Dr John M

cardiac electrophysiologist, cyclist, learner

COVID19 and Finding Effective Medical Therapies

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This post introduces a column I wrote over at TheHeart.org | Medscape Cardiology

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The good news is that most people infected with coronavirus don’t need a hospital or doctor. But some do. Some get very ill.

The maddening thing is that doctors don’t have an effective treatment for the virus. There are no cures. The Worldmeter today shows nearly 5 million infections and more than 300,000 deaths. And no effective therapy.

Excluding a possibly modest effect of Remdesivir, our care is supportive, which is medical jargon for giving simple things like oxygen, acetaminophen, IV fluids and letting the body do the rest.

That sentence makes supportive care seem simple, but it is not so with COVID19. The virus can cause havoc in the body. Damage to the lungs (pneumonia) gets most of the attention, but other organs can be harmed.

COVID19 and Clotting:

One system in particular that can go haywire is the clotting system (medical term is coagulation). Many studies have shown that patients ill with COVID19 can have excess clotting.

(It’s not well known, but our bodies do this elegant dance to keep the blood clotting factors and thinning factors in balance. Medical people call this equilibrium or homeostasis of the coagulation system.)

We now have blood tests that give us a window, albeit a somewhat opaque one, onto the clotting system. Also imperfect is the observation that patients with COVID19 can clot off intravenous lines, or on autopsy, clots can be seen in organs.

The worry about excess clotting (medical term is thrombosis) causes doctors to consider using drugs called anticoagulants, which come in many different forms–heparin (IV), low-molecular weight heparin (sub-q shots) and direct-acting oral anticoagulants (DOACs).

“If there are too many clots, you give clot-blocking drugs”…goes the Cartesian body-as-a-machine thinking.

Alas, the problem is a) infection control issues often makes it impossible to scan COVID19 patients, so we don’t know if they actually have clots in their organs, and b) anticoagulants can accentuate bleeding, which can be horrific.

Anticoagulants Work in Some Diseases:

In non-COVID19 patients, we know anticoagulant drugs work because we have done proper trials.

Take anticoagulants for patients with atrial fibrillation. We know these drugs work because in trials with thousands of AF patients who take the drug compared to thousands who take placebo, fewer people have strokes while taking anticoagulants. These trials also tally bleeds and thus doctors can know the net benefits, which favor the anticoagulants in selected patients.

Proper Trials = Knowledge:

The essential part of a proper trial is that the choice to use the drug or not (placebo) is random. That means in a randomized controlled trial (RCT) you end up with two balanced groups of patients. (Well, mostly balanced). This is crucial because if one group does better, you know it was drug, and not because one group was healthier, or sicker.

Trials, of course, take effort. You have to write a protocol, specify what you will measure and the types of patients to include or exclude, get ethical approval, recruit sites, consent patients, to name just a few tasks. You also have to blind the patients and doctors so they don’t know the treatment arms. This takes money and time. RCTs don’t make themselves.

The Limits of Observation:

In the COVID era, people don’t want to wait. So instead, investigators are recording outcomes on what happens to patients who have been treated.

These are called observational studies; people simply observe what happens after the fact.

Observational studies are deeply problematic for deciding what caused what.

A simple example: a heart surgeon decides to do an extra procedure during routine valve surgery, say, a closure of the left atrial appendage in the heart. It takes an extra few minutes and the idea is that closure of the appendage will reduce clots and that will reduce future stroke.

Then researchers look back, and voila, patients who had the extra procedure during valve surgery had fewer strokes than patients who did not have it. The procedure must work. Wrong.

The problem is that the surgeon’s decision to close the appendage was not random: thus, she may have chosen healthier patients to do the procedure on. And that is why the intervention looked good. We call this selection bias.

The Pressure of COVID:

My post over at TheHeart.org | Medscape Cardiology critiqued a study published in an influential cardiology journal. A group of researchers from Mt. Sinai hospital system in New York City looked back on about 3000 patients with COVID19.

They studied the association between the use of anticoagulants (or non-use) and death in the hospital. They specifically considered patients sick enough to require ventilators.

They found that patients who received the anticoagulants had better survival. One of the authors was actually the editor-in-chief of the journal that published the study. His name is Dr. Valentin Fuster and he is one of the most-cited most influential voices in cardiology today.

