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.)

Say No to Watchman

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Cardiology is on the brink of making a big mistake. We have embraced a new procedure called left atrial appendage occlusion.

You may be seeing the ads for a device called Watchman. Like this one> screen-shot-2016-11-11-at-6-00-03-am

The appendage-closure idea was a good one: during atrial fibrillation (AF), blood can pool in the left atrial appendage, and this promotes clot formation. (The LA appendage has many nooks and crannies.) So… if we could put a device in there, see image, this would block clots from getting out and causing stroke.  Also, once screen-shot-2016-11-11-at-7-07-14-amthe device has been in for months, the body walls it off and the patient can stop the anticoagulant drug (warfarin, or one of the new drugs, called NOACs).

Here is the problem: The Watchman device does not prevent strokes. When compared in the best test of medicine, the randomized controlled trial (RCT), the device was inferior to warfarin.

Another problem: advocates for the device have used selective reporting and publishing of trial results to alter the way patients and doctors perceive reality.

This week I published a detailed critical appraisal of the evidence for Watchman.

Here is the piece: Left Atrial Appendage Closure Should Stop Now.

The three take-home messages from that post are:

Take-home #1: In the first trial of Watchman v warfarin, called the PROTECT-AF study, complications were high. This finding, plus other irregularities led the FDA to reject the device and call for another trial.

The second trial of Watchman v warfarin, called the PREVAIL study, showed lower complication rates (good), but higher rates of ischemic stroke (the kind caused by clots) in the Watchman arm.

Take-home #2:  The tricky part of the selective reporting of Watchman began with the PREVAIL trial.

Here, the authors of PREVAIL published the paper (2014) with incomplete results–only 28% of patients had reached the 1.5 years of follow-up. In this very early look at the data, the results looked nearly equivalent, though there were still more strokes in the Watchman group.

Two months after that paper was published, the PREVAIL investigators reported longer-term follow-up from the study at a medical meeting and to the FDA. (Neither of which shows in PubMed searches.)

This new data showed 8 additional strokes in the Watchman arm and none in warfarin group. Now the PREVAIL study totals were 13 strokes in Watchman versus 1 in the warfarin group. With this new data, the endpoints of PREVAIL were NOT noninferior. Or, in clear language, inferior.

Yet, crucially, this updated data, which would turn the pivotal trial for this device negative, have not been published. Instead, the authors decided to publish a meta-analysis of multiple studies of Watchman, including softer registry studies.

By combining this mishmash of studies (meta-analysis) and by using a composite endpoint, the authors noted noninferiority of the device. But even in that meta-analysis, if you look at strokes due to clots, the results show more with Watchman.

It gets worse.

screen-shot-2016-11-11-at-7-35-21-amNot only is the more complete PREVAIL data not published, but leaders in the field of cardiology, including influential guideline writers, continue to cite the 2014 study that is published as noninferior, but is really inferior–if it had been updated. A reader of the published literature, therefore, would think the device is equivalent when in fact it is not. Even the majority of the FDA reviewers felt the device did not meet its efficacy endpoints.

A literature search in PubMed for two of the more prominent authors of the non-updated PREVAIL study and “Watchman,” shows 10 papers since the 2014 incomplete paper. One wonders why this important data has not been published. Could it be that it would turn the pivotal trial for Watchman into a negative trial?

In my post, the primary investigator of the study, Dr. Vivek Reddy, explains why that data is not published. It’s a complicated statistical explanation.

Take-home #3:  What about patients who can’t take anticoagulant drugs?

Proponents of the technology say we should use the device for patients who cannot take anticoagulant drugs because of bleeding. It’s true; for patients who have had AF, stroke, and bleeding, there are no good options.

But these patients were not included in trials with Watchman. That means we don’t know the device would work. The signals thus far suggest the device would not help these patients. For one, it doesn’t protect against stroke relative to warfarin. For another, even if it did reduce stroke by 1-2%, this benefit would be balanced by the 2-3% complication rate of implant.

What I believe should have happened for these difficult patients is the device been approved but only as part of a study. Nearly 4000 patients in the US have had this device, and if they were in a clinical trial, we’d be well along in knowing whether this device helps people who cannot tolerate anticoagulant drugs.

At the root of our embrace of this technology is the desire to help patients. But that benevolent drive should not blind us to the evidence.

Here’s the slide I usually start my critical appraisal talks with: screen-shot-2016-11-11-at-7-03-33-amJMM

Notes from ACC – Day 1

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IMG_3002The first day of the American College of Cardiology (ACC) meeting is like the first lap of crit or cross race. It’s a whirlwind. Your head spins. You are trying to get oriented, but as a part-time journalist, you also know that big news happens on the first day.

And oh did it ever.

One of the meeting’s most anticipated trials, was pulled from the program one hour before presentation. The PREVAIL trial was eagerly awaited because it studied a device that stood to change the practice of stroke prevention in patients with atrial fibrillation. The Watchman device is a plug of sorts that is inserted into the left atrial appendage (LAA). The idea is that most (not all) clots in AF come from the LAA. If this could be occluded, stroke risk would be reduced and patients would no longer need to take drugs that increase bleeding risk. There are millions of patients with AF, stroke is a dreaded complication and no one likes anticoagulants.

You can see why this is so big.

But then, the morning of the presentation, there came an announcement that the trial would not be presented because Boston Scientific, the makers of Watchman, breached the embargo. But the slides were still in the program. This created quite a stir. And journalism folks were already inflamed from the argy-bargy in the week leading up to the meeting: It seemed the trial would not be presented, then partially presented, then fully presented, now not presented.

These antics were not the reason why I wrote this decidedly negative opinion piece on the Watchman. I wrote it because the Watchman is not likely going to make it past FDA muster. And if it does, I would be very hesitant to adopt the technology. I gave eight reasons to be doubtful in the piece.

The other news of my day:

I was really happy to see theHeart.org journalism team again. They are a super-professional bunch and they are awfully nice to me. I’m like a Cat 4 in a 1-2 race when it comes to journalism.

Is Coke heart healthy?

Is Coke heart healthy?

I saw this picture in the expo. It’s hard to wrap your head around Coke being heart-healthy. Keep that cynicism about industry sponsorship of medical societies at bay, please.

I went to an interesting session on AF and athletes. (Look for an update later.)

I met Dr. James Beckerman (@jamesbeckerman)

I walked to dinner and ate an entirely vegan meal! It’s heart meeting after all.

Oh, and BTW: it was really nice out here yesterday.

I’ve already written my second piece. It address the issues of over-monitoring and noise pollution in the hospital. Here is Shelley Wood’s recap of the study. My opinion will be published soon.

For breaking news, theHeart.org team has it covered. Their home page looks amazing.

JMM

New Trials and Fibrillations post up: Thoughts on left atrial appendage occlusion to prevent stroke in AF

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There was a lively debate on this topic at ESC 2012.

One of the strategies proposed to reduce stroke in AF involves occlusion of the sack-like structure called the left atrial appendage. Two devices are being evaluated and nearing consideration for approval. There is a great deal of debate on these devices.

Here is my recap yesterday’s session.

ESC 2012: Left atrial appendage closure is NOT the therapy of choice for many patients with AF?

JMM