I was surprised that it was a featured study at the European Society of Cardiology congress early this month. I had thought we knew from pathology studies of young people who died of trauma that blood vessel disease (including in the coronary arteries) can begin early in life. Of course, pathology studies are limited because it’s a small sample of people who are unlucky enough to have died.

The Danish and Spanish team provide us a large systematic look at nearly 17,000 asymptomatic adults from young to older using modern imaging techniques. We actually learn some interesting and provocative findings. I write provocative because there is currently great interest among the tech community to inoculate themselves against heart disease.

The Study

The authors enrolled adults without disease and symptoms from five age strata. They then underwent 3D ultrasound of the carotid and femoral arteries as well as a coronary CT scan. The primary endpoint was the presence of atherosclerosis. It was not an outcome study. Nor was it a prospective study looking at progression in individuals.

There were 2000 adults in the age 18-29 and 60-70 group and 4000 each in the 30-39, 40-49, and 50-59 strata.

Findings

• More than half had silent atherosclerosis—63% of men vs 51% women.

• Even young people (18-29) had disease—8.7% of men vs 6.7% women. This rose to ≈ 90% by age 60-70.

• Plaque volume increased exponentially with age; in younger adults with coronary plaque, roughly 40-48% had a coronary calcium score of zero — meaning calcium scoring alone missed a substantial share of real disease.

• Clinical risk scores had terrible sensitivity. (This was a European study, so they used the SCORE2 classification vs the PREVENT or PCE that we use in the US.) The high-risk classification of SCORE2 had a great specificity of 99% (low false positive) but only 2% sensitivity. Meaning that if you used the clinical risk score criteria for high risk, you would miss almost everyone with actual silent disease. Even if you widen the net and include moderate risk on the clinical score, you still miss two-thirds of disease.

The authors gently suggested that these findings may have clinical value. They cite the low pick-up rate of risk scores and write that these scores and direct imaging capture different information, especially at younger ages.

[Our] results support the position that primary prevention strategies informed by imaging may improve risk assessment and may warrant starting early in life.

Comments

I laud the systematic nature of this study. It adds modern imaging of a contemporary population and documents what we have long suspected: blood vessel disease begins early and progresses throughout life, earlier in men but women too have progressive disease.

Some may be scared by these findings, especially in Danish and Spanish adults, as surely it would be worse in the Southeastern US. But I would not be scared.

First, the presence of atherosclerosis on an imaging test is still a surrogate marker. More and more, the outcome of interest in cardiology is not a shadow on an ultrasound or streak on a CT scan, but an MI or stroke. There is a correlation between extent of disease and risk of events, but it is only a correlation.

Second, I am also not put off by the fact that risk scores miss most cases of atherosclerosis. The job of the risk score is not to pick up a surrogate marker but predict risk of events so as to aid in primary prevention therapies (like cholesterol lowering meds, for instance). This study does not compare prediction from clinical risk scores vs anatomic imaging.

Third, perhaps the most important message from this study is limitation of coronary calcium screening. Andrew Foy and I have long argued that CAC scans have little value—in anyone. One of the many reasons for this is that they are much more likely to incorrectly misclassify a person. This study confirms that nearly half of people with actual disease had a CAC score of 0.

Fourth, I strongly disagree that these observations have any clinical use for improving risk assessment at any age. We know from the DANCAVAS I and DANCAVAS II trials, that a comprehensive cardiac screening program (including imaging) in Denmark (arguably a best-case-environment) did not improve mortality or major adverse cardiac outcomes. In fact, in DANCAVAS II, screening increased the risk of major bleeding.

If the authors wanted to use these findings to further study the risk prediction from anatomy vs risk scores, I would be supportive. This paper is interesting research, but I would be very reticent to unleash such screening into general populations—as it could lead to an increase in downstream testing and inappropriate stenting.

Finally, and this may sound unusual coming from a cardiologist, but one of the principles of early detection and screening for disease is that the better primary treatment becomes the less the impact of early detection through screening. My partners in interventional cardiology are truly amazing in their ability to stop heart attacks with urgent stenting. It is routine for a person to present with an MI due to an occluded vessel, be sent immediately to the cath lab, and have the artery opened with total preservation of heart muscle.

I make this point about the success of early intervention not to argue for total ignorance of heart health. On the contrary, I believe in the value of healthy eating, regular exercise and not ignoring common symptoms, such as new angina or difficulty breathing. But the quest to eliminate all risk of heart attack through intense imaging remains an unproven and likely unwise clinical strategy.

Atherosclerosis, like atrial and ventricular ectopy, and gray hair and wrinkles, and declining watts on a bike, surely remains part of the normal aging process.

Healthy living and exercise can slow the process, as can not smoking, and lipid-lowering therapy. But the idea that we must image our bodies to be healthier is unproven. Once again, I reiterate: be afraid of imaging when you feel well.

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I took my 70-something dad to the cardiologist. He is a retired bi-vocational farmer and truck driver who has chronic heart issues since a childhood bout with rheumatic fever. Our visits usually center on whether it is time for another surgical referral. This time something else took center stage.

My dad started to say, “my wife is worried about…” The doctor slipped in “your partner.”

My dad was confused. He did not go to Harvard and therefore did not appreciate the substance and importance of the correction. “No, my wife,” he said. “She couldn’t make it today.”

The doctor cut him off, and this time delivered a performance worthy of an Amazon Studios production about the importance of inclusive language, how words have meaning, and how these words impact health outcomes for millions of people.

My dad went quiet. He disconnected from the visit entirely — not because he is an evil misogynist, but because he could not work out why we were not talking about his heart.

I tried to mediate and steer us back to clinical care. It did not take. To that doctor, the correction seemed to be the most important work she did for any patient that day. Nothing clinically important was addressed.

We had to find a new cardiologist. His care was delayed about three months.

It Is Not One Doctor

Dad’s visit is emblematic of political leakage into the clinic, and medicine and public health’s growing obsession with politics.

Researchers matched primary care physicians to their voter registration records and then put clinical vignettes in front of them. Democratic and Republican doctors differed substantially in how seriously they rated some health problems and in what they recommended, which included the expected health issues Republican doctors might care more about than Democrats (e.g., cannabis) but also the unexpected (e.g., obesity). The gap held after adjusting for physician age, sex, religion, patient characteristics, and geography. Their conclusion, published in the Proceedings of the National Academy of Sciences: “Physician partisan bias can lead to unwarranted variation in patient care.”

Careers in our field are increasingly rewarded when you treat medicine and public health as the side hustle and a political agenda as the main work. A large share of work by trained physicians and epidemiologists now focus on areas that are rather distant to health.

• The American Medical Association asks physicians to add a question to the visit: are you registered to vote?

• The Association of American Medical Colleges published a style guide instructing medical schools to use “oppressed” when describing minority populations and even replace “minority” with “historically marginalized” in teaching materials.

• Multiple major societies now treat emissions reduction itself as a clinical responsibility: the American Academy of Family Physicians, American Academy of Pediatrics and other organizations explicitly encourage physicians to counsel patients on low-carbon lifestyle choices such as plant-forward diets and walking or cycling, instead of driving to work or medical appointments. To which JAMA published a piece urging clinicians to consider moving asthma and COPD patients off their metered-dose inhalers because of the propellant’s greenhouse emissions.

• Major obstetrics organizations and health system style guides now instruct clinicians and scientists to replace “pregnant woman” or “mother” with “pregnant person,” “birthing person,” or similar terms.

• Medical and public health schools embed a host of politically related training, rebranded as structural competency.

All of it under chants of “this is our lane.” Which means my father’s cardiologist was not freelancing. She was doing what her mentors, medical education, health systems, and professional associations had told her to do: elevate politics above medicine.

The shift has been so pronounced that the New England Journal of Medicine broke a 208-year silence to weigh in on the 2020 presidential election, although stopping short of a formal endorsement. Scientific American made the first official endorsement in its 175-year history, and Nature followed.

This past month the American Journal of Public Health published a study describing a get-out-the-vote campaign. In it health professionals and providers in “federally qualified health centers, hospitals, and medical schools” were supplied QR-code badges to wear that patients could scan to participate. Patient data provided in the QR-code response was then shared with TargetSmart, which bills itself as “the leading data, research, and media buying provider for Democratic campaigns.” Oddly enough the university institutional review board deemed the whole thing “not human research” exempting it from any ethical review.

What the Obsession Costs

You might think all of this is performative, academic theater that no one takes seriously, and it will never actually matter. You’d be wrong.

Medical and public health institutions have lost tremendous amounts of trust. In a survey of US adults, the share reporting substantial confidence in physicians and hospitals fell from 71.5% in April 2020 to 40.1% in January 2024. Concurrently, two-dose MMR vaccine coverage among American kindergartners fell from 95.2% during the 2019/20 school year to 92.4% during the 2025/26 school year.

A preregistered randomized trial told 4,260 Americans one of two things: that Nature had endorsed Joe Biden, or that Nature had redesigned its website. Among Trump supporters, learning about the endorsement sharply reduced trust in the journal, reduced trust in scientists generally, and made them 38% less likely to want to learn what Nature had to say about Covid-19 vaccines during a forced break in the experiment. Among Biden supporters it bought the journal nothing: they were no more likely than before to want to learn what Nature had to say about vaccines. The endorsement turned Republicans off without turning Democrats on. It signaled that Nature had entered partisan politics, and when participants were given the opportunity to engage with its scientific content, their behavior rightly reflected that signal.

