Dr John M

cardiac electrophysiologist, cyclist, learner

The Case Against Watchman

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Many readers have asked me to update my feelings about Watchman and other percutaneous appendage closure procedures.

The short answer is that I remain unconvinced that this is a beneficial procedure. New data has been sparse and unconvincing.

I’ve recently started a newsletter on Substack. It’s called Stop and Think. In the latest post, I have included a Watchman lecture I gave at the Heart Rhythm Society meeting in Boston.

I hope you subscribe to the newsletter. It’s about science and medicine.

Here is the link for the Case Against Watchman

JMM

Survey for Athletes with AF

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Hey Athletes:

My colleague, Professor Rachel Lampert, from Yale, along with the StopAF.org patient group, seek to learn more about how atrial fibrillation (AF) and its treatments affect athletic people.

If you are an athlete or if you regularly exercise vigorously, please give the Yale researchers a few moments of your time.

Here is the link to the survey.

Since I had AF in the past, I filled it out. It takes only a few minutes.

Prof. Lampert’s research into this area is important because AF affects people in vastly different ways.

It’s weird; while most AF stems from advanced age or lifestyle diseases (obesity, high blood pressure, alcohol excess and sleep apnea), endurance sport represents a special circumstance.

The added problem for athletes with AF is that most doctors do not (really) understand our goals and expectations. This sort of research sheds light on the inner workings of the athletic persona.

The other reason to do the survey is that Prof. Lampert is really nice.

JMM

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.

AF, Ablation, Stents and Five Nuances

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Joan has left an excellent comment on my recent 2019 AF ablation update.

She brings up many important issues. Let’s dissect it.

Q: Joan asks if it is common to see patients who think they are cured after AF ablation but are still in AF? 

A: The scenario I described in my previous post is not common, but it is not rare. Since AF ablation entails much instrumentation and many burns, it can affect how the heart feels things. The heart has its own nervous system; yes, the heart feels. Also, the bigger the procedure, the bigger the placebo effect. 

Q: If ablation doesn’t work, then I sure know a lot of people walking around who had ablation and are convinced it changed their lives. 

A: First, I did not say AF ablation does not work. I wrote that we don’t know; it has not been adequately tested in a placebo-controlled blinded trial. 

But let’s consider how ablation might change people’s lives without eliminating AF. 

The sites of ablation in the left atrium are close to neural inputs to the heart. It may be that we change how the heart perceives AF simply by instrumenting the heart and ablating in the areas near where the nerves attach to the heart. This statement should induce little surprise because the majority of people who have AF do not know it. All cardiologists have observed a huge disconnect between an actual heart rhythm disorder and its symptoms.

A Canadian study called DISCERN AF found that the ratio of asymptomatic to symptomatic AF episodes increased more than threefold after ablation.[1] In 2017, a study called CAPTAF found that AF ablation compared with drugs improved quality of life, but the improvement occurred without a statistically significant reduction in AF burden. Hmm?

Another problem with assessing “success” of AF ablation is uncertainty about the meaning of AF episodes. That sounds like a crazy sentence, as AF on an ECG defines the condition AF. The traditional way to determine ablation success is the absence of even 30 seconds of AF on any monitor. That makes little sense because if someone had persistent AF before the ablation and after the procedure has a couple of 30-second episodes a month, why isn’t that a success?

But it’s even more complicated than duration of AF episodes. We are beginning to understand that AF on an ECG may be an end-result of underlying atrial disease. In other words, the AF may be a symptom or sign of other stuff that is awry in the body and negatively affecting the atria. (Stress, high blood pressure, inflammation from fat around the heart, and many many other things.)

An apt analogy is infection and fever. When we get a bacterial infection, we also get fever. The treatment of a bacterial infection is to kill the bacteria with antibiotics not just relieve the fever with acetaminophen. Is AF ablation acting like acetaminophen—merely covering up something else?

This is a super disruptive notion because in the past we considered the electrical episodes of AF as a good surrogate marker for symptoms and a predictor of stroke. 

There are many studies showing a poor (temporal) relationship of AF episodes to stroke—meaning, when people with AF had stroke, they often had no AF episodes before the event. How could that be if AF caused stroke? What’s more, AF drugs reduce AF episodes but don’t reduce the rate of stroke? How could that be if AF caused stroke? Dr. Hooman Kamel has written one of the most important papers on AF. [2] He and his co-authors make the case that we need a new framework of understanding AF and stroke. I would say.

Q: You have done AF ablations for a long time, are your personal observations irrational or unscientific? 

As for my experience with doing more than a thousand AF ablations over 15 years, I believe the procedure helps people. I wouldn’t do it otherwise.

But I am not sure; and the procedure is expensive, invasive, risky and… it needs to be tested.

If medicine is to be scientific, we must ascribe to the Feynman principle: “the first principle is that you must not fool yourself and you are the easiest person to fool.”

Doctors have been fooled often. 

  • Cardiologists used to use pacemakers to treat benign fainting. Until this was reversed in a placebo-controlled trial.
  • Heart surgeons used to tie off the internal mammary artery to treat chest pain. Until it was reversed in a placebo-controlled trial. 
  • When I came to Louisville in the 1990s, heart surgeons were doing transmyocardial laser revascularization–burning holes in the heart for the relief of angina. This was reversed in a placebo-controlled trial. 
  • Neurosurgeons used to place embryonic fetal cells into the brain for Parkinson’s disease. This, too, was reversed in sham-controlled trial, which even involved drilling holes into the head of patients in the placebo arm. 
  • Orthopedists used to think knee arthroscopy for arthritis reduced pain. Nope. This common practice was reversed in placebo-controlled trial. Here is review article[3]describing five ortho surgeries, including the common procedure called vertebroplasty, which have been proven not to work by sham-controlled trials. 

