Yet spironolactone is not an easy drug to use. You have to get labs after starting it because it can cause high potassium levels, especially in patients with impaired kidney function or those taking ACE-I or ARB drugs. Both of these are common in patients with HF. In fact, whenever I write for spironolactone the EMR gives me a drug-drug interaction alert.

Foy smartly cited an observational study from Ontario published soon after RALES that showed that spironolactone use increased after RALES but so did potassium related complications. Crucially, the Canadian authors found no evidence that the extra spironolactone reduced heart failure hospitalizations.

Vinay wrote an adjoiner calling this an efficacy-effectiveness gap. Here is a slide I often show to learners.

Trials, it turns out, are the best way to test whether an intervention works (efficacy) but the worst way to assess who will benefit from it (effectiveness).

Foy and Vinay both point out that trials do two things that are not done in the real world: a) they select patients in whom the intervention has the best chance to work and b) trial procedures provide hypervigilant protection of patients.

Vinay points out that oncology trials recruit patients with good functional status and strong family support. I can vouch for this firsthand. We are a recruiting center in the Left vs Left trial of conduction system pacing vs biventricular pacing in patients with an indication for cardiac resynchronization therapy. Basically two ways to achieve CRT. Trial inclusion and exclusion criteria are strict, but that’s rarely the barrier. The barriers are whether the patient has the support, strength, cognitive ability or desire to participate in the trial. We exclude many patients because the trial won’t work for them.

Recruiting the best patients is one thing, but trial procedures are equally important. In RALES, for instance, Foy tells us that patients had numerous lab checks; many more than is routinely done or feasible in regular practice. He doesn’t say this but you should know that being in a trial is wonderful because not only do you have doctors but you also have an uber-detail-oriented research nurse who makes sure nothing falls through the cracks. Research nurses are like healthcare guardian angels. There are no research nurses in regular practice.

RALES is not an outlier when it comes to extraordinary procedures. The seminal beta-blocker trials that established these drugs in the post-MI setting had incredibly unrealistic monitoring. Read about the monitoring in the 1982 BHAT trial over at Cardiology Trials substack.

Nothing about selection of patients or trial procedures are nefarious. Rather it is an attempt to enhance efficacy. Does the drug or procedure work in this ideal environment?

Our job as clinicians is to figure out whether benefits seen in the trial environment can be duplicated in the patient in front of us. Clinicians need to focus on effectiveness.

Foy has some great rules:

I love these rules. They should be taught in every medical school and residency program.

Here is the problem though: doctors who apply these rules will use less of the anointed therapies. They face the tension of EBM enthusiasts who push things like “guideline directed medical therapy,” which sounds great in practice but can create mischief for many patients.

When I discharge a 90-year-old with a walker with tennis balls on it and severe kidney disease, the EMR tells me I am not using proper GDMT of her chronic HF. The average age of patients in the HF trials—mid 60s.

How or why, you wonder, could following GDMT become a tension or problem?

No field is more emblematic of the tension between Foy’s rules and guideline-mandated care than the treatment of patients with heart failure. The seminal trials of heart failure drugs were performed sequentially. ACE-I were first; then the beta-blocker trials tested adding on beta-blockers. In RALES, patients were on ACE-I and spironolactone was tested as an add-on. In the SGLT2i trials, patients were on the three drug classes. All of this was sequential. Most were done in stable ambulatory outpatients.

But now there is a strong push to start all these drugs at once and early, often in the hospital. Proponents cite observational studies showing that patients started on four drug classes right away do better. But these studies are flawed by huge doses of selection bias; of course a patient who can tolerate 4 new pills is more robust than those in whom a doctor would never attempt such an aggressive move.

Vinay rightly points out that a proper trial would test the theory that rapid sudden initiation of 4 drugs is superior to a sequential slow approach. This is the best way forward.

HF leaders worry that not starting drugs early and all at once risks undertreatment. This is a reasonable concern as inertia is clearly a barrier to the best medical care. I have seen both.

Yet I favor Foy’s approach.

Use of medical evidence is absolutely necessary. Otherwise we are like palm readers.

But efficacy in a trial is a lot different than effectiveness in the real world. The best doctors understand this. They are the doctors who I would want to care for me.

But they may not be the doctors with the best EBM scorecard.

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The concept is enticing: many diseases (heart and cancer, primarily) lie dormant before causing death. A scan could find these early, at a stage where surgery or medicine could cure. Doing this would extend life.

Even some doctors are fooled, saying they went into medicine to prevent disease not just throw pills at diseases that could be cured if caught earlier.

Of course, anyone who is tempted to fall for this folly fails basic numerical literacy.

That is, if a disease has a 1% prevalence (and many of the diseases found on these scans have an even lower incidence) and a test is 90% sensitive and 90% specific most of the “positives” are false positives.

To review the calculation. It’s disease prevalence multiplied by the likelihood ratio (sensitivity/1-specificity) equals the after test probability.