This was not one journal in one election. Three experiments with 6,281 Americans tested similar endorsements from the 2020 and 2024 election cycles. Trust in science fell across every dimension measured: the field’s perceived impartiality, its competence, even its benevolence. And the decline was, in part, driven by moderates, the people science should appeal to because of their baseline impartiality.

Moreover, the harms of these political efforts are about to be baked in. The medical and public health literature is the training data for the new wave of AI clinical and patient support systems and AI scientists. As journals, associations, and medical schools publish more political content, the AI systems built on that literature absorb it. Open AI recently disclosed that “every week, more than 230 million people turn to ChatGPT for help with health and wellness questions.” Could there be a scenario where a medical AI frames inhaler choice as a climate decision, nudging a user toward the climate-smart option when they are requesting information during an asthma attack? I hope not but it is possible.

We spend the public’s trust on gestures that turn the public against us and might even harm them.

What It Costs to Point Out the Error

The craziest part is that even pointing this error out comes with the cost of political retribution by medicine and public health’s ruling guard.

During the COVID-19 pandemic when I published a study in JAMA Internal Medicine about the dangers of promoting unproven therapies like Hydroxychloroquine I got emails praising me for standing up to the evil duo of Donald Trump and Elon Musk.

When I published about the rising rates of panic attacks during the COVID-19 pandemic, in the same journal, I got emails raising concerns that I was potentially undermining the importance of lockdowns.

Finally, when I wrote about how children in 2022 needed to attend school regardless of their adherence to reusable cloth masking mandates that had failed all evidentiary standards in randomized controlled trials I got emails asking why I had turned against science and many of my colleagues called for me to be dismissed from my faculty appointment.

In none of those cases was the objection that I was wrong. The objection was that I was on the wrong side. Following the data where it leads has become dangerous. When the crowd is motivated by partisanship over evidence being a good scientist signals you will not “always be with us.”

So let me be as clear as I can. I am not arguing that health disparities are unreal or unworthy of study, I have actively contributed to this subject on many occasions, including issues that have policy and political implications like abortion and gun violence. I did that work by providing evidence but without any value statements about what ought to be. I am arguing that a field, which has made political positioning a central product, has stopped being good at its actual job, and that the people who pay for that are the patients and public we swore to serve.

I also want to be sensitive to the people who pushed for a political agenda. It was not malicious. Many of them carry scars from a history where medicine did terrible things: Tuskegee, forced sterilizations, and more. But what actually produced those wrongs? Sterilization, for example, happened because a political movement decided which Americans should reproduce and physicians carried it out as good partisans. In every case the harm arrived the same way: a political agenda from outside decided what the patient was, and then medicine and public health followed.

That is not a story about politics being absent from the clinic. It is a story about politics being present. The remedy is not a better form of politics and/or more of it. It is less.

Neutral Ground

Neutrality is written into the physician’s pledge: “I will not permit considerations of age, disease or disability, creed, ethnic origin, gender, nationality, political affiliation, race, sexual orientation, social standing or any other factor to intervene between my duty and my patient.” It is written into the laws of war as well. Under the First Geneva Convention a field medic is required to treat the enemy soldier who was shooting at him moments earlier. That is the standard this profession set for itself under the worst conditions humans can encounter. If a medic can manage that in a trench, a cardiologist can manage it in an exam room for a patient who says wife.

I cannot even guess the political affiliation of my childhood pediatrician, all my research partners of more than a decade, or my professional heroes. Why would I ever need to know? Some will be Democrats, some will be Republicans, and some will be apolitical…but the work and calling we share is agnostic to politics. Politics follows the timeline of fads. The scientific method is meant to be more eternal.

None of this asks anyone to stop caring. Neutrality is not coldness; it is the harder form of caring, the discipline that lets a physician treat a patient she disagrees with or a scientist chase a question whose answer she may not like or choose for herself. Advocacy asks only for conviction, but we are called to a higher purpose, one that requires restraint.

Institutions owe the same discipline. A journal that endorses a candidate has decided it is no longer impartially pursuing evidence-based medicine. A funder that rewards the politically fashionable question has decided political findings should exist. An organization that leads with the conclusion it prefers rather than the evidence it has (or seeks) has decided the public cannot be trusted with truth.

Serving your friends is easy. Serving everyone is hard. Everyone includes the people who have said ugly things, who did not vote the way we voted, who have done real harm, sometimes even to us. A profession that cannot manage that has not become more moral. It has only replaced principle with tribalism and ultimately become more amoral.

My father’s cardiologist could have spent that visit on his heart. She spent it on a word triggered by a career spent working in a politicized profession. It cost him three months.

It is costing patients everywhere far more than that. Not one kind of patient. Every kind: white and brown, rich and poor, red state and blue state, urban and rural.

There is no illness that checks your politics before it takes you. There should be no clinic, no journal, and no health organization that does either.

John W. Ayers PhD MA is a computational epidemiologist focused on getting the public back in public health by harnessing new technologies for clinical and scientific translation: www.johnwayers.com

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So I thought long and hard before I made an appointment with her primary care doctor. As a seasoned emergency medicine physician, I know the drill: if you hang around the barbershop, you’re going to get a haircut. If you take an 86-year-old woman to a doctor, she’s going to get a lot of testing.

I waited three weeks. The hoarseness didn’t improve. I made the appointment.

For most of human history, people died suddenly— often as a result of infection, usually by the age of fifty, and almost always at home. It wasn’t until 1945 that life expectancy crossed the 70-year threshold for women. It was the 1950s before most Americans died in hospitals.

Today, end-of-life care is a topic of rigorous debate. It’s expensive: anywhere from 13% to a quarter of all Medicare spending is consumed by the 4% of beneficiaries in their last year of life. It’s also of debatable quality. And if you ask people what they want at the end of life, no one hopes for an expensive hospital death. What we want is a “good death”. 71% of us want to be at home and prioritize dying “without pain, discomfort, and stress.” Studies of bereaved family members concur, with higher quality care reported when hospice is initiated early, and ICU stays and hospital deaths are avoided.

We left my mother’s doctor with instructions to pick up a cane and have blood work drawn. We spent most of December in a vortex of testing. There was a referral to neurology and an appointment with the head and neck specialist. A scope solved the mystery of her hoarseness: a mass at the base of her tongue. This led to her first biopsy (unsuccessful), a CT scan, another biopsy (successful), a PET scan, and finally a verdict from the oncologist: large B cell lymphoma, present in her neck and magnificently aggressive.

Chemotherapy had a 5% chance of success.

We chose hospice.

In the 1960s, when Dame Cicely Saunders suggested an alternative philosophy for the terminally ill —one that minimized medicalization of death and maximized comfort— she was met with skepticism. Today, however, hospice is a beloved element of mainstream medicine. Over half of Medicare beneficiaries are enrolled in hospice when they die, and popular opinion of it is overwhelmingly positive. It’s also considerably less expensive than dying in the hospital.

For physicians, enrolling a patient in hospice care can be a great relief. I’ve lost track of all the ways I’ve seen people die: suddenly and slowly, peacefully and painfully. Once, to my horror, I declared a patient dead only to have her start spontaneously breathing again. Hospice, by contrast, signals an end to unrealistic expectations. No more monitors, middle-of-the-night blood draws, or futile care.

But what my mother’s death taught me was something that twenty-five years in emergency medicine hadn’t: how people die at home.

For family members, hospice can be complicated. True, it comes with services like nurses, social workers, and chaplains. And it’s generously funded by Medicare. But dying at home still means shifting from professional to family caregivers. It means intimate personal care, like bathing and feeding a loved one. Managing distressing symptoms like pain, agitation, and dyspnea. Changing adult diapers and administering suppositories. And it’s a 24/7 gig.

Throughout January, I did my best. We gave medication to suppress her secretions and ordered a hospital bed to keep the tumors from suffocating her. Soon after, we started morphine. She waffled between constipation and diarrhea, while I waffled between grief, exhaustion, and resentment. I often felt like a complete failure.

Like all parents, Carolyn Meyer was not perfect—but she was damn close. She loved me with a fierceness I didn’t fully understand until I had my own children. What the dementia hadn’t taken, the lymphoma did. I watched as she lost her speech, then her ability to swallow. And then she was gone.

In the aftermath, I am considerably more humble and less naive. I’m more intentional when I discuss hospice with my patients. Even with a quarter century of medical training, I wasn’t prepared for my mother’s death at home. And I’m not alone: about a third (32%) of hospice caregivers develop moderate-to-severe anxiety and depressive symptoms. Encouragingly, several new programs—including hospice homes, inpatient units, and death doulas—attempt to step into the breach between over-medicalization and family overwhelm. They show promise. Others have suggested expanding financial support for caregivers or in-home nursing support for highly symptomatic patients.

In 2017, the most common place to die once again became the home. With this shift, I believe we are headed for a reckoning. By 2060, a quarter of the US population will be over 65, and many expect their children to care for them— children who aren’t necessarily prepared to shoulder this responsibility.

What I’ve come to realize is that our loved ones deserve the good death they envision. But, in an era when most die protracted deaths from chronic disease, this means recognizing that death is not just about the right place, but also the right support. And it’s not just about the dying, but also the family who survive them.

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Mary C. Meyer, MD MPH has been an emergency medicine physician for 25 years and holds certificates in global health and climate medicine. From 2018 to 2024, she served as the director of disaster preparedness for a large healthcare organization in Northern California and responded to many disasters, including wildfires, power outages, evacuations, poor air quality, highly infectious pathogens, and staffing shortages.

