On-X Valve Reduced Anticoagulation Clinical Trial

FDA approved an investigational device exemption clinical trial of the On-X Prosthetic Heart Valve

Successful completion of the clinical study could result in the On-X valve becoming the only mechanical heart valve approved for low-dose anticoagulation therapy.

AUSTIN, TX — January 13, 2006 — The U.S. Food and Drug Administration (FDA) has approved an investigational device exemption (IDE) clinical trial of the On-X Prosthetic Heart Valve at reduced anticoagulation levels following review and approval by clinical centers. Successful completion of the clinical study could result in the On-X valve becoming the only mechanical heart valve approved for low-dose anticoagulation therapy.

Based on existing clinical data and the submitted protocol, the FDA has determined that a clinical trial of the On-X valve with three specific patient groups at reduced anticoagulation levels is clinically reasonable. The patient groups include low-risk aortic valve replacement patients, higher risk aortic valve replacement patients and mitral valve replacement patients. Higher risk patients include those with heart rhythm problems, left ventricular dysfunction, previous thrombo-embolism and condition of hypercoagulability.

The low-risk aortic patient group will be maintained using non-warfarin anticoagulation medication of clopidogrel (Plavix®) and aspirin. Higher-risk aortic patients will be maintained using warfarin (Coumadin®) at reduced International Normalized Ratio (INR) levels of between 1.5 and 2.0, plus aspirin. The mitral valve replacement patients will be maintained with warfarin at a target INR of 2.0 to 2.5 and aspirin. The first three months for all patient groups include traditional warfarin anticoagulation protocols. To ensure that patients remain within target INR range, each patient will be required to self-monitor their anticoagulation levels. Results of this self-monitoring will be communicated to the patient’s physician.

The investigation will be led by John D. Puskas, M.D., associate chief, Division of Cardiothoracic Surgery at Emory University School of Medicine in Atlanta, Ga., and is expected to be complete after five years of follow-up. It will involve 20 centers and 1200 patients.

“This is the first FDA trial to explore lower anticoagulation with mechanical heart valves,” said Dr. Puskas. “The On-X valve has design and material features that make us hopeful that it may function well at lower levels of blood-thinning medications. If this trial proves what we believe it will, On-X valve recipients will be able to take a lower level of anticoagulant, which will reduce the potential incidence of bleeding complications caused by taking the higher dosages of Coumadin normally prescribed after receiving a mechanical heart valve.”

According to The American College of Cardiology and the American Heart Association’s “Guidelines for Management of Patients with Valvular Heart Disease,” the standard of care for three-months postoperative is anticoagulation therapy with warfarin at an INR of 2.5 to 3.5 for both mechanical and biologic (animal) tissue valve replacement patients. Recommendations for biologic valve patients three months postoperatively are 80 to 100 mg/day of aspirin. After three months, mechanical valve postoperative anticoagulation therapy advises the use of warfarin at INR levels of 2.0 to 3.0 for aortic valve replacement patients without risk and 2.5 to 3.5 for aortic valve patients with risk and mitral valve patients. Although warfarin has a long history of safe use, it has the potential side effect of bleeding.

“The “holy grail” for cardiac surgeons implanting heart valves has been ‘A Valve for Life’,” said Sidney Levitsky, M.D., Cheever Professor of Surgery at Harvard Medical School and director of Cardiothoracic Surgery for CARE Group, Boston, Mass., and chair of the Reduced Anticoagulation Clinical Trial of the On-X Prosthetic Heart Valve Data Safety Monitoring Committee. “To avoid clotting, presently accepted mechanical valve postoperative care mandates high levels of anticoagulation with warfarin, which is associated with bleeding problems varying from minor episodes of hematuria (blood in urine) and melena (blood in stool) to intracerebral hemorrhage. If the approved FDA reduced anticoagulation study is successful, the On-X valve will become the safe valve of choice for a new generation of patients who are expected to enjoy a long life, and we will finally approach the concept of ‘A Valve for Life’.”

“The On-X valve may be the next step in the evolution of valve technology,” said Hillel Laks, M.D., professor and chief of Cardiothoracic Surgery and director of the Heart, Lung and Heart-Lung Transplant Programs at UCLA School of Medicine. “This study is significant because of the larger numbers of older valve patients who are living longer. Traditionally, these patients would receive tissue valves to avoid the bleeding risk associated with taking higher levels of Coumadin. However, when tissue valve patients live into their 80s and 90s, they run the risk of having replacement surgery in eight to 16 years when the tissue valve wears out. This FDA study has the potential for changing our choices in heart valves in the future. If we can show that it is safe to use a mechanical valve with low levels of Coumadin or alternative drugs that are safe–or even no Coumadin–the choice in these borderline older patients will be completely different.”