Dr. Fuster was impressed with the results and went to the media to say:

I can tell you any family of mine who will have this disease absolutely will be on antithrombotic therapy and, actually, so are all of the patients at Mount Sinai now.

The problem was that these observations were biased. The choice to use anticoagulation was not random. So you can’t know if the drugs made survival better or whether it was something else.

Multiple experts, writing on Twitter, identified a well-known bias called immortal time bias. The last link explains the problem. But this was only one of the many biases in this observational study.

The Harm of Observational Studies:

Remember in the beginning I wrote that there was no known therapy for COVID19? One of the main reasons is observational studies.

Take the case of Mt. Sinai hospital. Because of this study, and the influence of the researchers, and publication in a big journal, there is a protocol in which sick patients get treated with anticoagulants. A treatment is codified as standard of care. And if it is codified at a big hospital in NY, it will likely be codified in other hospitals.

Here is the issue: now you want to do a study to find out whether anticoagulants work. A patient is asked to participate, which means they could receive placebo. The patient does a Google search and up pops Dr. Fuster’s comments to the Washington Post alongside a headline saying anticoagulants have promise in COVID19.

In this setting, the patient as well as many doctors will no longer have that feeling of uncertainty about the use of anticoagulants. We call this equipoise. And without it, you can’t ethically do trials.

The lack of equipoise causes us to persist with unproven therapies. Take Hydroxychloroquine–we still don’t have a proper trial.

Smart people, people whom I respect, say that the desperation of COVID19 is such that we should use the data we have.

I do not agree. In my column, I argue that observational data may actually be worse than no data.

The title of it is: Some Data May Be Worse Than No Data in the COVID Era

JMM

The Case for Opening (some) Pools In COVID19 Pandemic

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The COVID crisis has decimated water exercise. Can we rethink pool closures?

A significant number of my older patients relied on pools for their fitness. During a pandemic, you can stay active or fit only if you have good legs and joints. Walkers, runners, and cyclists have no problem; they play outside in the Spring weather.

People with bone/joint problems, fitness swimmers, and young children who normally take swim lessons this time of year are out of luck.

Consider the place I swim—the Mary T Meagher Natatorium, named after Mary T, a Louisville native, who won Olympic gold in 1984. The place is an ode to Sparta. The expansive no-frills public facility has tons of space to socially distance. 

Before I tell you my proposal, let’s set out some givens on May 13.

  • Three months into this crisis literally everyone knows the deal: the coronavirus is not going away. It will be as dangerous next year as this year; 
  • Older people are more vulnerable, and they know it;
  • The virus travels via droplets so distance reduces your odds of infection;
  • Other health conditions, such as mental stress, heart disease, obesity, diabetes, immobility and arthritis, do not become less problematic during a pandemic;
  • People differ in their risk tolerance; some people see a 0.5% infection fatality rate as scary as heck, others see a 99.5% chance of survival. 
  • Hand washing reduces transmission. Masks might also reduce transmission.
  • Finally, and this is key, the community-level risk for the virus differs greatly across the US. Policy in New York City or Chicago ought not be the same for rural Kansas or Texas. 

I’ve said before that Americans are not stupid. We can, and we must, rely on people to make good decisions for themselves and their community.

Now to the proposal to open some public pools: 

Start with a big sign in front that says we are open but these are not normal times. 

You place a bunch of hand-sanitizer stations at the entrance.

Tell people to wear a mask and leave it at the poolside. 

Then let them swim, do water aerobics at a distance, and allow teenagers to teach toddlers to swim. 

After the workout, people put their mask on and leave. If they have to use a locker room or shower, that’s fine. I don’t know about women, but in the men’s locker room, social distancing comes naturally whilst being naked.

When schools open in the fall, and they must open, kids should play sports. This includes the swim teams. Teenagers have minimal risk from the virus. If they are mixing in schools, there is no reason not to let them mix on the field and in pools. 

Caveat: I realize that summer scenes of hundreds of children mixed with adults in public pools is more problematic. My proposal applies to opening pools for the purpose of fitness. 

An unintended positive externality: the act of allowing people to exercise in water would be a small step towards making peace with the virus. If people don’t want to risk catching the virus, they can stay away. 

If we let people go to the grocery, walk in crowded parks or shop at gardening stores, we ought to let them enjoy the water. 