Photo by Christina Radevich on Unsplach

In the emergency room, she was assessed by a neurologist whose note ended, “Not a seizure, admit to medicine, consult cardiology to rule out something cardiac.”

21st-century medicine is a team sport. In the hospital, we round with teams of doctors and students. The primary, generalist team frequently consults specialist teams. Whether in outpatient or inpatient settings, doctors also work with an amazing array of other healthcare professionals: nurses, medical assistants, certified nursing assistants, pharmacists, physical therapists, occupational therapists, chaplains, social workers, case managers, child life specialists...

Good care requires the work of generalists and specialists. As a general internist, I can confidently direct the care of many diseases and diagnose and initiate treatment for many more. There are also many for which I, and my patients, rely on my subspecialty colleagues. You would not want me taking out your gallbladder, doing your bronchoscopy, treating your lupus, or deciding on the appropriate therapy for your myeloma.

Subspecialists get a lot of glory (and money) in medicine these days. It should seem surprising that the doctor who takes care of everyone and everything makes significantly less than the cardiologist who deals not with the heart but with the heart’s specialized, pacemaker cells; the oncologist who specializes in diseases caused by mutations in a single type of precursor cell; or the ophthalmologist who focuses on a single layer of cells within the eye. (OK, my bitterness slipped out there.) But in the current system, specialists spend more time in training, so they need to be compensated accordingly.

Through career choice, filtering, and evolution, generalists and specialists end up being very different people. In 1953, Isaiah Berlin published the book The Hedgehog and the Fox. The book popularized the idea, attributed to the Ancient Greek poet Archilochus, that a fox knows many things while a hedgehog knows one important thing. That dichotomy applies well to the 21^st-century medical generalist foxes and specialist hedgehogs.

Generalists and specialists care for different patient populations

Patients are not triaged before seeing the generalist. There is no barrier (or even delay) between a patient of mine experiencing a symptom and me hearing about it. I occasionally have Patient Portal messages from 2 AM about a symptom that has resolved by the time I return the call the next day. Many concerns presented to the generalist do not have a demonstrable physiologic basis. Of those that do, most can be diagnosed clinically or with basic testing. A generalist carries with him hundreds of differentials, most of which consist of a handful of diagnoses.

Patients who see specialists have (usually/ideally) been referred/triaged by generalists. Patients referred to specialists fall into one of three categories:

1. They have been diagnosed with a disease (and possibly treated) but now require treatment that is best delivered by a specialist. I might need help managing late-stage CKD or Parkinson’s, or I need someone to do a joint replacement or a Whipple.

2. They have signs of serious illness that require specialized diagnostics. As testing has supplanted clinical acumen, this group of patients has become smaller. Sure, the oncologist to whom I refer a patient with lung cancer is likely to do further testing to determine the extent and genetics of the disease, but usually I know who to refer to because I know the disease I am referring. The diagnostic mysteries I refer require a diagnostic procedure I cannot perform or whose diagnosis is number 15 on my differential diagnosis; a differential that includes only 10 diagnoses.

3. They are people I could manage if I had had the time, interest, or bandwidth. I am embarrassed to admit that I refer patients because I sometimes just need to outsource one of their multiple problems.

Different populations lead to differences in clinical reasoning

While quizzing a medical student, a generalist will frequently mention a diagnosis, and then say, “but you never see that.” I include pheochromocytoma, relapsing polychondritis, hairy-cell leukemia, and Langerhans cell histiocytosis among these diseases. I have colleagues who have made whole careers out of these diagnoses I disrespect. The average generalist would miss diagnoses in the specialist population, while the specialist would bring down Medicare in a week caring for the generalist population.

The prognoses of the same disease differ in generalist or specialist practices

Because the generalist sees the average patient with common diseases, outcomes are dominated by those in the middle of the Bell Curve. Specialists see a selected group of patients. The patients I see with migraines have headaches that are easily controlled. My neurology colleagues will only see patients who have failed to improve with three lines of prophylactic and abortive therapy. Their view of migraine prognosis will be significantly darker than mine.

Generalists and specialists read differently

The generalists I know who work to stay abreast of the literature read broadly, consuming half a dozen journals, skimming abstracts, and diving deeply into only a few articles. Subspecialists often read one or two journals, cover to cover. This serves their purposes well. The generalist needs to have a sense of how all diseases are managed to know what their specialists can, cannot, and should not offer, while the specialist needs to be the final word on diagnosis and management.

The best in both worlds

The ideal generalist is accessible to a fault, knows how to diagnose and manage common concerns, knows what she doesn’t know, and knows what her specialists have to offer. It has been said about many fields — but I think it fits best the generalist — you want her to be a great generalist as well as the best cardiologist/neurologist/urologist who has not been trained in that field. The ideal generalist will provide good care of most everything you’re likely to experience. When you need specialty care, she will know the right person to send you to because she knows what that person can and will do.

The ideal specialist knows everything in his field that might be causing symptoms, knows the workup for even the most unusual causes, and is a pro at treating these diseases. When the ideal specialist excludes diseases in his purview, he refers back to the generalist, sometimes with suggestions regarding who might get involved next.

Both the ideal generalist and specialist communicate the intricacies of diagnosis, treatment, and prognosis with their patients and prioritize their patients’ goals and values.

Since medicine is hard and complicated, things do not always go well. Generalists fail when they manage problems outside their scope. More commonly, they fail when they overburden specialists by referring patients with problems that they should manage themselves. They also waste the time of specialists and patients alike by referring patients for whom the specialist has nothing to offer. Specialists fail when they burrow into holes that should be left unexplored, over-evaluating or overtreating. They also fail when they stray from what they know — sometimes tempted by the diffident generalist — referring to other specialists: “consult cardiology to rule out something cardiac.”

ST did well overnight on the general medicine service. Further testing was notable for a mildly elevated creatine kinase level. An echocardiogram was normal, and there was no ectopy on a cardiac telemetry. The team decided that although unlikely, a seizure was the most likely diagnosis. A brain MRI revealed a small infarct in the left temporal lobe. Carotid dopplers were normal. The neurology service was re-consulted. EEG findings increased the suspicion for a seizure.

ST was discharged on aspirin, a statin, and a seizure medication, as well as a 14-day cardiac monitor.

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Photos by Ray Hennessy (fox) and Alexas_Fotos (hedgehog) on Unsplash

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For the sake of argument I will stay with the traditional risk factors.

Current guidelines (experts) say we should give these patients oral anticoagulation (OAC) because [they think] the yearly stroke risk is around 1-2% per year. OAC reduces stroke risk by about 60%. But it also may increase bleeding.

But all this is based on old data from the warfarin trials 20-30 years ago. Things have changed. AF is much easier to diagnose and we can now find 1 hour of AF with a smartwatch.

Observational studies have found a declining incidence of stroke in patients with AF—even though the risk factors are increasing. Something about 2026 AF is less risky than AF in the 1990s.

One more thing before I tell you about the SINGLE AF trial. It’s not nothing to give a 55-year-old patient a diagnosis of AF and treat them with a daily anticoagulant. That’s a lot of tablets over the decades.

SINGLE AF Trial

South Korean teams randomized 1800 patients with AF and one risk factor to a direct acting oral anticoagulant (DOAC) or no DOAC. They then measured a primary outcome of stroke, systemic embolism, major bleeding or cardiovascular death.

These were 60-year-old patients, 75% male and about two-thirds had intermittent AF while one-third had persistent AF.

Here are the KM curves:

Notice the y-axis insert. After approximately 2 years of follow-up, a primary endpoint occurred in 4 of 901 patients (0.5%) in the DOAC arm vs 13 of 902 patients (1.5%) in the no DOAC arm. The absolute risk difference was -1.0% (95% CI, -2.0 to -0.1; P = .03).

Stroke events were even lower. Three vs ten strokes in the DOAC vs no-DOAC arm respectively. Major bleeding was even lower yet (3 vs 4) patients.

The yearly stroke risks were 0.55% in the control arm vs 0.15% in the DOAC arm. I also went into the supplement and learned that 7 of the 10 strokes in the control arm were modified Rankin score 0 or 1, which translates to either no or minor deficits.

Comments and Lessons

When assessing trials we ask whether the effect size is clinically meaningful and statistically robust.

Effect size: Times have changed with AF. It’s just not as risky as it used to be. In SINGLE AF, which had many patients with persistent AF, the stroke rate with no OAC was only 0.55% per year. While it was lower with DOAC, the reduction was small at 0.4% per year. That means you have to treat 250 patients with daily OAC to prevent one stroke. And 70% of the strokes were very mild.

When I wrote about this in Munich where it was presented at the ESC congress, I felt that if you did nothing, very little bad happened and if you did something (gave DOAC), very little harm came. The tiny effect size stems from a super low base rate of stroke when only one risk factor is present.

Statistical Fragility: You hardly need a calculator to posit that 3 vs 10 strokes in 1800 patients could occur by chance. A formal calculation of the fragility index is 2, meaning if 2 events occurred in the other group, statistical significance would be lost. This complicates matters because it’s possible that the absolute risk reduction is noise rather than true effect.

Translation is Hard

Another thing we do when assessing trials is ask about external validity. That is…how can we apply this to people we see in our clinic.

Modernity has complicated SINGLE AF trial translation. Let’s say a person has 2-hour episodes of AF on a smartwatch. We call this subclinical AF. The ECG rhythm is still AF, but it is unlike the AF that used to occur in the past. A patient in the year 2005 had to feel palpitations, then make an appointment at a doctor’s office and then get an ECG. IOW…they had to be in AF a lot longer than 1-2 hours.