1% x [.9/.1] = 9%. Meaning that if 100 people have a positive scan, 9 will be a true positive and 91 will be false positive.

We learn this basic stuff in medical school then it is promptly forgotten. It’s why mammography has such a hard time reducing breast cancer outcomes. The inherent problem is looking for low incidence conditions. Even a good test (90% sensitive and specific) produces more false positives than true positives when disease prevalence is low.

Every doctor can tell you horror stories of false positives. The person who has a coronary calcium scan and is found to have a lung nodule—who nearly dies during the biopsy procedure of the non-cancerous nodule, for instance.

But this self-evident medical fact is not the biggest problem with these total body scans. Let me show you two more.

First, in the opening paragraph of the Death of Humane Medicine, the late Dr. Petr Skrabanek laid out the biggest problem with this idea:

Health, like love, beauty or happiness, is a metaphysical concept, which eludes all attempts at objectivisation. Healthy people do not think of health, unless they are hypochondriacs, which, strictly speaking, is not a sign of health. Similarly, when our organs perform their functions perfectly, we are not aware of them. It is the absence of health that gives rise to dreaming about health, just as the real meaning of freedom is only experienced in prison.

The pursuit of health is a symptom of unhealth.

Healthy people do not think of health. The pursuit of heath is a symptom of unhealth. As I age, fewer ideas ring truer.

For the second problem, I cite the great book Conflict of Visions by Thomas Sowell.

The unconstrained vision holds that there are ideal solutions to every problem and that compromise is never acceptable. Just tweak human nature enough and you can fix all that ails society.

The constrained vision holds that human nature has never changed, cannot be modified and, here, compromise is essential because there are no ideal solutions, only trade offs. Constrained thinkers favor evidence to sort out these tradeoffs.

Now apply that frame to medicine.

Unconstrained thinkers dominate medicine. More is better. We can solve human disease. We just need to do more tests, give more drugs, keep innovating. Everything is modifiable. Of course, there is profit in being an unconstrained thinker.

The concept of total body scanning is unconstrained thinking raised to exponential levels.

I am a constrained vision person. I am shocked more doctors are not this way. It’s as if we ignore what we see everyday. We see patients survive an MI only to die a year later with pancreatic cancer; we see thousands of diseases affect our patients.

The idea that a scan or search from one disease could save you belies any sense of health and disease.

Religious people say people die when God calls them. I am not that religious but I am absolutely convinced that we die when it is our time. And it is only modifiable on the margins.

You wear a seatbelt (low harm) and do not ignore a bump in your armpit or new symptoms. You do basic things, mostly pay attention. I’ve seen cyclists call their new breathlessness asthma when it was an LAD lesion that could have been fixed before causing cardiac arrest. These are the “evidence” parts in the constrained vision.

Short of paying attention, the wealth of diseases that could kill you are hardly worth chasing. Better to healthily not pursue health.

Finally, the corollary of this philosophy pertains to doctoring: yes, doctors are supposed to treat the sick. Our job is to help people who are asking for our help. Prevention is best left to a person’s smart choices and good luck.

Dr Holly Morgan is cardiologist and researcher in the UK and was an author on one of the best cardiology trials of our time—the REVIVED BCIS2 trial.

Dr Sunil Rao is a cardiologist and researcher who has published many important trials in cardiology, both industry and government funded.

Today we address the tension in the two types of science funding.

Dr. Morgan commented on my lecture at the recent BCIS meeting in London. It was not my idea to speak on “the three worst interventional cardiology trials that changed practice nonetheless.” I could have easily and happily spoke on the three best interventional trials; but this was not my assignment.

My choice for the three worst trials in interventional cardiology were: FAME-2, TRILUMINATE, and EARLY TAVR.

FAME-2 established the use of physiologic measures of coronary stenoses. TRILUMINATE created enthusiasm for clipping tricuspid valves to reduce leakiness. EARLY TAVR tempted cardiologists to change the rule that we wait for patients with aortic stenosis to have symptoms before operating on the valve.

All three of these trials were industry supported. All three were designed to be positive before the first patient was enrolled.

And therein lies the core problem between industry and non-industry funded trials: industry funds trials to sell products.

Dr Rao is exactly right in his post on X. This does not necessarily mean industry-funded science equals bad science. In many cases (ICD, primary stenting for MI, statins, most HF meds), the confluences of interest between profit and societal benefit align. And industry-funded science leads to huge advances.

But. But. Profit and societal gain are not always aligned. In my opinion, profit takes precedence in industry-funded science. This is a problem because in the ideal world of medical science, experimenting with human subjects should only be to answer an important question.

There is some empirical evidence that I am correct. For instance:

In my lecture in London, I spell out how trial design guaranteed positive results of the three trials.

