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In This Week’s Podcast
For the week ending February 24, 2023, John Mandrola, MD comments on the following news and features stories.
Reporting About Fraud in Medicine
You may have seen the sweeping ProPublica investigation into overuse of peripheral artery procedures at the Veterans Administration (VA) Medical center in Wichita, Kansas. The case became public because of a whistle-blower. Medscape medical news has also published a version of the piece. The evidence presented thus far is worrisome.
That a VA hospital in Wichita had more expenses for vascular products than the top 10 VA hospitals combined is highly worrisome. There were records of meals, Apple products, and NASCAR tickets device reps gave to doctors doing these interventions.
According to internal emails, an ecological finding was that amputations increased over the time period — from about six in 2013 to 38 in 2018. The amputation data fits with the premise that there were too many percutaneous interventions.
Our vascular surgeons have drilled into my head that when it comes to peripheral interventions in the legs for claudication, less is 1000 times more. Yes, you can improve symptoms transiently with a peripheral balloon or stent, but late amputation risk goes way up. I like speaking with our vascular team because, even more than us, they promote exercise. When the calf hurts, they say walk some more.
Comments. First and foremost, one of the foundations of this country and one that cannot be understated, is due process. These are allegations, and the case is ongoing. If allegations can convict, we are doomed.
But there clearly have been doctors and hospitals guilty of fraudulent behaviors similar to those alleged in this case. My thoughts on such cases are yes, of course, it is important to bring them out in the open and adjudicate them fairly and punish the guilty. But it would be a mistake to think that outlier cases are representative of either the good or bad parts of medicine.
First the good: neither ProPublica nor the New York Times or any other news organizations will cover the vast amount of good that doctors, advanced practice caregivers, and nurses do each day. Even when we can’t cure, the amount of caring that happens as a regular matter never makes the news. It’s like anticoagulants in atrial fibrillation (AF). No one checks into the emergency department in the middle of the night to announce that they have not had a stroke.
If ProPublica followed a hospitalist or primary care doc or cardiologist around for a few days, what story could they write? Dr. Smith tries her best to help the sick patients under her charge. She succeeds a lot, but not always. She often works through lunch and worries about getting her kids picked up on time. No one gives her Apple products. A news story without a chapter with an industry rep buying NASCAR tickets and steak dinners means no clicks.
But these stories don’t represent the vast amounts of low-value care and even harmful care that populates the middle of the curve of medicine. This is my biggest criticism. The outlier cases don’t do justice to the everyday banal nonsense that is codified as therapeutic fashion.
Some examples: in cardiology, we burn money in our search for ischemia. Nuclear cameras run like printing presses at a mint. You have a twinge of chest pain lasting seconds, you get a nuclear stress test; you have AF, you get a nuclear stress test; you have run of non-sustained ventricular tachycardia on a pacer telemetry, you get a stress test.
Not only do these tests make big dollars, they feed downstream testing, coronary angiography, and stents. Once a stent goes in, you have a patient for life. I picked on stress testing, but you see it with echocardiography too. Someday, regulators will cut nuclear scans, and you watch them plummet in popularity.
Another example: coronary artery calcium scans. The experts say use them only to help with statin decisions. Yeah, right. In real life these are tickets to the fast train of stress tests, catheterizations, and stents. Healthy people made into patients—and sources of revenue.
Don’t even get me started on screening. In the NORDiCC randomized controlled trial (RCT) of colonoscopy in 85,000 patients, the risk of death from any cause was 11.03% in the invited group and 11.04% in the control arm.
And even if you defy statistical principles, like the GI professional societies urge you to do, and look at the as-treated patients, the risk of death from colon cancer goes from 0.3% to 0.15%.
Yet nothing has changed. Discussions of less expensive screening tools are not promoted. Discussion of the ludicrousness of trying to prevent death from one of thousands of disease, definitely not allowed. The GI professional societies had talking points on the null trial within days.
