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In This Week’s Podcast
For the week ending March 7, 2025, John Mandrola, MD, comments on the following topics: Listener feedback on asymptomatic aortic stenosis (AS), transcatheter aortic valve replacement (TAVR) vs surgical aortic valve replacement (SAVR), coronary artery calcium (CAC), and revascularization for patients with ischemic LV dysfunction.
Listener Feedback Number 1. On Feb 14, I misspoke about the NOAH and ARTESIA trials. I said NOAH was rivaroxaban vs placebo, but of course NOAH was edoxaban vs placebo. Two listeners noted that and I will change the transcript. Sorry for the mistake.
The second listener feedback is worth expanding a bit, based on new papers published in JACC.
Listener Feedback Asymptomatic AS
I received a note this week from a doctor for whom I have the highest respect for. He was in fact one of my mentors at Indiana and he was instrumental in me choosing cardiology as a career. I offer this to you because I put this person in the 99% of doctors I have worked with in the past three decades.
He did not agree with my opposition to operating on asymptomatic patients with severe aortic stenosis (AS). I felt the evidentiary support was weak, severe AS is not so simple to diagnose, and a change in practice pattern would lead to even more low-risk patients getting transcatheter aortic valve replacement (TAVR).
My mentor wrote: While I have been a loyal listener of TWIC, I was disappointed with your view on the timing of aortic valve intervention in patients with asymptomatic aortic stenosis.
I do agree with several of your points:
The asymptomatic patient with aortic stenosis is often not asymptomatic when the physician takes a careful history. My experience has been that when carefully questioned, patients with aortic valve areas of 0.75 cm2 or less are frequently symptomatic.
I also worry that increasing the indications for AV replacement, particularly TAVR, will result in an explosion of TAVR procedures. I also agree that the consequences of AV block requiring pacemaker implantation is an under-recognized issue.
And here’s a list of what he disagreed with:
Secondary cardiac damage impacts adversely on the prognosis of patients with AS and starts before the onset of symptoms or impaired left ventricular (LV) ejection fraction.
Accumulating clinical evidence supports the earlier timing of AVR with asymptomatic severe AS and those with upstream cardiac damage secondary to AS.
The use of cardiac magnetic resonance (CMR) to evaluate for late gadolinium enhancement may help to identify higher risk patients who need earlier intervention.
Several studies (i.e., DANAVR) are excluding patients with very severe AS - Vmax > 5 meters/second from randomization.
Unless asymptomatic patients are followed closely, the LV remodeling may lead to upstream sequelae including mitral regurgitation, left atrial enlargement, atrial fibrillation (as you know a very difficult condition to treat in the presence of severe AS), pulmonary hypertension, RV dilatation and tricuspid regurgitation (TR).
AS is not a benign disease. In a large US database of almost 600,000 adults from 24 hospitals, the untreated mortality of patients with mild AS was 24%, 34% for moderate AS, and 45% for severe AS. An Australian population database of over 25,000 patients showed similar results.
You and I grew up under the mentorship of Dr. Charles Fisch, who recommended a conservative approach to management of cardiac patients.
In general, this approach served me well during my career. However, I have changed my opinion with regards to early intervention for severe asymptomatic AS. Given the availability of excellent cardiac surgeons or interventional cardiologists, consideration of earlier intervention seems warranted.
Overuse of TAVR
Regarding the overuse of TAVR, especially in young patients, I want to make note of two papers recently published in the TAVR vs SAVR space.
One is an “updated” meta-analysis of RCTs of TAVR vs SAVR in low-risk patients. First author was Robin Reddy.
The attempt was to pool trials to assess outcomes. New trials have been published and older low-risk trials have reported longer term follow-up.
This meta-analysis included Partner-3, EVOLUT-low-risk, UK TAVI, NOTION, DEDICATE, and NOTION 2.
The main finding, published in JACC, was that about 5300 lower-risk patients were randomized 1-1 TAVR vs SAVR and at 5 years in the pooled survival analyses of reconstructed time-to-event analysis, TAVR was associated with a 20% reduction in the hazard of all-cause death (hazard ratio [HR]: 0.80; 95% CI: 0.66-0.97; P = .02) and a 19% reduction in the hazard of all-cause death or disabling stroke (HR: 0.81; 95% CI: 0.68-0.96; P = .01) compared with SAVR.
There was no difference in stroke (HR: 0.97; 95% CI: 0.74-1.26; P = .80).
The authors concluded:
In lower-risk patients, TAVR was associated with a reduced hazard of death and death or disabling stroke compared with SAVR, while rates of stroke were equivalent.
