CDU Contributing Editor
NEW ORLEANS, Louisiana Early detection and rapid treatment is one of the most effective strategies available to physicians for improving outcomes of patients with myocardial infarction. A variety of technologies are under development that are intended to improve the ability to detect a heart attack rapidly, while others are designed to help minimize the adverse consequences of an acute coronary event using novel modalities to support the heart or preserve heart tissue. At the annual scientific sessions of the American College of Cardiology (ACC; Bethesda, Maryland), held here in March, developers described the status of numerous technologies for use in the diagnosis and management of myocardial infarction (MI), as well as advances in remote monitoring and less invasive treatment of patients with heart disease. The technologies address a large market, since about 1.3 million people suffer a new or recurrent myocardial infarction each year in the U.S. alone. More than 380,000 of those individuals die, while many of the survivors suffer significant disabilities, including heart failure.
Minimally invasive technologies for the treatment of heart disease are also continuing to advance, improving outcomes for MI patients with coronary artery disease and helping to improve outcomes, particularly in high-risk patients. The latest developments in minimally invasive therapy for heart defects, including atrial-septal defects and Patent Foramen Ovale (PFO), also were described at the ACC sessions. The combination of minimally invasive therapy with drug treatment is another promising area, with significant improvements in outcome reported in trials described at the conference.
Early treatment improves outcomes
A number of companies are developing heart assist devices intended for use in MI patients, with encouraging results reported in clinical trials with some technologies, while others have, at least so far, failed to show benefit. Richard Smalling, MD, of the University of Texas Health Sciences Center (Houston, Texas), described animal studies using a left ventricular assist device (LVAD) under development by A-Med Systems (West Sacramento, California). The A-Med device is a percutaneous LVAD consisting of a pump and cannula that is inserted in the femoral artery and advanced to the aortic arch using a catheter. The placement procedure is very similar to that used by cardiologists to place stents or perform balloon angioplasty. Once in place, the pLVAD provides temporary left ventricular and circulatory support for patients with acute left heart failure. The advantage of the A-Med device is its ability to be quickly deployed, in a period of two to three minutes, providing rapid unloading of the left ventricle. The pLVAD can thus be placed prior to reperfusion, as opposed to post-reperfusion as is common using intra-aortic balloon pumps. Smalling's studies show that unloading of the heart prior to reperfusion results in a 50% reduction in infarct size vs. controls. As a further indicator, endothelin-1, a marker of tissue injury, was measured, and shown to be elevated in controls, but not in animals treated with the pLVAD. The difference was attributed to reperfusion injury, an effect that has been documented in animals, although its existence in humans is controversial. Smalling noted, however, that some patients do experience a dramatic worsening of their condition once an occluded artery is opened, and that devices such as the A-Med pLVAD may help prevent deterioration in many cases.
Other devices for temporary support of the heart include the TandemHeart centrifugal pVAD from CardiacAssist (Pittsburgh, Pennsylvania), the Cancion Cardiac Recovery System (CRS) from Orqis Medical (Lake Forest, California) and the Impella Recover from Impella CardioSystems AG (Aachen, Germany). The Impella Recover was first introduced in the European market in October 2003, and is a percutaneous device consisting of a 3 cm axial pump operating at 35,000 rpm. The device is priced at EUR 5,000, with ancillary equipment costing EUR 18,000. About 30 hospitals in Europe are using the Impella pump in experimental procedures. The TandemHeart Percutaneous Transseptal Ventricular Assist System, which has received 510(k) clearance in the U.S., requires a 21 Fr cannula for insertion, is placed in the left atrium and femoral artery for up to six hours, and relies on the existence of some right ventricular function to achieve adequate flow. The device has been used in about 200 procedures worldwide, and it is available at 17 institutions in the U.S. The Cancion CRS, which Smalling said has so far had limited use, has some advantages over other temporary pumps in that it uses a frictionless magnetic levitation pump. The CRS employs two cannulas, an inflow cannula in the femoral artery and an outflow cannula in the descending aorta. The device unloads the heart, a key factor in aiding recovery following an acute coronary event.