I could go on for many minutes chronicling all the low value care and harm in the middle of the curve of medical practice. But again, news organizations can’t do stories like that. The stories are too banal, and too problematic. They’d be labeled as cranks or promoters of misinformation if they tried to convince Americans that much of the care that they receive is low-value or potentially harmful.
More on Low-value Care: AF Monitoring and Stroke
I am moderating a session on AF screening at the Western AF Symposium tomorrow, so screening is on my mind. I missed an important study on AF monitoring and stroke that came out about 6 months ago in JAMA Neurology.
I got thinking about the issue because 2 weeks ago, I covered a subset of the STROKE-AF study which was first published in JAMA in 2021, an RCT in nearly 500 patients who had stroke caused by large or small vessel atherosclerosis. These are patients who normally would get antiplatelet and statin therapy.
In STROKE-AF, one group was randomly assigned to an implantable loop recorder (ILR) made by Medtronic. One group got usual care.
The primary endpoint was detection of AF lasting more than 30 seconds. With absolutely zero surprise, AF was detected 7 times more often in those with the always-on ILR.
At this month’s International Stroke Congress, we learned data on 3-year follow-up from STROKE AF. Recall that STROKE AF enrolled patients who had a mean CHADSVASC of 5 and had had an atherosclerotic-related stroke.
After 3 years of monitoring, the rate of detected AF had risen to 21.7% in the continuous monitoring arm, vs 2.4% in the control arm (hazard ratio [HR], 10.0; P < .001).
The senior author said that “This shows that 30 days of monitoring with an external patch is not sufficient to exclude the presence of AF. And this really argues for a strategy of immediate insertion of cardiac monitor placement if your goal is to look for AF."
We should recall that the monitor he is urging use of costs up to $10,000, and patients incur a monitoring fee every 30 days. This is where the low-value care comes in and remember what I said about most of the waste sitting in the middle of the bell curve, which will not attract the likes of ProPublica.
The core problem with detecting AF in patients who’ve had a stroke related to atherosclerosis is no one knows what to do with it.
Now to the study that I missed in August of last year; this is yet another paper from the prolific group in Copenhagen – first author Soren Diederichsen.
JAMA Neurology published this post-hoc analysis of LOOP where the two goals were to a) assess the stroke characteristics in patients who had an ILR for screening vs usual care; and b) assess the benefits of screening the highest risk patients — those who have had a prior stroke before beginning the LOOP trial. I mention this analysis because it’s a similar to STROKE-AF and it bears on a counter-intuitive aspect of AF screening.
First, two sentences on the main LOOP trial. This was an RCT of AF screening with ILR vs standard care in 6000 patients without AF but with high-risk features. There were no statistical differences in the primary outcome of stroke nor the secondary outcome of major bleeding.
In this post-hoc analysis, Diederichsen and colleagues looked at the main outcome of adjudicated stroke according to the modified Rankin scale (mRS) using a score of 3 or more as a cutoff for severe or disabling stroke.
They also took advantage of fact that in the main LOOP trial, both the ILR and control arms had about 17% of patients who had a history of prior stroke (remember, patients in LOOP did not have AF).
The total stroke count of the trial of 6000 was 315 events or 5.2% of the patients. In the primary trial, the stroke rates were 5.5% vs 4.4% and that 20% lower rate in the screening arm did not meet significance.
The main findings of the post-hoc analysis of types of strokes:
One in three strokes were classified as severe or disabling and there were no significant differences in either the ILR or control arm (Although we should note that the HR was 0.69 in favor of the screening arm and that is a 31% reduction. The problem is that the confidence intervals [CI] are wide because we are looking at a subset of the primary endpoint, hence low power and more chance of picking up noise).
The vast majority of strokes were ischemic; the most common were small vessel strokes.
Subgroup analyses looking at the severe strokes in patients who have a history of prior stroke found a bit of heterogenous effect: Whereas screening had no effect on reducing severe stroke in those with a prior stroke, there was a significant reduction of severe stroke incidence in the screening arm in patients without a history of stroke.
They also found similar trends in heterogenous effects for screening in patients with prior or no prior stroke for ischemic strokes and embolic strokes, though the numbers were even smaller.