One glaring example was in the TRILUMINATE trial of tricuspid valve clipping vs meds in patients with severe tricuspid valve regurgitation. One group got an invasive procedure with the clipping tool and one group got only meds. Patients knew their treatment. Imagine being in the meds group. Your brain thinks…crap I didn’t get the best option.

The primary endpoint included hard endpoints like death and heart failure and soft endpoints like a quality of life questionnaire. The results favored the invasive procedure but only on subjective quality of life measures. This design, of course, fails high school science because it ignores the placebo effect.

What bothers me most is that EVERYONE involved in TRILUMINATE knew this and went ahead with the trial anyways. It so happens that tricuspid valve regurgitation is super common. So the gain to the company that makes the clipping tools and the doctors who do the procedure are enormous.

The easy solution would have been to have a sham arm where one group had a placebo procedure. As a potential patient some day, this is the trial I would want. Because I believe there probably are a select few people with severe valve disease who would benefit. But with a biased trial, we will never know.

Non-industry funded trials, on the other hand, are far more likely to be done to answer a question.

Dr Morgan’s REVIVED BCIS2 trial, for instance, studied hard outcomes in two strategies (stents or meds) for treating patients with severe coronary disease and left ventricular dysfunction. Most of us believed these patients should have their blockages stented to improve blood flow to weak heart muscle. Yet the cardiology community was surprised, no shocked, that simple medicines performed as well.

The Solution for You and I

If we lived in an ideal world, all trials of new therapies would be conducted by independent research teams. That’s unlikely to ever happen.

So, I would propose the following specific approaches:

• Start the evaluation of a trial with an open mind. You know industry exists to make a profit. This is normal. It does not (always) equate to a biased trial.

• Evaluate the trial design and procedures in a neutral manner. In the seminal ICD trials, one group got an ICD and the other group did not. In the end, they measured the number of people who died. That’s mostly free of bias. The trials were positive and led to increased use of the ICD. Since it saved lives, both industry and society won.

• After looking at the design and procedures of a trial, consider the authors’ conclusion. Did they stay true to the primary endpoint? Or did they employ spin—distraction from null results on the primary endpoint. RITA 2 was the whopper of all examples of spin.

The more global general approach is:

To become better consumers of medical science. This is the goal of Stop and Think. It is the goal of Sensible Medicine. And the This Week in Cardiology podcast.

I did 8 procedures yesterday. All of them were easier and more likely to help patients than procedures I did 10 years ago. Industry innovation is largely responsible for these advances. So industry is not bad. We want industry to innovate; profits are not an enemy of medical science.

Yet we are Bayesians. Profit motive is a prior we must consider in the evaluation of a trial. But the prior is only a prior; the main question is the nuts of the bolts of the actual trial.

Appraisal of evidence is not a speciality. Not being bamboozled is one of the main jobs of the modern clinician. It is a lifelong pursuit.

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In both debates, my academic colleagues did not focus on the evidence underpinning the procedure. They mentioned evidence, but in only a guideline-sort of way. As if to say, it’s in the guidelines, it’s settled.

In one of the debates, my opponent cited the vast number of procedures that have been done since approval. The message: Mandrola, the majority of your colleagues love this procedure. You are an outlier? Are you smarter than the masses?

In the other debate, my opponent said he just knew the device worked. The studies I cited were old, and my analysis was technical. “John, most doctors can’t see the details in studies like you can.”

I’ve been stewing about these attitudes for a few days. I’ve heard them before, especially the one about doctors not being able to appraise studies.

This is embarrassing for our field. Of course doctors should be able to assess evidence. We are in the evidence-assessment business. When a patient seeks our help, we use our evidence-assessment skills to sort out the problem and the fix.

We should expect nothing less when it comes to assessing the evidence underpinning our therapies.

But that’s not what I see out there—in the hospital, clinic and speaking circuit.

What I see is that doctors simply accept what guideline writers put into those colored boxes. Which would be fine if guidelines were written by neutral Martians free of dualities of interests. But that’s not the case.

Let me show you some examples of dubious evidence, which a practicing doctor ought to know about and be able to use in clinic.

Example 1: Left atrial appendage occlusion proponents should be able to explain their enthusiasm for a procedure that had two failed regulatory trials against warfarin. PROTECT AF failed to pass FDA muster, and PREVAIL failed to meet noninferiority in its co-primary endpoint for stroke, embolism and CV death. Slide below.

I’ve been told that this is too nuanced for doctors. I disagree.

What this shows is that the upper bound (worst case) is that the Watchman device could be 2x worse than warfarin. And the NI margin was a whopping 1.75—meaning the trial had such a low bar that Watchman could be 74% worse and still meet noninferiority. But it didn’t. It was even worse.

Example 2: In heart failure, sacubitril/valsartan (Entresto) is preferred over basic generic ACE-I. I contend that every cardiologist should be able to explain their love of this drug given two facts: one is that its regulatory trial (PARADIGM HF) used maximum dose valsartan against medium dose enalapril, and we know that dosage of this drug class matters. The second is that no other trial of sacubitril/valsartan has delivered significant results. Why not?