Q: How can patients agree to be in a placebo-controlled procedure trial, and would insurance pay for it? 

The way ORBITA investigators arranged for a placebo arm of their trial was that all the patients were promised the stent procedure; the ones in the placebo arm simply had to wait a few weeks–after the treadmill test and questionnaires were done. For AF ablation, this period will be longer, probably six months to a year.

On the matter of insurance, in an American system of private insurance, providers can change each year. That means there is little incentive to keep people healthy in the long term. Thus, there is little incentive to pay for people to be in a placebo-controlled trial. But in most countries, the government pays for healthcare, and would have an extreme incentive to prove whether or not a costly procedure works.

Q: Stents are still being used. How could this be given the “weird” ORBITA study? 

The tricky thing about stents are that they work great for patients having a heart attack, but no study shows they work (on average) for patients with stable heart blockages. 

While the use of stents for stable blockages has decreased, the practice still continues in earnest. The way around this is use of different diagnoses. Instead of saying the stent is being used for stable coronary disease, doctors often label the symptoms as unstable angina. [4]

The core reason stents are being used despite numerous studies showing that they do not reduce heart attacks or death is that the clogged pipe theory of heart disease is deeply engrained–among doctors and patients alike. It will take decades to change this thinking. (Though there is one more trial testing stents; it’s called the ISCHEMIA trial and it’s had its share of controversy.[5])

Nobel winner Max Planck famously said that science advances one funeral at a time. This is often true in Medicine. 

Resistance to de-adopt unproven therapies is one of the reasons I am a medical conservative, and why I advocate for evidence of benefit before therapies are accepted.

References:

1.         Verma A et al.Discerning the Incidence of Symptomatic and Asymptomatic Episodes of Atrial Fibrillation Before and After Catheter Ablation (DISCERN AF): A Prospective, Multicenter Study. JAMA Intern Med2013; 173(2): 149–156. doi:10.1001/jamainternmed.2013.1561.

2.         Kamel H et al.Atrial Fibrillation and Mechanisms of Stroke Time for a New Model. Stroke2016; 47(3): 895–900. doi:10.1161/STROKEAHA.115.012004.

3.         Louw A et al.Sham Surgery in Orthopedics: A Systematic Review of the Literature. Pain Med2017; 18(4): 736–750. doi:10.1093/pm/pnw164.

4.         Wadhera RK et al.Association of the Hospital Readmissions Reduction Program With Mortality Among Medicare Beneficiaries Hospitalized for Heart Failure, Acute Myocardial Infarction, and Pneumonia. JAMA2018; 320(24): 2542–2552. doi:10.1001/jama.2018.19232.

5.         Rajkumar CA et al.‘Faith Healing’ and ‘Subtraction Anxiety’ in Unblinded Trials of Procedures. Lessons from DEFER and FAME-2 for End Points in the ISCHEMIA Trial2018; 11(3). doi:10.1161/circoutcomes.118.004665.

AF Ablation Update 2019

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Most years I write an update on any big developments in AF ablation.

This year’s version will be a short one. I have little new to report. But it’s worth reviewing some basic issues.

We still do not know the cause of atrial fibrillation (AF). That makes it hard to fix with ablation.

Knowledge Deficits:

To explain why not knowing the cause of AF impairs our ability to ablate it, it’s useful to compare AF ablation to WPW ablation. Wolfe-Parkinson-White or WPW syndrome causes rapid heart rates because of an extra pathway from the top to the bottom (atria and ventricle) of the heart. You can cure WPW by ablating the extra pathway–often with one burn.

The approach to AF is to use single burns (or cryo-balloon lesions) to electrically isolate the muscle bundles surrounding the pulmonary veins. Think of that one burn (used in WPW ablation) times 60-80 to form electrical fences around the pulmonary vein orifices. This is called pulmonary vein isolation or PVI. Studies show that it is the best technique for ablating AF.[1] It’s what we did in 2004 and it’s what we do now.

The problem is that sometimes AF is triggered by cells in the pulmonary veins, and sometimes it is not. That means we could be doing 60-80 burns in the heart and not going after the right target. There is NO way to tell. The good news, though, is that the pulmonary veins are involved often.

The other problem is that even when AF is being triggered by cells within the pulmonary veins (e.g. we are going after the right target), the lines of block from the burns are not durable, and over time, electrical activity can leak out through a gap in the line–thus causing AF.  The weirder thing is that sometimes these gaps occur in patients who don’t have AF after the ablation. IOW, the burns did not completely isolate the veins and AF still stayed away.[2] That observation suggests the burns hit something–but we don’t know what.

AF Ablation Remains Untested: 

The larger problem with AF ablation is that it has never been adequately tested. In medicine, to know if a pill or surgery really works, you have to test it against a placebo in a blinded trial. Emphasis on blinded. A new medicine cannot get approved unless it works better than a placebo. Procedures should require the same proof.[3]

AF ablation has never been tested against a placebo procedure–sometimes called a sham procedure. Every single study of AF ablation has been confounded by the patient and doctor knowing the treatment. Or, as we say, AF ablation trials are unblinded.