JMM 

Conflict of Interest: After fracturing my foot 2 years ago, I rediscovered the joys of swimming. Before the pandemic I often recommended swimming to my patients because there is something soothing about immersion in water.

Will the Uncertainties of COVID Science Resurrect Blogs?

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Health news was popular before the pandemic. Now, almost all news is health news.

It’s not only a rapt audience contributing to the deluge of COVID19 news. Two other factors: 1) the availability of preprint servers, digital archives where a scientific paper can be published without formal peer-review and 2) the attention economy.

Attention is currency. Since the business model of both scientific journals, internet-based medical news sites and mainstream media is attention (citations, views), both groups are eager to publish all that is COVID.

The slew of COVID papers are outpacing the normal vetting process. It happened with hydroxychloroquine. In normal times, a study as weak as the one which launched this unproven drug would have never passed muster.

Media has the same problem as medical journals. They struggle to keep up with the public’s need for COVID information. Vetting was far from perfect before COVID, but there used to be more time to assess a study, seek expert opinion and add a bit of caution.

For instance, pre-COVID, journalists would often get an embargoed copy of a study days before it was published. The luxury of time does not exist during the pandemic.

Enter blogs

Blogs were hip 10-15 years ago, but have given way to Instagram, Twitter, and podcasts. Content consumption via the printed word seems quaint.

But these days I find myself increasingly drawn to the raw and candid nature of un-edited blogs. Here is why: A study gets covered in mainstream media. It fits an anointed narrative. Once one media site covers it, others feel like they have to cover it as well. Then Twitter and Facebook amplify it.

Boom, a message becomes accepted, often codified. If slow science pre-COVID was imperfect, the fast science of COVID can be deeply problematic. I’ve already mentioned hydroxychloroquine.

Another example is a study showing that cities that started social distancing earlier and stayed with it longer had better economic outcomes during the 1918 flu pandemic.

That narrative aligned well with the notion that stricter/longer lockdowns were the right choice. Keeping the virus from spreading is good for health and good for the economy.

Here’s the problem: other researchers could not reproduce it. When they tried, they found noise instead of signal.

Where did I read that? No, not in the NYT or WashPo or NPR; they don’t have the time or the incentive to correct a story. I read it on a blog from a distinguished professor of statistics at Columbia.

Professor Andrew Gelman writes;

The larger issue is that there seem to be more outlets for positive claims than negative claims. “We found X” can get you publication in a top journal and major media coverage—in this case, even before publication. “We didn’t find X” . . . that’s a tougher sell.

Another example, one which I may opine on in coming days:

A prominent group of researchers in cardiology published an observational study of patients with COVID who received clot-blocking drugs called anticoagulants. The top-line result was that patients who got the anticoagulants did better.

One of the authors of the study is the editor-in-chief of the journal that published the paper. He’s influential. Mainstream media covered the story. The WashPo used an upbeat headline and weaved a positive narrative.

This, too, fits with another common theme: keep socially distancing because if you get the virus later rather than sooner doctors will have found better treatments. And this may be true, but the study on anticoagulants was far too flawed to make any such conclusion.

Where did I get that? Well, since this is cardiology, I could critically appraise it myself. But say I wasn’t a cardiologist.

I, or you, or anyone, could have read the blog of intensive-care doctor, Josh Farkas, who writes on topics related to ICU medicine. Here is his assessment of the study’s fatal problem, including something technical called immortal time bias.

Numerous sources of bias exist.  Perhaps most notable is immortal time bias – patients who live longer may survive long enough to be diagnosed with DVT/PE and be treated with anticoagulation (whereas other patients may die rapidly, before being able to be prescribed anticoagulation).

You might wonder how one is supposed to know if information from a blog is reliable. This is where thinking comes in; it’s under-rated. You start with the content. Make a judgement.

You can also use meta-data: for instance, a blog with adverts for life-hacks or proprietary supplements might downgrade your confidence. Keep in mind, though, that many medical journals make you watch an ad before looking at a study.

One of my favorite American heroes, Mr Rogers, famously said when you are scared look for the helpers. I wonder… in this scary pandemic will more people start looking for help from the doctors, professors and thinkers taking time to write online. One of my recent favorites is Marginal Revolution.

Medical studies often get discussed on Twitter on the day of publication. Indeed, it is a great place for watching and conversing in realtime, but, as Doctor Bryan Vartabedian writes, in a blog, the ephemeral nature of Twitter makes it a lousy place to park ideas.