Example 2a: Also in heart failure, the new mineralocorticoid receptor antagonist (MRA) finerenone is being promoted as the next new thing in treating patients with heart failure and a preserved ejection fraction (HFpEF). The regulatory trial called FINEARTS HF was positive, but this trial compared the drug to placebo. Yet I think every cardiologist who uses this drug should explain why they think it is better than the generic MRA drug spironolactone. That a new drug for HFpEF gets on the market without proving superiority to a generic is not too technical for a cardiologist.

Example 3: In some centers, cath lab staff are not sent home until the last stress test is read as negative. That’s because nearly all positive stress tests get sent to the cath lab for angiography. The sky is blue and you get an angiogram for a positive stress test. Well, I don’t think it too nuanced for doctors to explain why this is the norm when our government spent $100 million on the ISCHEMIA trial, where 5000 patients with positive stress tests were randomized to immediate angiography or conservative medical management and there was no difference in hard outcomes.

Example 4: Primary care clinicians don’t get off the hook. I would expect them to be able to explain the NORDICC Trial of screening colonoscopy. In this NEJM-published study, more than 84,000 people were randomized to be invited to screening or not invited. In the end, the risk of dying of colon cancer was 0.28% in the invited group vs 0.31% in the non-invited group and risk of dying was 11.0% in both arms. I do not think it is too technical for a primary care clinician ordering a colonoscopy to understand that the difference in colon cancer death in this most modern trial is 0.03%. And there was no survival advantage. (The response should not be that those who actually had the screening did better; if this is your answer, you fail critical appraisal 101. Because people who get the screen are different from those who did not.)

I will stop now. But my point is that doctors (and advanced practice professionals) are about to face a crisis. That is, when a patient comes to you with an AI-driven thread of questions regarding the evidentiary support of a proposed treatment, the answer better not be…it’s in the guidelines, or, I know it works, or, 500,000 procedures have already been done.

What will doctors be for, if we cannot be better at evidence appraisal than a large language model?

I propose that we reinvigorate the skill of critical appraisal.

If we can learn the biochemistry and organic chemistry, we can surely understand that putting efficacy and safety endpoints into a non-inferiority primary endpoint is an easy way to bias a trial.

But first, in the matter of first world problems, the This Week in Cardiology podcast did not upload properly to the Apple and Spotify platforms yesterday. The Medscape team promptly fixed the issue and the podcast can now be heard in full.

I make note of this because I spent the week studying the use of coronary CT scanning.

Here are a few words about this relatively new way to assess for coronary artery disease. When you present for evaluation of chest pain, we try to diagnose and treat the problem. While chest pain can have many causes, a primary concern is coronary artery disease or CAD.

In days of old there was only “functional” testing for CAD. That is, we stressed the heart, either with exercise or vasodilators, and then assessed for ischemia (demand > supply due to coronary disease).

Inducible ischemia shows up on either the ECG, echo, or nuclear perfusion images. If positive, stress tests provided “indirect” evidence for coronary disease. The doctor could then treat the patient for CAD or refer for invasive coronary angiography—wherein contrast is injected into each of the three coronary arteries.

(Of course, the multimillion dollar ISCHEMIA trial found that there was no difference in outcomes for sending patients with positive stress tests immediately to the cath lab for coronary angiography vs initial medical treatment. But no matter, the train from positive stress tests to the cath lab remains at full capacity in the US.)

Coronary CT scans offer a different way to diagnose CAD. We call these “anatomic” tests—wherein the doctor can see the blockage as contrast goes down the coronary. (Note, a coronary CT is different from a coronary calcium scan. The latter simply measures the amount of calcium in the arteries whereas coronary CT is an actual angiogram of the inside of the vessel.)

The promise of coronary CT is that non-invasive angiography allows a more accurate diagnosis of CAD. Because you can see it.

I was part of a meta-analysis of studies comparing functional and anatomic testing in patients with chest pain.

We found that use of CTA decreased the incidence of MI but increased the use of coronary interventions. CTA vs functional stress testing did not result in a decrease in cardiac hospitalizations or mortality. However, and it was a big however, we were forced by reviewers to include a trial that was dissimilar from all the others.

The question we asked was which method was better to evaluate patients with chest pain—CTA or functional tests. We wanted to include only trials that directly compared the two testing strategies. Those trials, when combined, showed no difference in any outcome.

Peer reviewers, however insisted that we include the SCOT-HEART trial, which found that adding CTA to the normal routine of testing reduced MI in the future. Adding SCOT-HEART drove the positive results (MI) of our meta-analysis.

But there were two issues with SCOT-HEART. One was that it did not directly compare CTA and functional testing. Instead it was a comparison of CTA + functional testing to functional testing alone. So we did not originally include it in our meta-analysis. Peer reviewers insisted, and we had two choices: include it or have the paper rejected.