We know from the NOAH and ARTESIA trials that oral anticoagulation has little to no net benefit in patients with short-duration AF. These were much higher stroke risk patients (CHADSVASC ≈ 4) but had yearly stroke rates of approximately 1%. DOAC reduced the risk of stroke a little but increased bleeding by as much.

So…if short duration AF is this low-risk, imagine a patient with only one risk factor. It’s going to be even lower than predicted in the subclinical AF trials. And that is what we saw in SINGLE AF.

Thus far, it sounds like I am making a case for no anticoagulation. But it is not that simple. Consider two patients who could have been (and likely were) in SINGLE AF.

• A 50-year-old with hypertension and short-duration infrequent AF on her smartwatch. This patient could do well on or off AC.

• A 64-year-old person (soon to be 65 years, a cutoff for another risk factor) with insulin-dependent diabetes and persistent AF would likely have a slightly higher stroke risk and would benefit from oral anticoagulation.

If you like algorithms, SINGLE AF is terrible news. Guideline writers will be unable to put the trial’s results into those simple colored boxes telling doctors what to do.

If you value the role of a thinking doctor, you love SINGLE AF. Because now we have to think about the specifics of our patients (eg. duration of AF) and learn their preferences. As I have written here often, maximizers will want to do everything to prevent stroke. For those people, OAC is the obvious answer. Minimizers will look at a 4 in a thousand risk reduction and think it unworthy of taking a daily pill for years.

SINGLE AF allows for both of those translations. And I really like that.

To be honest, much of modern cardiology is going this way. New therapies increasingly have small incremental benefits for which rational people feel differently about.

The final thing to say is that things change over time. We now know that lifestyle measures, such as weight loss, physical fitness and alcohol reduction can eliminate AF. If this happens in the months to years going forward, then the anticoagulation decision becomes easier: no anticoagulation.

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Others are increasingly skeptical, they question the need for annual covid shots in kids, the need to vaccine pregnant women for covid in 2026, for RSV and much more. The most extreme question vaccines broadly. Hesitancy has spilled to vital and important public health efforts like the MMR shot.

People argue about the causes of this hesitancy as well. Some groups, e.g. Amish, have a longstanding skepticism of vaccination, going back generations, which is hard to trace back to Robert F Kennedy Jr, but not impossible.

Debates on vaccines quickly require quite technical knowledge. Do covid shots increase miscarriage? Do they reduce miscarriage? How do we know? Randomized trials or observational studies? Are there unmeasured confounders in the observational study? Is there immortal time? The randomized trial conducted by Pfizer and on the package leaflet was powered to exclude what increased risk?

On television, the health pundits and vacuous anchors love to say “if you have questions, the best person to ask is your pediatrician”. This is repeated as a sort of legal disclaimer and a mantra.

The best person to discuss vaccines with is the pediatrician.

Of course, this is a data free claim. And there are reasons to doubt it. Are pediatricians really the best people to ask?

Of course, there is no doubt, pediatricians and doctors are fully capable of dispelling some vaccine myths, and answering many questions.

I'm worried this vaccine contains a microchip.

Don't worry, I can assure you it does not. (*correct answer)

That's a really simple question, that any doctor— even Dr. Google— could answer.

But simple questions start easy, but then can become complicated.

I've heard that the covid shot has an 80% rate of miscarriage

I can assure you it does not have an 80% rate. We would have seen that. (**correct answer)

Ahh, got it, so what is the lowest increased rate of miscarriage you can assure me has been excluded? What rate of miscarriage was excluded by the randomized control trial run by Pfizer which was aborted midstream? Was a 5% increased risk excluded?

**Crickets. That’s a Step 2 boards question.

Pediatrics training and practice provides very little information on vaccine regulatory science and evidence. A few follow-up questions can derail a pediatrician, and it isn’t their fault. It is because we never taught them the answers.

I'd prefer to spread these two shots out by a week.

Why do you say that?

I'm worried that giving the shots together will reduce the efficacy and increase the side effects.

Not to worry, we pediatricians know that you can give all the vaccines safely together.

I hear you say that. But don't you think the randomized control trial underlying that claim is severely underpowered, and the lower bound of the confidence interval for non-inferior antibody titers could result in, and is even quite compatible with, substantial clinical inferiority? Also what increased risk of side effects is the trial powered for? Take a look at the package leaflet…

*Crickets That is a Step 3 question.

Not only do I doubt that pediatricians know what is known and not known about vaccine science at the level needed to answer a thoughtful question on interference, I doubt the expert vaccine pediatrician researchers who proudly hop on the television know these details. In fact, their comments suggest to me they do not.

I love pediatricians. If I see a kid with a rash and a fever, I am the first to take their advice. But if I want to understand the evidence base for vaccines, particularly the most controversial areas, I doubt pediatricians are equipped to answer my questions. They have not even been taught the contours of the debate.

An intelligent parent who spends 5 hours reading about the intricacies of a single vaccine question— is maternal RSV vaccination associated with pre-term and lower weight babies?— what is known and unknown— could easily trounce a pediatrician in a conversation.

Should a healthy 29 yo first time pregnant woman get a covid vaccine at week 34 next month, in the year 2026?

Ask your Ob-Gyn

You might as well ask a fortune cookie. What is the risk of illness to a pregnant woman in 2026? What is the risk of hospitalization? What is the absolute risk reduction to mom and baby? What is the risk of AEs? Which is larger? What study is most relevant? What are the pitfalls of the observational studies cited by expert guidelines?

Good doctors are quick to admit what they know and don’t know. They embrace humility, but the average doctor in a busy day can become frustrated. They don’t have time for 50 questions. Given the rules and incentives in some practices a parent can be fired— told to seek care elsewhere.

But I just wanted to know the current hospitalization rate for children younger than 23 months with no known comorbidities, and the statistic you gave did not report the true denominator…. The mother protests, while being escorted out. Tell your baby the only treatment for his otitis media is supportive care, the doctor shouts as the door closes.

Doctor, don’t you think the regression discontinuity study from England, subsumes the Wales analysis for Shingles vaccine and dementia?

Find another doctor.

I don’t want to just pick on pediatricians. All medical fields have these oft-repeated statements that, if you really think about it, are closer to a fable than fact.

In oncology, we lie train fellows to lie.

The best treatment for your cancer is always a clinical trial.

I have heard that a thousand times. I was told to say it. When I struggled to mouth the words, they sent me to Guantanamo bay.

But it is clearly a lie. In some cases, sure, a trial is best, but in many cases the best treatment is the standard of care. Enrolling on a phase II study by a small company bloated with fresh capital proudly stating we have 3/11 stable disease on the trial (no PR or CR)— sweet jesus, that is not a good trial. And yet, our fellows are told, tell them…

The best treatment for your cancer is always a clinical trial.

Ahh, AI supports me claim:

Oh shucks, just when I starting thinking AI was getting smart…

Win some, you lose some.

There is no direct empirical evidence that a pediatrician is the best person to discuss vaccines with. There is plenty of reason to worry that the training has avoided the difficult questions and debates that currently shape modern vaccine hesitancy—can I delay the hep B shot 2 months if the mom’s ultrasensitive Hb assay is neg?— etc. There are reasons to worry there will be countervailing risks— like being fired from the practice. In short, I have my doubts.

My solution would be for medical organizations to curate and host the debates in the space, but that would require humility and political neutrality, which is unlikely to happen anytime soon.

If this post interests you, or outrages you, I ask you to do one thing. Listen to my interview with Reason magazine and ask yourself if there was something about vaccines you didn’t know that you learned. If you are still angry, please leave a comment.

It has been observed that a rising blast count during the waning moon and splenomegaly extending at least three fingers below the costal margin are associated with inferior outcomes, particularly among patients treated on a Friday or before a national meeting. Among 17 consecutive patients, chemotherapy with venetoclax for 12 days was associated with improved survival. Treatment duration was selected at physician discretion for reasons not entirely remembered. The survival benefit persisted on multivariable analysis after exclusion of two inconvenient subjects. Prospective validation is warranted but unlikely to be feasible, underscoring the enduring importance of the present series.

The traditional farmer’s almanac is a peculiar form of knowledge. It gathers observations about seasons, weather, planting, and recurring natural events, then uses those patterns to suggest future decisions. Its contents may be careful, accumulated over many years, and genuinely useful. Yet an almanac does not report the results of experiments. It records what has happened and forecasts what may happen again; it does not identify why events occurred or establish what would happen if one condition were deliberately changed.

Much of the hematology literature consists of retrospective cohorts, registries, prognostic models, molecular subgroup descriptions, and uncontrolled treatment series. These studies can be useful, especially in rare diseases. The risk is that they often adopt the language and appearance of hypothesis-testing science despite lacking a design capable of separating causal effects from selection, confounding, measurement, and chance.

The problem is not that hematology has too many almanacs. The problem is that we print them in the format of experiments and read them as though they were scientific proof.

What is almanac evidence?

Early modern English almanacs mixed calendars and weather predictions with medical guidance. In a review of 1,392 surviving English almanacs from 1640 through 1700, almost three-quarters contained preventive advice or advertisements for medical products and services. Modern biomedicine has even reclaimed the name: NCI-ALMANAC is a systematic screen of anticancer drug combinations explicitly intended to generate hypotheses for further testing.

That is the right way to use an almanac: as a catalog of observations and a starting point for tests, not their substitute. A transplant registry can describe relapse and non-relapse mortality. An AML cohort can associate a mutation with shorter survival. An institutional series can document responses to an off-label therapy. These are real observations.