Finally, and this is big: science is not supposed to be held up as law; it’s supposed to be corrected. Being wrong in science is normal. Humility is essential. More and more, I am interested in how we communicate that core tenet to the public.

The tension, of course, is that the public can’t handle uncertainty.

I wonder if that is true. Perhaps it is the opposite: is it the faux certainty that bolsters distrust and division?

JMM

Like Minds on COVID19

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At nearly the same time I posted yesterday, The Lancet published this editorial from Swedish epidemiologist Prof Johan Giesecke. Some excerpts:

It has become clear that a hard lockdown does not protect old and frail people living in care homes—a population the lockdown was designed to protect. Neither does it decrease mortality from COVID-19, which is evident when comparing the UK’s experience with that of other European countries.

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Everyone will be exposed to severe acute respiratory syndrome coronavirus, and most people will become infected

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There is very little we can do to prevent this spread: a lockdown might delay severe cases for a while, but once restrictions are eased, cases will reappear. I expect that when we count the number of deaths from COVID-19 in each country in 1 year from now, the figures will be similar, regardless of measures taken.

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Measures to flatten the curve might have an effect, but a lockdown only pushes the severe cases into the future —it will not prevent them.

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In summary, COVID-19 is a disease that is highly infectious and spreads rapidly through society. It is often quite symptomless and might pass unnoticed, but it also causes severe disease, and even death, in a proportion of the population, and our most important task is not to stop spread, which is all but futile, but to concentrate on giving the unfortunate victims optimal care.

Link to the paper here

JMM

Can We Discuss Flatten-the-Curve in COVID19? My Eight Assertions

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On Telehealth, an older couple asked me a tough question about COVID19. They asked whether this virus would either be gone or less dangerous in 6 months to a year.

It was a curious question. I replied, Why do you ask?

Doc, we have a big family with many children and grandchildren, most of whom live nearby. We miss them. We’ve been isolating, but it’s hard; we did it for 6 weeks. Doing it for a year or more would be miserable.

We saw on the news today that the battle with the virus would be long. A man called it a cruel new normal.

So doc, if you tell me the the virus will be gone in a year or it will be less dangerous to get infected later, then it makes sense for us to keep isolating. But if the situation will not be much different a year from now, we would just as soon see our family and take the risk. Of course, doc, we would still be sensible. We’d not visit if someone was sick; we would wash our hands and wear masks.

Indeed my patient was correct. Dr. Scott Gottlieb writing in the WSJ, did not mince words:

Hospitals and public-health systems will have to contend with persistent disease and death.

In essence, my couple asks whether flatten-the-curve policies save lives. Buried in that question are three other questions: namely, in one year, will the virus be 1) gone, or 2) less contagious, or 3) less deadly? If any of those three are true, then my couple could rationally decide to stay lonely for a year or more.

I study this new virus and this once-in-a-lifetime-situation every day.

I don’t think flatten-the-curve policies will change any of those issues. Let me explain my reasoning. I may be wrong; tell me if you disagree in the comments.

Flatten-the-Curve Purpose

You now know the famous curves–one with an early surge of disease, and the other flatter curve that spreads the infections over time. The y-axis is number of COVID19 cases.


In early March the COVID19 narratives were from Wuhan, Iran, Lombardy and Spain, places where surges overwhelmed hospitals. In the US, COVID cases spiked in NYC.

Early COVID19 surges were over-running some big-city hospitals. This was bad because it caused excess or preventable death–people who could have been saved were not saved because of shortages of ICU beds, dialysis equipment, staff and ventilators.

Social distancing policies and postponement of elective medical care were necessary to stop the excess deaths. These policies allowed time for hospitals to prepare for COVID19 cases and for doctors to learn how best to treat these patients. Exhibit A: not intubating patients early. 

Social distancing worked. The number of cases slowed and the US got into the blue part of the curve. But now, months later, the narrative has changed.

Change in Flatten-the-Curve Narrative

What was once flatten the curve to prevent over-running hospitals has changed to flatten the curve to save lives. Some likened moderation of social distancing to human sacrifice.

That change in framing, I believe, is misleading. I will argue that the cumulative deaths from COVID19 will not be reduced significantly by flatten-the-curve policies. And that this virus will be as dangerous to vulnerable patients in 6 months to a year. We should be allowed to debate this.