We always have to be very careful with subgroup comparisons, even when looking in the main trial. But this is a subgroup analysis of a post-hoc study. Numbers are low, and noise is possible, but these are plausible findings, right?
Why would picking up AF not benefit those who have had a previous stroke that was likely not related to AF?
I think it’s two forces coming together: One is that older patients, such as those in LOOP with positive risk factors but no AF have many reasons to have a recurrent stroke. So, competing causes of stroke is one force. The other force is that an ILR, like a smartwatch or smartphone, will pick up short-duration low burden AF. Who knows what this means? Who knows what normal is for an average 75-year-old person who has risk factors.
The authors are careful in their words. You should read the entire paper, but here is a sentence that stuck out for me.
Albeit not designed to investigate poststroke regimens, the current study does not support ILR screening for AF among patients with a history of stroke.
Wow. I don’t know about your shop, but at ours, there are a lot of loop recorders going in for screening purposes in patients who have had a stroke. I am not saying that every use of ILR is low in value. But I want to make the case that studies like CRYSTAL-AF and STROKE-AF, that report more monitoring means more AF and more anticoagulation, may or may not help patients.
For this, we need more data.
A Little ACC Preview: Bempedoic Acid
The American College of Cardiology (ACC) 2023 meeting will start next Saturday. In next Friday’s podcast, I will offer a more extensive preview. This week, I will post my choice for Top 5 trials at ACC. These are wild and biased guesses. But since many of you may not listen to the podcast until ACC starts, I thought that, today, I would discuss one of the biggest stories from ACC — one that will come out on the first day early in the morning.
The trial is called CLEAR-Outcomes, and it is a classic cardiac outcomes trial of the lipid lowering drug bempedoic acid. I know this will be a big deal because the company that makes the drug, Esperion, announced in a press release that the trial, with its 14,000 statin-intolerant patients, met its primary endpoint of first occurrence of cardiovascular death (CVD), myocardial infarction (MI), stroke, and coronary revascularization.
Some background. Bempedoic acid is a once-daily oral pro-drug that is activated in the liver and inhibits ATP-citrate lyase (ACL) which acts upstream from HMG-CoA reductase, which is blocked by statins.
As with statin treatment, bempedoic acid reduces hepatic cholesterol synthesis, resulting in upregulation of LDL receptors on the hepatocyte surface, which enhances clearance of LDL-cholesterol (LDL-C) from the systemic circulation.
I learned there that CLEAR-Outcomes is one of at least nine trials of this drug.
NEJM published one of these, the CLEAR Harmony trial, which was a one-year RCT of bempedoic acid vs placebo in about 2000 patients with atherosclerotic CV disease (ASCVD), heterozygous familial hypercholesterolemia, or both. Patients had to be on maximally tolerated statins and have an LDL-C > 70 mg/dL.
CLEAR Harmony found that the drug did not lead to a higher incidence of overall or serious adverse events (AE), and it led to a lower LDL levels. The trial was not powered for outcomes, though they were numerically lower in the bempedoic acid group.
JAMA published the CLEAR Wisdom trial, a short trial in 700 patients that also showed that the drug reduced LDL-C by a statistically significant 18% over placebo. Again, we can’t say anything about outcomes.
Both trials found no differences in AE. Bempedoic acid seems not to cause myalgias, but it does increase uric acid levels and gout occurs more often in active arm.
CLEAR-Outcomes enrolled patients with established vascular disease or high risk for vascular disease, statin intolerance, and an LDL-C of ≥ 100 mg/dL. Mean age was 65 years; mean LDL-C of enrolled patients 139 mg/dL. Bempedoic acid vs placebo.
At ACC, we will need to have our critical appraisal hats on. CLEAR-Outcomes was positive. Bempedoic acid met statistical significance for lowering major adverse cardiac events (MACE) in statin-intolerant patients.
Here are some big questions:
Was the result statistically robust? What were the CIs? You hope the upper bound was not close to 1.00 or no effect.