The category error begins when an association becomes a mechanism, an outcome after treatment becomes an outcome caused by treatment, or a subgroup discovered in the data becomes a biological entity.

Some observational studies can support causal inference when the intervention, comparator, population, time zero, and assumptions are defined in advance. Most small retrospective series are not designed this way. A Kaplan-Meier curve, a multivariable Cox model, or a propensity score can improve the description and adjustment of recorded data. None can account for patients who were never referred, tested, treated, or entered into the dataset. Statistics can make an almanac more precise. They cannot turn it into an experiment.

Why we need almanacs

Hematology is unusually dependent on descriptive evidence. Many diseases are rare, molecular subgroups are small, therapies change faster than randomized trials can mature, and important questions may never attract funding for research studies. Waiting for definitive evidence may mean having no guidance at all.

Almanac evidence can identify toxicities, estimate event rates, describe natural history, reveal exceptional responders, and expose practice variation. Almanacs are a powerful hypothesis-generating tool. A good almanac may be more useful than a poor trial.

The distinction is not a ranking of worthy and unworthy work. It is a statement about the kind of knowledge produced. A descriptive study should say, plainly, “This is what occurred in our selected population.” It does not need to inflate that observation.

Show us every patient

If a study is functioning as an almanac, it should accept the obligations of a good one: record faithfully, disclose completely, and allow readers to inspect the entries.

For a retrospective cohort of 100 or fewer patients, publication of deidentified patient-level data should be the default. A baseline table, a multivariable model, and a Kaplan-Meier curve are not enough. Authors should provide one row for every patient, including the clinically relevant baseline characteristics, treatment and timing, response, duration of response, relapse or progression, subsequent therapy, transplantation, last follow-up, survival time, vital status, cause of death when known, and the timing and reason for censoring. Authors should include as much molecular information as possible, including specific mutations and variant frequency. The report should also account for every screened, excluded, and omitted patient.

A Kaplan-Meier curve remains useful, but it compresses fundamentally different clinical courses into the same downward steps and censoring marks. A patient censored alive after six months because follow-up was lost is not equivalent to one who remains in remission at their five-year follow-up appointment. Both may appear as small ticks on the curve. Readers should be allowed to see the difference clearly.

“All the data” does not mean releasing the electronic medical record or compromising patient privacy. It means providing every deidentified patient-level observation needed to reconstruct the reported results and understand every inclusion, exclusion, event, and censoring decision. Dates can be converted to intervals, and uncommon identifying combinations can be suppressed. If some information truly cannot be shared, authors should state exactly what was withheld and why.

The ledger can be a downloadable spreadsheet, accompanied by a compact patient-level table or swimmer plot for readability. For 100 patients, this is not technically difficult and would usually require only a few supplementary pages. Complete patient-level reporting also preserves value for methods not yet developed. Future AI systems may detect meaningful patterns across many small cohorts, but no model can recover clinical trajectories irreversibly compressed into medians, hazard ratios, and Kaplan–Meier curves.

Journals should stop accepting small retrospective series without the underlying patient-level ledger. If a dataset is small enough for investigators to examine one patient at a time, it is small enough for readers to do the same. Statistical compression should not conceal important details, and many studies simply do not need statistics.

Label the almanac

The abstract should say whether a study is descriptive, hypothesis-generating, predictive, or designed for causal inference. That label should govern the title and conclusion. It would not diminish exploratory research. It would make the boundary between observation and interpretation visible.

Calling a study an almanac is not an insult. Careful records have value. But an almanac should act like one: label its observations honestly and show us the entries in their entirety.

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Neil Dunavin, MD is a hematologist-oncologist specializing in leukemia and stem-cell transplantation. He practices in the Chicago area. The author used ChatGPT to assist with drafting, editing, and condensing this essay.

There is no question that, at some point, most medical interventions are no longer warranted. Whether we are talking about screening tests (mammograms, PSA, colonoscopy), risk factor modification (statins, smoking cessation), or treatment of common diseases (hypertension), there comes a time when competing health threats make it unlikely that interventions will pay dividends. Sometimes the ratio of benefits to harms flips from favorable at a young age to unfavorable later in life.

When it comes to therapy discontinuation — deprescribing — doctors practice in a data-free zone. We estimate a patient’s individual life expectancy — not every American man will live 76.5 years; we guess at the continued benefit of therapy and weigh that against the harm of 1-5 more pills a day.

It is worth celebrating that we are seeing more studies that address therapy discontinuation:

In July, the NEJM published an article asking whether it is OK to stop lenalidomide in patients with myeloma: Continuous or Fixed-Duration Maintenance Therapy in Multiple Myeloma.

John posted a great article discussing an observational study published in JAMA, "Colorectal Cancer and Mortality Risk Among Older Adults With vs Without Adenoma on Prior Colonoscopy," whose goal was to tell us when enough is enough with colon cancer screening.

The last few weeks have brought us studies in The Lancet (SAGA/SITE) and the NEJM (STAREE) that shed light on when we should stop starting or start stopping statins. (I deeply love that sentence.)

Andrew, John, and I discussed SAGA/SITE on Fortnight; Vinay wrote about STAREE; and STAREE will likely appear on a future Fortnight, so I am not going to rehash the critical appraisal here. But since, of the four of us, I am probably faced with these decisions most, I wanted my uninterrupted say.

Atorvastatin is the most prescribed medication in America. Rosuvastatin comes in at number 9. They are spectacularly effective in people with vascular disease. They have a role in primary prevention, but the new lipid guidelines seem to have been written with the sole purpose of getting more people on statins at a younger age. Even though we don’t have strong data to support this ramping up of primary prevention, it makes some mechanistic sense: stop the early deposition of plaque.

It also makes sense that we should stop them at some point. Why? Because as you get older, targeting one disease, even if it is the most common killer, does not make a difference in the face of everything else conspiring to kill you. We do have vaguely related data from 2004 that starting statins in people (in their mid-60s) who are at high risk for all-cause mortality (those on hemodialysis) provides no benefit.

Takeaways from STAREE

STAREE studied a group of patients that I don’t see — I’m not even sure they exist in the US — people over 70, about half with hypertension, with “average” cholesterol levels, who are not already on a statin. To be part of this patient population, you also needed to be willing to start a statin and demonstrate adherence during a month-long run-in.

(Vinay commented on the irritating nature of this run-in period. The inclusion of a run-in period in STAREE means that any efficacy demonstrated will exceed the effectiveness in a real population.)

In the results table, with all the slicing, dicing, coupling, and uncoupling of endpoints, the only results that I think are independently important are that there was a decreased rate of nonfatal MI in the statin group (HR 0.58, 0.44-0.77, ARR 2%, NNT 50) and no difference in overall mortality (HR 0.91, 0.79-1.04).

How will STAREE affect my practice?

If I ever see a patient who looked like this, I would tell them I don’t really see a reason for them to start a statin. If they thought they’d definitely adhere, and decreasing the risk of MI a bit is important to them, and they wanted to start a statin, I’d write the prescription.

Takeaways from SAGA/SITE

SAGA/SITE looked at a population that I see EVERY SINGLE DAY: People in their late 70s and early 80s who are on a statin for primary prevention and would like to be on fewer medications. On the Fortnight podcast, we discussed the issues with this trial, mostly related to its power. All that aside, the results of the trial are clear and in line with my priors. If you look at a population of generally healthy older people, whether or not you continue a preventive medication makes no real difference.

It is worth considering the characteristics of the patients in this trial. The median age was 80; about 2/3 were women; 29·5% had DM; and 77·2% had hypertension. The mean BMI was 27·3 kg/m², and 61·7% had been on statins for more than 10 years. You can also bet that the 80-something-year-old patients participating in this trial were healthier than your average. Here is the survival curve for overall mortality.

How does SAGA/SITE affect my practice?

If a patient, similar to the ones in this trial, asked me if they could stop their statin, I’d say, “Absolutely!”

Whether I am going to start deprescribing statins in the 40% of my practice who are 75 and older gets to what we deprescribe, why we deprescribe, and the barriers to deprescribing. I always work to deprescribe unnecessary medications and those with toxicities that likely exceed their benefits. Benzodiazepines, aspirin, sleep aids, gabapentin, chronic NSAIDs, and PPIs probably lead the list.

I am also inspired to deprescribe medications when people are burdened by polypharmacy. I do this because there is a chance of unknown interactions and because I am obsessed with “cleaning up” medication lists and problem lists.

If we paid for our healthcare differently, cost would be a reason to deprescribe. This seldom comes up.

What undermines my deprescribing efforts? Often, my patients are more apt to continue a medication than to do an “N of 1” trial to see if they are getting any benefit from their PPI, gabapentin, or montelukast. Sometimes there is resistance to admitting the reality of one’s mortality. Accepting that there is not enough time left to benefit from a medication whose effect is measured over decades is not something everyone is willing to do.

Conclusion

In the end, STAREE will have little effect on my initiation of statins in older patients. SAGA/SITE will modestly increase my rate of statin deprescribing.

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This leaves me with the hard work of completing his column. Those are big, clip-in shoes to fill, and I will undoubtedly do a worse job.

Today’s study of the week is the STAREE trial— a 9000 person RCT allocating folks over 70 to Atorvastatin vs. placebo, and appearing in this weeks NEJM. It is part of a series of recent trials on this topic. This one took community dwelling adults with no history of vascular disease or dementia and mean LDL of 127, and after a 14 day placebo run in period to test compliance (PS: I hate this design feature— just makes in-articulable inclusion criteria and poor generalizability), randomized them to Atorvastatin or placebo. After 1 year, 20% quit taking the statin, after 6 years, 50% quit.