I know; exposing people to the risk of ablation without actually doing the ablation sounds nutty. But the list of procedures and surgeries proven useless when compared to placebo is long.

The most recent shock was stents in the heart for the relief of chest pain due to chronic and stable blockages in the coronary arteries. Millions of people worldwide have received stents, and both doctors and patients believed the metal cage relieved chest pain called angina. How could it not? The stent essentially fixes a 90% blockage to 0%.

Except … stents did not pass the placebo test!

In the ORBITA trial[4], a brave group of researchers from London randomized 200 patients with a single severe blockage and chest pain to either a real stent procedure or a fake procedure. The patients and the doctors taking care of them afterwards did not know which they had. To measure the effect of the stent vs the sham procedure, the researchers walked all 200 patients on a treadmill before and after the procedure, and, shockingly, there were no significant differences in exercise time, nor were there any significant differences in chest pain on questionnaires. In case you find this hard to believe, the ORBITA investigators counter the many criticisms of their trial in two worthy rebuttals.[5,6]

The message is clear– if fixing a 90% blockage does not relieve chest pain any better than a sham procedure, then it’s possible that the quality of life improvements reported after AF ablation might also be a big placebo.

A quick story: I did an ablation on a patient who had terrible AF. Terrible in that AF was causing depression, shortness of breath, dizziness and the man told me that he didn’t care if he died during the procedure, he could not live like this. I did the ablation and it went well. A year later, he told me in the office that I was a miracle worker. I had given him his life back.

Except … sit down for this... he was in AF!

I am giving a talk at the Heart Rhythm Society meeting this year on why we need a placebo-controlled trial for AF ablation. I will, of course, address the ethics of exposing a a hundred or so people to the risk of a sham procedure vs the ethics of exposing millions to a potentially worthless procedure. (For the record: I predict an AF ablation placebo control trial will show a large placebo effect, but also a real effect.)

Two new trials in AF ablation in 2018: 

The CASTLE AF trial[7] showed that for patients with heart failure and AF who have failed medicines, AF ablation reduced the rate of death and heart failure by about 12%. The trial results sound great, but it only included relatively young, mostly male patients who had moderate heart failure. Most patients with heart failure and AF are older and have multiple problems that make AF ablation unlikely to work.

Important point here: you should only apply trial results to patients like those in the clinical trials. We call this the external validity of a trial.[8] I have written about this: Treating the Individual, Not the ‘Average’ Patient.

The CABANA trial, which is not yet published, showed that for patients with AF and risk factors for stroke, AF ablation compared with medical therapy did not significantly reduce the rate of stroke, death, bleeding or cardiac arrest. CABANA did show that AF ablation reduced AF episodes, and it improved quality of life, but, of course, CABANA was unblinded and had no placebo control. That is crucial because it was done by doctors who believe in AF ablation.

Summary: 

AF ablation in 2019 is about the same as in 2018.

I recommend it as an option for people who have well documented AF that…

  1. cannot be reversed with lifestyle measures such as weight loss, treatment of sleep disordered breathing, control of blood pressure, attainment of cardiorespiratory fitness, and reduction of alcohol intake, and
  2. cannot be suppressed with medicine, and
  3. impairs one’s quality of life enough to warrant having an invasive procedure with a risk of serious complications in the range of 1-3%. This latter point is important because once you educate people about AF, they become less frightened, and, when less frightened, the AF often becomes less burdensome.

The AHA and ACC recently published an update to the 2014 AF treatment guidelines. I wrote a few words on the new recommendations.

Here is the column: Ten Thoughts on the 2019 AF Treatment Guidelines.

References:

  1. Verma A et al.Approaches to Catheter Ablation for Persistent Atrial Fibrillation. New England Journal of Medicine2015; 372(19): 1812–1822. doi:10.1056/NEJMoa1408288.
  2. Sauer WH, Callans DJ. The Tribulations of Atrial Fibrillation Ablation Trialists. Circulation: Arrhythmia and Electrophysiology2016; 9(1). doi:10.1161/CIRCEP.115.003738.
  3. Redberg RF. Sham Controls in Medical Device Trials. New England Journal of Medicine2014; 371(10): 892–893. doi:10.1056/NEJMp1406388.
  4. Al-Lamee R et al.Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. The Lancet. doi:10.1016/S0140-6736(17)32714-9.
  5. Francis DP, Al-Lamee R. Percutaneous coronary intervention for stable angina in ORBITA – Authors’ reply. The Lancet2018; 392(10141): 28–30. doi:10.1016/S0140-6736(18)31190-5.
  6. Al-Lamee R, Francis DP. Swimming against the tide: insights from the ORBITA trial. EuroIntervention2017; 13(12): e1373–e1375. doi:10.4244/EIJV13I12A217.
  7. Marrouche NF et al.Catheter Ablation for Atrial Fibrillation with Heart Failure. New England Journal of Medicine2018; 378(5): 417–427. doi:10.1056/NEJMoa1707855.
  8. Rothwell PM. External validity of randomised controlled trials: “To whom do the results of this trial apply?” The Lancet2005; 365(9453): 82–93. doi:10.1016/S0140-6736(04)17670-8.

Thoughts on the Apple Watch

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Apple products are cool. I love them.

But (even) Apple will struggle delivering health.

Making healthy people healthier is fraught with problems.

At the core of this issue are the many snags of screening people for disease.