My case has eight assertions.

First: the virus will not be contained. The chance for containment has long passed. The virus transmits before people know they have it and many patients never develop symptoms. It will be with us until an effective vaccine is both widely available and widely used. (See #6)

Second: Tests will under-perform. The high rate of asymptomatic disease, the low sensitivity of PCR tests (false negatives), imperfect specificity of antibody tests (false positives) and concerns over privacy mean that we should expect less from test and trace–even if proposed by a Nobel Laureate. Carl Bergstrom and others write persuasively on major barriers to contact tracing in the US. 

Third: US hospitals are now prepared and in little danger of being over-whelmed. In fact, many hospitals are so dormant they are nearing financial ruin. Healthcare workers have been furloughed due to postponement of elective work. I’ve talked to numerous colleagues in the US and the message is clear: hospitals are under-capacity and prepared for a “persistent” number of COVID19 cases during the coming months/years. Hospitals now have COVID response teams.

Fourth: Americans are not stupid. Before governors enacted lockdowns, economic activity and travel slowed, the NBA, MBL, NHL stopped their seasons and medical meetings were cancelled. People socially distance not because police are bearing down on them, but because it makes sense. The pictures of spring-breakers in Florida and crazies-with-guns in state capitals bring clicks to news organizations but belie the majority of sensible people in this country.

Fifth: Public-health surveillance has improved. Tests may underperform but they will not be useless. Tests will help signal coming hot spots and that will allow communities to act locally. Other technologies may emerge that help prevent surges. One cool example is the use of resting heart rate apps that might signal health officials early on.

Sixth: (I need a few paragraphs): Social distancing will not lower the infection fatality rate or IFR. Remember the red and blue curves? The y-axis of that graph is number of infections. Due to the contagion of this virus, the area under these curves is likely to be the same at the end of two years. Ok, then, if the number of cases is similar at two years, then the number of people who cumulatively die will not likely change either.

The only way fewer people die from COVID19 over time is if the IFR declines. Here is where American exceptionalism misleads people. Politicians have a strong bias to pump up optimism on any potential medical advance–no matter how dubious. (Exhibit B- hydroxychloroquine.)

That is not how Medicine works. History is replete with examples showing that drug development is super hard. But leaving aside the challenge of developing new drugs against a new virus, the basic math of COVID19 creates a huge barrier for success: already, more than 99% of people infected with this virus survive. A therapy that has a massive 50% reduction in death from a disease with 1% mortality (high estimate) delivers only a 0.5% absolute risk reduction.

What about Remdesivir? This antiviral may help a little. But even if you believe its ≈ 3% reduction of death was not due to chance (p = 0.06), the death rate in the remdesivir arm in that trial was 8%. Remdesivir is no game-changer.

COVID19 vaccine development is sobering. Most experts say a safe and effective vaccine is at least 18 months away. Again, the 99% survivability erects a huge safety barrier for vaccine makers. (I get that from Dr. Paul Offit.) Given society’s tension over vaccines, it would take only a tiny signal of harm to derail a coronavirus vaccine.

A slight hedge on the sixth assertion that IFR remains constant: some smart people say that getting the virus later may be better because doctors will be a little better at treating this disease. For instance, a year from now we may better understand how to use drugs that block clotting; we may have better vent protocols. These are big ifs. They may drive the IFR down a little but IFR is already low. Another benefit of infection in a year would be that most hospitals will likely allow family visitors.

Seventh: The more we test, the lower the IFR goes. Early estimates had it at 3%. Then it was revised downward to about 1%. Now most people put it at 0.1-0.5%. But that is still quite serious. You’ve probably read that 0.1% is similar to flu mortality. That is likely wrong. Dr. Jeremy Faust points out that flu mortality is grossly overestimated and is probably much lower than 0.1%.

Eighth: I wrote a piece on Medscape about the harms from COVID19 interventions. One of the points I made is that right now we count only deaths from COVID19. We stay riveted on day-to-day numbers. But the endpoint of this crisis is not next month but in 1-2 years. And when we get there, we have to count people who died from COVID19 and those who died from other causes.

This preprint from prominent researchers suggests a substantial proportion of excess deaths observed during the pandemic are not attributed to COVID19 and may represent an excess of deaths due to other causes.

