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In This Week’s Podcast
For the week ending February 6, 2026, John Mandrola, MD, comments on the following topics: Problems with the PREVENT score, a breakthrough in lipid-lowering therapy, a surprising benefit in stroke care, and more thoughts on statins and preventive care of heart disease.
PREVENT Score Problems
In the old days, we had risk scores like Framingham and the pooled cohort equation (PCE). They weren’t perfect, but they were decent. Recently, key opinion leaders have come up with the PREVENT score, which is supposed to be better because it includes 30-39 year olds — and that expands the age range, it adds heart failure (not just atherosclerotic cardiovascular disease [ASCVD]), it removes race as a predictor (supposedly improving equity), and it adds optimal social determinants index (SDI), and includes kidney function.
What’s more, PREVENT is derived from more recent data and therefore better reflects modern cardiovascular (CV) epidemiology.
Finally, let’s not forget the point of these risk scores: They are used to guide treatment. Instead of treat everyone with say a blood pressure (BP) of 135/90, the risk scores suggest treatment if a global 10-year risk reaches some threshold.
I go on about this because of a very, very provocative paper in JACC from the Kaiser Permanente group on using PREVENT equations in young adults.
They assessed performance and algorithmic fairness of base and SDI-augmented PREVENT equations in young adults aged 30 to 39 years, defining fairness as similar performance across racial and ethnic groups. An exploratory analysis was conducted among young adults aged 20 to 29 years.
The study included 160,000 young adults with varying races. The total incidence of CVD was low at 0.7%.
The main finding was that mean calibration found severe underprediction in non-Hispanic Black individuals. How bad: well, the PREVENT score underestimated risk by 46% in this group.
This could lead to substantial undertreatment of Black individuals with lifesaving cholesterol and BP meds.
The authors assessed whether adding the SD index would improve calibration in Black individuals. It did not.
My Comments
It’s ironic that the tool meant to prevent undertreatment of young adults may actually cause undertreatment of young Black adults specifically — the exact population with highest premature CVD burden.
Let me use a simple example: of a Non-Hispanic Black individual, age 35.
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BP 135/85, on no meds
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PREVENT predicts 4% 10-year CVD risk
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True risk might be 7%-8%
So the clinician sees 4% and says, "Low risk, let's try lifestyle modifications first, follow up in 6 months."
But it probably ought to be moderate risk, indicating treatment is best now.
Meanwhile, a Hispanic patient with identical values:
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PREVENT predicts 4%
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True risk ~4%
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Gets appropriate conservative management
I have said this a blue million times on this podcast, but prediction is hard, especially about the future. Recently I got smashed on social media for suggesting a young woman needn’t take statins because her overall risk was so low. Many suggested that we should treat regardless of overall risk, the thinking being that atherosclerosis is a slowly developing problem and longer exposure to lower LDL-C or blood pressure is beneficial. But if we take this logic we may as well start in the teen years, and treat everyone.
There must be some happy medium where we use risk to guide therapy. Perhaps we don’t have to hue so strongly to certain thresholds. For instance, there’s nothing magic about 7.5% risk threshold. What about 7.4%?
The thing that strikes me about this paper, is that epidemiology clearly tells us that non-Hispanic Black individuals have higher CV risk, and, at least in this population, PREVENT led to underestimation of risk and this would lead to undertreatment.
The risk score that was designed to be race-neutral performed worse on race, and it’s kind of a head-shaker. If I had a dollar for every instance in medicine where well-intentioned policy led to harm....
Things like the Healthcare Readmissions Reduction program — which penalized hospitals for high rates of readmissions — may have actually led to higher mortality in HF.
Many years ago I visited the EP lab of Dr Dave Wilbur in Chicago. Over the stimulator, he had a sign that read, in big letters, “Resist the urge to help.” Perhaps we need more of that in policy.
A New Breakthrough in LDL-C Management With an Oral PCSK9 Inhibitor
NEJM published the result of the CORALreef Lipids trial of the oral PCSK9 inhibitor enlicitide (en-liss-i-tide).
The study was presented at AHA but published this week.
I relooked at it. It’s impressive. About 3000 patients with elevated LDL-C, almost all on statins. Enlicitide vs placebo. The primary endpoint was LDL-C lowering.
Enlicitide worked, resulting in a -57% reduction vs -3% reduction in the placebo arm. In the 52-week trial, there were no safety signals.
My Comments
This may be my briefest commentary on a trial ever. This seems like a clear winner. It shreds non-HDL-cholesterol — on top of statins. The degree of reduction is similar to the injectable PCSK9 drugs, more than bempedoic acid, ezetimibe, and inclisiran.