The second issue with SCOT-HEART arose when the authors presented the five year results, which showed dramatic reductions in MI when adding CTA.

The title of my commentary at that time was: Five Reasons I Don't Believe an Imaging Test Improves Outcomes. See also my post on SCOT-HEART on Sensible Medicine.

I discussed this issue again on this week’s podcast. The short story is that the degree of reduction in MI in SCOT-HEART was outsized and hard to explain.

I went further into CTA imaging on last week’s podcast.

For instance, the test is used in much different ways in the US vs Scotland. In cost-constrained health systems the test is used to decrease the number of expensive angiography and stent procedures. They do this by believing in the evidence and treating any CAD medically. Because that is what the evidence shows.

In the US, it’s the opposite. Hospitals are buying CTA scanners and putting them in ERs and chest pain centers, because the anatomic test finds CAD at higher rates than functional tests. It does not matter that patients can present with totally non-cardiac pain and the CTA finds coincidental CAD.

The culture here is that CAD should be investigated with an invasive angiogram and stented if significant—despite the evidence showing there is no benefit. I call the CTA scanners in the US cash machines because they send more patients to the cath lab than functional tests did.

The other issue I went into on the podcast was a new twist on using CTA called fractional flow reserve or FFR from the CT. This proprietary test from a company called HeartFlow purports to tell doctors whether a partial blockage seen on CTA is tight enough to limit flow. And if it is, that is bad, and it should be fixed.

Of course, FFR is used in the cath lab as well.

My take is that FFR is a flawed measure, no matter where it’s used. I went into detail on one of the seminal studies of CT-FFR, called the ADVANCE registry. I found a darn mess.

Conclusion

Many smart people have advised me not to be critical of a test. A test is just a test. The problem are the humans who misuse the test. That advice fits here. A CTA is a simple picture of coronary arteries. Our job is to use it wisely. That it is misused is the fault of humans not the scanner.

Coronary artery disease is part of the diverse disease of atherosclerosis. CAD treatment therefore should focus on treating atherosclerosis: diet, exercise, good control of blood pressure and cholesterol for instance.

Placing stents in stable partial blockages does not reduce the chance of future MI or death. It’s a hard concept but it’s been borne out by every clinical trial ever done.

If a CTA finds CAD the treatment is not a stent but medical treatment. Then if medical treatment fails, a stent can be considered.

Here are the various places that you can find the podcast. It publishes every Friday afternoon.

This Week in Cardiology podcast on Medscape (with a transcript)

This Week in Cardiology podcast on Apple

This Week in Cardiology podcast on Spotify

I write to clarify one particular issue about flawed science. The executive order highlights the matter of science that does not replicate, likely because it is fraudulent.

Fraud is not the biggest problem with medical science. Not even close. The biggest problem is what I call “middle-of-the-curve” lousy science. If there are 10 problems with medical science, numbers 1-7 are simply poorly designed and inconsequential projects, which never had a chance of advancing knowledge.

The analogy for the middle-of-the-curve problem is modern clinical practice. While the criminals giving chemo or placing stents without reason are real, downright malfeasance is a rarity. Far more common is everyday low-value non-beneficial care that is performed as standard operating procedure. I call it therapeutic fashion. Coronary angiography after every positive stress test; screening elderly people for cancer; coronary artery scans for people on statins. I could make a long list.

I have no doubt that some small fraction of science is falsified, but far more common is the everyday lousy study.

Take observational comparison studies that are fatally biased from the beginning. Most of these studies have zero chance of eliminating bias. The attempts to match groups is a charade. Journals publish oodles of such studies every week. Sometimes these are popular papers, covered in big news sites.

The authors try not to couch the results in causal language, though they often fail. Yet it would not matter if a large language model scraped every causal verb from the manuscript; the truth is that the goal was to find causation. And it was hopeless. It shouldn’t have been attempted.

Yet incentives to publish are strong. The saddest thing is that the young people assigned to do these worthless studies could have spent this time learning clinical medicine (or cycling or reading or doing just about anything else).

Another example: the 29th substudy of an already underpowered randomized controlled trial. The general results of a trial have wide 95% confidence intervals, leading to uncertainty about the overall outcome. Then authors post-hoc break up smaller subgroups which have even less power. The most likely outcome is being fooled. These may be worse than worthless.

But perhaps the absolute worst type of middle-of-the-curve bad science are trials designed to be positive before the first patient is enrolled. These are marketing trials wherein nobody involved is interested in answering a question about nature.

The ATLAS trial compared two types of defibrillator and the endpoint had 4 of 5 components that could only happen in one arm. The OPTION trial compared safety of a stroke prevention device (which requires an invasive procedure) against a simple anticoagulant and used an endpoint that excludes bleeding from the procedure. This list, too, is long.