At the ACC sessions, Roland Hetzer of the Deutsches Herzentrum Berlin (Berlin, Germany) reported on recent results with another unique heart assist device, the INCOR axial pump. As opposed to the A-Med, TandemHeart, CRS and Impella devices, the INCOR is primarily intended for long-term support. Like the CRS pump, the INCOR axial pump incorporates the unique feature of magnetic bearing support of the impeller, eliminating friction that could result in wear of the mechanical parts, in principle providing almost unlimited life. The pump operates at 12,000 rpm to provide a blood flow of about 7 liters per minute, and it is undergoing clinical trials in Europe and China. Of the first 72 patients to receive implants of the INCOR device since June 2002, 31 have been implanted at Deutsches Herzentrum. Of those, 19 remained on device support at a mean follow-up of 127 days. No complications due to infection or inflammatory reactions have been observed, and there have been no detectable adverse effects attributable to the non-pulsatile flow generated by the device. The version of the INCOR pump used in the study incorporates an anti-suction algorithm, an improvement that appears to have eliminated problems seen with first-generation non-pulsatile pumps.
Other approaches intended to reduce the damage to the heart in MI patients include hyperoxemic therapy, hypothermia and facilitated percutaneous intervention, the latter approach involving a combination of coronary stenting with thrombolytic or cardioprotective drugs. Based on data reported at the ACC sessions by William O'Neil, MD, of William Beaumont Hospital (Royal Oak, Michigan), hyperoxemic therapy using the TherOx Aqueous Oxygen System from TherOx (Irvine, California), while proving to be safe, has not been shown to provide statistically significant benefits at 30-day follow-up, although earlier pilot studies demonstrated some improvement in ejection fraction, and certain patients (those with anterior MI) showed a 25% reduction in ST segment elevation and in release of creatinine kinase. In addition, results from the COOL MI study of hypothermia therapy using the Reprieve system from Radiant Medical (Redwood City, California), also discussed by O'Neill, did not show a significant reduction in infarct size or major adverse events vs. controls at one-year follow-up, although there was some benefit for patients with anterior infarction whose core temperature was lowered below 35 C. According to O'Neill, no trials evaluating techniques to avoid reperfusion injury in MI that have studied patients treated at five to six hours after symptom onset have shown benefit in the entire treatment group. However, in COOL MI, a subgroup of patients treated early achieved some benefit. Consequently, researchers are now focusing on earlier initiation of therapy. For example, a follow-on study of hypothermia treatment, COOL MI II, will evaluate initiation of cooling with the Radiant Reprieve system prior to reperfusion, perhaps when patients are still in the emergency department.
One approach for improving the salvage of myocardium in MI patients that has shown benefit is facilitated PCI, which combines primary PCI with administration of a drug that acts to prevent reperfusion injury. In the CASTEMI trial discussed by Dan Tzivoni, MD, of Hebrew University (Jerusalem, Israel) at the ACC sessions, high-dose Caldaret, a drug that inhibits the accumulation of excess calcium post-MI, was shown to provide significant reduction in infarct size vs. placebo, and it resulted in a very low 2.3% mortality rate at 30 days, the lowest ever observed in patients with ST-segment elevation myocardial infarction. The drug is under development by Takeda Chemical Industries (Osaka, Japan). The results support the contention that reperfusion injury is a real phenomenon, and they indicate that technologies effective in preventing such injury will have a significant role, provided they are implemented quickly once the patient reaches the hospital. The potential market for products used in acute circulatory support in MI patients is considerable, addressing over 500,000 patients annually in the U.S. alone as shown in Table 1.
Added promise for minimally invasive techniques
Another important segment of the market for products used in the treatment of coronary artery disease discussed at the ACC sessions is devices used in minimally invasive coronary artery bypass surgery. In particular, the use of beating-heart (off-pump) surgery techniques that avoid the use of extracorporeal circulatory support has now been shown to provide equivalent safety and one-year graft patency as compared to traditional on-pump, open-chest bypass surgery. As discussed by Petr Widimsky, MD, of Charles University (Prague, Czech Republic), the results of the PRAGUE-4 trial of 400 cardiac surgery patients showed no statistically significant difference between off-pump and on-pump surgery, although there was a trend for some benefit in the off-pump group. For example, in an analysis of the first 255 patients treated in the trial, mortality was 1.1% for the off-pump group vs. 2% for the on-pump group. Off-pump surgery was applicable to 84% of patients who were randomized to the off-pump group, demonstrating that not all CABG patients can be treated with such techniques, but patency at one year was similar at 91% in both groups for the cohort receiving arterial grafts. One-year patency was 59% in the on-pump group vs. 49% in the off-pump group for patients receiving vein grafts. Widimsky attributed the low patency for vein graft patients to poor-quality vessels in the treated patients. The study results are encouraging for suppliers of minimally invasive CABG devices, including Medtronic (Minneapolis, Minnesota), Guidant (Indianapolis, Indiana) and TFX Medical (Research Triangle Park, North Carolina), although the data represent a single-center experience. As discussed by Robert Harrington, MD, of Durham, North Carolina, the improved results in terms of lower mortality with off-pump surgery can be attributed to the introduction of advanced cardiac stabilization devices, and they are likely to stimulate wider use of off-pump techniques.