Here are 600 words I wrote for Medium: I’m a Heart Doctor. Here’s Why I’m Wary of the New Apple Watch

Here are my thoughts in the Wall Street Journal:  https://www.wsj.com/articles/apple-adds-heart-monitoring-fall-detection-features-to-its-watch-1536792518

And the Washington Post:  https://www.washingtonpost.com/technology/2018/09/14/what-cardiologists-think-about-apple-watchs-heart-tracking-feature/?utm_term=.3dd8d07c74f0

And The Atlantic:  https://www.theatlantic.com/technology/archive/2018/09/the-new-apple-watchs-heart-monitoring-is-complicated/570115/

And MarketWatch:  https://www.marketwatch.com/story/apple-watch-wants-to-monitor-your-hearts-health-and-cardiologists-say-it-could-make-you-worry-instead-2018-09-13

Even Slashdot:   https://science.slashdot.org/story/18/09/14/2125223/what-cardiologists-think-about-the-apple-watchs-heart-tracking-feature

My colleague Patrice Wendling from theheart.org |Medscape Cardiology captured some of my positive comments on the watch: https://www.medscape.com/viewarticle/902018

If you like academic prose, here is an editorial I co-wrote on AF-screening for the influential medical journal, JAMA-Internal Medicine: Screening for Atrial Fibrillation Comes With Many Snags

JMM

Also … You can hear my thoughts on the five top cardiology stories each week on my podcast: This Week in Cardiology. The link on iTunes is here: https://itunes.apple.com/us/podcast/this-week-in-cardiology/id991125169?mt=2

How dangerous are NSAIDs in patients with AF?

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One of the most commonly asked questions in the office is the treatment of arthritis pain. This comes up because of the concern over taking NSAIDs (non steroidal anti-inflammatory drugs) in patients who are on anticoagulants (such as warfarin, or dabigatran, rivaroxaban, apixaban).

My views on this matter have changed.

But first, I want to mention a study published in JACC that addressed the issue of NSAID use in pts with AF who take an anticoagulant.

This was a sub-analysis of the RELY trial, which pitted dabigatran vs warfarin. Remember, in the original RELY trial, the 150mg dose of dabigatran did better than warfarin at reducing strokes and had similar rates of bleeding

This sub-study looked back at nearly 3000 (of 18,000 total) patients who used NSAID at least once during the trial.

The results were not surprising:

  • NSAID use increased the risk for major bleeding.
  • GI bleeding in particular was almost double w NSAID use
  • NSAID use also associated w/ a 50% increase in ischemic stroke.

In a news piece on theheart.org|Medscape Cardiology, senior author Dr M Ezekowitz said “avoid NSAIDs in patients in anticoagulated pts.” An editorialist, Dr. Sam Schulman, said telling pts to take acetaminophen is not a solution, as most patients say it does nothing for their arthritis because it’s not an anti-inflammatory agent.

These used to my views. It was simple. Avoid NSAIDs when on AF drugs because they are dangerous.

I can’t believe it took me many years to change from this decidedly doctor-centric, non-patient-centered point of view.

I am now much more opened-minded about NSAID use.

My change started on social media. I remember pontificating on NSAIDs dangers when a smart person on Twitter suggested the competing dangers of immobility in older people with pain. That made me think. Then, you can add to that concern, the new revelations on the addictive properties of opioids.

And finally, perhaps most importantly is the problems of concluding NSAID danger from this sort of observational analysis. The authors acknowledge many limitations of their paper:

  • No info on dosing
  • No info on reasons for taking NSAIDs; baseline data did not capture presence of inflammatory diseases.
  • Crucially, we don’t know whether pts who took NSAIDs had more bleeds and ischemic strokes because they were sicker or because of the drug.

My NEW approach to patients with the problem of arthritic pain and AF is…

  • Suggest acetaminophen first. I think a lot of its non-effect stems from the nocebo effect: pts think it won’t work. I’ve looked at the arthritis literature and acetaminophen’s inferiority to NSAIDs in blinded studies is not clearly demonstrated.
  • Talk about dosing. NSAID dangers probably depend on dose. I try to get patients to use less of it.
  • Discuss risks of both immobility and drug adverse effects

I no longer just proscribe NSAIDs because they are dangerous. Life is dangerous.

JMM

How Hubris Impairs the Care of the Elderly

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An elderly man with atrial fibrillation (AF) asks whether to continue taking a clot-blocking drug to prevent stroke.

This is the gist of a case my colleague Dr Anish Koka recently posted on Twitter. It’s a great thread. Click here to get to the discussion.

The first question Anish raised was whether you would keep a 101-year-old man with AF on an anticoagulant. For the sake of argument, you could make him a her, or you could make him or her 91 years old.

Let’s just say it is a very old person with AF.

The pro-side of using the drug is that the more elderly one is, the more the risk of stroke, and the more devastating a stroke would be. Age is a major predictor of stroke.

The scenario here is similar to the quandary we had with thrombolytic (clot-busting) therapy for heart attacks in the era before stenting: older patients with heart attacks had more risk from the blockage (death, heart failure) but they also had more risk from the clot-dissolving drug (brain bleeding.) Because of the high consequences, the drug delivered greater risk reductions but at the cost of a greater chance of devastating bleeding.

Use of the anticoagulant in an elder therefore provides a robust degree of probability benefit in the future.