I know many people worry that the new administration has cut science funding. I don’t. Because every week, when I review medical evidence, I see tremendous amounts of waste.

The solution of course is to foster science that has every characteristic shown in the slide below:

I don’t know if Vinay, Marty and Jay can reduce the amount of worthless science, or hold industry to higher standards, but the state of medical evidence is really sick. It is need of big changes. Incremental is not going to cut it.

I’m happy to give a new group a chance. JMM

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Two studies presented at the recent American College of Cardiology meeting serve as excellent examples of the misplaced incentives in medical science.

In the column, which is written for a medical reader, I discuss the DapaTAVI and STRIDE trials.

In DapaTAVI, investigators randomized patients after a transcatheter aortic valve implantation or TAVI. One group got the SGLT2i dapagliflozin; the other group got standard care. (No placebo tablet).

Patients who get TAVI are older and have multiple conditions that predispose to fluid buildup requiring diuretic therapy.

After one year, 15% of patients in the dapagliflozin group had a primary outcome event of death or heart failure event (urgent visit or hospitalization) vs 20.1% in the control arm. That 28% lower rate reached statistical significance, rendering the trial a win for the SGLT2i dapagliflozin.

The problems I had with the trial were:

• The control arm did not get a placebo tablet. That means patients and doctors knew the treatment assignment.

• The driver of the positive primary endpoint was not death but a HF event. That’s a problem because the decision to have a patient come in for an “urgent visit” or hospitalize a patient is made by a clinician. Knowledge of treatment assignment could bias the decision. For instance, one option for patients with HF symptoms might be to have the patient take an extra oral diuretic tablet at home, which would not count as an endpoint event.

• The other problem with using “HF hospitalization” is that older patients can be admitted to the hospital for many reasons. The authors don’t report total hospitalizations, so we can’t know whether reducing HF hospitalizations reduces the burden of healthcare.

My main criticism however is the basic idea of the trial. We know that SGLT2i drugs are fairly potent diuretic drugs—which means they pull fluid from the body, via the kidneys.

I argue in the column that you could give an SGLT2i drug to any patient after any cardiac procedure and it would likely lead to fewer “HF events”. They used TAVI in the study, but it could be after an ablation, stent or bypass surgery.

DapaTAVI therefore should not be used to expand the indication for SGLT2i drugs. Yet more than 40 news outlets covered the trial, nearly all with positive headlines.

The STRIDE trial was worse. This was an industry-sponsored and -run trial of semaglutide vs placebo in patients with peripheral artery disease who have claudication (pain in the muscle with exercise due to inadequate blood supply.)

The authors measured walking time on a treadmill as a primary endpoint. As most of you can imagine, walking time on treadmill is highly susceptible to coaching and motivation. Who hasn’t run an extra 400 with prompting? Proper blinding is mandatory with such an endpoint.

And herein lies the fatal flaw of the study. Patients on semaglutide will surely know they are on it; they lose weight, have easy satiety, and often nausea.

The difference in walking time was modest. Not even a 100 feet more compared to placebo. Yet it reached statistical significance, rendering STRIDE a positive study and publication in the influential LANCET journal.

The increase in walking time is similar to the old and generic drug cilostazol. Yet more than 35 news outlets covered the trial with positive headlines.

Yet the modest increase in exercise time on semaglutide could have been due to placebo effect. One way to know if there is unblinding in a trial would be a simple blinding test. This was not done in STRIDE.

Conclusion:

Evidence-based practice relies on clinical trials. I laud investigators who do trials.

Yet it saddens me that trials-designed-to-be-positive make it to the big stage of a meeting and garner publication in major medical journals.

The upstream causes of this problem are complex. One cause is surely profit motive. STRIDE is a good example of an industry-designed trial made to expand an indication for their drug. In my opinion, it does not get reach that level.

The Spanish government funded DapaTAVI. Here, the upstream problem involves doing trials that deliver positive results. I would have bet a lot on DapaTAVI being positive. When it comes back modestly positive only for a subjective bias-prone endpoint, medical science is not advanced.

I don’t have a solution to this problem—other than to sharpen critical appraisal skills so as not to be bamboozled.

JMM

Since I was invited to EHRA, I leave for Vienna on Friday. I don’t like that the meetings conflict, but I am a heart rhythm doctor first, and a cardiologist second.

ACC always features important trials. I will cover these in spoken form on the This Week in Cardiology podcast and in written form at TheHeart.org | Medscape Cardiology. Surely one or two will make the Study of the Week over at Sensible Medicine.

I did write my usual ACC preview column. Much like I choose studies for the podcast, here I simply pick the 5 trials that interest me most. It’s a highly biased selection.

A notable observation comes in comparing the first two late-breaking trials at ACC. One trial seeks to understand a common but mysterious condition. The second trial seeks to expand an indication for an expensive drug. I called it science vs marketing.

Stay tuned. I will be active on X and writing a lot in the coming weeks. If you are in Vienna, please do say hi.

