UPDATED May 14 // BOSTON — Insights reported here about the thrombus known to form on left atrial appendage (LAA) occluder devices, which has long raised concerns over embolic risk, could help identify ways to single out susceptible patients for preventive management, researchers propose.
The risk for such device-related thrombus (DRT) being identified was about 3.7% in more than 1700 patients implanted with the Watchman (Boston Scientific) LAA closure device. The cohort had been assembled from four prospective studies of the device.
Among those known to have DRT, the adjusted risk for stroke or systemic embolism was more than tripled compared with the risk without DRT; the adjusted risk for hemorrhagic stroke was even higher.
The strokes seemed to occur within about a month of DRT formation in about half of cases, which suggests that DRT is at least sometimes causing the event, said Vivek Y. Reddy, MD, Icahn School of Medicine at Mount Sinai, New York City, when reporting the findings here at the Heart Rhythm Society (HRS) 2018 Scientific Sessions.
The analysis was also published online in Circulation to coincide with the HRS presentation, with lead author, Srinivas R. Dukkipati, MD, also from the Icahn School of Medicine at Mount Sinai.
There were also suggestions that DRT was most likely to develop after patients went off oral anticoagulation (OAC) or when anticoagulation levels were suboptimal, he said.
"It is important to keep the data in perspective. The majority of DRT patients did not experience stroke or systemic embolism. And the majority of stroke and systemic embolisms did not occur in DRT-positive patients," Reddy noted. The findings, he added, apply to patients on the OAC regimen used by the current cohort.
Watchman was approved in the United States with the recommendation that patients receive OAC for 6 weeks after implantation, he noted, after which they would be receiving dual antiplatelet therapy out to 6 months and aspirin alone thereafter.
Independent predictors of DRT in the cohort included a history of cerebrovascular events, permanent AF, vascular disease, and increased LAA diameter. A higher left ventricular ejection fraction (LVEF) seemed to protect against its formation, Reddy noted.
Table 1. Possible Predictors of or Protectors From DRT on Watchman, Adjusted Odds Ratio (as Published)
|Endpoints||Adjusted Odds Ratio (95% CI)||P Value|
|History of transient ischemic attack or stroke||2.31 (1.26 - 4.25)||.007|
|Permanent AF||2.24 (1.19 - 4.20)||.012|
|Vascular disease||2.06 (1.08 - 3.91)||.028|
|LAA diameter (per 1-mm increase)||1.06 (1.01 - 1.12)||.019|
|LVEF (per 1% increase)||0.96 (0.94 - 0.99)||.009|
If such patient features actually turn out to be risk factors for DRT, they could potentially help identify patients who would benefit from heightened surveillance using transesophageal echocardiography (TEE), according to Reddy.
In the two randomized trials contributing patients to the current cohort, PROTECT AF and PREVAIL, TEE was performed 45 days, 6 months, and 12 months after Watchman was implanted. It was performed at 45 days and 12 months in the two prospective registries, Continued Access PROTECT-AF (CAP) and the ongoing Continued Access to PREVAIL CAP2.
Measures that might help increase DRT detection or provide rule-out reassurance include increasing the surveillance schedule in practice to include the 6-month TEE, Reddy said. But, he added, that would increase exposure of all Watchman recipients to the risks of TEE, which is more invasive than transthoracic echocardiography.
Or, "we could escalate the TEE monitoring strategy for patients with DRT risk factors. But I think we need to understand those a little bit better," he said. "Another option, the one that I favor, is to delay the first TEE. Instead of doing it at 45 days, perhaps do it later at the 3- to 4-month time point."
Regardless, whenever DRT is detected, "anticoagulation should be promptly resumed."
Some observers have questioned the strength of Watchman's evidence base and therefore conclusions based on it. In PROTECT-AF, for example, Watchman "failed to establish reasonable assurance of safety and efficacy," said Sanjay Kaul, MD, Cedars Sinai Medical Center, Los Angeles, California, who was not involved in the Watchman analysis.
"The second pivotal randomized trial, PREVAIL, also failed to establish noninferiority for the two efficacy endpoints at both short- and long-term follow-up, and only met noninferiority for safety based on an objective performance criterion," Kaul told theheart.org | Medscape Cardiology by email.
"If this were a new drug or biologic, the quality and the quantity of evidence would not have been sufficient to pass the regulatory muster," he said. "The findings described in the current report must be interpreted within the context of this shaky benefit-risk balance of the device."
Reddy noted that the current results "may only be relevant for the Watchman device, though it's likely, I would argue, that these general concepts apply to other devices."