The down side of keeping an elder on an anticoagulant is the higher risk of bleeding. Older people have a higher rate of harm (bleeding) from the drug.

Evidence cannot help us here. There are no studies that include patients in their ninth or tenth decade. The word for using evidence acquired in 60 year-olds to the very elderly is… foolish.

Also foolish is the idea of letting the patient decide. How the hell is the patient supposed to know the right answer? The way we frame this decision will surely sway the patient. Yes, it’s right to share the decision with the patient, but the advisor need be square on the decision at hand. Giving patients a menu of choices is akin to abandonment.

This decision, like so many in medicine, requires judgment. It also means resisting hubris.

The typical hubristic reasoning in this case means considering two potential errors. An error of omission occurs here if we choose not to use the anticoagulant and the man has a stroke. We omitted the drug and that omission played a role in his stroke. An error of commission occurs if we choose to use the anticoagulant and he suffers catastrophic bleeding. We committed him to preventive therapy and that commission played a role in his demise.

Many doctors struggle with this choice.

The struggle exposes our hubris. We are falsely confident that we control outcomes of a person who has lived for decades.

I strongly believe we do not control this person’s outcomes.

One need not consult actuarial tables to assess the chance of a 90 or 100 year-old person dying in the next year. It’s high–whether we recommend preventive therapy or not.

That being said, I would not take the nihilistic view that there isn’t a correct answer.I believe there is a best answer.

It is: do not use an anticoagulant.

During a recent trip to the University of Calgary, my electrophysiology colleague Dr George (Yorgo) Veenhuyzen taught me an important lesson about decision making under uncertainty. It applies to this scenario.

The lesson goes like this: when there is true equipoise of a treatment (a complete counterbalance), and that treatment has potential harm and added cost, the right answer is not to treat.

Of course it is. The doctor’s golden rule is first, do no harm.

In the very elderly, there is no proven benefit of anticoagulant drugs. This would require a study of very elderly people. There isn’t one; nor will there ever be. There is however a well-known increased risk of harm due to bleeding and added cost of the drug.

I would also add to my Canadian friend’s logic that people who have been lucky enough to live to old age deserve the right to avoid iatronegensis–or harm brought by us.

In this particular case, Anish tells us the elderly man did not continue with the anticoagulant. He went on to suffer a stroke.

Anish tempts us with further choices: should we “do nothing” or should we recommend clot extraction using the new devices.

This is an easier question to answer. The same thinking applies, only with a special caveat. Of course, I would not recommend a femoral access and invasive procedure in a very elderly man. The studies of these devices were done in much younger patients. Plus, it takes little experience to know the difficulties and potential harm of threading catheters up the blood vessels of 90+ year-olds.

But I would also argue that “do nothing” is not the alternative. One of the greatest errors of our time, one that frustrates me immensely, is the idea that not doing invasive procedures equates to doing nothing. How many times have I heard a nurse or doctor say “we have nothing to offer?”

We have plenty to offer people at the end of life. We can offer caring. Nowhere in the definition of caring is doing invasive procedures.

We can care for this man by attending to his needs and by trying to relieve any of his suffering.

Another thing we can do is reframe our thinking. Rather than bemoan this man’s fate, we could celebrate the fact that he lived a long life, one that will be mostly compressed without much morbidity. That is, assuming he receives adequate palliative care.

Finally, in this era of death denial and increasingly invasive medical technology, it would be wise to heed the words of the late Ivan Illich, a critic-philosopher, and once catholic priest.

In his prescient book Medical Nemesis (circa 1975), Illich wrote of three forms of iatrogenesis wrought by the medical establishment. Clinical iatrogenesis is harm from medical error. Social iatrogenesis is the medicalization of normal life.

But the most insidious form of harm from the medical guild is a cultural iatrogenesis–or medicalization that corrupts the essence of what it is to be human.

Illich wrote that “the medicalization of society has brought the epoch of natural death to an end. Western man has lost the right to preside at his act of dying.”

JMM

Musings on the CABANA trial — AF ablation vs Drugs

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Last week at the Heart Rhythm Society meeting in Boston, Dr. Douglas Packer from the Mayo Clinic presented results of The Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial.

I cannot remember a more consequential HRS (Heart Rhythm Society) meeting. Before and after the presentation, CABANA talk dominated conversations amongst colleagues.

I wrote a column directed at an audience of doctors for the theHeart.org | Medscape Cardiology. You can find it here>  CABANA: Initial Thoughts on AF Ablation vs Drugs

CABANA is important. AF ablation is big business. Hospitals, doctors and the companies that make equipment for the procedure make lots of money from AF ablation. What’s weird about all this growth is that we have not had solid evidence that the procedure improves outcomes, such as stroke or death.

That’s the question CABANA addressed.

You take patients with AF who feel poorly and you put half the group on anti-arrhythmic drugs and the other half get ablation. Then you follow them for years and measure how many in each group have strokes, bleeding, death or cardiac arrest. Those four outcomes were called the primary endpoint. CABANA had many other secondary endpoints–how much AF occurred, quality of life, hospital admissions, etc.

CABANA works like a typical clinical trial: ask a question, then randomly assign patients to different treatments and decide what outcome to measure. The random assignment to treatment group is key because in ideal conditions the only difference between the group is the treatment–drugs or ablation.

The authors hypothesis held that ablation would be superior to drugs for reducing the primary outcome. Remember the primary outcome was disabling stroke, death, bleeding or cardiac arrest. Since the groups are randomized, and all other things equal, then if the ablation arm had fewer events, we could say ablation is superior. Or ablation caused the fewer events.

