping for air." Slovin says the company did a physiological analysis of why congestive pulmonary edema is so frequent in diastolic heart failure patients. He explains that because of dysfunction of the left ventricle, after the diastolic cycle, it remains full because it is unable to push blood into the body. Blood backs up in the left atrium because it can’t flow into the full ventricle. The pulmonary vein, which pulls blood from the lungs toward the left atrium, experiences extremely high after-load, causing the lymphatic system to generate fluids. Swelling of the tissues results, often in the legs and ankles, but also in the lungs, to the point where a patient suffers shortness of breath especially when lying down.

Keren came up with a novel solution sparked by insights from pediatric cardiology and interventional cardiology, where there has recently been a flurry of development in the area of transcatheter PFO closure. In the fetus developing in the womb, a flap exists between the left and right atrium—a patent foramen ovale—allowing oxygen-rich blood to bypass the immature lungs and nourish the body. In most people, this flap closes after birth. In 20% of the population at large, the flap persists, contributing to a risk of stroke. Thus, in recent years, companies have developed percutaneous occlusion devices to seal off the unwanted opening in the inter-atrial septum. In the process of sealing off the PFO in some HF patients, it was anecdotally observed that a large percentage of the patients died within months of the operation, because left atrial pressure rose to a dangerous level.

Atria’s founders conceived of a uni-directional valve to be implanted on the wall that separates the left from the right atria (the inter-atrial septum). The valve would create an opening to shunt the excess blood from the left side to the right side of the atrium to reduce left atrial pressure without causing any reduction in cardiac output. Because the valve is one-way, it should avoid the risk of blood clots entering into circulation. The valve delivery method is percutaneous via the right femoral vein, in the manner of PFO closure devices. Slovin says, "We are going in percutaneously through the venous system; we are reaching the right atrium, puncturing the inter-atrial septum, and placing our valves." The company hopes to get a reimbursement code that looks something like a cross between percutaneous valve repair and transcatheter PFO closure.

To date, Atria has raised $4 million from Pitango Venture Capital and private investors, and it is in the midst of raising a $7 million round that it hopes will take it to first-in-man studies.

On the Road to Recovery

The minimally invasive revolution in heart failure is ushering in a new era where interventions have the opportunity to go beyond the palliative treatments available today, by potentially reversing or halting the progression of chronic heart failure. It is also opening the field, once again, to venture investment. The long and uncertain progress of left ventricular assist devices, accomplished over decades, not years, is not the typical venture capitalist’s idea of an exciting investment. But many of the new interventions for heart failure discussed here will be in the clinic in a year or two and venture capitalists seem to be happy to help them get to that point; a dozen or so venture-backed heart failure companies have been founded in the last five years, and just two of them--Orqis Medical and Paracor Medical--have raised more than $60 million each.

The approaches are varied, and they won’t necessarily take market share from each other. HF is a multi-factorial disease, resulting in a cascade of structural changes, and no one believes one magic bullet will solve the problem; there will be room for many types of interventions, and for the skills of all three specialties that treat heart failure patients: cardiovascular surgery, interventional cardiology, and the emerging heart failure specialty. It is even likely that some of these approaches will be used in concert with each other, or with alternative emerging therapies such as stem cells or electrical stimulation for the repair of damaged myocardial tissue.

There is evidence that the heart, under certain circumstances, can be repaired; small numbers of patients whose ventricular assist devices were removed because of device failure were found to have spontaneously improved native heart function. In the field of regenerative medicine, in late August 2007, a research group out of the University of Washington and Geron Corp. and headed by Charles Murray, MD, PhD demonstrated the successful restoration of cardiac activity and new vessel growth in the hearts of rats treated with the group’s cocktail containing embryonic stem cells. Young companies like Orqis Medical are even beginning to position their devices as therapies for heart failure recovery. There’s a great deal of hope in heart failure right now, and although myocardial recovery still remains a passionate wish, rather than a certain goal, meanwhile, the new minimally invasive devices can do a great deal to help patients with chronic heart failure live full lives.