“After decades of heart valve research and design, we have developed what could be the first prosthetic heart valve to combine the durability of a mechanical valve with the reduced complication rates of tissue valves,” said Jack Bokros, Ph.D., MCRI’s founder and chairman. “The approval to conduct this reduced anticoagulation study is further evidence that the On-X valve merits study under this protocol. The success of the study could provide proof that the On-X valve is truly a breakthrough medical advance in heart valve prosthetics, providing patients with the benefits of both mechanical and tissue valves: a valve that will last a lifetime without the potential complications of taking high dose anticoagulants.”

Clinical centers and patients are now being recruited for the On-X reduced anticoagulation study. The study is limited to 1,200 patients and 20 institutions. Interested parties should contact John Ely, Executive Vice President of Regulatory and Clinical Affairs for MCRI, at 888-339-8000 ext. 226 or ely@mcritx.com. Information and updates for this and other On-X Prosthetic Heart Valve studies are located at www.onxvalves.com or by contacting MCRI.

Until the completion and analysis of study data, MCRI continues to recommend standard anticoagulation therapy as presently prescribed by various professional societies for the On-X valve.

Other Non-Randomized Reduced Anticoagulation Trials in Progress
For the past year, a non-randomized observational study of On-X valve patients under standard labeling indications with an INR target range within–yet at the lower limits of–American College of Cardiology and American Heart Association guidelines, has been conducted by Cardiac Surgical Associates (CSA) and the Tampa Bay Heart Institute. The study employs home monitoring to aid control of the anticoagulant therapy. The study has not reached significance, but according to Vinay Badhwar, M.D., “the observed results of our non-randomized reduced anticoagulation trial with the On-X valve are extremely encouraging. The lack of bleeding complications and the combination of a durable prosthesis with manageable low INR anticoagulation is providing patients with significant lifestyle improvements.”

In South Africa, 438 On-X valve patients have been followed (95 percent) for five years. The patients are documented to have varying amounts of anticoagulation. Approximately 14 percent of On-X patients were categorized as having “unsatisfactory” or anticoagulation below 1.5 INR. Another 29 percent had “no” or “unknown” anticoagulation, which was attributed to poor patient compliance to established protocols. The remarkable aspect of the study is that among aortic, mitral and double valve replacement patients, only one (0.2 percent per patient year) patient experienced thrombosis.

More about the On-X Prosthetic Heart Valve
The On-X valve is the result of a breakthrough in medical grade carbon technology: On-X Carbon. In addition to providing a more thrombo-resistant surface, the pure On-X Carbon enabled MCRI to make significant valve design changes that resulted in a prosthetic that treats blood more like a natural valve. It is well documented that the On-X valve does not produce the turbulence and blood damage commonly produced by other mechanical heart valve prosthesis and therefore significantly reduces the potential for life-threatening blood clots.

First implanted in 1996, recent clinical evidence suggests that patients implanted with the On-X heart valve may be able to forego or reduce the dosages of anticoagulation therapy traditionally required by mechanical heart valve recipients.

The FDA approved the On-X aortic and mitral valves for commercial use in the United States on May 30, 2001, and March 6, 2002, respectively. More than 40,000 On-X valves have been implanted since 1996.

About Cardiovascular Disease and Heart Valve Replacement
Cardiovascular disease is the number one cause of death worldwide. The American Heart Association reports that 95,000 surgeries were performed in the United States to repair or replace malfunctioning or diseased heart valves in 2003. According to a June 2004 report issued by Millennium Research Group, life-threatening heart valve disease, including stenosis and regurgitation, affected approximately five million people in the United States in 2003. Millennium Research Group predicts the heart valve market will generate more than $650 million by 2008 due to advances in minimally invasive techniques, the increasing incidents of cardiovascular disease and the aging population.

About MCRI
Medical Carbon Research Institute (MCRI) develops heart valve replacements that significantly improve the quality of life for patients. Jack Bokros, Ph.D., and his associates founded MCRI in 1994 to advance prosthetic heart valve technology by capitalizing on their new form of pyrolytic carbon. The On-X valve design was awarded a 2002 Medical Device Excellence Award in the Implant and Tissue-Replacement Products category. MCRI also provides OEM services utilizing its patented On-X Carbon to manufacturers of other medical products, including orthopedic joint and spine implant devices. MCRI is headquartered in Austin, Texas, and maintains a wholly owned subsidiary, MCRI Deutschland GmbH, in Hannover, Germany.

On-X Life Technologies, Inc. (On-X LTI) was formerly Medical Carbon Research Institute (MCRI).

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