PROTECT-AF: Device closure of LAA may provide alternative to warfarin to prevent stroke in AF

Susan Jeffrey

March 28, 2009

Orlando, FL - Device closure of the left atrial appendage (LAA) may provide an alternative to warfarin therapy as a stroke prevention strategy in patients with nonvalvular atrial fibrillation.

Dr David R Holmes Jr

Results of the Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) showed that in AF patients who were candidates for warfarin therapy, device closure of the LAA using the Watchman device (Atritech, Plymouth, MN) was associated with a reduction in hemorrhagic stroke risk vs warfarin, and all-cause stroke and all-cause mortality outcomes were noninferior to warfarin.

Safety events, particularly pericardial effusion, were more common in the device group, but these have decreased over time with procedural modifications and enhanced training, the researchers noted.

Of the patients receiving the device, 87% were able to stop warfarin therapy. "And so, it's an alternative to warfarin therapy to occlude the left atrial appendage," principal investigator Dr David R Holmes Jr (Mayo Graduate School of Medicine, Rochester, MN) concluded.

The results were presented here during the i2 Summit at the American College of Cardiology 2009 Scientific Session s. The trial was funded by Atritech.

Thrombus accumulation

Watchman LAA system (Source: Atritech)

Atrial fibrillation is the most common cardiac arrhythmia, affecting more than three million people in the US, a number expected to climb to 16 million by 2050, Holmes said. Patients with AF have about a fivefold increased risk for stroke, mostly thromboembolic events. About 90% of the thrombus accumulation that is the source of thromboembolism occurs in the left atrial appendage.

Warfarin has been the "cornerstone" of medical therapy for these patients but is difficult to maintain within the therapeutic range and requires frequent monitoring and dose adjustments, he said. It is estimated that only 50% of those patients eligible for treatment are receiving warfarin, because of compliance or tolerance issues.

The Watchman occluder used in this trial is one of several devices being developed for occlusion of the LAA as an alternative to warfarin treatment for these patients. The occluder is placed distal to the ostium of the LAA to occlude flow and prevent the migration of thrombus forming in the appendage.

The PROTECT-AF study was a prospective randomized trial comparing closure of the LAA with long-term warfarin therapy. In the study, 800 patients from 59 enrolling centers in the US and Europe were randomized in a device-to-control ratio of 2:1.

Patients were followed with transesophageal echo at 45 days, six months, and one year, were seen for clinical follow-up biannually up to five years, and had regular INR monitoring while on warfarin. The researchers used a Bayesian sequential design, accruing patient-years of follow-up with a first analysis done at 600 patient-years and every 150 patient-years thereafter. Enrollment also is continuing in a continued access registry, he noted.

Patients included were those with documented nonvalvular atrial fibrillation who could take long-term warfarin, but they could have not have any indication that would require warfarin. CHADS2 scores had to be >1; 65% of patients in the trial ultimately were CHADS 1 or 2, relatively low risk, but all had been referred because their physician had recommended they go on warfarin treatment, Holmes noted.

After randomization, patients either began treatment with warfarin or underwent device implantation. Device patients also were treated with warfarin until day 45, to allow endothelialization; thereafter, warfarin was discontinued.

Some 87% of patients receiving the device were able to discontinue warfarin at day 45. Reasons for continuing warfarin after that point included observation of flow in the LAA in 30 patients and physician order in 13. "Some of the doctors just felt a little uneasy about it, and there were some patients who developed other problems during that time," such as deep venous thrombosis requiring warfarin, Holmes said during the discussion after his presentation. By month 12, 93% were off warfarin permanently.

The primary safety end point included device embolization requiring retrieval, pericardial effusion requiring intervention, and cranial, gastrointestinal, or any other significant bleed.

"Patients in the Watchman group didn't do as well from the standpoint of primary safety," Holmes said; there was a twofold increase in safety events in the device group, the majority of which were pericardial effusion.

PROTECT-AF: Primary safety results

End point Device >events, n Device rate (95% CI) Control events, n Control rate (95% CI) Relative risk (95% CI)
Primary safety results (900 patient-year cohort) 48 8.7 (6.4-11.3) 13 4.2 (2.2-6.7) 2.08 (1.18-4.13)

The primary efficacy end point included all strokes, including ischemic and hemorrhagic, cardiovascular or unexplained death, and systemic embolization.

Results on primary efficacy were "just the reverse" of the safety end point, he noted. "The patients who received the Watchman device had primary efficacy rates that were improved, and noninferiority criteria were met," he added, with a relative risk reduction of 32%.