Was the result clinically significant? You hope for a statin-like effect of a 25% relative risk reduction (RR). And you hope that any relative risk reduction translates into a substantial absolute RR. If an expensive new drug reduces the risk of a nonfatal cardiac event by 1%, that’s going to be a hard sell.
Perhaps the most important question will be what the authors say about the statin-intolerance. The authors define it this way: Statin intolerance that started or increased during statin therapy and resolved or improved when statin therapy was discontinued, resulting in an inability to tolerate either:
Two or more statins at any dose;
One statin at any dose and unwilling to attempt a second statin or advised by a physician not to attempt a second statin.
Statin intolerance is a real quagmire. And it’s a place where I am sure this drug company sees a potential gold mine.
Here’s my take: on the one hand, all of us see patients who are absolutely convinced that they feel bad because of statins. But we know that in blinded trials, the rate of statin discontinuation does not differ from placebo.
And then there is one of my favorite trials — SAMSON. Here James Howard and colleagues at Imperial College London enrolled 60 statin-intolerant patients into a 12-month N-of-1 trial in which patients spent one month taking a statin, a statin placebo or no tablet. Patients recorded symptoms every day on a phone. You all may know the results, but if you don’t, sit down.
Patients felt best during the no-tablet months. But they had nearly the same symptoms during the months they took statins or placebo.
In other words, statins cause side effects but it’s not the statin chemical, it’s merely the act of taking the statin. After the trial, half these statin intolerant patients were successfully able to restart statins.
The editorial of the Journal of the ACC paper was titled: “That Myalgia of Yours Is not From Statin Intolerance.” So, organically, or scientifically speaking, true statin intolerance is rare. But I, like you, see patients, and it is hard to discuss SAMSON in an office visit and convince patients to take the beneficial drug.
Critical Appraisal and Evidence-Based Medicine Advocates
Medscape Oncology has published an editorial from Dr. Ravi Parikh. It’s titled, “Why Evidence-Based Medicine Enthusiasts Could Use a Lesson In Persuasion.” You all should read it. The way to communicate critical appraisal is something I struggle with.
Dr. Parikh tells a story that centers on an invited speaker who disagreed with his views on the use of observational studies. What could be more relevant? Parikh sees value in these studies. The unnamed speaker did not—and said so strongly.
Parikh then launched into an argument against what he felt was a too aggressive approach to critiquing the evidence base.
“There is little nuance to these takedowns. The tone is too vitriolic. And, frankly, many of these individuals would probably prefer to tweet or release a podcast rather than pick up the phone and call investigators or policymakers to describe their views.
“In short, the modern evidence-based oncology movement has succeeded in bringing awareness to the perils of observational data, surrogate endpoints, and faulty control arms, which is a good thing. But the delivery of this message has come at a price. It has created division among researchers, policymakers, and patients and ultimately may be harmful to patients.”
One of Parikh’s recommendations was to use more pathos, or an appeal to emotion. Tell more stories of patients harmed by low-value therapies. This would be more persuasive, rather than the searing use of logos. Seriously, you should read the piece. Sanjay Kaul called it thoughtful and nuanced. And we should all surely be listening to Sanjay Kaul.
For me though, I disagree with many of these arguments.
While I am all for respectful, and try to avoid personal critiques, I believe poorly done science with inappropriate conclusions deserves strong and clear rebuke. Society and patients are harmed when medical science allows for low-value or harmful care.
Tone is over-rated. Science that is spun can have devastating effects on patient care.
in my opinion, scientists ought to be a bit more resilient and open to debate. The panels of cheerleaders at late-breaking trials really bugs me.
It’s why I like social media. Sure, there are bad critiques, bad ideas, mean people, but where else can people go to get something other than the bland editorials in journals, friendly talks at meetings, and podcasts from professional societies?
With all its blemishes, I like the freedom of the open online digital space. Let me know what you think. I am interested.
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Cite this: Feb 24, 2023 This Week in Cardiology Podcast - Medscape - Feb 24, 2023.