That is NOT what happened.

The number of primary endpoint events in the ablation and medication were very close–not even close to a statistical difference. The first line of the authors conclusion was that “ablation did not produce a significant reduction in the primary endpoint and all-cause mortality.”

Controversy:

After Dr. Packer presented the main results he then showed results depending on treatment received. In procedure trials some patients cross arms. (If drugs did not work, patients could have ablation, for instance.) So being randomized to an arm does not mean you have to stay in that arm. About 27% who were in the drug arm crossed over to the ablation arm while 9% in the ablation never received the ablation (mostly because of a change in mind.)

The authors knew this would happen and planned for it statistically. But crossovers do complicate the analysis.

Dr Packer showed the as-treated event rates and here the results favored ablation–with lower rates of the primary endpoint. This led some leaders in the field to say ablation was indeed superior.

But you can’t say this.

Statisticians call the use of as-treated comparisons scientific malfeasance. This sounds harsh, but the reason they say it is because when you analyze by treatment received you don’t preserve randomization. And, when groups aren’t randomized, you don’t know whether it was the ablation that caused the improvement or some other confounding factor.

The as-treated analysis essentially becomes an observational study — which make only associations, but not causation claims. (For instance, there are numerous observational studies showing that patients have fewer strokes after ablation, but no one uses these as proof because in observational studies, the reason is likely that healthier people have catheter ablation.) In CABANA, the patients that crossed over were likely different from those that stayed in the drug arm.

A Cautious Interpretation of CABANA: 

One way to interpret CABANA and preserve scientific rules is to say the trial did not actually compare ablation vs drugs as was intended but rather it compared the strategy of ablation vs initial medical therapy with ablation for recurring symptoms.In this scenario, there can be no claim that ablation is superior to drugs for reducing major outcomes, but we can preserve the possibility that ablation remains a reasonable option for selected patients with AF.

Safety:

Packer presented the safety outcomes of ablation vs drugs. He did not make any formal comparisons, but I tallied the total number of each and there were far more complications in the ablation arm. Surprisingly, there were no deaths related to the procedure, no atrial-esophageal fistulas and no major strokes. This is surprising because about a 1000 people had AF ablation.

Two things to remember about safety is that CABANA was done in experienced centers. I doubt that real-world everyday AF ablation is as safe as it was in CABANA. Second, the complications of AF ablation can have immense downside; they are asymmetric. When a middle-aged person has a stroke, or death from the procedure, this is especially tragic because he or she would surely not have died anytime soon of the AF.

The last thing to say about these results is that they are not yet published in a journal. That means it has not made it through peer review. We will learn more from the published paper.

Where to go from here: 

First, since CABANA found no significance difference in outcomes, we are left with the idea that ablation is done to improve symptoms or quality of life. This is a good goal for any treatment, but it’s hard to sort out how much ablation helps when patients and doctors know who received it. It’s why drug trials have a placebo control.

At least three investigators I spoke with are now planning a placebo-controlled sham trial. In this sort of trial, patients and caregivers are blinded to whether or not an AF ablation is done. Half the group will get a basic EP study, and ablation of arrhythmias on the right side, and no ablation in the left atrium–where AF comes from. The other half gets regular AF ablation. Then no one knows, and the patient is followed.

The history of such placebo controlled procedures have shown that many interventions we thought worked did not do any better than a placebo procedure–renal denervation, vertebroplasty, and placing stents in coronaries for relief of angina.

I know, this may upset some of you. Indeed, a quick-thinking response to doing a sham-control trial is that is unethical to expose patients to a fake procedure. But when you think harder and slower, you realize that the far greater ethical dilemma is exposing millions of people to a risky procedure that produces mostly a placebo effect.

Second, CABANA does not change my current clinical practice. I see no reason to offer more or less AF ablation. I will still do the same general things:

  1. Assess the patients to find out why AF is occurring. Then treat that problem. If it’s obesity or sleep apnea, AF gets better with weight loss and better sleep. If the AF occurred because of transient stress, wait for the stress to past. If the AF occurs because of alcohol, counsel the person to drink less. If AF occurs because of excess training, reduce training.
  2. Remove fear and educate patients. This is the biggest thing. Many patients want stuff done because they fear AF. We teach them about AF and we warn that often times the most dangerous thing about AF can be our treatments. This sometimes takes multiple visits.
  3. If the patient has risk factors for stroke (age, high blood pressure, diabetes, prior stroke, heart failure, blockages elsewhere), we counsel on the benefit/risks of anticoagulation.
  4. If the AF is causing an excessive pulse, we give drugs to slow the rate, so as to prevent heart failure.
  5. If AF persists and if it causes symptoms, then we try drugs. I often use drugs in as needed way. For people with AF once or month or so, they can take an AF drug at that time.
  6. I reserve AF ablation for patients who continue to have AF despite treatment of risk factors and use of AF drugs. I remain a cautious AF ablation doctor.

CABANA has not changed this approach.

Why is Science Emotional?

The final thing to say about CABANA is that its failure to show benefit in outcomes caused some to be disappointed, sad even. Some acted as if it was a failure.

This is a weird view of science. CABANA and trials like it deserve our respect whether or not they show benefit of an anointed procedure or drug. Scientific experiments should be designed to find truth. If the truth is that AF ablation is not better than drugs, then that is really good to know.

