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In This Week’s Podcast
For the week ending July 21, 2023, John Mandrola, MD comments on the following news and features stories.
A listener sent me a copy of a review sent by the American College of Cardiology (ACC) to its members. This was a review of the MONITOR HF trial.
MONITOR HF was a small randomized controlled trial (RCT) of CardioMEMS-guided management vs standard of care in patients with heart failure (HF). Its primary endpoint was quality of life measured by the Kansas City Cardiomyopathy Questionnaire and it favored the CardioMEMS arm. The trial also reported fewer hospitalizations for HF (HHF) but the study had only a fraction of the numbers in previous trials (eg, GUIDE HF) and was not powered for clinical outcomes.
I had full coverage of MONITOR HF on the June 2 podcast. It’s one of the most difficult studies I have reviewed in a long time.
This was an industry sponsored trial without blinding.
Unlike GUIDE HF, the MONITOR HF trial randomly assigned two groups without blinding. One group knew they got a fancy monitor and the other group knew they did not.
They measured a subjective outcome.
Of course, the lack of blinding could also influence the clinicians’ decision to admit a patient for HF. Despite this fatal flaw, Lancet allowed them to draw strong conclusions. And Lancet assigned the editorial to an academic with strong financial ties to the maker of CardioMEMS. The editorial mentioned the blinding issue but spent seven paragraphs praising the device.
The email from ACC — which also takes funding from industry — had as its interpretation these 200 words.
“The MONITOR-HF trial is the first study to demonstrate improved quality of life and functional status associated with remote invasive hemodynamic monitoring using the CardioMEMS-HF system in HF irrespective of LVEF (left ventricular ejection fraction) . The CardioMEMS-HF group also experienced fewer HF hospitalizations, an association previously observed in both the CHAMPION and the pre-COVID-19 analysis of the GUIDE-HF trials. As the overall GUIDE-HF analysis yielded a neutral result, current American HF guidelines assign remote invasive hemodynamic monitoring a Class 2b recommendation. The current findings provide clinical- and patient-centered outcomes data to support the utility of the CardioMEMS-HF system in the management of class III HF, even in the setting of high rates of optimal GDMT for HFrEF (HF with reduced EF).
“Furthermore, these are the first data studying the device in a European health care system. As remote monitoring requires sustainable infrastructure to coordinate patient care outside the immediate clinic setting, additional data across different health care delivery and payer systems provide important information. Unlike CHAMPION and GUIDE-HF, this was an open-label study with no sham implantation in control patients. However, the positive results observed in both HF hospitalization and objective markers of congestion such as NT-proBNP and mPAP reduce the likelihood of a clinically significant placebo effect in the treatment arm.”
No. No. Double No. This breaks the rules of basic science.
This mailer from ACC bothers me so much, not because another low-value device will get expanded use -- because overuse of low-value devices is rampant -- but I am sad for the scientific enterprise.
MONITOR HF was a totally flawed study from its design. Subjective endpoints without blinding are worthless, and the investigators know it.
Emphasis on HHF when there is nowhere near enough power and no blinding is also worthless, and the investigators know that too.
The Lancet editors knew all this. The peer reviewers must have known it, yet there it is in the Lancet.
Then there is positive accompanying editorial of a broken trial from an author with serious conflicts of interest.
To make matters worse, our own ACC sends a glowing interpretation – glossing over the central flaw — to its many members.
The MONITOR HF story is so brazen. Help me listeners. Tell me I am wrong about this. Make me feel better.
More feedback. My friend and former partner, the skeptical cardiologist, Anthony Pearson, sent me a Tweet from the American Heart Association (AHA) that promotes a podcast called Close the SPACE (Secondary Prevention of ASCVD [atherosclerotic cardiovascular disease] Care Education Summit).
He writes “Sure enough "Through a collaboration with Novartis, the American Heart Association has created a four-part podcast series called ASCVD Perspectives."
You will never guess what drug Novartis makes? Yep. Last week I covered the US Food and Drug Administration’s (FDA) expansion of the indication of the small interfering RNA agent inclisiran. The thing is that inclisiran approval is based primarily on its ability to lower LDL-cholesterol. There has yet to be an outcomes trial. The drug will surely be costly.
The problematic area is the collaboration of professional societies and industry. I don’t like it. If the outcome trial with inclisiran is positive, I will cover it as such. But the fact that AHA, ACC, European Society of Cardiology (ESC), Heart Rhythm Society, and Heart Failure Society of America, let themselves be advertising platforms is problematic.
Maybe I am wrong. Let me know. To me, professional societies ought to be advocates of neutral critical appraisal. You can’t do that if you have dualities of interest.
Conduction System Pacing
Electrophysiology (EP) can be specialized but one area the medical field should know about is the utter transformation in cardiac pacing. In hospitals that have an EP doctor implanting devices, there are strong movements to place the right ventricular (RV) pacing lead into the conduction system.
That doesn’t sound super-interesting, I know. Why would a general cardiologist or general internist care about where we are putting pacing leads?
What makes this change important to all is how it pertains to evidence-based practice.
And the use of evidence is a core tenet of this podcast.
