Low-dose warfarin plus aspirin was associated with significantly less bleeding without significantly increasing thromboembolic events compared with standard-dose warfarin in patients who underwent aortic valve replacement with the On-X (On-X Life Technologies) mechanical valve in the PROACT study.
The researchers also found a higher rate of thromboembolic events with dual antiplatelet therapy (aspirin plus clopidogrel) compared with aspirin plus standard-dose warfarin.
The final results of the PROACT study were published in the June 19 issue of the Journal of the American College of Cardiology.
"This trial has been more than 10 years in the making," lead author, John D. Puskas, MD, Department of Cardiovascular Surgery, Mount Sinai St Luke's, New York City, told Medscape Medical News. "The goal was to explore if this particular mechanical valve can be used safely with reduced doses of anticoagulation, and results show that yes, it can."
"Our results are a great advance for mechanical valves," he added. "Patients needing a valve replacement can now receive the On-X mechanical valve with lower doses of anticoagulants and consequently lower bleeding risks."
Puskas noted that a shift is occurring away from mechanical valves toward biological valves to avoid the risks for thromboembolism linked to mechanical valves and the bleeding risks associated with anticoagulation.
"The new catheter-based approaches can only use biological valves as they have to be rolled tightly to fit into the catheter and mechanical valves are not flexible enough," he said. "However, mechanical valves can last a lifetime whereas a biologic valve needs to be replaced every 10 to 15 years. So in my view, for a young patient it is worth having full surgery one time only, but mechanical valves still require long-term anticoagulation to avoid thromboembolism, and this carries a bleeding risk."
For the current study, Puskas and colleagues wanted to investigate less aggressive antithrombotic strategies with one particular mechanical valve, the On-X valve, which is believed to be less thrombogenic than other mechanical valves.
"Unlike other mechanical valves, the On-X valve is made from pure carbon and contains no silicone, which results in a smoother, less thrombogenic surface," Puskas explained. "Also its flared cylindrical shape leads to more laminar blood flow and reduced turbulence, again contributing to lower thrombogenicity."
The PROACT study tested two different antithrombotic regimens in two different populations of patients undergoing aortic valve replacement: 201 patients without thromboembolic risk factors were randomly assigned to receive dual antiplatelet therapy or standard warfarin plus aspirin, and 375 patients with one or more thromboembolic risk factors were also randomly assigned to lower-intensity warfarin plus aspirin (target international normalized ratio [INR], 1.5 to 2.0) or standard warfarin plus aspirin (INR, 2.0 to 3.0).
"We didn't feel it was appropriate to randomize higher-risk patients — those with a measurable risk of clotting — to antiplatelet therapy without anticoagulation, so we divided the population into two risk groups," he said.
Randomized treatment did not start until 3 months after valve replacement, and all patients received standard-dose warfarin plus aspirin for the first 90 days.
"The On-X valve has a cuff that is thrombogenic and needs to be endothelialized, so for the first 90 days while endothelialization was taking place, we felt full-dose anticoagulation was required," Puskas said.
The low-risk arm was terminated because of excess cerebral thromboembolic events (3.12% per patient-year vs 0.29% per patient-year) in the dual antiplatelet group at up to 8.8-year follow-up, with no differences in bleeding or all-cause mortality.
"Our results show that dual antiplatelet therapy is not appropriate for patients with mechanical heart valves," Puskas said. "Initially patients seemed to be doing well on aspirin plus clopidogrel, but later on there was a string of thromboembolic events."
He suggested that this may have been due to the development of clopidogrel resistance. "While all patients included had good clopidogrel responsiveness at the start of the trial, we retested patients later in the trial and found that some had developed nonresponsiveness to clopidogrel."
However, results were better in the high-risk group; those receiving lower-intensity warfarin had significantly lower rates of major bleeding (1.59% vs 3.94% per patient-year; P = .002) and minor bleeding (1.27% vs 3.49% per patient-year, P = .002) up to 8.7-year follow-up, with no significant differences in thromboembolism (0.42% vs 0.09% per patient-year, P = .20).
"When plotting bleeding risk and thrombotic events versus INR there seems to be a sweet spot at an INR level of 1.5 to 2.0," he said. "That is the level we were aiming at in the low-dose warfarin group based on previous indirect evidence, and that is indeed the level that showed the optimum bleeding/thrombotic risk."
On the basis of earlier results of this study, the use of this lower anticoagulation level with the On-X valve (after 90 days of full-dose warfarin) has been approved in the United States and Europe.
This is the only valve to have approval for this low dose of anticoagulation. "All mechanical heart valves are different — each has a subtle different thrombogenic character, so I think it would difficult to be able to extrapolate these results to other valves," he said.
The results with low-dose anticoagulation have, however, been extrapolated to low-risk patients with On-X valves. "I think we can assume that if high-risk patients are better taking lower doses of anticoagulation, then lower-risk patients will be too," Puskas said.
PROACT-2 is now being planned to test one of the new oral anticoagulants in this setting.
In an accompanying editorial, Richard P. Whitlock, MD, and John W. Eikelboom, MD, Population Health Research Institute, Hamilton, Ontario, Canada, and Deepak L. Bhatt, MD, Brigham and Women's Heart & Vascular Center, Boston, Massachusetts, note that while the PROACT trial met its prespecified noninferiority outcome, "it is not possible to conclude that the combination of reduced-intensity warfarin and aspirin is entirely noninferior to the combination of standard-intensity warfarin and aspirin," as this would have required a much larger study.
They conclude that: "Given the importance of bleeding in predicting adverse outcomes, patients who are treated with lower-intensity warfarin after receiving an On-X mechanical valve would be expected to gain substantial benefit from a treatment that reduces bleeding without compromising efficacy."
They point out that another trial — LOWERING-IT — has also suggested better results with lower-intensity warfarin in patients undergoing bileaflet mechanical aortic valve replacement, and these two trials together "should stimulate further high-quality research evaluating optimal warfarin intensity in all types of contemporary mechanical bileaflet valves."
The PROACT study was funded by On-X Life Technologies, manufacturer of the On-X valve, and was conducted under an investigational device exemption provided by the US Food and Drug Administration. An academic steering committee designed the trial and was responsible for oversight of study conduct and reporting of all results and takes responsibility for the accuracy and completeness of the data analyses. Paskas has disclosed no relevant financial relationships, although one of the coauthors is an advisor for On-X and another was an employee of On-X. Disclosures for the editorialists are available with the published editorial.
J Am Coll Cardiol. Published June 19, 2018. Abstract, Editorial
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Cite this: Reduced-Intensity Warfarin Safe With On-X Heart Valve - Medscape - Jun 21, 2018.