However, even they note in the next sentence that:
Most patients have not yet undergone 5-year follow-up, and so these findings may change as further longer-term data become available. The present data are informative for lower-risk patients and treating clinicians, but further randomized trials and longer-term follow-up are required, particularly in younger patients.
Comments
I find this is a troubling study. Though the authors offer the duration of follow-up caveats there are many other caveats.
First, at least two of the included trials included intermediate risk patients. It’s an age-old problem with meta-analyses because you simply have to be cautious about what studies are included.
Second issue was that the authors did not have individual patient-level data and instead used a procedure with software to extract the coordinates of the published Kaplan-Meier survival curves, along with information on the number of patients at risk and the total number of events.
Their aim was to reconstruct the underlying time-to-event data for each treatment group. They then used these reconstructed data to generate, and pool estimates of survival probabilities and HRs.
While this software-heavy technique has been published and has been used, there are substantial limitations—many of which are beyond the scope of my methodologic limitations. JACC does offer a nice accompanying editorial from Joshua Wallach and David Cohen which describe some of these. I guess my point would be if you had trials with similar duration of follow-up and similar patients and you could make an individual patient analysis, you could simply pool data rather than extrapolating things from graphs from PDFs.
The editorialists also emphasize the duration of follow-up issue noting that only two trials, representing < 25% of the cohort, contributed data through year 5. They recommend that the authors continue to update the meta-analysis. But I wonder why publish such a limited meta-analysis now. The fact that it had a positive result for TAVR makes me wonder.
Another paper I found via a reference in the meta-analysis is super sobering. The reference went to a presentation at NY Valves by Dr Mayra Guerrero of a national inpatient sample that—and sit down for this—in patients aged 50 to 64 years with symptomatic severe aortic stenosis, TAVR was the mode of aortic valve replacement for 41.8% of patients in 2020 (increased from 14.2% in 2016).
The authors of the meta-analysis write:
this is not an approach currently supported by the available randomized data (including this analysis), and before TAVR is adopted for very young patients, dedicated randomized trials would need to be conducted with long-term (∼10 years) follow-up and consideration given to the lifetime management of these patients.
That is, and has been, my main point for years on this podcast regarding TAVR.
Indeed, TAVR has been a great innovation, but the momentum and application of TAVR to very young and lower-risk patients is not evidence-based nor wise. That 41% of AVR procedures are TAVR in patients aged 50-64 is ludicrous.
Coronary Artery Calcium (CAC)
We are back again talking about the 40-year-old imaging test without outcomes data. Because, why? Because JAMA has published an RCT of using CAC to guide preventive therapy. The paper is making the rounds on social media.
Australian authors asked the question of whether combining CAC score with a preventive strategy can be used to reduce plaque progression in intermediate-risk patients with a family history of coronary artery disease (CAD).
This was a prospective, randomized open-label trial done in seven hospitals. Patients were asymptomatic adults who had a first degree relative with CAD before age 60.
The authors screened around 1100 patients with a family history. Patients could not have a statin indication such as LDL-c >193. All patients were statin naïve.
Those with CAC 0 or CAC > 400 were excluded. They randomized about 450 patients to either the CAC-score informed group vs standard care. The mean CAC score in groups was 64-72. The average pooled cohort equation 10-year risk was 6.6 to 7.2, so, basically, this trial studied patients just below the ACC, AHA threshold for statins at 7.5%
The CAC-informed group was nurse-led in which the participants’ CAC images were used to communicate about disease. And, importantly, after all this education, everyone in the intervention group started lipid-lowering therapy, most often with statin.
The usual-care group had standard education from their primary care clinicians about CAD prevention, and the GP was blinded to the CAC score. None of these patients were recommended for statins.
The primary endpoint of this trial was total plaque volume, with further analysis for calcified and noncalcified plaque volume on a coronary computed tomography angiography (CCTA) done at 3 years.
Results
After 3 years of follow-up, the CAC score-informed group showed significantly greater reductions LDL-C levels (-51 vs. -2 mg/dL, P < .001) compared to usual care. But this should be obvious because one group got statins and the other did not.
The primary outcome of total plaque progression was significantly lower in the CAC score-informed group compared to usual care (15.4 vs. 24.9 mm³, P = .009).
Secondary outcomes also favored the CAC score-informed strategy:
Noncalcified plaque progression: 5.6 vs. 15.7 mm³ (P = .002)
Fibrofatty and necrotic core plaque volume: -0.8 vs. 4.5 mm³ (P = .02)
Plaque progression differences remained significant after adjusting for baseline plaque volume, age, sex, waist circumference, blood pressure, and lipid profiles in multivariate analysis.
