Aug 04 2023 This Week in Cardiology

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In This Week’s Podcast

For the week ending August 4, 2023, John Mandrola, MD comments on the following news and features stories.

A Conference and Some Listener Feedback

First, I want to say thanks to Dr. Sheldon Litwin for the kind invite to speak at the Charleston HFpEF Conference at the Medical University of South Carolina. What a great city. And now I have an evidence-heavy lecture on heart failure with preserved ejection fraction (HFpEF). It was a great conference. Congratulations.

I received two very interesting emails last week. One, from a prominent full professor in academia, concurred with my strong concerns regarding jumping to causal inference from non-random observational studies.

But he also warned me not to underemphasize the role of these sorts of studies in creating hypotheses to be tested in randomized controlled trials (RCTs). He used the example of conduction system pacing, arguing that the many observational studies in this field created a stimulus to fund the upcoming RCT.

I appreciate this point, and will keep it mind, but would also add that systemic bias in observational studies can be so strong, that it may actually destroy the equipoise needed to do an RCT, or at least substantially delay the RCT. But that, of course, would be on us as clinicians. We mustn’t let observational studies entrench a therapy into fashion.

A second email, from a young academic in Europe, urged me to consider why there are so many flawed observational studies in the literature. His take was that the need for young people to use publications as a currency of advancement is a cause. He notes that this type of research is attractive because it allows cardiologists to publish in a short space of time.

I appreciated this quote:

“The "need to publish" promotes a culture of doing relatively quick research using low-hanging fruit- that is research that is frequently observational and retrospective and adds very little to our actual understanding of a problem.

“If we wasted less time on this kind of research and spent more on collaborating to answer questions properly, we would be doing our patients a great service by investing time in actually answering clinically relevant questions with appropriate science.

“To do this we need to stop judging colleagues based on the number of publications and we need to stop measuring success with this metric.”

Thank you for the feedback, the kind words, and the reviews of the podcast. Every time someone writes to me I learn something. And I love learning.

Heart Surgeons Dissent

Two American cardiac surgical groups, the American Association for Thoracic Surgeons (AATS), and the Society of Thoracic Surgeons (STS), have written a rebuttal of sorts to the new coronary artery disease (CAD) revascularization guidelines.

The first thing to say is that there were in fact new CAD revascularization guidelines from the American Heart Association/American College of Cardiology (AHA/ACC) etc. This was published in late July. Two surgeons were on these guideline committees but ended up withdrawing their authorship.

They had three major objections to the guidelines. All of these objections date back to the 2021 guidelines. Surgeons had hoped that their objections then would have been heard and incorporated in the new guidelines. It may have been heard, but it was not incorporated in the new guidelines.

So the surgeons wrote a rebuttal. Sanjay Kaul suggested that the rebuttal be termed a minority dissenting opinion, much as the US Supreme Court does. I really love this idea. And will return to it at the end.

Issue Number 1. The 2021 and now this 2023 guideline have downgraded coronary artery bypass grafts (CABG) vs medical therapy in patients with three-vessel disease with from class 1 to class 2a in patients with an EF > 35% and 2b in patients with normal left ventricular (LV) function.

You recall that the reason CABG had that class 1 recommendation was the old data from the 1980s-1990s. These studies were actually non-significant, but an influential, perhaps, the most influential meta-analysis in all of cardiology was done by Yusef and colleagues in 1994.
Yusef and colleagues found that when you combined the CABG vs medical therapy trials, there were substantial survival benefits with CABG over medical therapy.
The AHA and ACC guideline writers downgraded the old CABG vs medical therapy recommendation for two reasons – one was by saying that the data were outdated. The other was inferences from the ISCHEMIA trial.

ISCHEMIA was a strategy trial. Early invasive vs conservative approach in patients who had moderate to severe ischemia. There were no significant differences in either approach at 3.2 years. Remarkably, the patients in the invasive arm had revascularization done almost 60% more than medical therapy. Revasculatiion in the trial could be with percutaneous coronary intervention (PCI) or CABG. PCI predominated by a factor of 74% PCI/26% CABG.

The AHA/ACC guideline writers inferred from ISCHEMIA that revascularization vs medical therapy was quite comparable to revascularization in patients with good LV fuction and ischemia on stress testing. Hence the downgrade.

But the surgeons, rightly in my opinion, push back. They argue:

CABG was only 26% of the revascularization group. That’s too small a sample size.
ISCHEMIA was only 3 year follow-up – too short for CABG to show its mortality advantage.
The choice to have PCI or CABG in the trial was not random, but up to the docs at the trial site. This could have led to bias in sicker patients getting CABG.
ISCHEMIA patients were not representative of patients who usually get CABG in the community. For instance, fewer than half of the patients in the trial had LAD disease.
Another wrongheaded issue with applying ISCHEMIA to CABG recommendations was the inherent assumption in ISCHEMIA that CABG and PCI were on equal footing as revascularization strategies.
1. Here the surgeons point to the 10-year follow-up of the SYNTAX trial, which was PCI vs CABG. This trial showed a strong trend to worse survival from PCI vs CABG; hazard ratio (HR) 1.19 (0.99-1.43); but in a subgroup of patients with three-vessel disease, death was 40% higher with PCI.
2. They also cited FAME 3, which compared surgery vs fractional flow reserve-guided PCI in patients with three-vessel CAD. This trial reported 50% better freedom from death, myocardial infarction (MI), repeat revascularization, or stroke among the patients randomly assigned to CABG vs PCI.