Our goal as doctors is not to instrument as many people as possible, but to help as many people as possible.

Yes, there are some purists who say the trial was not powered to find benefit–meaning, the null results of CABANA could be wrong and there was actually a benefit, but the trial did not detect it because it did not have enough patients or had too many people not getting the treatment they were assigned.

This is a reasonable argument, though one must remember that if a treatment is really superior, it should not take thousands of patients to show that it works. Saying a trial found no difference  because it is underpowered often means that the two treatment arms are minimally different.

JMM

PS: I will not accept comments that contain personal anecdotes of AF. These are problematic because one of the first rules I tell patients is not to compare their AF or their AF treatment to others. AF affects people in many different ways.

Thoughts on CABANA — The biggest study in AF ablation in years

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(The CABANA trial is slated for release in two days at the 2018 HRS Meeting. Here is a preview.)

Technology has made modern life easier. This is good for lots of things, but not for avoiding atrial fibrillation (AF).

As people in Western society grow older, heavier, less physically active, more distracted, and perhaps more anxious, the growing epidemic of AF should surprise no one.

AF is a serious condition that can impair quality of life and cause complications such as stroke and heart failure. AF drugs are woeful, risk factors are hard to modify; these realities have led many experts to embrace catheter ablation of AF. Favorable reimbursement for AF ablation has also not hurt its growth.

Increasing enthusiasm for AF ablation, however, has occurred without robust outcomes evidence.

  • Does creating scar in the left atrium make people live longer or have fewer strokes?
  • Is the risk of the procedure balanced by better outcomes in the future?
  • Are AF episodes (recorded on monitors or smartphones) a good surrogate marker of trouble? We already know that AF ablation reduces AF episodes compared to drugs, but to what end–does this reduction in episodes translate to less stroke, longer life or or fewer  heart failure admissions?

This is why The Catheter Ablation vs Antiarrthymic Drug Therapy for Atrial Fibrillation (CABANA) trial[1] may be the most important trial in modern electrophysiology. Dr. Douglas Packer from the Mayo Clinic is set to present CABANA findings this week at the 2018 Heart Rhythm Society Scientific Sessions.

Here is a primer on what to expect:

We must first consider the type of patient included and excluded in the study. CABANA is an outcomes trial so the authors wanted patients with AF who had an increased risk of complications. They included patients similar to those in the famous rate- vs rhythm-control outcomes study called the AFFIRM trial[2]—those over the age of 65, or, if under 65, with at least one risk factor for stroke. Patients had to have documented AF and be eligible for both ablation and use of at least two drugs.

The authors excluded young patients with AF who had no risk factors, those who had already failed two or more drugs and those who had reversible causes of AF, such as post-op AF or alcohol-induced AF. Patients with hypertrophic cardiomyopathy and those with previous ablation were also excluded.

CABANA compared left atrial ablation (mandating pulmonary vein isolation) to medical therapy. Ablation could be done with various RF catheters or a cryoballoon.  Medical therapy could include either rate or rhythm-control drugs—which is important.

The distribution of rate vs rhythm medication used in the comparator arm deserves attention. It’s good that both rate- and rhythm-control strategies were allowed, because if only rhythm control drugs were allowed and then ablation did better, one could argue that ablation beat an inferior comparator. Letting doctors choose either rate-or rhythm-control mirrors regular practice and thus improves the external validity (generalizability) of the study.

Since CABANA is an outcomes trial, we also have to note any baseline differences in patients. Randomization usually sorts this out, but if more patients in one group received non-vitamin-K-oral antagonists, for example, that would be important.

CABANA recruited patients from more than 100 centers worldwide. That’s a lot of data and patients to keep track of. We must keep an eye out for dropout. One always looks at the rate of dropout vs the difference in outcomes. It hurts reliability if the trial has a 3% dropout rate and the absolute difference in outcomes was only 1%.

Clinical trials must choose an endpoint to measure. In CABANA, the original primary endpoint was mortality. That’s a good endpoint because it’s easy to count and not susceptible to bias.

The problem with death as an endpoint is that AF isn’t life-threatening in the short-term, and to show a difference in death rates requires a lot of patients. About halfway through the trial, CABANA leaders along with the data safety monitors met to address two problems–a lower than expected event rate, and slower than projected accrual of study subjects.

They did not have access to any treatment-specific outcomes but decided to change the endpoint to a composite of four outcomes–total mortality, disabling stroke, serious bleeding, or cardiac arrest.  Overall mortality was changed to one of many secondary endpoints.

Changing the primary endpoint allows for more events to accrue and makes finding differences between the treatment arms easier. But it also complicates understanding the trial because one has to see which of the primary endpoints “drove” the result.

One must also consider that two of four primary endpoints (disabling stroke and serious bleeding) are susceptible to ascertainment bias.

To learn more about adjudication of endpoints, I reached out to trialist Dr Milton Packer who explained in an email that in an unblinded trial, like CABANA, sorting out a disabling stroke from a non-disabling stroke could be tricky. All CABANA centers were ablation centers, so Packer asked, “Were investigators more likely to identify and report strokes that occurred in non-ablated patients? Remember, he added, the adjudication process only operates on reported strokes.”

Packer identified another tricky part of the CABANA results—the choice to analyze data using a time-to-first event approach. Here, a major bleed that occurs before a disabling stroke will mask the stroke. That means all strokes that occur in the trial may not be counted in the primary endpoint.