Two more things: this Friday, on TWICPodcast, I will discuss one of my favorite biases—collider bias. Collider bias is the great explainer of nearly every purported paradox in cardiology. Teaser: despite hundreds of articles in the medical literature there is no such thing as the obesity or smoker’s paradox.

Finally, congratulations to Professors Jay Bhattacharya and Marty Makary on being confirmed as NIH director and FDA commissioner. Both were voices of reason during the pandemic. I look forward to a new chapter in medical science and regulation.

As always, thank you for the support. I do have fun writing and thinking about medical science. JMM

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My session assignment this year was a roundtable on the management of AF during the “blanking period” after ablation.

I took the opportunity to propose eliminating the blanking period.

I give credit for this idea to Drs. Mohammed Ruzieh and Andrew Foy. We recently wrote together in the American Heart Journal Open in favor of jettisoning the blanking period after AF ablation. We titled our piece Patients’ Lives Don’t Pause for the Blanking Period.

I also have a Medscape piece up on our argument as well.

My proposal at Western AF was not well-received. A few commenters agreed but most argued that we should still have a period of time after AF ablation where recurrences don’t count.

Let me tell you how the blanking period got established and then the reasons Ruzieh, Foy and I think it is wrong think.

Background

Much like cardiac surgery causes AF in the weeks post-op because of injury and inflammation, thermal lesions given in the left atrium during the ablation could also stir up arrhythmia. At least that is the theory.

My field came to the conclusion that some cases of AF in the weeks after ablation were not a failure of the procedure (due either to a wrong target or pulmonary vein reconnection from inadequate lesions) but rather inflammation that would subside with time. In fact, some early cases of AF never recur.

The challenge was that having AF in the blanking period greatly increased the probability of late recurrence of AF (procedural failure) but the correlation was not perfect.

The fact that some early AF resolve gave rise to the blanking period. Then it became ensconced. As if the sky is blue and we have blanking periods after ablation.

Blanking periods were also self-serving for ablation proponents. Because, In trials of ablation vs drugs, the ablation arm got a free ride for 90 days.

Reasons for Eliminating the Blanking Period

Reason 1: The blanking period falsely elevates our perceived success rate of AF ablation. A Vancouver-led group recently re-analyzed an ablation trial called Circa-Dose and found that shortening the blanking period from 12 to 8 weeks dropped the success rate of AF ablation by a statistically significant 5% (from 55% to 50%). Other papers have replicated this observation.

But you hardly need empirical studies, right? AF recurrences in the blanking period are common. Not counting episodes favors the ablation arm of studies.

Reason 2: No other areas of cardiology have such a blanking period.

At Western AF, I showed the example of the ISCHEMIA trial of delayed vs invasive strategies for patients who have positive stress tests. The main composite endpoint of the ISCHEMIA trial was not significantly different with either of the two strategies but controversy ensued over the rate of MI, which was one of the components of the composite primary endpoint.

For the primary endpoint, all MIs were counted, including those occurring immediately after the stent procedure. This comparison found no differences.

A secondary endpoint of non-procedural-related MI (see image) found that not counting MIs from the stent procedure resulted in the invasive arm having a 33% lower rate of MI. IOW, adding a blanking period in the ISCHEMIA trial led to fewer MIs. (But of course, patients cannot exclude an MI because it occurs after a procedure.)

Another example of how a blanking period causes faulty interpretation of a trial came in the OPTION trial of left atrial appendage closure plus AF ablation vs oral anticoagulation after AF ablation.

Here, the primary safety endpoint (bleeding) was found to be superior in the left atrial appendage closure arm. But, the trialists designated the safety endpoint to exclude bleeding at the time of the procedure (e.g. a blanking period). A secondary endpoint of all bleeding found similar rates. IOW, without the blanking period, there was no advantage to the appendage closure device.

Reason 3: Ablation of AF has changed. Pulsed field ablation (PFA) uses electrical energy rather than thermal energy. PFA is also delivered through bigger multipole catheters. It’s faster, safer and likely leads to more durable ablation.

Why is that important? Because a recurrence of AF after PFA ablation more likely implicates a wrong target problem rather than a recurrence of conduction through the line of block that we attempt to create with point-to-point RF or cryoballoon ablation.

A recent study supports this notion. After reviewing more than 300 cases, investigators found that any AF that occurred more than 4 weeks after a PFA ablation was 100% predictive of more recurrences and a failed procedure.

Conclusions

It no longer makes sense to have a blanking period after AF ablation. A patient admitted to the hospital for AF one week after an ablation surely feels this negative outcome should count.

Of course, the caveat I offered the Western AF audience was that doctors have two mindsets. (We wear two hats if you will.)

One hat is our science or evidence hat. Here, we should surely count all AF episodes because it is the proper way to evaluate outcomes in studies. All AF counts for the patient and it should count in trials.