PROTECT-AF: Primary efficacy results

End point Device events, n Device rate (95% CI) Control events, n Control rate (95% CI) Relative risk (95% CI)
Primary efficacy results (900 patient-year cohort) 20 3.4 (2.1-5.2) 16 5.0 (2.8-7.6) 0.68 (0.37-1.41)

Some of the efficacy stroke events were also counted as safety events, Holmes noted. There were five periprocedural ischemic strokes, three of which were related to air embolization during the procedure. There were six hemorrhagic strokes in the control group and one in the device group, a stroke that occurred 15 days after the procedure when the patient was still being treated with warfarin. Of six patients in the control group who had a hemorrhagic stroke, four died, he noted.

For all strokes, event-free probability was improved and noninferiority criteria met, he noted. Ischemic strokes were higher in the device group, 14 events vs five events on warfarin, but hemorrhagic stroke was lower in the device group, meeting superiority criteria.

PROTECT-AF: All stroke, hemorrhagic stroke and ischemic stroke by intervention

End point Device event rate (95% CI) Control event ate (95% CI) Relative risk (95% CI)
All stroke 2.6 (1.5-4.1) 3.5 (1.7-5.7) 0.74 (0.36-1.76)
Ischemic stroke 2.4 (1.3-3.9) 1.6 (0.5-3.1) 1.53 (0.654-5.43)
Hemorrhagic stroke 0.2 (0.0-0.6) 1.9 (0.7-3.7) 0.09 (0.00-0.45)

They found a time effect in the frequency of pericardial effusion; although serious effusion occurred in 5.0% overall, it fell from 6.5% in early patients to 4.4% in later patients, Holmes noted.

Dr Martin Leon (Columbia University, New York), who acted as a moderator for the session, pointed out that although the frequency of pericardial effusion did improve over the course of the trial, "there were still a fair number of pericardial effusions, and these are some of the most experienced operators in the US and the world. As this is potentially available to an open audience of interventional operators, are you confident that the training is robust enough so that these safety factors will not emerge and become problematic in a real-life setting?"

Holmes responded that the ongoing continued access registry includes 20 experienced centers and 10 additional centers that did not participate in the trials. "And the frequency in the first 100 patients is 1%," he said. Factors that have improved these numbers are the development of a shorter device, greater experience with the procedure, and the use of different approaches that have reduced trauma to the LAA.

"So I think those rates of now 1% are going to be much more what we will see as the device rolls out, rather than the 4% or 5%," he said.

Holmes speculated that the device might be an option for up to 70% of patients with nonvalvular AF. He noted that the device is scheduled to go before the FDA advisory panel on April 23.

Used first in non-warfarin-eligible patients?

After the presentation, invited discussant Dr A John Camm (St George's University of London, UK) first pointed out that the trial is small by the standard of trials that compared anticoagulation strategies. "I'm sure that most of you are surprised we're talking about a trial of some 600 to 800 patients, in a noninferiority design against warfarin for the prevention of thromboembolic events, essentially, and yet in the world of antithrombotic medication, similar trials involved not 600 to 800 but 6000 to 8000 patients."

The Bayesian sequential design used in PROTECT-AF is becoming standard, he noted, but "many object to the multiple looks involved in such a trial design." Examining the safety and efficacy end points on a noninferiority basis was "ethically highly justified," given the established efficacy of warfarin in this population.

However, Camm pointed out that the INR control in this trial was "certainly real life, but it was not ideal, and it was not up to the standard that we would expect nowadays in an antithrombotic-medication study."

He also cautioned that the results should be viewed in the context of new antithrombotics that are "around the corner, but they're not here yet; there are many slips between cup and lip."

If there are possible indications for this approach, it will probably be in high-risk patients who cannot tolerate anticoagulation, because of bleeding complications or significant issues with compliance. "Or alternatively, left atrial occlusion therapy may also be considered in moderate- to high-risk patients undergoing ablation procedures for atrial fibrillation."

Finally, Leon called on Dr Horst Sievert (CardioVascular Center Frankfurt, Germany), who has one of the world's largest experiences with LAA closure, for his thoughts on these findings.

Sievert called PROTECT-AF "clearly a landmark study, one of the very few positive trials that we have in interventional cardiology these days." However, although PROTECT-AF was done in patients who can take warfarin, "I think in clinical practice we will start using this technique in those patients who cannot, and only later on when we see in practice that this really works, then will we continue to those patients who can also take warfarin."

The study was funded by Atritech. Mayo receives research support from Atritech and may receive royalties. Camm reports he has consulted for companies that make antithrombotic medications.

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