Low-Dose Anticoagulation Appears Safe, Effective With New-Generation Heart Valve

Nancy A Melville

May 07, 2013

MINNEAPOLIS, MN — A newer-generation bileaflet mechanical aortic valve used for valve replacement shows success in allowing patients to be safely and effectively managed with low doses of anticoagulant therapy, potentially sparing patients the need for aggressive warfarin anticoagulation that can increase the risk of bleeding[1]. Those are interim results from the Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) study of high-risk aortic-valve-replacement (AVR) patients at 36 centers around the country, presented here at American Association for Thoracic Surgery 2013 Annual Meeting .

In the trial, patients randomized to receive lower doses of warfarin were able to maintain safe international normalized ratio (INR) rates while showing significant reductions in the risk of bleeding and no increase in stroke risk, compared with those receiving standard warfarin doses.

"In terms of major, minor, or total bleeds, we saw a significant benefit in the test [low-dose] group compared with the control group, with highly significant p values," said lead author Dr John D Puskas (Emory University School of Medicine, Athens, GA).

"Looking at ischemic stroke, etc, there were no significant differences between the low-dose and standard-treatment groups, nor were there differences in mortality."

The interim results reflect assessment of 375 patients whose preoperative risk factors for thromboembolism (TE) required AVR and who met high-risk criteria including chronic atrial fibrillation, left ventricular ejection fraction <30%, ventricular aneurysm, an enlarged left atrium of >50 mm in diameter, and spontaneous echo contrast in the left atrium.

Lower-Dose Warfarin, Lower Target INR

The patients were randomized to receive either lower-dose warfarin (n=190; INR 1.5–2.0) or to continue standard-dose warfarin (INR 2.0–3.0), for three months following mechanical AVR with the On-X mechanical valve (On-X Life Technologies, Austin, TX) between September 2006 and December 2009.

All of the patients received 81-mg aspirin daily, and INR was adjusted according to home monitoring. Their mean age was 55.2, and 79% were male.

The patients' concomitant procedures included CABG (27%), aortic-aneurysm repair (14%), and other procedures (25%).

With an average follow-up of 3.42 years, the patients in the low-dose warfarin group had a mean INR of 1.89, compared with 2.50 in the standard-dose group (p<0.0001).

The low-dose group meanwhile had significantly lower major and minor bleeding event rates, and there were no significant differences between the two groups in terms of stroke, transient ischemic attack (TIA), or total neurological events. There were no significant differences in all-cause mortality between the low-dose and standard-dose groups.

"Tight INR control is very important to limit adverse events, and the findings suggest that patients with this aortic bileaflet mechanical valve may be safely managed in select patients with INR 1.5 to 2.0 with [reduced-dose warfarin and] aspirin 81 mg per day," Puskas said.

Older-generation mechanical heart valves have been associated with long durability, but with the need for more aggressive anticoagulation therapy. Biological valves offer an alternative of not requiring long anticoagulation but have a shorter longevity, of about 10 to 20 years.

The Good Without the Bad

Dr A Pieter Kappetein (Erasmus University Medical Center, Rotterdam, the Netherlands) noted that the study had several limitations, including a relatively small size and the trial design.

"The difficulty with this type of study design is choosing the right noninferiority margin, the so-called delta," he said. "Because there are no meaningful data comparing warfarin with placebo with prosthetic valves, there is no ability to construct traditional noninferiority boundaries.

"Furthermore, when you lower the anticoagulation treatment, you will always lower the bleeding events, [there is] no doubt about this, while valve thrombosis and thromboembolic events may increase," he added.

"However, you cannot put two events in a composite end point of a noninferiority trial if they do not point in the same direction. It may well be that bleeding events will decrease more than thromboembolic events will increase."

Puskas responded that "the thrombotic events and hemorrhagic events are indeed not moving in the same direction, and this is what we would expect. What we're really looking for is to determine a sweet spot where those two curves intersect.

"I don't have a financial interest in the [On-X] company, but I can say I am impressed with the design of the valve, from an engineering and materials point of view, and this study is really to see if this design will move those curves in a direction that is more attractive to patients."

Puskas and Emory University have a research agreement for the PROACT trial with On-X Life Technologies. Puskas and Emory have no other financial relationship with On-X Life Technologies. Kappetein has no conflicts of interest.


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