CDU

Cardiovascular therapies often require patients to make very tough choices.

In the category of heart valve replacement, the choice is critical and anxiety-producing:

• a mechanical valve – which can last as long as the person, but comes with, for some, a slight but irritating clicking noise – and the need for a life-long regimen of anticoagulant drugs;

• or a tissue valve – which usually requires only an early anticoagulant regimen, but may need replacement after 15 or 20 years, and perhaps at a time in life which offers extreme surgical risk.

Currently, this market battle is being won by tissue valves, with about two-thirds of valve replacements in the U.S. using the tissue product, and trailing only slightly behind mechanical valve replacements in Europe with about 47% of the market.

The key decider in this debate is probably the avoidance of life-long anticoagulation therapy required by the mechanical products and the potential adverse effects, the worst being bleeding.

Now, mechanical valve manufacturer Medical Carbon Research Institute (MCRI; Austin, Texas), is attempting to tip back the balance with a new study that it hopes will show its On-X Prosthethic Heart Valve will enable a significantly reduced amount of anticoagulation drug therapy. Recently MCRI reported FDA approval of the Reduced Anticoagulation Clinical Trial of the On-X Prosthetic Heart Valve trial and internal review board okay.

Clyde Baker, president of MCRI, told Cardiovascular Device Update that pursuit of this kind of study is a “natural progression” for use of the On-X, based on 10 years of implant experience since its early-90s approval, the data from these uses and a variety of usage circumstances, including “confirmatory” trials.

The company reports more than 40,000 On-X valves implanted since 1996.

Baker acknowledges that demonstration of the need for lowered drug use will give the company some marketing heft for the valve – and he puts sector share for the On-X at about 5% in the U.S., about 10% worldwide – but that more than marketing is involved.

“It eliminates the fear that patients have of having to have a reoperation [for a new tissue valve] perhaps at 80 years old. They can make a decision for a valve that will last for the rest of their life with a low risk of bleeding” and a lowered rate of thrombosis.

The trial will enroll 1,200 patients, focusing on three groups of disease severity: low-risk aortic valve replacement patients, higher risk aortic valve replacement patients and mitral valve replacement patients. (Higher risk patients 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.

These ratios (a 1.0 ratio being that of essentially normal anticoagulation, according to Baker) compare to current standards of postoperative anticoagulation therapy with warfarin at 2.5 to 3.5 valve replacement patients. The current standards will be followed for three months postoperatively and then reduced, with the patients self-monitoring their anticoagulation levels.

The investigation will be led by John Puskas, MD, associate chief, Division of Cardiothoracic Surgery at Emory University School of Medicine (Atlanta) and will require follow-on evaluation over five years,

“This is the first FDA trial to explore lower anticoagulation with mechanical heart valves,” said 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.”

The relevant features cited by the company enabling this include the use of medical-grade carbon, branded as On-X Carbon, which MCRI says provides a more “thrombo-resistant” surface, plus design features which it says allows the On-X “to treat blood more like a natural valve.” Specifically, it says these features reduce the turbulence and blood damage that may lead to clots.

While the On-X was designed to be a “blood-friendlier” valve, Baker says that what was required to push forward into the reduced-drug study was the accumulation of long-term data indicating that this path would work.

He points, for instance, to a non-randomized observational study over the past year by Cardiac Surgical Associates (Fort Myers, Florida) and the Tampa Bay Heart Institute (Tampa Bay, Florida) of On-X at the lower limits of drug regimen guidelines and employing home monitoring of anticoagulation.

The study has not reached significance, MCRI said, but according to Vinay Badhwar, MD, “The observed results . . . 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.”

Also in South Africa, 438 On-X valve patients have been followed for five years. The patients are documented to have varying amounts of anticoagulation. About 14% of On-X patients were categorized as “unsatisfactory” having anticoagulation below 1.5 INR. Another 29% had “no” or “unknown” anticoagulation, which was attributed to poor patient compliance to established protocols.

“The remarkable aspect of the study,” said the company in a statement, “is that among aortic, mitral and double-valve replacement patients, only one (0.2% per patient year) patient experienced thrombosis.

“The On-X valve may be the next step in the evolution of valve technology,” said Hillel Laks, MD, professor and chief of Cardiothoracic Surgery and director of the Heart, Lung and Heart-Lung Transplant Programs at UCLA School of Medicine. And he said that the 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.”

Sidney Levitsky, MD, Cheever Professor of Surgery at Harvard Medical School and director of Cardiothoracic Surgery for CARE Group (both Boston), is chair of the data safety monitoring committee for the trial. Levitsky said that if the study is successful, the On-X “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,’” terming this the “holy grail” of valve replacement.