Dr John M

cardiac electrophysiologist, cyclist, learner

Still Negative on Watchman

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Many readers have contacted me to ask whether my negative viewson left atrial appendage occlusion with Watchman have changed since 2017.  

The short answer is no. My views are even more negative today. 

In 2016, I published an editorial on theHeart.org | Medscape Cardiology arguing that this procedure should stop. One of the rebuttals was that it was a blog post, not an academic editorial.

Months later, Andrew Foy, Gerald Naccarelli and I put the same argument into academic-speak and the influential journal Heart Rhythm published it.[1]

I have debated and presented this topic multiple times in the US and Europe. 

The newest data on Watchman have reinforced my negative view.

Efficacy Issues: 

Two studies published in 2018, one from Watchman investigators,[2]and the other from independent French researchers,[3] found high rates of device-related thrombus on follow-up echocardiograms (Translation: clot stuck to the device). This is not surprising since the Watchman is a foreign body left in the heart.

This data also helps explain why, in the Watchman vs warfarin trials, ischemic stroke (due to blockages) rates were HIGHER in the watchman arm. 

Both these papers reported that clots on the device go away with clot-blocking drugs called anticoagulants. That’s an existential problem because the main reason for having the device put in is to avoid the need for anticoagulation. 

Procedural Complications Higher After Approval: 

A group of researchers from the University of Kansas assessed the safety of Watchman after its FDA approval.[4] 

They used the FDA MAUDE database to assess the rate of complications divided by the number of implants.

This figure from their paper shows the higher rates of procedural complications after approval. Most sobering is that events in MAUDE surely under-estimate the true incidence of complications. 

Moral Hazards:  

You should also know about the moral hazards faced by US hospitals and physicians putting in this device.

Boston Scientific, the maker of Watchman, charges the hospital a large upfront fee to start a left atrial appendage occlusion program. Then they create price incentives that kick in if a hospital does “enough” Watchman procedures. To break even or make money with this device, one has to do a not-small number of procedures.

Given the asymmetry of information in the doctor-patient relationship, this moral hazard is downright ugly.

Unmet Need: 

During my debates and in discussions with colleagues at my hospital, I am asked what to do for patients with atrial fibrillation who are at high risk for stroke and cannot take anticoagulation.

Some doctors feel they have to offer this procedure as an option. This, I believe, is wrong-headed. 

If a patient had cancer and studies showed chemotherapy did not work for that type of cancer, the doctor should not offer the chemotherapy—in the name of “doing something.” 

In Medicine, doctors should not offer therapies that do not work. 

I have studied the evidence—not the spin–for left atrial appendage occlusion and this much is clear: it is an invasive procedure with a high risk of complications, and when it was compared to anticoagulation, it did not prevent ischemic strokes. 

Patients who could not take anticoagulants were excluded from the Watchman trials. While the absence of evidence is not the same as evidence of absence of an effect, the data we have on Watchman predicts higher risk patients will likely do worse with Watchman.

Summary: 

I do not recommend this procedure. Period. There are ongoing trials now in Europe. If these trials show benefit, I will reconsider this approach.

I am a medical conservative.[5]

This means I recommend expensive invasive procedures only when the benefit is greater than the harms. This is not the case for left atrial appendage occlusion with Watchman.

References:

1.         Mandrola J et al.Percutaneous Left Atrial Appendage Closure is Not Ready for Routine Clinical Use. Heart Rhythm. doi:10.1016/j.hrthm.2017.10.007.

2.         Dukkipati Srinivas R. et al.Device-Related Thrombus After Left Atrial Appendage Closure. Circulation2018; 138(9): 874–885. doi:10.1161/CIRCULATIONAHA.118.035090.

3.         Fauchier L et al.Device-Related Thrombosis After Percutaneous Left Atrial Appendage Occlusion for Atrial Fibrillation. J Am Coll Cardiol2018; 71(14): 1528–1536. doi:10.1016/j.jacc.2018.01.076.