So let’s talk about the most recent conduction system pacing (CSP) vs RV pacing study published in JACC-EP, which is becoming an excellent journal.
This was a two-center study done in Singapore of patients who had pacemakers implanted.
It was not randomized. One group got (typical) RV pacers and the other group got either His bundle pacing or left bundle branch (LBB) area pacing — basically CSP.
The primary composite outcome was HHF, upgrade to biventricular (BiV) pacing or death.
The results favored CSP, by a lot.
I am not even going to tell you the numbers because this is too flawed an analysis to draw conclusions from. Why? Because of this single sentence in the methods section. Always go to the methods section.
“The decision to choose between CSP and RVP was based on the operator’s personal preference.”
Comments. As many of you know, I am a CSP evangelist. LBB area pacing delivers superb pacing parameters, as well as those gorgeously narrow QRS complexes. You can pace the ventricle without causing the dyssynchrony that comes with RV pacing. It avoids the 10% to 20% chance of pacing-induced cardiomyopathy.
But the skeptics are correct. We have scant data to support this.
The literature is full of studies like this one. They are unreliable. This is not the way to prove our technique works.
What’s more, you can add up all the observational studies that favor CSP over RV pacing and even taken together, they add up to unreliable evidence.
I remind you that Grady’s 1992 meta-analysis of hormone replacement therapy (HRT) in post-menopausal women included more than 30 observational studies favoring HRT in post-menopausal women, and boom, one RCT, the Women’s Health Initiative, overturned all of them.
That’s the thing about non-random comparison studies — when a clinician chooses the therapy, not randomization, you cannot exclude the problem of confounding/selection bias.
The size of the observational study cannot negate a systemic bias. You could have 800, 8000, 80,000 patients and it doesn’t matter.
Fortunately, CSP will be tested in RCT form in both the United States and Europe, and we will know. One caveat here though: while non-random observational data is terrible for causal inference, observational data, like registries, can help provide information on things like procedural complications and temporal patterns. The mandatory Society of Thoracic Surgeons registry of aortic valve replacement is a shining example of good use of observational data.
Like you, I see a lot of patients taking fish oil supplements — fish pills, as I call them. Some are supplements, some are prescription strength, but they are all just fish pills.
The idea is that fish is good for you, derived from the observational data from the Inuit in Greenland, who have a high dietary intake of marine omega 3 fatty acids and low incidence of vascular disease. But it’s hard to eat that much fish, and then there is the problem of mercury intake with high fish intake.
There have been a number of large CV outcomes trials with different formulations of fish oil. Other than icosapent ethyl and the REDUCE IT trial, most are null. REDUCE IT is challenging to interpret because the mineral oil placebo increased lipid levels.
At least three of these trials have found this peculiar but strong signal of increased risk of atrial fibrillation (AF).
A large meta-analysis led by the group of Christine Albert found a use of marine omega-3 fatty acid supplements was associated with an increased risk of AF (n=2905; hazard ratio [HR], 1.25 [95% confidence interval [CI], 1.07–1.46]; P = 0.013).
In meta-regression, the risk was dose dependent
Why would fish oil increase AF? No one knows. Why did the VITAL trial — in patients without CVD — not find the higher AF signal with fish oil treatment?
It’s a bit of mystery. I’ve been in the habit of telling patients with AF to stop their fish pills.
Well, a large group of eminent authors, first author Frank Qian, have published, a large observational study exploring fish oil and AF risk.
This was a big effort. They used 17 prospective studies that had data on the actual levels of omega-3 fatty acid concentrations in both blood and adipose tissue.
I will surely oversimply their methods but basically, they had the number of AF episodes in these studies. Then they correlated omega-3 fatty acid levels (EPA, DPA, DHA, and EPA+DHA) with the incidence of AF, with statistical adjustments. They tried to harmonize the data across studies because the studies were so different.
They found provocative results. Unlike the RCTs which have shown higher AF risk, they noted:
Circulating EPA levels in blood or adipose tissue was not significantly associated with AF;
Higher DHA, EPA+DHA, and DPA levels were associated with lower AF risk;
The results were overall consistent by lipid compartments and across prespecified subgroups, including elevated cardiovascular risk status.
That is interesting, isn’t it? How do we reconcile the higher risk of AF in trials of prescription strength fish oil vs these findings?
The first thing that I hope comes to mind is that observational studies have a risk of confounding. These are non-random comparisons. But in this case, the authors have levels of marine fatty acids. That may mitigate the bias concern somewhat.
But the levels also explain the discrepant results. In this observational study, the levels of marine fatty acids were much lower than in the trials. Both the authors and editorialist explain that the levels in these prospective studies reflect habitual fish intake rather than high dose supplementation.
The main message therefore may confirm what I have been saying on this podcast and in clinic for years: eat fish, not fish pills.
The larger message is that prevention of heart disease is never going to be about one thing. Humans are not cars.
Good diet is important. A Lower LDL is important. Not smoking is important. Good blood pressure and normal glycemia, too. And exercise. And stress. And sleep. And inflammation. And of course, good luck.