In my column I cited an older study by Raj Chetty and co-workers that finds a strong association of lower income and lower survival. And that is the rub with COVID19 interventions: they make poor people even poorer. The rich just work from home. It is possible, therefore, that our social interventions will be especially hard on the disadvantaged.

I realize that no person overtly dismisses the harm from economic shutdowns. My friend Dr. Dan Morgan expresses my frustrations well in this thread. Why can one safely critique a drug for COVID19 but not massive public health interventions?

Conclusion:

I did not have a clear answer for my couple. But after thinking and writing about this question it seems that the most reasonable approach in this crisis is transparent information–no matter how stark. And, crucially, we must have space for public debate.

I hate this virus. I wish it never came. But we can make it worse by avoiding hard discussions on tradeoffs, the limits of modern medicine and risk.

JMM

P.S. At 173 comments, I cannot keep up the moderation. Thanks for your interaction. I have closed the comment thread.

The Debacle of Hydroxychloroquine and Azithromycin for COVID19

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I discussed the use of hydroxychloroquine and azithromycin for patients with COVID19 on my March 27th edition of This Week in Cardiology Podcast.

This is an important topic not only because of the specifics of treating patients but also vital because it shows how easily human beings can be misled.

Here is a an edited transcript of my words:

A conversation I had with my Dad this week made me realize the seriousness of this matter. My Dad is a retired insurance executive with a background in electrical engineering. 

He is smart, but I could not convince him that the evidence prompting people to advocate for this drug violates the principles of eighth-grade science class. 

Dr. Fred Masuodi, a thoughtful cardiologist, wrote with candor.

I am not shocked that our president can be misled about shoddy evidence but I am dismayed that so many doctors have been bamboozled. 

Note, I am publishing this column two weeks after the podcast and still doctors in my city and across the world are using this drug combination. In fact, our hospital and others have had to design ways to monitor for cardiac side effects from the drugs.

See this Tweet:

A few quick words on the French study that sparked the hype of hydroxychloroquine (HQ)/azithromycin (AZ).

Originally published in preprint form, the paper was published the next day in a journal in which one of the authors was editor-in-chief.

The problems with this study are numerous:

First, it was not randomized. 26 COIVID + patients hospitalized in Marseille were in the active arm. 16 patients in surrounding areas served as controls. 

Of the 26 HQ treated patients, 20 completed the study. Of these, 6 also received azithromycin. 

The endpoint of the study was not clinical. Rather it was the surrogate endpoint of viral load. The duration of the study was 6 days—even though the original plan was for eval of PCR data on Days 1, 4, 7, 14. 

Main result: On day 6, most of the 16 control patients vs about half of the 14 HQ treated patients, and none of the 6 HQ+AZ treated patients were PCR positive. The authors concluded the drug regimen helped clear the virus. 

Here is the kicker – 6 of the 26 patients in the active arm were not followed-up. But not because they were lost; they were not included because 3 worsened and required ICU care, 1 died, and 1 stopped because of nausea.

Imagine if these 5 of 6 patients were included in the results. My friend Luis Correia from Salvador called the practice of taking patients who do poorly out of your analysis an “unstudy.” An eighth-grade student would fail her science project if she removed selected subjects from the experimental arm.  

My summary: So this non-randomized, surely confounded, tiny study, with surrogate endpoints, published in one day in a journal with an author who was editor in chief, with 5 of 6 active arm patients who worsened and were not included in the final analysis has caused doctors, people who are supposed to be trained in science, to promote this potentially dangerous combination boggles my mind. 

In a NEJM editorial Dr. Fauci and others outline lots of potential treatments for COVID19. In a disease that well more than 90% of people survive you cannot just treat a handful of patients and say, see, they got better.

COVID19 is not heart disease. We don’t need to follow patients for years to get an answer, The disease course is over in weeks. That means proper randomization will give answers by late spring and summer. 

Not doing proper science would only compound the crisis this virus has caused. 

That’s the end of the podcast transcript. Here is an update over the past two weeks.

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The same French investigators have published another paper now with 80 patients rather than 26. Again the endpoint was not a clinical endpoint, such as not dying or not being admitted to an ICU but viral load.

