At ESC, a new paper on coronary artery calcium scanning came out. Almost immediately, I saw cardiologists on social media saying some version of this:
“Why get a CAC? It won’t change management.”
Think about what that means. A test that directly measures atherosclerotic plaque in the coronary arteries is dismissed because “it won’t change management.” In other words, the treatment decision has already been made.
I think the reality is simpler: CAC can create uncomfortable situations.
- A 45-year-old with high LDL but a CAC score of 0.
- A 60-year-old with “normal labs” but a CAC score of 400.
Now the conversation becomes harder. Guidelines become less convenient. And the doctor has to explain risk.
The same risk category. Very different risks.
Ironically, the new paper demonstrates exactly why CAC can matter.
Among people considered borderline risk by PREVENT, the observed 10-year cardiovascular event rates were:
| CAC score | 10-year event rate |
|---|---|
| 0 | 1.9% |
| 1–99 | 3.9% |
| 100–299 | 7.4% |
| ≥300 | 14.3% |
These people were in the same general risk category. Yet depending on how much coronary plaque was actually present, observed event rates ranged from 1.9% to 14.3%.
That seems pretty relevant to me.
CAC doesn’t always fit neatly into a predetermined pharmaceutical pathway. But it answers a very important question: Do you actually have plaque?
That question becomes even more interesting when you look at two other major studies presented around ESC: STAREE and SAGA/SITE.
Statins work. Who benefits enough?
Statins work. They reduce cardiovascular events.
They also seem to harden and stabilize plaque, increase plaque calcification and, in some studies, modestly shrink plaque volume.
But they also have real side effects. They cause insulin resistance and diabetes, particularly in women. They deplete vitamin K2 and CoQ10 and are very likely to cause muscle aches.
The two studies from ESC make me question how much the known positive effects translate into the outcomes patients ultimately care about, particularly in older adults being treated for primary prevention.
Who will benefit, and who will be harmed?
In my own career, I have seen severe statin reactions requiring hospitalization, including rhabdomyolysis with kidney failure requiring acute dialysis and severe thrombocytopenia, a low platelet count. These experiences have included near-fatal cases.
STAREE: events and disability-free survival
STAREE randomized 9,971 adults aged 70 or older without cardiovascular disease, diabetes or dementia to atorvastatin 40 mg or placebo.
After approximately six years, atorvastatin reduced major cardiovascular events by about 30% in relative terms.
So again, statins work.
But in absolute terms, we’re talking about a couple fewer events per 100 people treated. And there was no significant improvement in disability-free survival, an outcome encompassing death, dementia or persistent physical disability.
SAGA/SITE: what happened when older adults stopped statins?
SAGA/SITE looked at essentially the opposite question. It randomized 1,160 adults aged 75 or older who were already taking statins for primary prevention to stop or continue treatment.
Stopping statins caused LDL to jump dramatically. Yet after three years, the results were:
| Outcome | Stop | Continue |
|---|---|---|
| Death | 7.2% | 7.9% |
| Major CV events | 5.0% | 4.4% |
Stopping statins was noninferior for all-cause mortality.
This doesn’t mean statins don’t work. They clearly reduce cardiovascular events. But it does make me question the magnitude of the real-world benefit in some patients.
Do not stop or change a prescribed statin based on this trial without discussing it with your prescriber.
Cognition: a question worth studying
STAREE found no significant reduction in dementia despite substantially lowering LDL and reducing cardiovascular events.
We also have a small prospective withdrawal/rechallenge study in patients with Alzheimer’s disease. MMSE scores improved by 1.9 points after statins were stopped, then worsened by 1.9 points when statins were restarted.
Small study. Open label. Definitely not proof.
But withdrawal, improvement, rechallenge and worsening is a signal worth studying.
Patient selection matters
So no, I’m not saying statins don’t work. They work.
I’m asking a different question: Who actually benefits enough to justify treatment?
If we’re treating 100 people for years to prevent a couple of cardiovascular events, without clearly improving mortality, dementia or disability in these older primary-prevention populations, then patient selection matters. A lot.