The effect of the CAC score-informed strategy was particularly pronounced in participants with CAC scores >100.
The authors enthusiastically wrote that “these data support the use of CAC score to assist intensive preventive strategies in intermediate-risk patients.”
Two editorials accompanying the manuscript were supportive.
Comments
But I don’t agree. In fact, I strongly disagree. While I nearly always laud those who take the time to randomize, the amount we can take from this trial is small.
The trialist themselves tell us about serious limitations: 13% of patients were excluded from the final analysis due to poor image quality or technical limitations. Given the small differences in a surrogate outcome that could be a lot.
They also tell us that plaque progression is a surrogate endpoint. I would emphasize, as I did last week, that if previous studies suggest that myocardial infarction (MI) is a poor surrogate for CV death, then surely plaque progression is a long way from telling us anything important. I am not an imager, but the little reading I’ve done suggests that characterization of plaque components can be challenging.
What’s more, even if you accept the surrogacy of an image on CTA, I don’t, but if you do, this is really a study of a strategy of statin use vs non-statin use. I am not sure how the CAC score figures in. Not only that, but patients in the open label trial in the nurse intervention group could have behaved differently (e.g., lived more heart healthy) based on the nurse intervention and the knowledge that they were in the active arm of a trial.
Of course the trial ends up with less than 200 patients in each arm. There was no power to detect clinical outcomes, yet proponents can use a short-duration, surrogate-positive JAMA study to further promote CAC scanning. I remain steadfast in my opposition to this test.
Thankfully, JAMA did include one “related article” wherein the Northwestern authors outline three areas where CAC scans should not be used: one is in young patients, because a CAC of zero is not that reassuring; another time to avoid CAC in older patients where calcification is common and the patient already satisfies statin use based on the PCE. And the third scenario is repeating the CAC scan, which should have no role.
CABG, PCI, or Meds for Ischemic LV dysfunction
European Heart Journal has published a very interesting paper from the authors of STICH/STICHES and REVIVED BCIS. Both were shocking trials because I can’t imagine we here in Louisville would have managed to randomize even one patient.
Basically, the authors took individual patient data and did cross-trial comparisons. Looking at groups (i) medical therapy (MT) in REVIVED vs MT STICHES, (ii) MT-REVIVED vs CABG, and (iii) PCI REVIVED vs CABG. Important to note here that neither trial was coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) vs meds. It actually was CABG plus meds vs meds alone in STICH and PCI plus meds vs meds alone. In other words, PCI and CABG were add-ons to medical therapy for these heart failure with reduced ejection fraction (HFrEF) patients who happened to have severe CAD.
STICH – CABG vs medical therapy in 1200 patients with an EF < 35% and CAD amenable to CABG. Key point for this podcast: randomized patients between 2002-2007. 5-year results, which were the primary analysis, were that a primary outcome of death from any cause occurred in 41% of patients in the medical arm vs 36% in the CABG arm. That was HR of 0.86 and CI that went from 0.72-1.04, so not significant. The difference in deaths was only 26 deaths in a trial of 1200 people.
STICHES was the 10-year extension of STICH . The effect size at 10 years was nearly identical at 0.84, a 16% reduction with CABG. But because there were more deaths, 59% vs 66% the result reached statistical significance with CI from 0.73-0.97 and P = .02. Though we must remember the 5-year-results were the pre-determined primary analysis. It was still only a delta of 39 deaths over 10 years in 1200 patients.
REVIVED BCIS enrolled similar patients with LVEF < 35%, multivessel CAD amenable to PCI and viability to either PCI plus medical therapy vs medical therapy alone. Over 3.5 years, there was no significant difference in the primary endpoint of death or heart failure hospitalization (HHF). Death too was no difference. In fact, absolutely nothing was different. Not EF, not quality of life, no subgroup was better with PCI.
As I said when I introduced this topic, it’s hard to imagine randomizing a patient into any of these trials. I ask you now to pause the treadmill or shift to an easy gear and close your eyes and imagine the angiogram of one of these patients. See the image of severe multivessel CAD and a bad ventricle.
Now imagine putting this patient into an arm with just tablets, leaving all those high-grade coronary stenosis and the resulting ischemia. That would never happen here. Such a patient would have a hotline to stents or bypass depending on the anatomy or mood or business of the operators. My point is that medical therapy did amazing. Yet neither of these trials have gained much popularity, at least here in the US.
The most recent study combined these trials using actual source data (the CRF) with an idea of comparing outcomes of patients with medical therapy alone in STICHES and REVIVED, and to estimate whether CABG would provide any incremental benefit over modern medical therapy as used in REVIVED, and thirdly to compare outcomes between CABG and PCI.
