Burden of Anticoagulation Can Be Reduced in Some Patients With Mechanical Valves

DAPT failed for low-risk patients, but low-dose warfarin led to less bleeding with no increase in thromboembolic events in high-risk patients.

Burden of Anticoagulation Can Be Reduced in Some Patients With Mechanical Valves

Patients at high risk for thromboembolism who undergo aortic valve replacement with a mechanical valve can safely take less than the standard dose of warfarin after 3 months, according to results of the PROACT trial. The study also evaluated whether dual antiplatelet therapy (DAPT) is effective for those at low risk of thromboembolism, but ultimately found that warfarin is still needed in these patients.

“The fundamental importance of this trial is that it changes the calculus of risk and benefit for mechanical valves,” said the study’s lead author John D. Puskas, MD (Icahn School of Medicine at Mount Sinai, New York, NY).

High-risk patients in PROACT who were managed on warfarin with an INR of 1.5 to 2.0 plus 81 mg of aspirin had fewer major and minor bleeding events than those treated with standard warfarin with a target INR of 2.0 to 3.0 plus 81 mg aspirin. Rates of stroke, TIA, all thromboembolism, and all-cause mortality were similar between groups.

In an interview with TCTMD, Puskas said mechanical valve replacement with low-dose warfarin should be weighed as a gold standard against TAVR, valve-in-valve, and multiple biological valve strategies in younger patients.

“I think the whole field has discounted mechanical valves as an ‘old’ thing that we don’t do anymore, and I think in some ways we’ve thrown the baby out with the bathwater,” he observed. “If you’re 65 or 70, getting a TAVR and then planning on another TAVR when you’re 85 makes sense. But, if you’re 45 or 50, the patient is better off with a mechanical aortic valve. It’s better than any other therapy today.”

The study was published online ahead of the June 19, 2018, issue of the Journal of the American College of Cardiology.

DAPT Fails, Low-Dose Warfarin Reassures

In the multicenter PROACT trial, 576 patients at low or high risk for thromboembolism underwent AVR with the On-X valve (On-X Life Technologies, Austin, TX). All received conventional anticoagulation with standard warfarin (target INR 2.0 to 3.0) and 81 mg aspirin daily for the first 3 months. Thereafter, the low-risk cohort (n = 201 patients) was randomized to DAPT with clopidogrel (loading dose 300 mg, followed by 75 mg/day) plus aspirin 325 mg/day or to standard warfarin (target INR 2.0 to 3.0) plus 81 mg aspirin per day. The high-risk arm was also randomized at the 3-month mark, either to reduced-intensity warfarin (target INR 1.5 to 2.0) plus 81 mg aspirin or to standard warfarin and aspirin.

To TCTMD, Puskas said while the low-risk cohort seemed to do well in the first few years of follow-up, a signal of increased thromboembolic events led to the termination of the DAPT arm; those patients were advised to switch to standard warfarin. Cerebral thromboembolic events occurred at a rate of 3.12% per patient-year in the DAPT arm vs 0.29% per patient-year in the standard warfarin and aspirin arm (P = 0.02) after 8.8 years of follow up. Blood tests of DAPT patients showed that more than one-quarter were no longer responsive to clopidogrel, Puskas noted.

“I would attribute the failure of the low-risk arm of the trial to the development of unresponsiveness in a portion of those dual antiplatelet therapy patients,” he added. “When we told all of those patients that they had to start taking Coumadin, many of them refused.” Puskas said a number of those patients chose to stay on the DAPT and aspirin regimen against medical advice.

Hype and Hope

“There was a lot of hype and excitement around the potential for DAPT for valve-related anticoagulation, but clearly we are not at that stage yet in terms of mechanical valve technology,” said Munir Boodhwani, MD, MSc (University of Ottawa Heart Institute, Canada), who commented on the findings for TCTMD. He added that studies of non-vitamin K antagonists (NOACs) as anticoagulation for valve patients have also shown an excess of thromboembolic events, suggesting that warfarin “still is required as the anticoagulant of choice for mechanical aortic valves.”

In the high-risk PROACT patients randomized to reduced-intensity or standard warfarin, there were no differences in the composite primary endpoint of major or minor bleeding, thromboembolic events, and valve thrombosis events. However, major, minor, and total bleeding were less frequent in the reduced-intensity group. Among the secondary endpoints, rates of prosthetic endocarditis and valve reoperation also were similar between groups.

At 5 years, total bleeding events favored the low-dose warfarin strategy over the standard-dose strategy (P < 0.001).

An Option, But With Caveats

The interim report from the PROACT trial resulted in the 2017 American Heart Association/American College of Cardiology guidelines’ conclusion that a lower INR target of 1.5 to 2.0 should be considered for patients with an On-X bileaflet mechanical aortic valve and no additional thromboembolism risks.

To TCTMD, Puskas said mechanical valves are much more durable than biological valves, and with the need for less warfarin, provide the best solution for younger patients, particularly young women of childbearing age. He cautioned, however, that standard-dose warfarin must be used for the first 3 months after valve implantation, until the relatively porous part of the valve becomes incorporated into the heart, and then the switch to the lower dose can take place.

But Boodhwani said clinicians need to keep in mind the full spectrum of options available for young patients with aortic valve disease.

“For young patients who are active, who don’t want the burden of anticoagulation, aortic valve repair and Ross procedure are important options to consider,” he noted.

One integral part of the PROACT trial was that patients were required to do home INR monitoring. Overall, compliance with monitoring was high.

“You need a certain level of motivation and a certain level of knowledge and understanding to be able to undertake a home-monitoring program,” Boodhwani cautioned. “These things need to be taken into consideration when we translate these findings to the general population because there are a subset of people who may not be able to manage their own anticoagulation, and others who can’t afford it.” The home INR monitoring was provided free of charge to study participants.

Extrapolating to Modern Mechanical Valves

Puskas and colleagues say their results are specific to On-X valves, which are thought to be less thrombogenic than conventional mechanical valves because they do not contain silicone and are engineered to create low gradients that are maintained over decades.

But editorialists led by Richard P. Whitlock, MD, PhD (Population Health Research Institute, Hamilton, Canada), say the results support the suggestion that giving less intense anticoagulation than is currently recommended may also apply to newer-generation bileaflet mechanical valves.

They add that another trial, LOWERING-IT, reached the same conclusion about the feasibility of reduced-intensity warfarin in patients who received the titanium LivaNova Bicarbon Aortic Valve (LivaNova; Mirandola, Italy).

“Taken together with the results of the LOWERING-IT trial, these data should stimulate further high-quality research evaluating optimal warfarin intensity in all types of contemporary mechanical bileaflet valves,” Whitlock et al write.

  • The study was funded by On-X Life Technologies, and was conducted under an investigational device exemption from the US Food and Drug Administration.
  • Puskas and Boodhwani report no relevant conflicts of interest.
  • Whitlock reports receiving consulting fees and speaking honoraria from Armetheon, Boehringer Ingelheim, and Novartis.