CABANA also includes 13 different secondary endpoints ranging from hard endpoints like death to softer endpoints like quality of life. One endpoint that you can expect to be better with ablation is freedom from recurrent AF episodes. But what if ablation dramatically reduces AF but there are no or minimal differences in outcomes? You see the problem: AF episodes might be a lousy surrogate measure. That would have great implications for digital AF screening.

Finally, the lack of a placebo controlled ablation arm will limit interpretation of subjective endpoints. I am sorry, but it’s true. Consider two key secondary endpoints, the decision to admit to the hospital for cardiovascular reasons and quality of life scores. Knowledge of the treatment arm surely affects these outcomes.

If CABANA finds no difference in mortality or stroke, and the only reason to ablate AF is to relieve symptoms, then a placebo-controlled AF ablation trial will be required.

Here are two posts I’ve written on AF ablation and placebo: Is AF ablation a big placebo?  and on theHeart.org | Medscape Cardiology: Could Ablation for AF Be an Elaborate Placebo?

References:

1.         Packer DL, Mark DB, Robb RA, et al. Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) Trial: Study Rationale and Design. American Heart Journal. 2018.
2.         A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation. New England Journal of Medicine. 2002;347:1825-1833.

Take-home messages from Western AF 2018

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The Western AF symposium may have had corporate sponsors, but it was no boondoggle. The sessions start at 0715 and go through 1830. Your head spins at the end of the conference. I learned a lot.

Here are some fast-writing thoughts:

New Energy Source for Ablation

Electroporation looks to be a promising new energy source for ablation. The problem with RF-energy, or cryo-energy, is collateral damage. The atria lie close to the esophagus, coronaries and phrenic nerves.

Electroporation “ablates” heart tissue without damaging structures nearby. It’s also called pulsed field ablation. This is damn early data. We have to wait for more studies.

Sham Trial for AF ablation is coming:

I wrote about this on theheart.org | Medscape Cardiology in 2016.

As long as the target for AF ablation is reduction of symptoms, then it has to pass a sham control.

Professor Carina Blomstrom-Lundqvist presented results of the CAPTAF trial, which was a study of AF ablation in relatively young people. She found that the difference in quality of life score after ablation was not driven by the difference in AF burden at 12 months. Translation: some people feel better after AF ablation but still have AF. That is provocative.

Two leaders in the field made comments on this:

In addition to comments from two of the giants in EP, I also spoke with another (unnamed) leader in EP who said his group has talked among themselves about doing a sham trial but did not want to broadcast it for fear that someone else beats them to it.

We need the sham trial to sort out the placebo effect of ablation. Look up the ORBITA trial.

Left Atrial Appendage Closure Meets little Resistance:

There were multiple talks on left atrial appendage closure. All of them positive. Again, Professor Gerhard Hindricks took to the Q & A microphone and expressed concern of the evidence in support of this procedure.

During one session in which a panel of EP doctors expressed great enthusiasm about the procedure, Dr. Elaine Hylek, an internal medicine doctor and trialist for anticoagulant drugs, stood up to the mic and said, “you guys are scaring me.”

Her concerns are similar to mine:

  • The evidence suggesting LAAO is noninferior to warfarin are not convincing
  • The device has not been tested in patients ineligible for anticoagulants (these higher risk patients may be less likely to benefit.)
  • The device has not been tested against the direct-acting oral anticoagulants, dabigatran, rivaroxaban and apixaban.

AF and Heart Failure:

Western AF celebrated recent publication of CASTLE-AF.

CASTLE-AF compared ablation of AF vs continued medical management in patients with heart failure. AF ablation reduced death rates and hospital admission for heart failure.

My comments on this trial induced great criticism from Dr. Milton Packer, a heart failure expert. Dr. Packer’s concerns centered on the methods of the trial.

Professor Jon Kalman (Melbourne, Australia) gave a talk that may have changed my mind about AF and heart failure. He discussed a recent study from his group called CAMERA-MRI. They studied patients with AF and heart failure, comparing a rate control strategy vs ablation. Patients in the ablation group had much greater improvements in heart function (as measured by the ejection fraction).

What this data might change is the idea that AF causes heart failure (heart muscle weakness) only if the rate is excessive. In CAMERA-MRI, all patients had good rate control. Those with heart rate control improved their EF by 4.4%. But those in the ablation group improved by 18%.

It’s possible therefore that the AF itself, the irregularity, or something else, contributes to weakness of the heart. CAMERA-MRI isn’t the only study that found this. The Bordeaux group published similar findings in 2004.

Heart rate control remains a crucial part of treatment for AF.  If you don’t get good heart rate control, heart failure is likely.

But the combination of previous studies on AF ablation and heart failure, and CAMERA-MRI and CASTLE-AF all point towards a benefit for ablation in suitable patients.

The latter point is key: CASTLE-AF enrolled young, mostly male patients with only moderate degrees of heart muscle weakness. This data does not apply to the vast majority of patients with heart failure who are older and have multiple other problems. EPs mustn’t run amok offering ablation to patients unlike those in the CASTLE-AF.

And we still need to answer Dr. Packer’s criticisms of CASTLE-AF.

Finally, Dr. Doug Packer from Mayo gave a prelude to the CABANA trial. This comparison of drugs vs ablation in older patients with AF will look at hard outcomes, like death and stroke. It will be a landmark trial for our field.

JMM

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