Surgeons would also add a large meta-analysis of CABG vs medical therapy trials to the criticism of using ISCHEMIA to downgrade CABG vs medical therapy.

This was the 2022 Gaudino and colleagues paper. Here they combined patients from STICHES, MASS-II, BARI 2D and MASS-1 and found initial allocation to CABG was associated with greater periprocedural risk of death but improved long-term survival compared with medical therapy. The survival advantage for CABG became significant after the fourth postoperative year and was particularly pronounced in younger and non-White patients.

All in all, I agree with the surgeons. Based on evidence, and when there is a long-time frame there was little strong reason to downgrade CABG vs medical therapy I would also say though that medical therapy has become impressive, and I wonder what a new SYNTAX trial of medical therapy vs CABG would show now. I bet it would be quite similar.

ISSUE Number 2. The surgeons push back on the contention that PCI has become an equivalent revascularization strategy.

I have already mentioned the trend to better survival in SYNTAX for three-vessel disease. EXCEL – left main disease PCI vs CABG — clearly favored CABG for survival, and even in NOBLE, which was PCI vs CABG in left main disease, there were fewer late MIs and fewer repeat procedures though similar survival.

I also concur with the surgeons that, while PCI has made great strides, in patients with multivessel disease and left main disease, CABG has the edge.

The surgeons also raised an issue about too much emphasis in the AHA/ACC guideline for radial artery access. I will leave that out of the discussion because it’s pretty specific to surgery.

The Big Meta point is important. The surgeons have sort of blazed a new way forward that I like. That is, they have published a dissent of sorts. This is a great idea!

I have been on guidelines writing committees and ultimately there is a vote as to how to grade something. That vote may be close. But that is not reflected in those silly colored boxes that codify a treatment.

What would be nice for clinicians to know is that a treatment choice has significant disagreement.
One way for that to be known is for a group to write dissenting guidelines, much as is done in the US Supreme Court.
These dissents would be evidence-based and include arguments as to why the same evidence could be interpreted multiple ways.

Sure, this might complicate quality scores or performance metrics, but in my mind, it would be a very good thing.

Aspirin for Primary Prevention

Daily Aspirin Challenged in Primary Stroke Prevention: ASPREE

I don’t know about you, but 5 years on from the three big and null aspirin (ASA) for primary prevention trials in 2018, I still get in wrestling matches about stopping ASA when it is used for primary prevention.

A recent sub-analysis of the ASPREE trial further strengthens the argument for stopping ASA, especially in the elderly.

Recall that ASPREE was a big RCT that randomly assigned 19,000 older (median age 74 years) patients to low dose 100 mg coated ASA or placebo.

The New England Journal of Medicine published three papers on ASPREE. One looked at mortality, which was 14% higher in the ASA group, which met significance with a confidence interval (CI) 1.01 – 1.29.
Another ASPREE study looked at major adverse cardiac events (MACE) and bleeding. This found that no difference in MACE but a 38% higher rate of bleeding.
A third looked at death, dementia, or physical disability and found no differences.

The newest study, in JAMA Network Open, was a secondary analysis of ASPREE. It looked at ischemic stroke and intracranial bleeding (ICH). Stroke and ICH were prespecified secondary endpoints. Recall again the trial had 19,000 patients.

Overall the rate of stroke was low — only 6 per 1000 person years. (I think of that as less than 1%)
FIRST STROKE. A first stroke was experienced by 4.7% of those receiving placebo vs 4.6% receiving aspirin (HR, 0.97).
ISCHEMIC STROKE. This was 11% lower in the ASA arm but it did not reach statistical significance; HR 0.89 0.71-1.11. Noteworthy for the atrial fibrillation (AF) docs out there, small-vessel disease was the most common cause of stroke.
HEMORRHAGIC STROKE. Strokes resulting from intracerebral hemorrhage were less common than ischemic strokes, and the rate of hemorrhagic stroke recorded with ASA, 0.5%, was not statistically significantly greater than that with placebo 0.4%.
TOTAL INTRACRANIAL BLEEDING. The totals of stroke and other categories of intracranial bleeding were significantly greater among individuals treated with ASA (1.1%) vs placebo (0.8%); HR, 1.38; 95% CI, 1.03-1.84; P = .03).
The NET. Among 1000 individuals taking 100 mg/day of low-dose ASA over 5 years, there were 2.5 fewer ischemic strokes at the expense of 3.5 cases of intracranial hemorrhage, a finding that did not meet the threshold for statistical significance.