Although it is becoming less popular in the drug-eluting stent era, particularly as the latest trial data show very similar long-term outcomes for stenting vs. surgery, CABG in particular minimally invasive off-pump surgery represents an attractive option for patients with more complex coronary artery disease, as well as for payers in today's cost-sensitive healthcare environment. As shown in Table 2 below, the cost-effectiveness of bypass surgery expressed in terms of cost per life-year saved is superior to any other contemporary coronary intervention.
Another application of heart surgery that is rapidly migrating to the use of minimally invasive techniques is the closure of heart defects such as PFOs and atrial-septal defects. Such defects are responsible for a significant number of strokes, and, with stroke now the third-largest cause of death in the U.S., are attracting increased attention within the cardiology community. There are about 500,000 new ischemic strokes annually in the U.S., a third of them cryptogenic, and about 50% of patients who suffer a cryptogenic stroke have PFOs. They are estimated to occur in about 25% of the population. Worldwide, about 500,000 people may have a stroke caused by PFO annually, according to NMT Medical (Boston, Massachusetts), manufacturer of the CardioSEAL, one of the devices available in the U.S. for percutaneous PFO closure.
According to Michael Salinger, MD, of Bonnockburn, Illinois, who discussed PFO therapy at the ACC sessions, interventionalists would treat one PFO for every 12 coronary stent procedures performed if all qualifying PFO patients were treated. Before the availability of transcatheter closure devices, surgery was the primary modality used for PFO closure. However, surgical closure, in addition to being invasive, does not ensure freedom from events, with an approximate 10% occurrence of events following surgical closure. Medical treatment using agents such as aspirin and warfarin is another strategy that has been routinely employed, but that is not entirely effective and requires lifelong adherence to a rigorous drug regimen. Two percutaneous PFO closure devices are approved for use in the U.S. under a humanitarian device exemption, including the CardioSEAL and AGA Medical's (Golden Valley, Minnesota) Amplatzer PFO Occluder. Patients must have a history of recurrent stroke in order to qualify for treatment based on the device labeling. However, according to Salinger, the Amplatzer Septal Occluder, which has full PMA approval, and the CardioSEAL with QwikLoad, which also is FDA-approved for use in selected patients with complex ventricular septal defects, both are used off-label for PFO treatment.
More than 13,000 PFO procedures have now been performed worldwide, according to NMT Medical. While demonstrating a substantial clinical experience, that figure also indicates a minimal penetration of the available market, since about 250,000 patients may require PFO closure each year. So far, results from registries and non-randomized studies cited by Salinger show favorable results for device closure vs. medical therapy for PFO, with a 2.7% adverse event rate for devices vs. a 7% rate for medical therapy. NMT Medical has initiated a large randomized clinical trial, CLOSURE 1, which will enroll 1,600 patients at over 100 sites in the U.S. to evaluate PFO closure with the STARflex, a fourth-generation device that includes a self-centering mechanism, vs. medical therapy. Another large randomized trial, CARDIA STAR, will evaluate the Cardia Star PFO closure device from Cardia (Burnsville, Minnesota), in up to 300 patients recruited at 50 U.S. centers. The Amplatzer PFO Occluder also is being studied in a randomized trial comparing device treatment to medical therapy, the RESPECT clinical trial. That trial is to enroll 500 patients, but recruitment has been slow. As of March, only 12 patients had been recruited for the trial since patient enrollment began last fall.
Improving early detection of MI
With substantial benefits from early treatment of heart attack patients in lowering mortality and improving long-term outcome, there is a growing priority on developing technologies to improve the ability to detect an MI at an early stage. Inovise Medical (Newberg, Oregon) exhibited Audicor Version 2.0 at the ACC conference. It was developed to provide a more effective tool to detect MI in diagnostically difficult patients in the ED or chest pain clinic, potentially allowing more rapid initiation of treatment, and thereby reducing infarct size and mortality. The Audicor system is a module that adapts to the leads of an existing ECG system to pick up third and fourth heart sounds in addition to the electrical signals monitored in a conventional electrocardiogram. The system utilizes a proprietary algorithm to analyze the ECG and heart sound data to provide a 32% to 76% relative improvement in sensitivity for the overall diagnosis of MI. The system is particularly useful for MI detection in the presence of confounding conditions. The Audicor can be adapted to mate with any ECG system, and is currently available for use with instruments from GE Healthcare (Waukesha, Wisconsin) and Philips Medical Systems (Bothell, Washington). Inovise plans to establish partnerships with a number of ECG manufacturers to include the Audicor technology as an integral component of their systems. OEM agreements already have been announced with Mortara Instrument (Milwaukee, Wisconsin) and Welch Allyn (Skaneateles Falls, New York).