Elsewhere I discussed a much smaller French study with about a tenth as many participants.

Vinay Prasad's Observations and Thoughts

Should folks older than 75 take a statin?

If you are over 75 and have not had a cardiovascular event, you face a choice— take a statin or not…

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a month ago · 178 likes · 67 comments · Vinay Prasad MD MPH

That study failed to find an improvement in all cause mortality, though it had improvements in nonfatal MI. This study shows a very similar pattern. Fewer non fatal MIs and strokes with statin therapy.

Co-Primary endpoint of disability free survival - null

Some online claim the study provides a reassuring note about dementia— it is pretty uninformative actually.

The confidence interval is a mile wide— a 3% or 5% increase in dementia would be horrific, and the study can’t exclude even a 20% increase. A 13% decrease would be amazing fwiw. That’s like half a shingles shot ;).

What is the take away?

Even among people who enroll on this study, pass a 2 week placebo run in period, half throw in the towel by 5 years. If you were assigned to Atorva, you had less nonfatal heart attacks, less revascularization, less non fatal stroke.— I believe these are real findings and not spurious for the simple reason they are realized in…. well basically, every single statin trial ever. You also don’t live longer.

My takeaway is the following

Please stop running trials like this. Make Atorva over the counter, and let people do whatever they want. Taking it won’t increase or decrease mortality. It might avert some non-fatal events and stents, but probably won’t change your lifespan. Some might think that is worth it, others might not. Even those who enroll in a study throw in the towel quite a bit by 2 and 6 years. Real world adherence will be worse.

What about dementia?

In order to get a clean dementia read out, we will need a mega sample size. The ongoing study PREVENTABLE is not big enough. I suspect it’s CI will also be too wide to be helpful.

If you need a million person randomized trial to learn more about a topic, haven’t you already answered your question?

I personally don’t cook with nonstick pans— I use cast iron, or metal. You might do the same, or the opposite. I tend to believe cast iron is healthier, even though the pan is much heavier. You might not like the weight or the fact it retains heat. You might believe the opposite— non stick is healthier.

Should we take taxpayer money to figure out who is right?

What if we ran a 500 person trial for 4 years— well that isn’t big enough, you might say to capture the wrist injuries with cast iron.

What if we ran a 9000 person trial over 8 years— still not big enough to see the reduced cancer risk of cast iron— I cry.

What if we ran a 20,000 person trial over a decade? What about a million people, ten million? When does a question become less of a research priority and more of a personal preference?

What if we found out that no matter the difference, you aren’t going to buy cast iron, and I might not feel reassured to use nonstick.

I think we forget that researchers running studies love to talk about how important the question is, but they are biased by one thing. Handing them 100,000,000 dollars keeps them employed for a decade. They have research assistants, nice offices, skip clinical time, all working on the non-stick vs cast iron project.

Another statins trial for the elderly with 20,000 person sample size. Let me predict the results— a reduction in nonfatal mi, stroke, ambiguous all cause mortality, ambiguous dementia. Aka no new information.

If we want to use taxpayer money to fund a jobs program, why not go back to National Parks. Build more trails. More lodges and cabins. Go back to FDR and the works progress administration. We probably will do more to improve the health of 70 year olds— by making it easier to hike and experience nature— than another statins trial.

“Oh, wait, Prasad makes an interesting point, lets randomize a billion dollars to statins trials or building more trails….,” a researcher still trying to get out of clinic.

For those interested. Yes, I know statins “won” on nonfatal MI despite not 100% attrition. Now we need someone to get a grant to study “if only everyone took the statin for the full time….”

In its recently launched Voices section, an expert clinician blog featuring short personal essays, the venerable New England Journal of Medicine published an article by Dr. Kemi Doll, one of its six inaugural contributors. Entitled “Jason Arday and the Perils of Being Black in Academia”, the article expressed the strong personal reflections of an accomplished Black physician-scientist to the tragic Arday affair. Though the Journal makes clear these pieces are not peer reviewed and don’t represent the views of the Journal, this article raises serious questions about the goals of the Voices section and the editorial process responsible for publishing them. If not further explained and defended by the editors, this contribution may undermine the reputation of the journal as a reliable source of evidence-based medical information, and those concerned about this outcome have a responsibility to present their reasoning.

The focus of the article is the tragic story of Jason Arday, a young Black professor of educational sociology at Cambridge University whose academic accomplishments and many aspects of his life story were recently revealed to be fraudulent. This produced voluminous press coverage, an investigation by his employer Cambridge University, his resignation and soon thereafter his death, likely by suicide. This is both a personal and institutional tragedy with many intersecting dimensions that will continue to stimulate diverse reflections on its causes and implications.

Let me start by identifying several things that are not the basis for my critique of the Journal piece. First, the Journal has the editorial freedom to publish opinion pieces, including those such as Voices that lack peer review. Second, both racism and academic careers are appropriate topics for the Journal, as they represent important issues for the medical profession and medical science. Third, the author, a highly successful Black physician scientist, is free to publicly express her personal reflections on Arday’s death and its meaning to her and, as she believes, other Black academics.

Given the above points, what is my critique of this specific piece being published in the Journal? My concern begins with a high-level view of the role of the New England Journal as a distinguished repository for evidence-based, peer-reviewed research, educational material and, increasingly, opinion. The Journal’s reputation was built by doing this well, though as in all endeavors, mistakes have been made from time to time. In launching the Voices section, the Journal chose a group of experts from different medical fields to contribute regular opinion pieces without peer review. But even without peer review, most would assume some level of editorial oversight of submitted pieces. Even if well-chosen Voices contributors require minimal editorial oversight, it’s hard to imagine editors refraining from reading, reviewing, and if necessary, modifying pieces with obvious errors or logical flaws - which brings us to the current paper.

Dr. Doll’s Voices columns have a focus on careers, mentorship and related matters, and my reading of her prior columns reveals that to be the case. In the Arday piece she used his tragic death to make several strongly worded points. While these reflect the author’s reactions and conclusions, and may have been valuable to her readers, they should have evoked an editorial response, as, among other flaws, the piece was unclear, made several unfounded assertions, and was highly emotional. The editors responsible should have noted these attributes and sought appropriate changes to the text, while maintaining consistency with the goals of the Voices section.

Start with the opening sentence, “They are trying to kill us”. The “us” refers, or so it appears, to all Blacks in academia. This is obviously hyperbolic, though the author denies this possibility without providing any evidence. She also fails to define the “they” who seek to do the killing, apart from referencing the “ever-present winds of white-supremacy and anti-Blackness”. A responsible editor should have questioned this opening.

Though many facts about Arday’s life and career are less than entirely clear, there is plentiful evidence to support widely circulated conclusions about his serious personal and academic flaws. Yet, the author states, “I don’t care whether any of these allegations against Prof. Arday were true”, a statement that should have invoked editorial intervention, and has drawn repeated commentary on social media as a flagrant weakness of her argument. Why? Her sentiment that the truth of the matter is unimportant conflicts with values fundamental to scholarship, science and medicine, values the Journal must endorse. She didn’t need to dismiss the importance of the truth of the allegations to convey her personal distress caused by Arday’s career-ending exposure, or her career concerns as a Black academic.

Given her role as a Voice columnist whose assigned mission is facilitating careers of physicians, including Black physicians, hyperbolic claims whose effects on Black physicians are more likely to impair than encourage their success should be questioned. And casually consigning unidentified white colleagues to the category of white supremacists, or people trying to kill their Black colleagues is surely not a path to creating a more diverse and inclusive community- it’s an approach that will drive us apart.

Of course, Dr. Doll is free to publish this article, as others are to support or criticize it. And as stated earlier, the Journal is free to use its platform for the article, as it did in this case. But members of the biomedical community who read, support and in many ways depend upon the Journal should feel free to question the process leading to its publication, the judgment of the responsible editors, and the effects of the article’s publication on the Journal’s reputation and the well-being of the community it serves. As a publication of the Massachusetts Medical Society, the society’s members should be willing to engage in spirited discussion of these issues.

Stepping back from this specific article, this case also raises broader questions about the role of opinion pieces on controversial topics in medical/scientific journals like the New England Journal and others. Editorials are a longstanding and valued feature of medical publications, as are invited perspectives; their quality largely reflects the reputation of the journals and the effectiveness of their editorial boards in confronting important issues. One criticism of prevailing practice has been that, on some controversial topics, editors have done a poor job of ensuring that a range of alternative positions appear in their pages. This is true for submissions subject to review and editorial decision-making, and is even more likely in a series such as Voices, which lacks peer review, and has an obscure editorial process.

I have been a strong advocate of open inquiry and constructive dialogue in medicine and higher education more broadly. My advocacy reflects the belief that the search for truth requires that, on controversial topics, serious alternative views should be respectfully engaged, rather than ignored or silenced. Despite my objections to key elements of her column, I obtained some insights from the piece by Dr. Doll, and vigorous engagement with her views will enhance the possibility of productive dialogue. My objection is not to the piece having been published, or to the need to engage with its perspective, but to its publication in the New England Journal of Medicine with inadequate editorial review for a journal of its stature.

I look forward to further discussion of the Arday affair, its implications for the wellbeing of faculty and higher education, and the future approach to publishing pieces in the Voices section of this venerable and important publication.

The treatment is very interesting. The Merck product, pembrolizumab, is a checkpoint inhibitor that we have used for years. The Moderna product is an mRNA vaccine designed specifically for antigens associated with an individual’s cancer.

