"A lot of therapies make people feel better in the moment, but they may only live better to die sooner," says Fred McCoy, president of cardiac rhythm management for Guidant (Indianapolis, Indiana). "That doesn't seem to be the case with this therapy," referring to the company's Contak Renewal CRT-D resynchronization defibrillator, which last month won the CE mark and recently received its first patient implant in Europe in preparation for full market release. McCoy says the product is on schedule for full market launch in Europe "shortly after the summer," with hope also of winning FDA approval about then or later in the year.
The Contak Renewal is one of the growing number of combination therapy devices in the cardiovascular sector that pursues the strategy of managing, not just one defect, but a complexity of heart activity parameters. Thus the device bundles resynchronization technology with tachycardia therapy and also adds significant new monitoring capabilities, a feature that takes it one step beyond the company's Contak CD device. The combination of resynchronization, defibrillation and monitoring is designed, McCoy told Cardiovascular Device Update, to increase not just "survivability" but also to provide a high quality of life during those additional years given to the patient to live. He adds, "It really represents an advanced-generation technology in a first-generation timeframe," and says that the company spent $125 million over the last decade in developing the technology.
"This is the area where we'll have the most important product development," McCoy says. "It is the first purpose-built cardiac resynchronization therapy built from the ground up. The device is advanced-generation, but more importantly, it provides advanced information about the patient." Here, the key is the device's ability to measure heart rate variability and provide enriched information about that variability to the physician. Heart rate variability, McCoy says, "has long been recognized as a key indicator of patient wellness. The more a person is in heart failure, the more the heart tries to compensate with a high rate." Thus, he notes that the heart of a heart failure patient often will race along at 100 beats per minute while the person is at rest and fails to show the proper rate changes with different types of activity.
"What the physician looks for," he says, "is a heart rate that changes – down at rest, up at exercise. And so the ability of this device is to clearly establish and portray heart rate variability, to provide key information about patient wellness." The critical technology enabling this is an accelerometer, a component used in adaptive rate pacemakers and defibrillators to measure movement, McCoy calling it a sort of "proxy for exercise" that helps serve as an indicator of the person's activity.
McCoy says that the Contak Renewal device is a concrete expression of a primary "umbrella concept" for Guidant. "We are working relentlessly to deliver more information about the patient while we simultaneously have the device do more things automatically, which makes it dramatically easier for physicians to use." The device represents one of the new technologies which Ron Dollens, president and CEO of Guidant, told shareholders at the company's annual meeting will drive double-digit growth in the second half of the year and at the same time support product development into the future. Key to this opportunity will be the regulatory progress for the device over the next few months. In Europe, the Contak RenewalCRT-D must be implanted in 30 patients, with 30-day follow-up of those patients before full market release in that region.
The device also will be considered by the FDA at a panel meeting this month, along with the Contak-CD. Fast-track clearance would make the devices available to the 400,000 people in the U.S. newly diagnosed as heart failure patients each year – of about 5 million overall. McCoy predicts "between 10,000 and 20,000 could receive this technology in the very early going" and estimates potential sales of $150 million to $200 million in the first 12 months on the market. He adds, "Those numbers may be conservative. We won't know until approval, until we put it on the market."
Elsewhere in the product pipeline:
AtheroGenics (Alpharetta, Georgia) an emerging pharmaceutical company focused on the treatment of chronic inflammatory diseases, released encouraging preliminary results of a Phase II clinical trial of AGI-1067, an oral agent for the treatment of restenosis after percutaneous coronary intervention (PCI), or angioplasty. Analysis of the results indicated that six months after angioplasty, the blood vessels of patients who received AGI-1067 had greater luminal diameters of their coronary arteries than those patients who received placebo, the company said. This improvement showed a statistically significant dose response. At the highest dose of AGI-1067, the increase in the size of the target blood vessel was similar to that achieved with probucol, the active control drug in CART-1 (Canadian Antioxidant Restenosis Trial), which has been shown in previous clinical studies to reduce restenosis rates significantly following angioplasty without stent deployment. An unexpected apparent benefit of drug treatment affected the use of the method typically specified for analyzing primary endpoint in a restenosis study. Because of this apparent early drug benefit on coronary arteries, AtheroGenics has not yet determined whether CART-1 met its primary statistical endpoint as pre-specified in the protocol. A full analysis of the safety and efficacy data is under way and expected to be announced later this year. To date, there are no approved drugs for the prevention or treatment of restenosis after angioplasty.