From the abstract: A rapid fall of nasopharyngeal viral load tested by qPCR was noted, with 83% negative at Day7, and 93% at Day8. Virus cultures from patient respiratory samples were negative in 97.5% patients at Day5

This case series adds no useful evidence because without a control group you don’t whether the same number of patients would be virus free with no therapy.

Please note that I am not the only one with a problem with this study. Ivan Oransky writes on his blog Retraction Watch that the International Journal of Antimicrobial Agents finds that the French article

does not meet the [International Society of Antimicrobial Chemotherapy’s] expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.

Other scientists have posted critiques on PubPeer.

My friends, this is not about the nitty-gritty of medical evidence. This is about basic scientific principles that underpin the modern practice of medicine.

What separates the doctor of today from the faith healers of medieval times is the use of evidence.

I understand that this virus creates fear. But that is not a reason to abandon the scientific method and evidenced-based practice.

Like you, I spent the first few weeks of this crisis anxious and fearful. Now, I worry as much about the fact that my colleagues have accepted this therapy based on what is more like an unstudy than a real study. What does it say about the medical profession that normal doctors are doing this?

For the record, I think it is highly unlikely, though not impossible, that this drug combination helps people with COVID19.

But given the toxicity of these drugs, especially in older patients with or susceptible to heart disease, the only proper action is to randomize patients to either standard care or the drug combination and follow them for the 2-4 week course.

The statistician Darren Dahly has an excellent and short video explainer on the basics of proper trial.

JMM

2020 Mandrola Update

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Many things have changed in my life.

I still practice electrophysiology full-time in Louisville. I still write. And I still love endurance exercise.

You haven’t seen many blog updates because my writing has taken different forms.

One is academic writing. In 2019, I co-authored 21 academic papers. Here is a link to the papers on PubMed. This has been an exciting turn. I love being on the steep part of the learning curve for new stuff. Make no mistake: I am a beginner-academic.

Much of my academic work centers on the state of medical evidence. One of the studies I am most proud to have worked on is this evaluation of the prevalence of spin in the cardiovascular literature. Sadly, language designed to distract is damn common in medical science. Caveat emptor.

I am also grateful to Dr. Roderick Tung from the University of Chicago for inviting Baptist Health Louisville to participate in the first ever head-to-head randomized controlled trial of His-bundle pacing. This study garnered the big stage at the Heart Rhythm Society meeting and its findings were published in two leading cardiac journals–JACC and Heart Rhythm. (We kept the spin to a minimum!) Being part of an RCT was almost as nifty as pacing the his bundle.

  • That image is intoxicating.

A cool thing about the time we live in is the ability to have mentors all over the world. Here, Dr. Andrew Foy and his team at Penn State University in Hershey PA, deserve mention. Andrew is a true academic; he has helped me understand research methods. We have published many papers together, including my favorite: The Case for Being a Medical Conservative. Kudos and gratitude to the American Journal of Medicine for publishing our essay, and not putting it behind a paywall. Thanks also to the EconTalk podcast for devoting a show to the conservative approach to medical practice.

Another writing form that occupies a lot of my time is podcasting. Every week, I review the top 3-5 studies in cardiology. The podcast is called This Week in Cardiology. It’s produced and published by theHeart.org | Medscape Cardiology.

I was wrong about podcasts. Years ago, when my editor approached me about doing a weekly podcast, I was resistant. But now I hear from listeners all over the world. The strength of the podcast as a medical educational form has been stunning.

Malcolm Gladwell said (or wrote) that he started Revisionist History because he was afraid that if he didn’t, his writing would not reach younger people.

I think Gladwell was right. Most (but not all) the people who reach out to me to say they listen to TWIC are young. This makes me happy because I love teaching.

I still write for Theheart.org | Medscape Cardiology. You can find my columns at Musings From Mandrola. One thing you should know about Medscape is its professionalism. The news and editorial team have given me great faith in journalism. My columns may be called blogs, but the editorial oversight and fact-checking there far outpace most academic articles I have published.

The other major change in the way I create content is the lecture. In 2019, I was honored to speak in Park City, New Orleans, Phoenix, Vilamoura Portugal, San Fran, Chicago (at an oncology meeting), Paris, Venice, Rzeszów, Poland, Edinburgh, Scotland, Los Angeles, Salvador Brazil and Philadelphia. Meeting colleagues across the world is a thrilling life experience.

Three special notes: doing real cases in Poland with Piotr, Pasquale, and Jaro.