The primary outcome of this pooled analysis was the composite of all-cause death or hospitalization for heart failure. Secondary outcomes were individual components of the primary outcome, cardiovascular death, and myocardial infarction.
The MT arm in STICHES was the reference group for the between trial comparisons. Keep in mind that even though this was RCT data, the comparisons were observational. The groups were different, for instance, the mean age of patients in REVIVED was nearly 10 years older than STICH. So they had to do adjustments — just as is done with non-random comparisons.
OK – there were a total of 1900 patients in the two trials. The mean age combined was 63 years and mean LVEF 27%. Enrolment to REVIVED was from 40 sites exclusively in the UK, whereas participants in STICHES were enrolled from 127 sites in 26 countries. Follow-up was a lot different. 10 years in STICHES and 3.5 years in REVIVED.
The primary outcome of death or HHF. First comparison was of the two medical therapy arms. It was 40% less in REVIVED (HR, 0.60; 95% CI, 0.48-0.74). In the propensity matched cohort it the HR was even lower MT REVIVED vs MT STICHES at 0.46
Comparing the reference arm of MT in STICHES to CABG the HR was 0.8, compared to PCI in REVIVED it was 0.59. In other words, CABG was 20% better and PCI in REVIVED was 41%. I just told you though that MT in REVIVED was also 40% better than MT in STICHES.
Finally, in the propensity matched group, MT in REVIVED was 38% better than CABG. And in the PCI in REVIVED vs CABG in STICHES, PCI was 39% better.
Similar or directionally similar HR were seen with all-cause death and CV death.
The authors concluded that:
Patients with ischemic cardiomyopathy receiving medical therapy in REVIVED-BCIS2 had better outcomes than those in STICHES, with or without CABG surgery. Further trials comparing CABG, PCI, and medical therapy in this population are warranted.
Comments
We have to be careful. It’s a well-done careful analysis and on paper the patients look similar, (e.g., bad CAD and bad ventricles), but the trials recruited at different times and in different geographies. These are different patients.
Nonetheless, patients in the medical arm of REVIVED, which is far more contemporary than STITCHES, yet still, started recruiting before angiotensin receptor-neprilysin inhibitors (ARNIs) and SGLT2 inhibitors were available, had much lower rates of death, HF and CV death than either arm of STITCHES. MT in REVIVED beat MT in STICHES and CABG+MT in STICHES.
PCI in REVIVED also looked better than CABG in STICHES.
I think the finding we can be most confident in is the improvement in medical therapy over time. We have new drugs and probably a more aggressive mindset when it comes to using medical therapy. Though some of the better outcomes could be explained by the fact that patients with mitral valve disease were allowed in STICHES (surgery) but were excluded from REVIVED. So REVIVED may have had healthier patients—even though they were older.
The second finding that is striking is that modern medical therapy—in REVIVED—was also much better than CABG, though I must highlight the caveats of non-random comparison. I am somewhat confident in this finding because if you think about priors you have 3 of the 4 CABG vs meds trials in the 1980s as negative, and in the 1980s there was like ZERO medical therapy. I apologize to my surgical colleagues but the evidence underpinning CABG for multivessel stable disease over modern medicine is not strong.
So, at worst, the superiority of medicines in REVIVED vs CABG in STICHES is hypothesis-generating, and I think warrants a modern day repeat of the CASS trial in patients with HFrEF and CAD. The authors of this paper tell us there will be such a study though it will be single center.
The result I am least confident about is the PCI superiority of CABG given the differences in baseline characteristics, geography, and time frames. Though this too needs to be compared head to head. The authors describe a STICH 3 consortium wherein the two modes of revascularization will be compared.
My prediction is that in the next 5 to 10 years, young cardiologists will come to see the value of medical therapy much more so than people of my generation have.
Orthopedic Issues in Cardiologists
A preview for next week. I’ve been seeing a lot of posts on social media and some articles on orthopedic issues in cardiology. In fact, last winter I had cervical fusion surgery. I am fine now.
Literally none of these posts or articles question the causal relationship between cardiology and orthopedic injuries. It’s just assumed that wearing lead, leaning over a table for years, causes bone and joint problems.
The level of evidence for causation would make Bradford Hill turn in his grave. I have found mostly surveys. In other words, a list of anecdotes. It’s as if 50- to 60-year-old cardiologists don’t do anything else in their life to cause stress on their neck and backs.
I will explore the evidence and come back next week with my formal assessment. Consider this topic an exercise in causal inference and judging of evidence.
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