Boehringer Ingelheim (Ingelheim, Germany) is planning to enroll about 5,000 patients in the Telmisartan Randomized AssessmeNt Study (TRANSCEND) trial in aCE iNtolerant subjects with cardiovascular Disease, calling it the largest cardiovascular protection trial ever conducted in patients intolerant to angiotensin converting enzyme (ACE) inhibitors. The study, announced at the European Society of Hypertension meeting in Milan, Italy, will examine the effects of the angiotensin II receptor antagonist (ARB) Micardis (telmisartan) on this patient population. TRANSCEND twill parallel the objectives of the company's ONTARGET cardiovascular protection trial, initiated in May, investigating the role of an ARB in the prevention of stroke, myocardial infarction, hospitalization for congestive heart failure (CHF) and cardiovascular death. ONTARGET lead investigator Salim Yusuf, of Hamilton, Ontario, said the TRANSCEND study "examines the effects of an ARB in a much-neglected group: individuals who cannot tolerate an ACE inhibitor." The double-blind, parallel-group TRANSCEND study is expected to last about 5 years. The study's primary objective is the comparison of treatments with respect to the composite endpoint of cardiovascular mortality, stroke, acute myocardial infarction and hospitalization for CHF.
CardioVention (Santa Clara, California) has developed a new, compact heart-lung bypass system which surgeons report has been safe and effective in reducing the blood trauma and morbidity often associated with conventional heart-lung machines. In a feasibility study for the system's manufacturer, Valavanur Subramanian, MD, chairman of the department of surgery at Lenox Hill Hospital (New York); Jose Navia, MD, chief surgeon at Hospital Austral (Buenos Aires, Argentina); and a medical team from the Cleveland Clinic Foundation (Cleveland, Ohio) tested the CORx System in seven patients who each underwent a coronary artery bypass procedure. Initial results showed that, compared to the blood circuitry of larger heart-lung bypass machines, the small unit – slightly larger than a soda can – functions with one-10th the amount of surface area exposed to blood and with minimal to no priming volume required for activating the system. The effect of priming, known as hemodilution, thins the patient's blood, reduces its oxygen carrying capacity and compromises other body functions. By reducing hemodilution and the surface area exposed to blood, the company thinks that the new system may play a critical role in minimizing platelet loss, blood damage, blood transfusions and systemic inflammation. "This is the first major advance in heart-lung bypass technology in more than 20 years," Subramanian said. "While the data is still under evaluation, the system functioned remarkably well in oxygenating blood, removing carbon dioxide, providing adequate circulation and taking over the heart and lungs during bypass surgery. Because the system maintained excellent hemodynamics, it should enable better heart access in beating-heart procedures." For use in both traditional stopped-heart and beating-heart surgery, and for valve replacement and repair procedures, the CORx System was designed to avoid many of the harmful effects of current heart-lung bypass technology. Because it is so small, the system's fluid circuitry minimizes foreign surface contact, while providing optimal oxygen and carbon dioxide transfer and maximum micro-air filtration.
Centocor (Malvern, Pennsylvania) had its product, ReoPro, evaluated in two studies, TARGET and ADMIRAL, that were published in the New England Journal of Medicine. The studies show that ReoPro – a GPIIb/IIIa receptor blocker – plus a stent reduces the chance of having a heart attack or the need for emergency revascularization in two different patient types. The TARGET study showed ReoPro was superior to tirofiban in a range of patients undergoing scheduled stenting procedures. In the ADMIRAL study, patients receiving ReoPro showed a nearly 53 percent relative risk reduction in the composite endpoint of death, second heart attacks and emergency revascularization out to six months, compared to placebo.
Corvas International (San Diego, California) completed the planned enrollment for the multi-center Phase IIa safety trial of its injectable anticoagulant, recombinant Nematode Anticoagulant Protein c2 (rNAPc2), in patients undergoing elective percutaneous transluminal coronary angioplasty. The company said final results will be available later this year.
CryoCor (San Diego, California), a spin-off from CryoGen, has announced launch of a new trial of its Cardiac CryoAblation System to treat atrial fibrillation. The system employs a catheter to deliver cryogenic energy to specific areas of the heart in order to correct arrhythmias. The therapy employs temperatures of minus 80 degrees Celsius or lower, delivered to the cells implicated in the arrhythmia. Besides pursuing the CE mark, CryoCor said it is on track to file for an investigational device exemption with the FDA for U.S. clearance and expects to launch its U.S. trials in late August or early September. Because of trial and follow-up timelines, approval isn't expected until late 2003, the company said.
Jomed (Beringen, Switzerland) said it is starting a U.S. multicenter clinical study of its treatment for coronary saphenous vein grafts. The study will use the Jostent Coronary Stent Graft to treat patients with deteriorated vein grafts. Jomed said it expects to finish the BARRICADE trial and submit findings to the FDA for premarket approval in 2002. The FDA granted humanitarian device exemption for the Jostent in January for use in treating acute coronary artery perforation. Jomed develops products for minimally invasive vascular intervention.