Comments. In my mind, this strengthens the main finding from ASPREE that ASA provides no benefit and possibly a slight increase in harm in older patients, when it is given for primary prevention.

The slight decrease in ischemic stroke is countered by an increase in intracranial bleeding. It also bolsters my view that the main reason to see older patients in cardiology clinic is to reduce medicine burden. Yes, deprescribe.

My tired old saying is that primary prevention therapies are designed to make people live long enough to get old. When they get old, it is often time to stop these drugs. In the case of ASA, however, there is little to no benefit to even younger patients.

FISH Oil Is Back in the News

Two weeks ago, I reported on an observational study that combined 17 prospective studies that had data on the actual levels of omega-3 fatty acid concentration and AF incidence.

The Journal of the ACC published the paper and it found that:

The circulating EPA level in blood or adipose tissue was not significantly associated with AF.
Higher DHA, EPA+DHA, and DPA levels were associated with lower AF risk.

This was interesting, and provocative, because of the clear signal of increased AF risk seen in clinical trials. These signals were well documented in a meta-analysis, first author, Baris Gencer in Circulation. This found a clear dose-dependent signal of increased AF that was greater in trials testing more than 1 gram of omega-3s per day.

The discrepant results were explained by the idea that in the observational analysis, levels were lower, and more consistent with fish intake rather than high dose supplementation.

Well, a Norwegian group has added more heft to the fish oil/AF relationship. Peder Myhre and colleagues have published a secondary analysis of the OMEMI trial.

OMEMI was an RCT published in 2020 that compared 1.8 gm of omega-3 fatty acid vs placebo (corn oil). The supplement had 930 mg of EPA and 660 mg of DHA.
The trial included 4000 patients, mean age 74 years, who had a recent MI; high risk-adults.
Primary endpoint was a composite MACE of MI, revascularization, stroke, death, heart failure hospitaizations.
Follow up 2 years. They also measured serum fatty acid levels.
It was a null result – HR 1.08 with CI 0.82-1.41.
OMEMI had as its secondary endpoint AF incidence. This almost made significance – 7.2% in fish oil group vs 4.0% in the placebo arm; HR 1.84 but super-wide CI at 0.98-3.45. and a P-value of 0.06.

The most recent substudy aimed to assess risk and potential mediators of AF and a new finding they called “micro-AF.”

They defined micro AF as short, AF-like activity, defined as sudden onset episodes of three or more consecutive supraventricular beats, irregular RR-intervals, and absence of P waves, lasting less than 30 seconds. I went to the source reference and found a picture and it looks like what I call atrial junk. It’s not exactly the classic Haïssaguerre-like focal AF.

At baseline, about 75% of these 4000 patients had no history of AF.
During follow-up, 43 patients had new onset AF; 39 were detected during a standard follow-up and only four by thumb-ECG-screening.
In addition, 27 patients had episodes of micro-AF, yielding a total of 43+27 or 70 patients with new-onset AF and/or ‘micro-AF.’
The source reference also found an association of micro AF with the development of AF.
The main finding was that, in the fish oil group, 11.9% had AF/’micro-AF’ (28 AF, 18 ‘micro-AF’) vs 6.5% in the placebo group; HR 1.90 (95%CI 1.16–3.11), P = 0.011.

Some other interesting findings:

Micro AF was higher in the fish oil arm by about the same margin – 6.1 vs 3.3.
Then they also noted a graded relationship with EPA but not DHA concentration.
In a complicated-type mediation analysis, they surmised that changes in EPA explained almost 70% of the increased EPA risk.

Comments. This subanalysis strengthens the AF/fish oil risk association. It suggests that EPA was more of a culprit that DHA. It also, weakly, suggests that EPA may play a role in AF by inducing micro-AF or atrial ectopy.

The way I would parse the trial data vs the observational data I presented 2 weeks ago is four pronged:

There is clearly a strong dose dependent signal from RCTs that fish oil increases the risk in AF.
Previous work has correlated AF risk with EPA more than DHA.
The higher rate of atrial ectopy or micro AF may be a mediator.
Observational nutritional studies are at high risk for confounding. That is, healthier people take fish oil, and their healthiness may explain the lack of an AF signal.

While we still don’t know the mechanism as to why fish oil causes AF, there is a clear enough signal that I tell patients about it.

The other advantage of telling patients about this, is that it’s an indirect way to give time to heal AF. AF often has a varied natural history. It often goes away. If you ablate early, you may attribute ablation success to the spontaneous remission of AF.

My AF went away. My partner’s did too. I’ve seen two patients this month whose AF went away with time. If you tell patients to stop fish oil and give it a month or so, you may reduce the number of people you put at risk for atrial esophageal fistula from ablation.

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