That’s why the notion to promote one pill, one drug, one diet is always going to be incremental. If you want to truly impact heart disease, it requires a change in societal norms, and I am afraid we are going in the wrong direction in the United States. The ESC meeting is going to be in Amsterdam next month. The last time I was there, I watched hordes of kids riding their bikes to school. That seems like a good start to a lifelong lower risk of vascular disease.
One of the things about this podcast is that I try to give appraisal free of bias. I am proud of my lack of industry conflicts. But one area that I have clear bias is in exercise. I am addicted to endurance exercise. I am like the rat who must run on the wheel.
Last week, an exercise study made the rounds on both legacy media and social media; 98 news outlets covered the JAMA study with the title: “Accelerometer-Derived “Weekend Warrior” Physical Activity and Incident Cardiovascular Disease.” Before I read a single word, I was skeptical. Putting ‘weekend warrior’ in the title just seemed like too much trying for attention.
The Harvard team, first author Shaan Khurshid, used the UK biobank cohort study to compare the association of moderate to vigorous physical activity achieved over 1 to 2 days vs moderate to vigorous physical activity spread more evenly throughout the week with the risk of CV events.
They studied three patterns of physical activity: Active weekend warrior (WW; more than 2.5 hours in 1 to 2 days), active regular exerciser (more than 2.5 hours spread more evenly through the week) and a control group of inactive persons.
The Biobank had accelerometer derived data, which is better than self reported data.
There were nearly 90,000 people, age 62 years. Half female. About 42% were in the WW group, 24% in regular exercise group, and 33% in the inactive group. Then they do the adjustments.
Both activity patterns were associated with:
Lower risk of AF. HR .78 for WW and .81 for active regular.
Lower risk of MI HR .73 for WW and .65 for active regular
Lower risk of HF HR .62 for WW and .64 for active regular
Lower risk of stroke. HR .79 for WW and .83 for active regular
Physical activity concentrated within 1 to 2 days was associated with similarly lower risk of cardiovascular outcomes to more evenly distributed activity.
The manuscript was impressively short. The editorial was massively long.
I can make it simple. Weekend exercise is better than no exercise. But in my opinion, this is a bad idea for many people. Physical activity is not just for reducing AF, MI, stroke, and HF. Health transcends CV outcomes.
My idea and what I tell patients is that a little exercise is like a health pill, one that is way better than a fish pill.
Every day. I say, you should do something for 15, 20, 30 minutes. A walk, an exercise bike, a swim, whatever. Golf does not count. Something sustained. Every day.
The mistake people make is thinking of it as training. It’s not training. It’s just movement that’s sustained over a period of time.
If you want to build up to more, fine, but do something every day.
When I grew up, my maternal grandfather lived with us, in our dining room. He did a little exercise every day. He almost made it to 100. Even when he couldn’t walk well, he did daily exercises in his bed or chair. I recall him doing these once in an ICU bed.
You want exercise to be ingrained into life. Like the Dutch kids riding their bikes to school. I don’t doubt that a Harvard group studying a healthy volunteer group in the UK can show that WWs have similar CV outcomes to regular exercisers. But that’s only one small part of exercise’s role in health.
The New England Journal of Medicine (NEJM) has published a big RCT comparing diets. Yes. An RCT in the nutrition space. That in and of itself is worthy of celebration, since so much of nutrition science is marred by worthless observational studies of blueberries, coffee, etc.
This was the Mediterranean–DASH Intervention for Neurodegenerative Delay, aka the MIND diet, which is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been possibly associated with a lower risk of dementia.
The MIND diet emphasizes consumption of plant-based foods, including green leafy vegetables, nuts and berries, fish, and olive oil. The diet limits the intake of foods with high levels of saturated fat and sugar, such as red or processed meat, butter and margarine, whole-fat cheese, pastries and sweets, and fried foods.
The patients were 70 year olds, mostly female, who had no cognitive decline, a positive family history of dementia, a body mass index greater than 25, and a poor diet.
The trial tested the MIND diet with mild calorie restriction vs control diet with mild calorie restriction.
The trial went for 3 years.
The primary endpoint was the change from baseline in a cognition score. Secondary outcome was brain-MRI derived measures.
The trial was null. Both groups improved similarly in global cognition scores. MRIs also looked the same.
Comments. I present this to you because it is the way forward to know things. Observational studies looking at foods putatively associated with better cognition are hopelessly confounded. The people who eat nuts and berries and organic stuff are surely different in many ways from people who don’t eat those kinds of foods. You cannot control for all these variables.
You can criticize this study because it’s hard to know how much people adhered to the diet. You could say that the control arm would be motivated by being in a study. I believe the main problem in this study and in all studies of diet and lifestyle is that it is so limited in time. MIND went 3 years.
But surely the prevention of dementia, if it can be prevented by lifestyle, is longer than 3 years. It’s a lifetime. Like those Dutch kids riding their bikes to school.
Anyways. Congrats to the authors. Congrats to NEJM for publishing an RCT that had null results. This allows me to close on a positive note.
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Cite this: Jul 21, 2023 This Week in Cardiology Podcast - Medscape - Jul 21, 2023.