Which brings me back to CAC.
Why wouldn’t I want to know whether my patient actually has coronary atherosclerosis? And why wouldn’t I want more options once I know?
Why every patient may not need the same pathway
This is also why our recent ezetimibe paper is important.
We looked at patients who developed marked LDL elevations while following carbohydrate-restricted ketogenic diets.
Among the 12 patients treated with ezetimibe without a statin, median LDL fell 50.4%, an absolute median reduction of 137 mg/dL.
Ezetimibe is generic. It’s inexpensive. It works through intestinal cholesterol absorption rather than inhibiting cholesterol synthesis.
Our study was small and retrospective. It does not prove cardiovascular benefit in this population.
But it raises another question worth studying: Why are we acting as though every patient with an elevated LDL needs to travel down exactly the same therapeutic pathway?
How our view of PCSK9 inhibitors changed:
Toward Health has re-evaluated PCSK9 inhibitors as the evidence has developed. Lowering LDL cholesterol, preventing cardiovascular events and reducing deaths are different outcomes. Our earlier concerns about mortality deserve to be explained alongside our current conclusion.
Early evidence, 2017–2019: FOURIER (2017) reduced major cardiovascular events but did not demonstrate a reduction in all-cause or cardiovascular mortality. Both were numerically higher with evolocumab: all-cause deaths were 3.2% versus 3.1%, and cardiovascular deaths were 1.8% versus 1.7%. Neither difference was statistically significant.
ODYSSEY OUTCOMES and its 2019 mortality analysis need a distinction: all-cause deaths were lower with alirocumab, 3.5% versus 4.1%, but the result was only nominally significant because the trial’s prespecified testing hierarchy had already stopped at a nonsignificant outcome. Cardiovascular mortality was not significantly reduced. The early trials therefore did not establish a consistent, definitive survival benefit across the class.
Why the mortality reanalysis concerned us: A BMJ Open reanalysis, submitted in 2021 and published in December 2022, found discrepancies in FOURIER death classifications using regulatory clinical-study reports. After readjudication, cardiovascular deaths were more frequent with evolocumab (relative risk 1.20; 95% confidence interval 0.95–1.51). This was a concerning signal, although it did not establish that the drug increased mortality. The investigators could not re-evaluate nonfatal events. We regarded the mortality and reporting questions as reasons for caution.
What changed our assessment: We have now reviewed the longer-term and newer evidence:
- FOURIER-OLE (2022) associated earlier evolocumab treatment with fewer cardiovascular events and cardiovascular deaths. These were exploratory comparisons of earlier versus delayed initiation; both groups received evolocumab during the extension.
- The long-term ODYSSEY OUTCOMES analysis (2023) supported sustained cardiovascular benefit and reassuring safety through follow-up of up to five years, with more injection-site reactions than placebo.
- VESALIUS-CV (2026; online 2025) strengthened the evidence in high-risk patients without a previous heart attack or stroke: five-year coronary death, heart attack or ischemic stroke risk was 6.2% versus 8.0%, an absolute difference of 1.8 percentage points.
After this reassessment, we agree that PCSK9 inhibitors such as alirocumab (Praluent) and evolocumab (Repatha) can be effective options for selected patients with coronary artery disease or other high-risk conditions. This updated position reflects the evolving evidence, while keeping cardiovascular-event reduction distinct from a claim of universal survival benefit.
For plaque regression, separate imaging trials, GLAGOV and PACMAN-AMI, found greater coronary plaque regression when a PCSK9 inhibitor was added to statin therapy. These findings do not establish that CAC scores will fall. Treatment remains individualized to disease burden, overall risk, existing therapy, tolerability and patient preferences.
Start with the disease. Understand the patient.
- Measure the disease.
- Understand the patient’s absolute risk.
- Understand why their LDL may be elevated.
- Discuss the magnitude of benefit.
- Discuss potential harms.
- Choose the intervention that makes sense for that patient.
That seems like medicine to me.