And meeting in real life, the Professor Darrel Francis:

And to you Dr. Andrew Flapan: thank you to the power of ten.

Finally, on the exercise front, I have retired from criterium and cross racing. These are for the young. I still ride my bike but no more in anger.

To fulfill my exercise addiction, I have gone back to running. This year, while in Poland, I ran the Rzeszów Maraton–an unforgettable memory. Thanks Arek, Magda and Piotr. This image is from the start. The image at the end is different. Hey Arek?

I know; the maraton is silly. But I will try another in 2020–to redeem myself for cracking in the last 10k in Poland.

Far smarter is a 5k run by the sea. Thank you, Dr. Luis Correia

If you don’t use Twitter, you should. It’s a brilliant medium for those interested in medical science. I am here @drjohnm

JMM

Change and the Case for Being a Medical Conservative:

By

When my favorite podcaster, the economist Tyler Cowan, asked Dr. Ezekiel Emanuel what nonobvious advice he would give to medical students today, the answer surprised me.

The famous bioethicist said: 

I do think that this is probably the most exciting time in American medicine in a century, since really about 1910, 1920. And it causes a lot of anxiety for people, so I want to be sympathetic to that….

…We would prefer no change. But I do think, if you can go with the change, this is a super exciting time when lots of things are changing, and you can have a real positive impact in shaping the future, probably for at least half a century.” 

I am not precisely sure what change he refers to, but you can feel change. 

  • Electronic records have replaced paper charts;
  • More patients contact me via electronic sources; 
  • I often crowdsource (with colleagues across the globe) difficult cases in real time;
  • Advanced practice clinicians are replacing physicians, especially docs without a specific procedure or skill;
  • Clinicians increasingly serve as translators of medical evidence.

But one thing that will never change about the practice of medicine is that there is a right way to do it.

Three colleagues and I recently described the right approach.

It is The Case for Being a Medical Conservative.[1]

My co-authors: Andrew Foy is an academic cardiologist at Penn State. He got it started with an outline. Adam Cifu, an academic internist at the University of Chicago, and Vinay Prasad, an academic oncologist at University of Oregon, made significant revisions. 

We felt that it was time to set out what it means to be a medical conservative because the rapid pace of innovation and the democracy of digital media have tested the resolve of slow-adopting skeptical clinicians. 

Here is a Twitter thread I did on the paper.

Some highlights: 

A medical conservative is not a nihilist; we adopt new therapies when the evidence is compelling.

Too often, medical evidence is hyped and the benefits to patients are small. The medical conservative, therefore, has to be skillful in assessing evidence. 

It’s not always easy to assess evidence. I recently co-authored a systematic review[2 ]that found that manipulative language, or spin, pervades the cardiac literature. I urge you to read this paper. You would think science would be dispassionate; it is not.

The medical conservative asks a simple question: 

Would an unbiased patient, who had perfect knowledge of an intervention’s tradeoffs, voluntarily choose to adopt it, and taking into account differing patient resources, pay for it?

Medical conservatives worry about the commercialization of medicine because too often medical progress occurs under the pretext of science without meaningful improvement in patient outcomes. 

This careful approach to “progress” sometimes puts the medical conservative at odds with content experts—who are often enthusiasts for the procedure that they do. 

Atrial fibrillation ablation proponents are a good example. Unlike me, many of my colleagues are so sure the procedure works that they oppose a proper placebo-controlled trial. Yet, every single study of AF ablation has been unblinded—patients and their doctors know the treatment assignment. This is nuts. No novel drug gets approved unless it’s proven better than a placebo. 

The medical conservative sees medical progress as slow and hard. That is because nature has provided the human body with natural healing properties. We understand and embrace how little the clinician affects outcomes.

Finally, the medical conservative does not oppose innovation, we simply place the burden of proof on those who innovate.

Dr. Emanuel is right; change is happening. But the conservative approach to medical practice remains a bedrock principle.

I am a proud #medicalconservative. 

JMM

Ref:

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

2.         Khan MS et al.Level and Prevalence of Spin in Published Cardiovascular Randomized Clinical Trial Reports With Statistically Nonsignificant Primary Outcomes: A Systematic Review. JAMA Netw Open2019; 2(5): e192622–e192622. doi:10.1001/jamanetworkopen.2019.2622.

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.

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