DRT is an issue with all catheter-delivered LAA occluder devices. For example, as covered by theheart.org | Medscape Cardiology, the risk for DRT was about 5% in registry studies of patients implanted with Watchman or the Amplatzer Amulet (St Jude Medical/Abbott). The patients had been considered to be at too high risk for bleeding to receive OAC with warfarin.
Detection of DRT in that mixed cohort seemed to elevated the risk for ischemic stroke or transient ischemic attack (P = .008) by a factor of eight.
Despite modifications to the occluder devices and growing operator experience, DRT seems to be a persisting issue, and the risk for it occurring is likely always to be "in the background" for patients receiving them, said David B. De Lurgio, MD, Emory Saint Joseph's Hospital, Atlanta, Georgia.
"What is a little alarming is that the risk for DRT remains and extends well beyond the standard of care of anticoagulation," he said as the assigned discussant following Reddy's presentation.
De Lurgio and other observers at the HRS sessions seemed to note the irony that LAA occluders are intended in patients with AF to replace or at least reduce dependence on antithrombotic therapy, which could increase their risk of bleeding.
But antiplatelets and OAC are seen as needed to a greater extent than hoped in the early days of the transcatheter devices. Warfarin or other OAC, it turns out, are essential in the weeks after their implantation, but it's uncertain exactly how long most patients would need to be on it for adequate protection.
"There's a big question mark about when are we out of the woods. And is that something we can't predict based on patient profile or any other factors," De Lurgio said. However, there may be "some predictive value" to patient features indicating high stroke risk prior to LAA occluder implantation, he said. Such patients probably retain that high risk status after receiving the device.
"In my opinion, the incident rate of DRT of 3.7% likely represents an underestimate. The thrombus might have embolized by the time TEE was done. And it adversely affects the overall benefit-risk profile of the Watchman device," said Kaul.
"There are no strong predictors of DRT," he continued. "People who develop DRT are at three- to fourfold greater risk for developing ischemic stroke or systemic embolism. Therefore, prolonged OAC beyond the recommended 6 weeks is required for risk mitigation, thereby negating the raison d'être for Watchman to begin with."
Given the current findings, Kaul said, "the case for recommending the Watchman device over OAC, especially new oral anticoagulants, just became even more difficult to make."
De Lurgio said, "I do believe that DRT mitigates the benefits of left atrial appendage closure, relative to warfarin, with these devices. However, it doesn't mitigate the benefits of left atrial append closure with these devices relative to no therapy, and I think that's a very important take-home message."
The 1739 patients in the analysis, about a third of them women, had a mean age of 74 years and a CHA2DS2-VASc score of 4.0 and were followed for 7159 patient-years in the four studies. DRT was identified by TEE, either scheduled or unscheduled, in 3.7%.
Stroke or systemic embolism in patients positive for DRT occurred at the rate of 7.46 per 100 patient-years; the rate was 1.78 per 100 patient-years in those without DRT.
Table 2. Adjusted Rate Ratio for Events on Watchman, Patients with DRT vs No DRT (as Published)
|Endpoints||Adjusted Rate Ratio (95% CI)||P Value|
|Stroke or systemic embolism||3.55 (2.18 - 5.79)||<.001|
|Ischemic stroke||2.60 (1.46 - 4.64)||.001|
|Hemorrhagic stroke||7.98 (2.12 - 29.94)||.002|
|Disabling or fatal stroke||3.14 (0.93 - 10.62)||.066|
|Major bleeds||1.78 (1.13 - 2.81)||.013|
Neither all-cause mortality nor cardiovascular mortality was significantly different in the DRT vs no-DRT groups.
In the current series, De Lurgio noted, the elevated risk for hemorrhagic stroke in patients with DRT was probably the result of anticoagulation that was restarted once the thrombus was identified. And that, he said, suggests that perhaps there's a role for OAC using drugs that have demonstrated risk for intracranial hemorrhage compared with warfarin, "should we see DRT," he said, referring to some of the new oral anticoagulants.
PROTECT AF, PREVAIL, CAP, and CAP2 were funded by Boston Scientific. Reddy discloses receiving grant support from or serving as a consultant to Boston Scientific, Abbott, and Biosense-Webster and having equity or investment interest in Javelin and Surecor. Dukkipati had no disclosures. Potential conflicts for the other authors on the publication are in the report. De Lurgio discloses receiving compensation for services from Boston Scientific.
Heart Rhythm Society (HRS) 2018 Scientific Sessions. Abstract B-LBCT02. Presented May 11, 2018.
Circulation. Published May 11, 2018. Abstract
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Cite this: Strokes From Clot on Watchman LAA Closure Device: Oral Anticoagulation Insights - Medscape - May 13, 2018.