Doctors also must be clinicians and use judgement. Not having a blanking period does not mean that we need to take patients back for second ablations after an early recurrence. We can Stop and Think, and assess each patient and their specific situation. A blanking period should not obstruct clear thinking.

“The legacy journals are dying…”

“Blogs like Sensible Medicine are the future.”

I hope he is right; but I am not so sure. Here is a screenshot of an editorial from Dr. Harlan Krumholz, an academic cardiologist at Yale. He wrote this in 2017 when he finished his tenure as editor-in-chief of Circulation: CV Quality and Outcomes.

Krumholz made a compelling case for the death of journals. He wrote that they were too slow, too expensive, too limited, too unreliable, too focused on the wrong metrics, too parochial, too static and too powerful.

Seven years have passed from that essay. You know what Dr. Krumholz does now?

He is editor-in-chief of JACC—the biggest cardiology journal. Grin.

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My Diagnosis

Ten years ago, as a hobby, instead of bike racing, I started writing, and now podcasting, about medical studies. I’ve also co-authored more than 70 academic papers and peer-reviewed many more.

My diagnosis: the dissemination of medical evidence is a mess. In fact, I think we have regressed in the last decade.

Every Tuesday, I start searching for studies to discuss in my This Week in Cardiology podcast. During the weeks of big medical meetings, it’s easy to find studies to discuss. It’s not that easy during the weeks between meetings.

The thing is…journals publish the same number of studies every week. Which means that many, if not most, of these studies contribute little or zero to medical progress. Typical examples of pointless studies: small underpowered trials, single-center case series, or, the worst, observational non-random comparisons, which are hopelessly marred by confounding biases.

I ask myself: why would the authors spend time on such a project? The time commitment is massive; not only to do the grunt work of data collection and writing, but then submitting the paper to the journal, withstanding the many rejections, and answering numerous peer reviewer queries.

If the paper describes a new observation or important trial results, then, yes, it is worth it. I estimate that less than 10% of published papers fulfill this worthiness category. Yet it continues, week in and week out.

I think of a young learner putting in these hours to get a publication and it makes me sad. The reason trainees do this is to get a better training or faculty position—at a branded institution. It’s especially sad that being a dedicated clinical trainee is not enough.

But now, looking back after nearly three decades of practice, and one decade of academic work, I am convinced this time would be better spent doing any number of other things. Things like learning to be a better doctor, training for a marathon, reading non-medical books or working on writing or public speaking would be better than first-authoring a paper that does not increase medical knowledge.

An Inflection Point

Dr. Krumholz and Livingston highlight the reasons Vinay, Adam and I started Sensible Medicine. It’s why Andrew Foy, Muhammed Ruzieh and I chronicle the seminal trials over at Cardiology Trials.

We recognized that medical people had almost no where to go get an independent point of view.

Indeed, Krumholz was most right about journals being parochial. The reason is obvious: the business model of journals is advertising. Industry supports medical publishing. So it’s impossible to publish an editorial exposing the flaws of an industry-supported study. Sure, a few carefully worded critical sentences are allowed, but that is it.

Proponents of medical journals will cite their gate-keeping role. Editorial judging and peer-review prevents the dissemination of bad science. You can’t just publish a preprint and let the public decide, goes the thinking. Grin. Do not read Richard Smith, the former editor of the BMJ.

Medical meetings are worse. When late-breaking trials are presented, the discussant spends most of their time congratulating the authors—even if the trial was designed as marketing rather than science.

Social media used to be a place to find critical appraisal. No more. Now the key opinion leaders, the Top People, are there to thwart anyone who dare question a trialist’s choice of comparator or endpoint. One of the most influential doctors in the US referred to anyone who speaks up as the “peanut gallery.”

Together, these forces keep medical evidence inside the metaphorical gates. I’ve heard Eric Weinstein refer to this as the GIN, or the gated institutional narrative. Left atrial appendage occlusion, tricuspid valve clipping, and ARNI drugs all provide benefit. Period. Stop asking questions. But outside the gates of the institution, people-without-conflicts look at these trials and think…really?

Thinking outside the gates is what this newsletter is for. It’s our goal at Sensible Medicine and Cardiology Trials.

Independent medical appraisal is at a severe disadvantage. We can’t offer people a prominent position at an academic medical center; nor can we expect people to attend a medical meeting focused on critical appraisal.

But perhaps the Internet and the reader-supported model gives us a chance. For instance, a handful of journalists have broken from their legacy positions to become a powerful voice. The Free Press, Racket News, Slow and Boring and Silver Bulletin have made their mark. Marginal Revolution has been there even longer.

That’s our goal too: to put critical and independent thinking out there—as normal. We give permission to be skeptical but not cynical about medical practice.

There has to be a place for such thinking. For now, it is on Substack and podcasts.

Thanks for your support. Happy New Year. May the next year be one of clear thinking. JMM