And a pill is always going to be better than a weekly injection. It’s just easier. I can’t see how this drug doesn’t help patients, though we need to remember this wasn’t an outcomes trial. LDL-C is still a surrogate. It happens to be a very reliable surrogate for ASCVD, but it’s still a surrogate.
The authors tell us that Merck is sponsoring a large outcomes trial called CORALreef Outcomes trial, with a projected completion date of December 2029.
And of course the major headwind in the US will be cost, because you can be sure Merck will price the drug quite high.
A Win for the Factor XI Inhibitor Asundexian – OCEANIC Stroke Trial
A couple of years ago, the promise of Factor XI inhibition as a safer oral anticoagulant took a huge hit when the OCEANIC-AF study of asundexian vs apixaban in patients with atrial fibrillation (AF) had to be stopped early because of higher stroke rates in the Factor XI arm.
At the time in November 2023, the decision was made to continue the OCEANIC Stroke study of asundexian 50 daily vs placebo in patients with noncardioembolic stroke or high-risk transient ischemic attack (TIA). These are the type of stroke patients planned for antiplatelet therapy either with single antiplatelet therapy or dual antiplatelet therapy (DAPT).
OCEANIC Stroke had a primary endpoint of ischemic stroke, and primary safety endpoint of bleeding, along with many secondary endpoints.
Trial results were presented in New Orleans at the International Stroke Congress. I don’ t think there’s a paper yet but I did find the Slide Deck thanks to Dr Mike Gibson.
Inclusion criteria:
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Participants aged ≥18 years, within 72 hours of symptom onset: − Noncardioembolic ischemic stroke (NIHSS ≤15) or high-risk TIA (ABCD2 6 or 7)
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History of atherosclerosis or evidence of plaque on imaging or non-lacunar stroke on imaging
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Plan for antiplatelet therapy, single or dual
Exclusion was atrial fibrillation or another source of cardioemboli.
This was a huge trial of over 6000 patients per arm, most of whom had CV disease or CV risk factors. Mean age 68. Just under one third had interventional therapy with endovascular or thrombolytic therapy. About two thirds were on DAPT.
The main result was a 26% reduction in recurrent ischemic stroke over 3 years (hazard ratio, 0.74; 95% CI, 0.65-0.84). Absolute risk reduction numbers were 6.2% vs 8.4% over the time of the trial. That’s a 2.2% absolute risk reduction and a number needed to treat (NNT) of 45.
Major bleeding was 1.9% vs 1.7%. And importantly, when they showed subgroup analysis, it looked like this benefit was pretty much preserved in all subgroups, including stroke subtypes.
My Comments
Well, this is clearly a positive trial. No safety signals and a clinically meaningful reduction in ischemic stroke. In addition the Kaplan-Meier curves seem to separate over time, meaning the NNT lessens over time.
And it’s a breakthrough because the only thing available for non-embolic stroke survivors has been antiplatelet drugs, and now we have a drug that reduces risk in addition to antiplatelets.
Importantly, the asundexian benefit was seen across all subgroups of stroke in the trial. For instance, it was beneficial in small-vessel stroke and cryptogenic stroke as well.
One question that I have and perhaps you do too: asundexian was clearly inferior to apixaban in OCEANIC AF. This was due to lack of efficacy in stroke prevention. One theory was that dosing was insufficient.
But why did it have such a positive effect here in noncardioembolic stroke? Perhaps the dose is enough for this group of patients but not a pure AF group. It’s curious to me. Maybe you have ideas.
Anyways, I suspect this trial will be enough to gain approval for this indication of this new medication.
Statin Side Effects
You have heard it a gazillion times: statins have all kinds of side effects. Well beyond muscle complaints to hepatic dysfunction, depression, impaired cognition, sleep disturbance, acute kidney injury, or renal failure, interstitial lung disease, and even pancreatitis.
These reports come from observational nonrandomized studies, but they do get put into statin product labeling lists, otherwise known as Summaries of Product Characteristics (SmPC)
Well, the Cholesterol Treatment Trialists collaboration (CTT) have published a meta-analysis of 66 statin vs placebo trials of more than 123,000 patients looking specifically at 66 undesirable outcomes that have been attributed to statins.
The trials included atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin. They had individual patient-level data.
Using a statistical technique to correct for multiple comparisons. Similar to, but not exactly like, the Bonferroni correction method.