The impact of the news on the stock market was immediate and (to my amateur eyes) impressive.

You’d think this kind of reception would be in response to a lead article in Lancet or NEJM. But no, the cheering and stock frenzy was in response to a press release. You can follow that link and read it yourself, but really, I have pretty much told you everything it includes. Once you read it, you realize that all the coverage of the study is true churnalism. Not our definition, but the Dictionary.com definition of churnalism:

A form of journalism that is characterized by a lack of original research and fact-checking and by reuse of existing material such as press releases.

We certainly go a bit nutty with our critical appraisal shtick here at Sensible Medicine, but the amount that we don’t know after reading this press release is shocking. Who are the patients? What is the severity of their disease? What are the dropout rates? What is the relative risk reduction, let alone the absolute risk reduction? Are they even close to showing a mortality benefit? How bad are the adverse effects? What is the cost? (Oh wait, I forgot, we don’t care about costs.)

I think the science behind this treatment is cool. I also really want it to be effective. Although we have made enormous strides in its treatment, malignant melanoma can still be an awful disease. But I don’t see any reason to get excited based on a press release. These are two companies that have everything to gain if this treatment is successful, reporting on a study that they designed. This is like if I were to tell you that John, Vinay, and I have conducted a study showing that buying a subscription to Sensible Medicine has an overall mortality benefit, and that we might show you the data someday.

Ok, those are my swipes at Merck, Moderna, Wall Street, and the media. How about RFK Jr.?

RFK Jr. has made no secret about his skepticism regarding mRNA vaccine science. He made headlines last year when he canceled $500M dollars in federal funding for mRNA vaccine research. If we eventually get an actual journal article about the Merck/Moderna trial (I am sure we will), and the results are as promising as the press release suggests (I expect they will show marginal benefit over present therapies), how will our HHS secretary respond? I suggest three possibilities.

1. Unfortunately, the most likely possibility is that he will say nothing. Public figures seem completely unable to admit mistakes these days.

2. He will say that he has nothing against mRNA technology, only the COVID vaccine. He will say that he knows that even safe and effective therapies have toxicities. No drug or drug development process is all good or all bad; it is all about how we use our therapies. If a safe therapy is used in a huge population that does not need it, the therapy will be ineffective and harmful. This was the issue with COVID vaccines after the initial series or after a COVID infection. The story might be different in patients with melanoma.

3. What I would love him to say is that he was wrong about mRNA vaccines and that no drug or drug development process is all good or all bad… (see #2 above). He would then go on to say that the run-up in the stock price indicates that mRNA vaccine science clearly has a robust market to support it and therefore it does not need the support of federal dollars.

This will be a great story to follow in the coming years. I hope we end up with a great new therapy for melanoma and an honest assessment of it from the federal government.

I expect to be disappointed.

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Yet increasingly guidelines conflict with one another, or a professional society “objects” to a guideline produced by another professional society. For example, there are now numerous recommendations for screening for breast cancer. The American Cancer Society recommends women be screened yearly for breast cancer between the ages of 45 and 54 (optional beginning at age 40), whereas the United States Preventive Services Task Force (USPSTF) recommends biannual screening between the ages of 40 and 74. Recently, the American College of Radiology (ACR) objected to the new breast cancer screening guidelines of the American College of Physicians (ACP), suggesting they were outdated. Different recommendations from influential societies confuse the public and clinicians.

Guidelines may differ or be controversial for various reasons. First, guidelines may not be addressing the same question. When comparing guidelines on the same subject, readers need to carefully assess the precise issue that is being addressed. Are the guidelines focused on high-risk (and how is that defined) or normal-risk individuals? Are the guidelines assessing the same outcomes?

Second, the time period for the review of the literature may be different. It takes time to produce a guideline. When evidence is evolving, the date of the guideline and the actual “evidence” included in the review might lead to different conclusions.

Third, specialists and generalists often view the same evidence differently. We suspect this is the root cause of the ACR objection to those of the ACP regarding breast-cancer screening. Most specialists focus on case-finding, confirming disease, whereas generalists focus on screening, identifying the potential for disease. These are two very different cognitive activities (specificity vs sensitivity), and likely, over time and with experience, produce different views of the same data.

Fourth, is the concern about financial conflict of interest. In the US, most physicians are now employed and salaried, with fewer in so-called private practice. There are three different potential financial conflicts of interest for salaried physicians. First, many salaried physicians can still receive a bonus based on their clinical activity, especially for procedures such as screening colonoscopies. Second, even if an individual does not directly benefit from performing more diagnostic tests and instituting treatments, the person’s institution benefits. Third, physician experts are used by companies to promote their products, and these relationships are often not fully disclosed. The rigor of disclosure of financial COIs differs substantially among groups issuing guidelines. Do we think that financial conflicts of interest influence guidelines produced by specialty societies — yes. But we do not believe that they are the important reason for differences in guidelines between specialist and generalist societies, or that generalists often find specialty societies’ recommendations to be too aggressive with respect to diagnostic testing and treatment.

It is almost impossible for journals to review guidelines. The process of creating guidelines requires the creation of a multidisciplinary panel, defining the questions to be addressed, conducting a systematic review of the literature, assessing the quality of the evidence, drafting recommendations that are then reviewed by panel members, and finally producing a manuscript for publication or posting on a website. No single individual can do this effectively. Thus, when guidelines appear in journals (or on a society website), often with an accompanying editorial, readers should be aware that these were not “peer-reviewed” in the same manner as original research reports.

The grading of evidence is complicated. The Canadian Task Force on Preventive Health Care (CTFPHC) and USPSTF, launched in 1976 and 1984, respectively, established methodological standards. The USPSTF has published a manual detailing how it grades evidence. The CTFPHC adopted the Grading of Recommendations Assessment, Development and Evaluation (GRADE) in 2010. GRADE has become ubiquitous, with many professional societies using it to develop their guidelines. One challenging issue for all grading systems is whether they are reliable: meaning, would a different group examining precisely the same question with the same data reach the same conclusions? At a time of concern about replicability and reproducibility in science, given the laborious process of developing guidelines, it is not clear how to deal with the lack of data about reliability.

The USPSTF recommendations have traditionally been among the most influential in the US, even more so when they were tethered to the Affordable Care Act. Insurers must pay for A and B recommendations without cost sharing. Although many have championed this policy change, others have raised concerns that it may have inadvertently “politicalized” the USPSTF, with members recognizing the importance of A and B recommendations, regardless of the data, and perhaps influencing how they interpret the evidence.

Improving the Reporting of Published Guidelines

Professional societies and federal agencies will continue to produce guidelines. Indeed, the numbers are likely to increase as societies try to help their members provide high-quality care. The Trump Administration has halted the work of the USPSTF, but hopefully this is temporary. Given that journals, if guidelines are submitted to them, cannot truly peer-review them, what can those who produce and publish them do to improve their quality?

First, guidelines should be dated, with an expiration date, perhaps no longer than 3-5 years. New evidence is constantly emerging, and guidelines need to be updated regularly. Minimally, if no new evidence has emerged, a society could “re-endorse” a guideline. Guidelines that exceeded the expiration date should be removed from websites or at least noted as such.

Second, when publishing a guideline, the journal could insist that the authors follow the current recommendations for guidelines – the AGREE reporting checklist. Admittedly, like all the reporting guidelines, AGREE was developed through a Delphi approach, but it is an attempt to produce high-quality reporting recommendations. Published guidelines in a journal or on a website should include an assessment of adherence with AGREE.

Third, journals should clarify their role in publishing the guideline. Limited peer review should be acknowledged, and the journal should clarify its role as a dissemination vehicle.

Fourth, guidelines should contain a discussion of any recommendations that are different than those of other guidelines. This will at least help clarify for clinicians and the public why guidelines may differ.

Fifth, guidelines should contain information about how committee members were trained in their system of evaluating evidence and producing recommendations. Many guidelines detail their evidence system but not how members were trained to use it. Given that so little is known about reliability, at least some information about training may be valuable.

Sixth, editorials that comment about a newly published guideline should include both a generalist and specialist perspective.

Seventh, professional societies that criticize the guidelines from other groups should do so with evidence, and not simply “object” to them. If we want to restore faith in medicine and science, that needs to be done with data, not simply words.

Guidelines are here to stay and may proliferate given that AI can now conduct literature searches, and perhaps even “grade” the quality of the evidence. It would be interesting to see if different LLMs would produce a similar guideline given a precise question, for example, at what age should an average-risk patient begin screening for breast cancer, or what should be the target for low-density lipoprotein in a high-risk patient. We suspect AI will be helpful in determining if new evidence has emerged and a guideline needs to be updated. Guidelines are important, but they are not the definitive word on how to care for patients – that requires a discussion between patient and clinician – and what is best for that person.

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Howard Bauchner, MD, is a Professor of Pediatrics and Public Health at the Boston University Chobanian & Avedisian School of Medicine. He is also a Visiting Scholar at the National University of Singapore. Dr. Bauchner is also the former Editor-in-Chief of JAMA and the JAMA Network (2011-2021) and Archives of Disease in Childhood (2004-2011).

Frederick P Rivara, MD, MPH, is Professor of Pediatrics and Adjunct Professor of Epidemiology at the University of Washington. He is also the former Editor-in-Chief of JAMA Pediatrics (2000-2017) and JAMA Network Open (2018-2024). He continues as an active clinician, mentor, and investigator.

