Low Warfarin and Carbon Valve Safe in High-Risk Patients

Reed Miller

April 15, 2011

April 13, 2011 (New Orleans, Louisiana) — Preliminary results from the high-risk arm of PROACT presented at the American College of Cardiology (ACC) 2011 Scientific Sessions show the all-carbon On-X valve (On-X Life Technologies, Austin, TX) is safe with lower levels of anticoagulant therapy than normally prescribed to patients with mechanical aortic valves [1].

Primary investigator Dr John Puskas (Emory University, Atlanta, GA) presented early results from the high-risk aortic-valve-replacement arm of PROACT, the only arm of the trial that is fully enrolled. As hypothesized, patients with an On-X valve treated with lower-than-standard doses of aspirin and warfarin after three months on a standard regimen had the same composite rate of thromboembolism and hemorrhage as On-X patients who stayed on the standard regimen throughout the follow-up.

All 185 patients in the high-risk arm received an On-X valve as a replacement for a defective aortic valve and were considered to have a high potential for thrombotic or bleeding events. All patients were maintained with standard anticoagulation therapy for the first three months after surgery and then randomized into the low-anticoagulant group or the control group. The low-anticoagulant group was switched to a daily dose of either 81 or 325 mg of aspirin plus warfarin to achieve an INR target of 1.5 to 2.0. Patients randomized to the control group continued with standard anticoagulation therapy--aspirin and warfarin to achieve an INR of 2.0 to 3.5 throughout the trial, the target set in the ACC/AHA guidelines for treatment of patients with a replacement aortic valve. The average follow-up so far is about 16 months, with a total of 247 patient-years of data collected. Eventually, the investigators expect to collect 6000 patient-years of data.

During the study period, five low-anticoagulant and four control patients died. The low-anticoagulant group had 2.5 bleeding events per patient-year, vs 4.4 per patient year in the control group, but the stroke rate was 1.3% per patient-year in the low-anticoagulant group vs 0.4% per patient-year in the control group. For the combined end point of stroke and thrombotic and bleeding events, the rates were 3.8% per patient-year in the low-anticoagulant group and 4.9% per patient-year in the control group.

Puskas said that the goal of the study is to convince the FDA to let On-X label the valve as safe with lower doses of anticoagulation, thereby providing the durability of a mechanical valve with doses of anticoagulant drugs closer to those given tissue-valve recipients. And "one day we may be able to offer a durable mechanical heart valve with no blood thinner in selected patients," he said.

The PROACT study, launched in 2006 at 40 centers, is also enrolling a lower-risk arm and a mitral-valve arm. The aortic-valve arm is comparing standard anticoagulant therapy with clopidogrel therapy in patients with the On-X aortic valve considered at relatively low risk for thrombotic or bleeding events. The mitral-valve arm is comparing anticoagulant therapy targeted to INRs of 2.0 to 2.5 vs standard anticoagulant therapy in patients with an On-X mitral valve.

The company expects to complete the trial by 2014.

Valve Material Reduces Clot Risk

Puskas explained that patients with an On-X valve, which has been on the US market for about 10 years, may be able to get by with lower doses of anticoagulant because of the unique all-carbon material and design of the device.

The On-X carbon material is a pure form of isotropic pyrolytic carbon created with a patented process that, unlike other carbon materials used for heart valves, does not require silicon alloying to ensure wear resistance. Earlier carbon valves were made out of carbon with about 8% silicon, because the technology did not exist to mill pure carbon thin enough to make a valve leaflet, Puskas explained. "When you polish pure carbon you can get an exceedingly smooth surface, to which platelets and blood don't really stick very much, but if you polish a silicon-carbon composite, the silicon over time tends to pit and leave very tiny irregularities in the surface."

The valve's "trumpet-mouth end" guides blood through with a laminar--instead of turbulent--flow at a lower pressure gradient than most mechanical valves, preventing damage to the blood. The laminar flow also allows the leaflets inside the cylinder to close more quickly and to open more completely than leaflets in most valve designs, Puskas said. Because the leaflets close faster, they regurgitate less blood back through the valve, and "as a result of that lesser leak, the designers of the valve are able to be luxurious about intentionally allowing some leakage around the hinge points of the leaflets, and it's those hinge points where clotting can occur and the valve can stick," Puskas said. "So by designing leaflets that intentionally leak a little bit around the hinges, but close so quickly that the overall leakage is much less than in the predecessor valves, you can have your cake and eat it too. You have a valve that leaks very little, but leaks where you want it to leak; it washes the hinges to prevent clots from forming there."

INR Monitoring at Home

Puskas told heartwire that he expects one of the "important contributions of PROACT will be to show the superiority of home INR monitoring" vs periodic monitoring at the physician's office. On-X has provided all of the patients in the study with home INR monitoring so that they can keep continuous track of their blood's ability to clot and adjust the anticoagulant therapy accordingly.

The Home INR Study (THINRS) found that weekly self-testing of INR levels did not significantly delay the time to a first stroke, major bleed, or death in patients on warfarin compared with monthly in-office testing with a higher-than-average level of clinical care, but home INR testing did help patients keep their INR within therapeutic range and improved patients' satisfaction with their anticoagulation therapy and quality of life.

Puskas said that there is already evidence that patients whose INR varies widely are more prone to complications than patients who can keep their INR more stable, and he expects that the trial will be able to show that patients are better able to maintain a level INR if they can monitor it on their own without visiting their doctor. He said the trial will collect over 100 000 data points on home INR testing.

Puskas has no financial relationship with On-X.