GE Healthcare exhibited its latest entry in the coronary CT imaging market, the 64-slice LightSpeed CVCT. The new system could help speed patient treatment because of its more rapid imaging time, requiring only three to five heartbeats to acquire a high-resolution image vs. 16 with 16-slice imaging. In addition, the move to 64-slice technology allows reduction in the use of contrast in imaging procedures by about a factor of two. In addition to rapid non-invasive imaging of the coronary arteries, the new $1.8 million system also has applications in brain and stroke imaging. For example, the entire circle of Willits can be imaged in a single scan. GE said the primary applications will lie in cardiovascular imaging.
Another approach to early detection of MI is to measure markers appearing in the serum that are indicative of plaque instability or rupture. A test for one new marker, myeloperoxidase, is being developed by Prognostix (Cleveland, Ohio), a spin-off from the Cleveland Clinic (also Cleveland) that recently received $5 million in funding. At the ACC sessions, researchers from Osaka City General Hospital (Osaka, Japan) described promising studies with the marker demonstrating its involvement in plaque destabilization. Prognostix plans to develop a test to measure the level of myeloperoxidase in blood that can be used to identify individuals at increased risk for MI. The test could potentially be used in conjunction with other biochemical screening markers to select high-risk individuals who could then be subjected to further testing with various combinations of noninvasive imaging methods such as magnetic resonance or computed tomography imaging.
Other new patient monitoring technologies were exhibited at the ACC conference by suppliers including GMP Wireless Medicine (Fort Lauderdale, Florida) and Microlife (Taipei, Taiwan). GMP Wireless recently introduced the LifeSync wireless ECG system, which can be used with any existing ECG system to eliminate the need for interconnecting cables between the patient and an ECG monitor. The system employs Bluetooth wireless technology to allow transmission of ECG data from the patient to an ECG monitor up to a range of 30 feet. The LifeSync consists of two $1,400 modules, one that is connected to the monitor's ECG leads and a second that is worn on the patient's arm and connected to the patient leads. A set of disposable patient leads costs $30. The system can help reduce nosocomial infections in the hospital by avoiding cross-contamination due to organisms that colonize ECG cables, which include antibiotic-resistant organisms. GMP Wireless launched the LifeSync in the U.S. market in January. The product will target the market for vital signs monitoring products, which is expected to exceed $1 billion in the U.S. this year, as shown in Table 3.
Products that offer an increase in patient mobility and convenience such as telemetry monitors comprise the most rapidly growing segment of the market. The LifeSync is not intended to replace telemetry, but rather to provide the advantages of wireless monitoring for patients who are now tethered to bedside ECG monitors. The LifeSync also offers advantages when patients undergo imaging procedures, since its radiolucent leads eliminate clutter due to conventional ECG wires in bedside diagnostic X-rays, and allow continuous 12-lead monitoring under fluoroscopy.
Improved monitoring of patients outside the hospital also is helping improve the management of patients with cardiovascular disease. Microlife exhibited its BP 3BTO-A blood pressure monitoring system for patient use, which offers the same accuracy as hospital blood pressure units, as shown by a clinical study conducted at Guy's and St. Thomas Hospital (London). The device is worn on the upper arm, and includes software that averages three separate measurements to improve accuracy. Microlife will introduce the monitor in the U.S. next month via a distribution agreement with CVS Pharmacy (Woonsocket, Rhode Island). Another segment of the home/ self-monitoring market highlighted at the ACC exhibits was prothrombin time/INR monitoring for anticoagulation management. A number of suppliers, including HemoSense (Milpitas, California), Roche Diagnostics (Indianapolis, Indiana) and the International Technidyne (Edison, New Jersey) unit of Thoratec (Pleasanton, California) now offer FDA-cleared devices for self-monitoring of PT/INR, and some suppliers are experiencing growing demand for the products. Quality Assured Services (Orlando, Florida), for example, now has 5,000 patients participating in its self-monitoring program who test once per week. QAS has found that patients in its program remain in the target PT/INR range 70% of the time, vs. only 55% for patients managed in coumadin clinics. However, liability issues are slowing adoption in the U.S., according to some suppliers, since physicians are liable for the patient's use of the instrument, and must also absorb the up-front cost of the instrument in some cases. Self-monitoring of INR has been widely adopted in Germany, however, and suppliers are now seeing growing adoption in Israel, Australia and New Zealand.