4.         Jazayeri M-A et al.Safety profiles of percutaneous left atrial appendage closure devices: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 to 2016. J Cardiovasc Electrophysiol2018; 29(1): 5–13. doi:10.1111/jce.13362.

5.         Mandrola J et al.The Case for Being a Medical Conservative. Am J Med2019; 0(0). doi:10.1016/j.amjmed.2019.02.005.

Left Atrial Appendage Closure Does Not Prevent Strokes

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Our cautionary left atrial appendage occlusion (Watchman) editorial is now published in a prominent medical journal, called Heart Rhythm. My co-authors are Drs. Andrew Foy and Gerald Naccarelli from Penn State. It was a peer-reviewed version of my previous theheart.org | Medscape Cardiology column.

Watchman and other similar devices are plugs that occlude the left atrial appendage in an attempt to reduce the odds of stroke in patients with atrial fibrillation. It was a nice idea but it did NOT work.

The link is here> Percutaneous Left Atrial Appendage Closure is Not Ready for Routine Clinical Use

In the allotted 2500 words, we argued that…

1. The noninferiority signal from the first Watchman-vs warfarin clinical trial, PROTECT AF, was driven not by a reduction of ischemic stroke but by a reduction of bleeding-related strokes and cardiovascular death. We make the case that these latter findings were spurious–a play of chance. The FDA agreed as they did not approve Watchman based on the PROTECT AF trial. Indeed, FDA reviewers found other technical problems with PROTECT AF, in addition to the spurious findings.

2. The FDA required the Watchman investigators do another trial. The second pivotal trial, called PREVAIL, also studied Watchman vs warfarin. But here FDA agreed to let investigators borrow patient-years from PROTECT AF, and allowed for a Bayesian analysis of PREVAIL. That meant PREVAIL began with a 97.1% chance Watchman was noninferior to warfarin. The cutoff for noninferiority was 97.5%. All Watchman had to do was get in the ballpark of warfarin and PREVAIL would have been positive. It did not.

Watchman went the wrong way–in dramatic fashion. Sit down for this: After all the PREVAIL study patients had reached follow-up, there were now 14 clot events (13 strokes; 1 embolus to the body) in the Watchman group and only 1 stroke in the warfarin arm. The event rate was 7.6 fold higher in the device arm. The investigators called this endpoint the proof-of-concept endpoint. So … Watchman massively failed in its proof-of-concept test. The pivotal PREVAIL trial found that Watchman missed noninferiority in both its efficacy endpoints.

3. The third argument we made critiqued the meta-analysis that was published at the same time these dramatic PREVAIL findings came out. In our paper, we did our own meta-analysis on the two trials and found significant heterogeneity, which is a bad thing for meta-analyses. Heterogeneity–here, PROTECT AF went in a different direction than PREVAIL–means you are comparing apples and oranges. Most experts in statistics say high heterogeneity of the combined trials prevents drawing conclusions from the meta-analysis. What’s more, the meta-analysis did not refute the higher rate of ischemic strokes in the Watchman group.

4. Our fourth argument centered on the uncertain reasoning behind the idea of closing the appendage as a stroke-prevention strategy. Static blood in the appendage is not the only reason patients with AF have stroke. It turns out that thicker blood (hypercoagulability) and damage to the lining of blood vessel/atria (endothelial dysfunction) play significant roles in stroke. (See Virchow’s triad.) Patients with AF, especially those with other conditions, such as diabetes, coronary heart disease, valvular disease, hypertension, etc, harbor other reasons–besides the appendage–for having stroke. In short, appendage closure is a focal solution for a systemic problem. Thus, we are utterly not surprised it did not prevent stroke better than warfarin.

5. The fifth argument addressed the dubious net clinical benefit of the device. Net benefit means the benefits outweigh the harms. Let’s assume you felt that Watchman benefits were neutral to warfarin. They are not, but let’s just assume. First you have to know appendage plugs are foreign bodies in the heart. This means aspirin or some other clot-blocking drug is required to prevent clots from sticking to the device. We showed in the paper that antiplatelet drugs (mainly aspirin) confer the same bleeding risk as warfarin or the NOACs. I know this sounds crazy. Everyone thinks aspirin is safer. When used in the elderly, the evidence suggests otherwise. (Read our paper to find out.)