Anyways, they found no association of statin therapy with 62 of the 66 adverse events listed on product summaries. The four positive associations were:
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Transaminase elevation: 0.30% per year statins, vs 0.22% per year with placebo
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Other liver function test (LFT) abnormalities: 0.25% per year statins, vs 0.20% per year placebo
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Urine composition alteration: 0.21% per year statins, vs 0.18% per year placebo
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Edema: 1.38 statins, vs 1.07% placebo
My Comments
Once again, we see that when you review blinded randomized trials, adverse events are minimal to none with statins. The effects on liver biochemistry, urine composition, and edema are not clinically meaningful.
The authors conclude that the undesirable effect sections of statin product labels might overstate risks and mislead clinicians and patients, and should be revised to better support “informed, evidence-based decision making.”
I also am drawn to one of the most clever studies of this decade, when Dr James Howard led the SAMSON trial, which was an N of 1 trial in patients with statin intolerance. These patients were randomized to alternating months of statin tablets, placebo tablets, and no tablets. Patients kept their daily quality of life scores on an app. The authors found that the best months were no-tablets but...but...provocatively, they felt equally as bad whether they were taking a statin or a statin placebo. The conclusion was that the act of taking a statin tablet caused adverse effects and it did not matter whether there was any statin in the tablet.
I remain a neutral Martian on statins. I tell patients, or anyone interested, that the drug reduces CV events in the subsequent 5 years by about 25%. Higher-risk people (to a point, not dialysis or advanced HF people) get more benefit. Whether that benefit is worth taking a pill every day is 100% preference-sensitive. But what is clear is that there is an extremely low risk of adverse events. (The safety caveat here, though, is that we don’t know about potential long-term risks because trials don’t go for 20 years.) Dr Rod Hayward calls these “unknown unknowns” with statins.
And that caveat hints at the major weakness of this meta-analysis. Namely, that when you meta-analyze trials, even with patient-level data available, you can only assess for short-term effects that have a high-enough incidence to be detected. Rare adverse events (AE) or AEs that may accrue over 10 years will not be seen. That’s not a knock on the CTT team. Rather it’s just a limitation of knowledge.
This is why I think statins should be over-the-counter. People can do their risk calculation. They can assess their fear of coronary artery disease (CAD) and decide on whether the disutility (hassle) of taking a pill is worth the reduction.
A New Report on Heart Disease Statistics
This was a monster paper led by Dr Rishi Wadhera from Beth Israel in Boston. The author list includes some of the best thinkers in cardiology today.
I will not, nor could I, drone on with all the statistics of heart disease in 2026 — but I do want to highlight one important observation relative to the statin discussion I just mentioned.
The most notable statistic in this paper was the dramatic reduction in CAD and acute myocardial infarction (AMI)-related mortality. While everyone knows heart disease remains a leading killer, Figures 24 through 26 in their paper show a steady and substantial decline in CAD-related mortality. It’s the same for AMI. There has been a decreasing burden of AMI hospitalization as well as AMI mortality rates. Figure 29 shows what we all see in our hospitals. It’s increasingly uncommon for people to die from AMI.
I think we forget this good news. Now, you could tell me: John, CAD and AMI mortality are lower because of better prevention. So we should continue to push harder on it. Like more statins. And it’s hard for me to deny there is a component of causality in better preventive care. But I am not sure it’s a very large driver of the better outcomes. For me, smoking reduction is surely a large factor in cardiovascular outcomes, but even larger may be our interventional cardiologists.
This podcast heaps plenty of criticism for excessive revascularization in stable patients, but...but....I strongly believe that the acute treatment of AMI has been one of the greatest medical advances of our generation. Since door-to-balloon time became a thing, and hospitals ramped up care pathways, and our profession — together — made it standard to open occluded coronaries faster, heart disease has been greatly diminished.
Not only has it improved survival, but it has greatly diminished the numbers of ICD-eligible HF patients. Rare is it for me to implant a primary prevention ICD due to ischemic cardiomyopathy. Why? Because infarcts rarely get left long enough to cause LV dysfunction. They get fixed.
I make this point because the better a treatment of a disease gets, the less benefit there is to screening and early detection. There’s no better example than breast cancer. As breast cancer treatment gets closer to cure, the value of screening diminishes.
I think we are approaching something like that with AMI. While I am not advocating for telling people not to care about things like blood pressure, BMI, and cholesterol, it simply becomes harder to contextualize a 10% vs 8% 10-year risk of a non-fatal MI.
Cardiology has been good for humanity. Our progress isn’t done. But the progress we have made does indeed affect decision-making regarding prevention and early detection.
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Cite this: Feb 06, 2026 This Week in Cardiology Podcast - Medscape - Feb 06, 2026.
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