The Medicines Co. (Cambridge, Massachusetts) disclosed results from the first part of its REPLACE program, a Phase IIIb/IV randomized trial evaluating Angiomax (bivalirudin) in patients undergoing angioplasty. Part one, which compared Angiomax to heparin using GP IIb/IIIa inhibitors according to institutional practice in 1,056 patients, showed patients randomized to Angiomax experienced fewer complications such as death, myocardial infarction, revascularization or clinically significant bleeding. The company also disclosed that part two of the REPLACE study will be blinded and will enroll at least 6,000 patients in the U.S., Canada, Western Europe and Israel. Part two is expected to reach completion in 2002.
Medtronic (Minneapolis, Minnesota) released its Starfish Heart Positioner in the U.S., adding to its suite of products for facilitating beating heart bypass surgery. Available for immediate shipment, the Starfish will be paired with the Octopus3 Tissue Stabilizer to form the new Octopus System. According to the American Heart Association, more than 500,000 coronary artery bypass surgeries are performed in the U.S each year, and more than 20% are being performed on a beating heart rather than a stopped heart, which is supported by the heart-lung machine. The Starfish is designed to address challenges a cardiac surgeon may face while performing beating heart bypass surgery. One major challenge the product was designed to address is preserving the natural hemodynamic function of the heart as it is positioned for bypass grafting by creating a large, still and clear working space where the bypass grafts can be sewn precisely into place. The Starfish, along with the Octopus3, is designed to improve access to all the heart's coronary arteries, including those on the back of the heart, and decrease the hemodynamic deterioration caused by the manipulation of a beating heart. The Starfish is a disposable, retractor-based device comprised of silicone suction appendages, an articulating arm and a mounting clamp. The silicone appendages conform to the surface of the heart and enable the surgeon to position the beating heart in such a way as to ensure access to the coronary arteries that need to be bypassed. In other product news, Medtronic said it received FDA clearance for a device-based therapy that reduces the debilitating symptoms of atrial fibrillation. The treatment is delivered by a system that includes the Medtronic GEM III AT implantable cardioverter defibrillator (ICD) and the InCheck AT Patient Assistant. The InCheck AT Patient Assistant is a hand-held device that tells patients when their heart is experiencing atrial fibrillation and they can then use the device to initiate atrial therapy, outside of the physician's office or clinic. When used with the InCheck AT Patient Assistant device, the system helps patients restore sinus rhythm at the touch of a button, allowing them to resume the activities of daily life, according to the company. Medtronic also received FDA clearance to market its PercuSurge GuardWire Plus Temporary Occlusion and Aspiration System. Available outside the U.S. since 1999, the GuardWire Plus system is the first distal protection system available in the U.S. and is indicated for use in diseased saphenous vein grafts, according to Medtronic. The GuardWire Plus system is introduced at the start of an interventional procedure and replaces the standard angioplasty guidewire during the entire procedure. The lesion is first crossed with the GuardWire Plus, which has a balloon at its distal tip that is inflated to occlude the vessel and provide distal protection. Interventional cardiologists then use the GuardWire Plus to advance an angioplasty balloon and/or a stent to the treatment site. Embolic particles that are generated during the angioplasty or stent procedure remain suspended in the occluded vessel. Upon completion of the procedure, the Export Aspiration Catheter is advanced, and the atherosclerotic particles are aspirated.
Novoste (Norcross, Georgia) reported receiving FDA clearance for a longer version of its source train used in its system for treating in-stent restenosis. The agency has approved a 40-mm radiation source train after earlier receiving approval for a 30-mm version of its coronary radiation therapy device last November. Both devices are indicated for use in patients with blockages inside previously placed coronary stents. Approval of the 40-mm device was based on results of the START 40 Trial, presented last November at the American Heart Association meeting. The purpose of this trial was to evaluate the safety and effectiveness of the Beta-Cath System with a wider therapeutic margin relative to the coronary intervention than the margins evaluated in the original START (Stents And Radiation Therapy) Trial, in which a 30-mm radiation source was used.