Another drag on net benefits are the procedural complication rates. This is an invasive procedure, one that requires pushing stiff sheaths into the thin-walled appendage. The average rate of serious complications is about 6%. That is, if you use the best studies. Think about that; think about this as s a gamble. You get a device that is supposed to prevent future stroke (probability benefit) but you start the gamble with a 6% chance of serious harm.

6. Finally, we took on the prevailing idea of using the device in patients who are ineligible to take anticoagulant drugs. It’s crucial to know these patients were excluded from the trials. There is no reliable data on these patients. There is only speculation. One of the most damming pieces of evidence against the use of appendage closure in ineligible patients–besides the dangers of antiplatelet drugs–is that the likelihood of appendage sources of strokes go down as patients get sicker.

I don’t recommend LA appendage closure.

A clear-eyed view of the data suggest it’s worse than anticoagulation. And for those patients who cannot take anticoagulation, all the signals point to more harm than good.

JMM

New Data Increase Caution on Left Atrial Appendage Occlusion

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I remain concerned about the irrational exuberance among some of my colleagues toward left atrial appendage occlusion devices for the prevention of stroke in patients with atrial fibrillation.

In short, these devices are plugs that doctors place into the left atrial appendage. The idea is to stop clots from forming or escaping from the left atrial appendage. It was a good theory because the appendage can be a place that harbors clots.

One of the barriers to overcome with these plugs is prevention of clots on the device. The plug sits in the left atrium exposed to the low flow of blood in that chamber.

Foreign bodies exposed to blood leads to clotting; it’s exactly why metal stents used in coronary arteries render the person dependent on potent clot-blocking drugs. The appendage plug, too, needs drugs to prevent clots from forming on it.

Here’s the problem: many of the patients getting these devices are getting them because they have had major bleeding events while taking anticoagulants like warfarin or NOACs.They are deemed ineligible to take drugs that block the body’s clotting system.

But anti-platelet drugs, e.g. aspirin, can cause bleeding–especially in the elderly. See the BAFTA trial.(Ref below).

Two studies chosen as featured presentations at the European Heart Rhythm Meeting did not deliver any reassurance of these devices.

Both studies looked at real-world data on how the device performs when used by regular doctors outside the clinical trial. Real-world observational studies are important because a therapy (drug or device) may not deliver the same outcomes when used outside the protective confines of a trial.

A French study took data from numerous centers in an effort to study the presence of clots on the device, and the influence of anti-clotting drugs to prevent these clots.

A German study, sponsored by industry, also looked at the presence of clots as well as overall complications from the procedure. This study took data from more than 61 centers across the world.

The details of the studies are included in my column: Real-World Data on Left Atrial Appendage Closure Does Not Reassure

The gist of these studies was that clots on the device are not rare; potent clot-protecting drugs are likely required to prevent clots (at least for a period of weeks-months); the presence of clots increase the risk of stroke, and finally, major procedural complications are in the range of 4%.

These findings bolster my already cautions approach to this procedure.

Remember, left atrial appendage closure is a preventive procedure. Its benefit is a probabilistic one in the future. If you start with a 3-4% major complication rate, future risk reductions have to be higher than that to deliver a net gain. Thus far, the data from the randomized controlled trials don’t show that it is.

Why my colleagues are speeding ahead with this risky procedure is hard for me to understand. The conclusion of my analysis of these two most recent studies is that we need a head-to-head comparison of the device versus no therapy in patients who cannot take clot-blocking drugs. My prediction is that the device will be no better or worse than no therapy.

JMM

Reference:

Mant J, Hobbs FDR, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. The Lancet.370:493-503.

(Note, I do not use the term blood-thinner. Anticoagulants (warfarin and NOACs) and anti-platelet (aspirin and clopidogrel) drugs do not thin the blood; they inhibit parts of the normal clotting system.)