Photo by Javier Allegue Barros on Unsplash

Discontinuation of statins for primary prevention of atherosclerotic cardiovascular disease in adults aged 75 years or older (SAGA/SITE): a multicentre, open-label, pragmatic, non-inferiority randomised trial

In the meantime, enjoy.

But I concede that a group of patients who cannot easily tolerate OAC remain untested. These patients were excluded from the clinical trials. So we don’t know whether a LAAC procedure would be better than no oral anticoagulation. I doubt it, but the truth is I don’t know.

What I do know is that the procedure only protects patients from one type of AF-related stroke: stasis in the left atrial appendage leading to cardio-embolic stroke.

LAAC provides no protection against the many other forms of stroke. In fact, the INTERHEART study from McMasters found that the population attributable risk (PAR) for AF and stroke is below 20%. Meaning that in a model where all AF could be eliminated in a population, we would reduce stroke by less than 20%.

Another premise that everyone agrees upon is that if LAAC provides a net benefit (stroke and bleeding reduction) it takes years. That’s because you must overcome the finite (2-5%) upfront risk of harm from the procedure. If a patient dies in the year or two after the procedure, they did not have time to benefit.

Patient selection, therefore, is critical. You have to pick patients with minimal competing risks of stroke and who otherwise have a good expectation of survival.

Now let me show you an email from a doctor who works in middle America. I will change some of the details to preserve anonymity:

I have an 81 year old nursing home patient with Vascular Dementia, HTN, COPD, Paroxysmal Atrial Fib, who is s/p Pacemaker Placement some years ago. He is wheelchair-bound, but due to his dementia tries to get up and occasionally falls, so he has been on no anticoagulation since prior to my assuming care.

His son took him to the cardiologist, who now recommends Eliquis, followed by Echocardiogram, Carotid US, and Cardiac Stress Testing, all in preparation for doing a Watchman Procedure.

I am now trying to convince the son that these will most likely be of no benefit, and actually very likely to cause some harm in this frail, demented 81 year old who falls.

This is such a common occurrence - when I think more positively I attribute it to the cardiologist being trained to do these things and trying to “do something” to help him; in my uncharitable moments I think the specialists see these elders as untapped gold mines waiting to be prospected - maybe it’s both.

To show you that this extremely poor choice is not an outlier, here is a slide that I show of four recent studies that document how badly doctors are choosing to use this device.

The reason that older frail patients are such poor candidates for the preventive procedure are that a) they have a higher procedural risk due to frailty, b) they have tons of competing risks of stroke, like in the case above, vascular dementia means that there is severe disease of the brain blood vessels, and c) patients who die in 1-2 years cannot gain any probabilistic benefit from the device.

The solution is obvious: you do an RCT randomizing older adults with anticoagulation contraindications to the device vs nothing. The group randomized to nothing goes to lunch the day of the procedure and incurs no risk of bleeding, tamponade or device leaks. I would predict that such a study would be stopped early for harm in the device arm.

The problem is that I cannot convince enough colleagues that there is equipoise to do such a trial. That baffles me because I do not understand how their brains connect the lack of benefit in the 6 LAAC vs OAC trials to benefit in a group of sicker patients who were excluded from these trials. It reminds me of the old debate that doctors were worried that randomizing post-MI patients with ventricular ectopy to the placebo arm of CAST was unethical.

Perhaps you have ideas. To be sure, financial conflicts play a strong role, but I believe it is more than just money driving this misthink.

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I am updating my previous post for two reasons. First, I heard a story on NPR that had me yelling at the radio. I was going to pitch the TRAVERSE study as an article to cover on This Fortnight in Medicine, but before I emailed the group, I checked whether we had already covered the study. I found that I had already written about it. Second, after reading my early version, I realized I had learned something since my first writing, so now I’ve got even more to criticize.

An aspect of primary care medicine that never excites me is what I (disparagingly) call cosmetic medicine. For me, this is the type of medicine practiced when a doctor gives a fancy medical name to a symptom that is part of the human condition (fatigue, achy muscles, grief, loss of libido, dysthymia…) and medicalizes it, offering a treatment, usually without evidence that it even helps. Of course, any of these symptoms could be a symptom of a serious medical condition that requires treatment — I shamelessly refer you to chapter 18 of Symptom to Diagnosis: Fatigue. This is not what I am talking about. I am talking about pharmacologic therapy for just plain old “I wish I had more energy; I felt better when I was 26 than I do now at 56.”

Enter testosterone replacement therapy. Androgen deficiency is a real problem that needs to be evaluated and treated. It can be caused by failure of the testes to produce testosterone or by a problem further up the “pituitary-hypothalamic axis.” It has a defined differential diagnosis and evaluation. This is not what I am writing about.

Over the last couple of decades, testosterone has been aggressively marketed. You’ve almost certainly seen an advertisement encouraging you to “Ask your doctor about low T.” These commercials are aimed at people with an array of non-specific symptoms – fatigue, decreased libido, decreased energy, fewer spontaneous erections, low or depressed mood. I imagine that the companies behind these ads know that if every man with these symptoms gets tested, many will be found to have slightly low testosterone with no apparent cause. If you understand the normal distribution and how we define a normal blood test result, and are, or know, a man over 45, you realize this is an ENORMOUS market.

Now you might say, “Whatever, what’s the harm? If the guy’s testosterone is a little low, replete it. Maybe he feels a bit better, even if it is just the placebo effect.” Well, this might sound OK if you are OK with over-treatment and mild ethical lapses, but what if testosterone repletion is associated with harm? There is reason to be concerned that testosterone repletion might be harmful, associated with cardiovascular events, and prostate cancer.1

That introduction brings us to the NEJM article Cardiovascular Safety of Testosterone-Replacement Therapy, the TRAVERSE Study. This study was done because the FDA demanded safety data from the companies that were making money selling testosterone (and no doubt funding all those damn low-T ads). The study was “supported by AbbVie, Acerus Pharmaceuticals, Endo Pharmaceuticals, and Upsher–Smith Laboratories.”

Patients

The study enrolled men, 45 to 80 years old, with cardiovascular disease or elevated cardiovascular risk. The men had at least one symptom of testosterone deficiency (decreased sexual desire or libido, decreased spontaneous erections, fatigue or decreased energy, low or depressed mood, loss of axillary or pubic hair or decreased frequency of shaving, or hot flashes) and had two fasting serum testosterone levels of less than 300 ng per deciliter. The lower limit of normal in our lab is 180. Patients with very low testosterone levels (< 100) were excluded, as were men with prostate cancer or an elevated PSA.

Intervention and Endpoints

The participants were randomized to testosterone gel or a placebo, and a system to allow for dose adjustments without causing unblinding was established. This was designed as a non-inferiority study. The primary endpoint was the first occurrence of a component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Results

5246 men were randomized. The study's headline was that testosterone treatment was not associated with an increase in cardiovascular events. A primary endpoint occurred in 7.0% of people in the testosterone group and 7.3% in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for non-inferiority).

Limitations

What I have come to appreciate more since I first wrote about this article is that it was inappropriate to design this trial as a non-inferiority study. Vinay will cover this in depth in one of our upcoming videos. Non-inferiority studies are most appropriate when testing treatments whose primary benefit is decreasing treatment burdens, costs, or harms relative to an existing standard. A well-done non-inferiority trial assures us that we are not sacrificing efficacy in switching to a substitute treatment.

This is not the case here. These are patients who (supposedly) had symptomatic hypoandrogenemia. We should be testing if treatment, with its associated harms and benefits, is better than no treatment. An appropriate study would have been powered for both benefits and harms. This is one of those studies designed more to sell a product than to help patients.

The banal results of the study (you remember, primary endpoint 7.0% in the testosterone group and 7.3% in the placebo group) are not the whole story. There is at least a signal (a term I generally hate) for injury associated with testosterone therapy. There was about a 1% increase in AFIB and acute kidney injury in the treated group in a study with a mean follow-up of less than 3 years.

Most importantly, the results of this study are essentially meaningless. First, the increase in testosterone levels in the treated group was remarkably small. While the placebo group maintained levels of about 250, the treatment group peaked at a mean of about 350. The design of the study had the testosterone dose titrated to levels of 350-750. Underlining the fact that patients were under-treated, 61.4% of patients in the testosterone group stopped therapy, almost identical to the 61.7% of patients who stopped placebo. About two-thirds of people on treatment and placebo thought, “This is doing nothing, it's not worth taking.”

What prompted me to rewrite this article was neither my newfound irritation regarding the misuse of non-inferiority studies nor my continued antipathy to cosmetic medicine; it was the NPR story. On this report, one of the authors of the TRAVERSE study seemed shocked, shocked I tell you, that their article — one supported by drug companies to get a warning label removed — would be used to increase sales. He said:

We used the drug in a very specific way, and we have a very reasonable answer. But I would not feel good if our study resulted in the unrestrained use of testosterone in ways that we didn't study.

Conclusion

This study tells us that homeopathic doses of testosterone — ones that barely change blood levels of testosterone (the process measure) and have so little effect on how people feel that 60% of them stop the medicine — are sort of safe. These results do nothing to reassure anyone that using testosterone for “cosmetic medicine” is safe. In practice, when we (I use the first-person plural pronoun liberally here) treat low testosterone, we titrate the dose up every 2-4 weeks until there is a response in target symptoms, elevated testosterone levels, or other abnormal blood test results. This is clearly not what was done in this study.

I expect that this study was designed to satisfy the FDA while minimizing the chance of discovering adverse effects. I am not sure how an author can be surprised that the results of a study funded by pharma would be used to sell more pharmaceuticals. If you play in the mud, you should be prepared to get dirty.

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