Pfizer (New York) released results of a new study of its calcium channel blocker Norvasc (amlodipine besylate) for treating high blood pressure in patients with diabetes and severe renal disease. In the Irbesartan in Diabetic Nephropathy Trial (IDNT), initiated by the Collaborative Study Group, 1,715 patients received either a placebo, an angiotensin II receptor blocker (ARB), Avapro (irbesartan) or Norvasc. Patients also received additional medications – except other ARBs or angiotensin converting enzyme inhibitors (ACE-Is) – to further reduce blood pressure to goal if necessary. The patients assigned to the placebo group were mainly treated with diuretics and beta-blockers. "These new data dispel the notion that in diabetic patients with high blood pressure, calcium channel blockers like Norvasc might not be as effective as diuretics, beta-blockers or ARBs in preventing the cardiovascular complications of hypertension," said Murray Epstein, MD, professor of medicine, renal division, University of Miami School of Medicine (Miami, Florida). The study's primary objective was to determine the effects of these treatments on the progression of renal disease. Irbesartan was shown to slow the progression of renal disease. The effects of treatment on cardiovascular complications such as heart attacks and stroke also were examined, as diabetics are two to four times more likely to have heart disease or suffer from stroke than non-diabetics. "Therapy with multiple medications is indispensable to bring blood pressure to goal in the vast majority of these difficult-to-treat patients. The IDNT results clearly support the use of Norvasc to reach these goals," said Dr. Hubert Pouleur, senior medical director in Pfizer's cardiovascular group. "ARBs or ACE-Is alone rarely bring blood pressure down to levels recommended in these patients, and often we have to use two or even three drugs to reach goal levels." In the study, which was sponsored by Bristol-Myers Squibb/Sanofi, Norvasc was shown to be effective in helping to lower blood pressure in renal patients, the company reported. Cardiovascular complications of high blood pressure such as death, heart attack, stroke, congestive heart failure and amputation were similar in patients taking Norvasc (23%), irbesartan (24%) or traditional medications (25%) such as beta-blockers or diuretics. ARBs and ACE-Is share some mechanisms of action, and many clinical investigators believe both ACE-Is and ARBs provide direct vascular and cardiac protection.
Somanetics (Troy, Michigan) released results of a 56-patient study performed at the University of Louisville Health Science Center (Louisville, Kentucky) that demonstrated that brain blood oxygenation, as monitored by the company's Invos Cerebral Oximeter, may decline during cardiopulmonary bypass surgery, even when blood pressure is considered to be adequate. In one-third of the cases, brain blood oxygenation declined despite an apparently adequate blood pressure (mean arterial pressure above 70 mm Hg), the company reported. Invos is the only noninvasive and continuous monitor of changes in regional oxygen saturation of a patient's blood in the brain commercially available in the U.S. The results of an earlier 306-patient study performed at Hackensack University Medical Center (Hackensack, New Jersey) demonstrated that using Invos to guide the management of brain blood oxygen saturation during cardiac surgery decreased neurological injuries by 55%. Renal failure, which can be a significant and costly complication of cardiac surgery, decreased by 45% and overall hospital length of stay of monitored patients was reduced by 1.37 days.
St. Jude Medical (St. Paul, Minnesota) began the first U.S. implants of its Symmetry Bypass System Aortic Connector, a sutureless anastomosis device for coronary artery bypass grafting (CABG) surgery. The system was developed by the St. Jude Medical cardiac surgery division's anastomotic technology group. Two procedures were performed at the Mayo Clinic (Rochester, Minnesota) on May 24, following FDA 510(k) clearance to commercially market the Aortic Connector. Kenton Zehr, MD, assistant professor of cardiac surgery at Mayo, performed the first procedures and subsequently completed three more using both on-pump and off-pump techniques. This device is the first in a line of mechanical connectors and delivery systems St. Jude is developing for the CABG market. The second product in the Symmetry Bypass System, the Coronary Connector, was first implanted in November 2000 and is currently in clinical evaluation outside the U.S.
Thoratec (Pleasanton, California) received FDA approval to market its TLC-II Portable VAD Driver in the U.S. The TLC-II is a small, lightweight device used to power the Thoratec Ventricular Assist Device (VAD), which pumps blood to the body in heart failure patients awaiting transplants or recovering from open-heart surgery. More than 30 patients were enrolled in this clinical trial at six leading transplant centers in the U.S. Thoratec develops medical devices for circulatory support and vascular graft applications.
Vascular Architects (San Jose, California) said it has received FDA 510(k) clearance to market its aSpire Covered Stent and Controlled Expansion Delivery System in the U.S. for treating tracheobronchial strictures. The company had recently received CE mark approval to market the device in Europe for treating peripheral vascular disease. The stent is a spiral nitinol stent covered by a thin layer of ePTFE, which is designed to provide greater lumen wall coverage than metallic stents. The stent is available in lengths of 2.5 cm, 5.0 cm and 10 cm and diameters from 6 mm to 14 mm. The stent is delivered using the company's Controlled Expansion delivery system. The stent and its delivery system are currently being clinically evaluated in the U.S. under two separately approved investigational device exemptions for the treatment of iliac and superficial femoral artery occlusions, and of dysfunctional arterio-venous access grafts. Vascular Architects makes devices for treating peripheral vascular disease and nonvascular obstructions.
World Heart (Ottawa, Ontario) reported last month that its Novacor left ventricular assist device (LVAS) was used in the first implantable heart-assist device implant procedure in central Eastern Europe. The operation took place at the Institute for Cardiovascular Diseases of Fundeni Hospital (Bucharest, Romania). The Novacor LVAS is an implantable, pulsatile pump that assumes most of the heart's pumping function, responding to the demands of the recipient's physiological state, the company said. The system was approved for sale in Europe in 1994.