COMMENTARY

CMS Proposal on Watchman Is the Right Decision

John Mandrola

Disclosures

December 04, 2015

The idea to close the left atrial appendage as a means to prevent stroke in patients with nonvalvular atrial fibrillation was a good one. The research conducted to answer this question was exemplary.

After many meetings, conducted over 6 years, the Food and Drug administration finally approved the Watchman (Boston Scientific) device. The labeling called for use "in patients with nonvalvular atrial fibrillation who are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores; are deemed by their physicians to be suitable for warfarin; and have an appropriate rationale to seek a nonpharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared with warfarin."[1]

With that degree of leeway, specifically the words "appropriate rationale,"—or, in Wilford-Brimley-speak: "You don't really want to take rat poison the rest of your life, do you?"—Watchman was set to be a blockbuster. (Brimley actually testified to that effect at an FDA hearing.) Think of the impact: Watchman promised a procedural way to prevent AF's most devastating complication—stroke. There are millions of people with AF.

But then the group with the real power in US healthcare, those who pay the bills, the Centers for Medicare and Medicaid Services (CMS), said no. In a decision memo ,[2] the CMS "proposed that the evidence is sufficient to determine percutaneous left atrial appendage closure therapy using an implanted device is not reasonable and necessary." The memo restricted use of Watchman to clinical studies and registries, and it set out seven conditions that must be met before implantation. These included use only in patients with contraindications to warfarin (an exclusion criterion for the two trials[3,4] on the Watchman device) and a formal shared-decision interaction using an approved decision tool.

In short, payers studied the same data as FDA and came to the opposite conclusion. It's important to clarify that this is only a proposal. It may not be the final word. The memo is open for public comment—which will likely be vigorous in its opposition. A final decision is due in February.

My public comment is that the CMS is correct. If you read the Watchman trials, FDA transcripts, and consider the definitions of reasonable and necessary, I can't see how you get to any other conclusion.

Higher Bar for Preventive Therapy

We must remember that LA appendage closure is designed to prevent something that could happen in the future. The most likely outcome for patients with AF and risk factors for stroke is nothing. An untreated patient with a CHA2DS2-VASc score of 5 enjoys a 90% chance each year of not having a stroke.

When we perform elective procedures, it's worth noting that if our patient weren't in the hospital having the procedure, he would be home doing his normal routine—because he isn't acutely ill. Although the name Watchman exudes a brand of benign protection, it is not a small procedure. The patient with AF who agrees to this strategy gambles that letting a cardiologist get vascular access, perform a transseptal puncture and push a stiff sheath against a thin-walled structure to deploy a foreign body will make an unlikely future event even more unlikely.

Given the physician's charge to, first, do no harm, the evidence for recommending this sort of gamble must be strong.

It is not.

The Evidence

The PROTECT-AF trial[3] compared Watchman and warfarin in 707 patients with AF (mean CHA2DS2-VASc=3.2). The results did not pass FDA muster. Although Watchman proved noninferior to warfarin for the primary end point, a composite of stroke, cardiovascular death, and systemic embolism, the FDA had concerns about excess adverse events related to the procedure. These concerns, along with the confounding effects of concomitant antithrombotic drugs and subjects not receiving assigned treatments, led the FDA to ask for another trial.

The PREVAIL trial[4] compared Watchman and warfarin in 407 higher-risk patients (mean CHA2DS2-VASc=3.8). Researchers excluded patients with indications for chronic clopidogrel and added a second primary end point to address LAA occlusion proof of concept and a third primary end point for procedural safety.

The good news from PREVAIL was that procedural safety improved. It was the opposite for efficacy. Due to an increased number of ischemic strokes in the device arm, Watchman failed to reach noninferiority in either primary efficacy end points. When PREVAIL and PROTECT-AF were combined,[5] hemorrhagic stroke rates were lower in the device arm, but FDA reviewers noted disparities in how events were adjudicated and combined aspirin-warfarin use in four of 10 patients with hemorrhagic stroke in the control arm. The clear message from PREVAIL was that the device did not prevent strokes nearly as well as warfarin.

Plausibility of PREVAIL

Inferior performance of LA occlusion compared with systemic anticoagulation should not be surprising. Virchow's triad[6] applies to AF. Mechanical occlusion of the appendage, even if performed flawlessly, does not affect the endothelial dysfunction and prothrombotic factors present in patients with AF and cardiac risk factors. The fact that Watchman was inferior to warfarin for ischemic stroke in the higher-risk cohort of PREVAIL, but noninferior in the lower-risk patients in PROTECT, lends credence to the notion that sicker patients have less to gain from focal solutions for systemic diseases. A meta-analysis[7] of studies looking at location of left atrial clot in patients with AF showed that nonappendage sources of thrombus increase with increasing risk factors.

The US Learning Experience

We have learned a lot from these trials. One lesson is that percutaneous LA appendage closure is feasible and relatively safe. That is key, because the next question is whether appendage closure is better than no treatment in patients who cannot take anticoagulation.

Warfarin-ineligible patients were excluded from the randomized controlled clinical trials, so we don't know whether the device would help them. At the last FDA advisory hearing, both patients and doctors urged committee members to approve the device so that it could be used in this patient subgroup. They assume benefit; they should not. Procedural risk may now be lower, but it is not insignificant. The CMS proposal is right to allow Watchman for anticoagulation-ineligible patients with the caveat that it is done within a clinical trial or registry. This way, we can avoid the European experience [8] with the device: 10 years of use and essentially no real-world data.

Another lesson is what we could achieve with better use of proven therapies. Proponents of Watchman cite the extremely low risk of ischemic stroke in the warfarin-treated arm of PREVAIL. This is not a fluke. PREVAIL centers should be commended for their skillful use of warfarin. They achieved a time in therapeutic range (TTR) of 68%, which is high compared with contemporary anticoagulation trials.

Better warfarin management is neither mysterious nor impossible. All that has to happen is a decision to make anticoagulation a priority. Dismissing warfarin as too hard to use is like saying we can't help people lose weight or stop smoking. It's nonsense. The moment you make anticoagulation measures similar to CHF measures, strokes and bleeding events would plummet.

Reasonable and Necessary

In PREVAIL, the second primary end point, a composite of ischemic stroke or systemic embolism, excluding the first 7 days after randomization, was called the proof-of-concept end point. Due to an excess of ischemic strokes, Watchman did not reach noninferiority in this category in the updated analysis presented to the FDA. That result was not an outlier. In PROTECT-AF, ischemic strokes were numerically higher in the Watchman group. Reasonable means logical and fair-minded. Such an assessment of a proof-of-concept end point that failed leads one to conclude that the device is not effective.

Necessary means something is required or essential. The most positive take of Watchman evidence cannot push it over this high bar. Even if Watchman came out superior to warfarin in both clinical trials, we now have experience with the direct oral anticoagulants, which have many advantages over warfarin—primarily their reduction of intracranial hemorrhage.

JMM

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