Mar 17, 2023 This Week in Cardiology Podcast

John M. Mandrola, MD


March 17, 2023

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast, download the Medscape app or subscribe on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only.

In This Week’s Podcast

For the week ending March 17, 2023, John Mandrola, MD comments on the following news and features stories.

Pacing in HFpEF

JAMA has published the RAPD HF trial first author Yogesh Reddy from Mayo clinic. An elegant cross-over study involving rate-adaptive pacing during exercise, presented at ACC seemingly challenged my excitement about a breakthrough pacing study from last month.

MyPACE published last month in JAMA-Cardiology, first author, Maggie Infeld, studied patients with HFpEF who already had pacemakers. These were special pacers in that pacing rates could be increased with preservation of normal PR intervals and without causing RV pacing.

They used 3 types of pacers—those with conduction system pacing (CSP) leads that pace the ventricle without causing RV dyssynchrony, CRT pacers which also preserve PR and prevent RV dysynchrony, and standard dual chamber pacers with atrial pacing.

myPACE did not focus on exercise pacing rate. Instead, they randomized patients with HFpEF to a personalized accelerated pacing program or usual care. The average heart rate in the active arm was about 75 vs 65 in the usual care.

They showed that QOL, BNP, patient activity and AF rates were all better in the higher pacing arm.

Crucially, due to the special pacemakers, myPACE researchers could increase pacing rates and know that the PR interval could be preserved, as well as synchronous biventricular contraction.

When I discussed myPACE, I was careful to say that implanting pacers willy-nilly in patients with HFpEF is not one of conclusions we should take from that study.

Instead, the notion that lower heart rates in patients with stiff ventricles is a dogma that may need to be overturned.

Now to the RAPID HF trial.

Reddy and colleagues recruited patients w HFpEF who met the criteria for chronotropic incompetence.

Basically, it is as it sounds: the inability to raise one’s HR to what it should be during exercise. The problem here is that HR increases are highly variable, and it is also really hard to know what HR should be.

The study included 32 patients who had pacers implanted and did a crossover study wherein one group had AAI-R (or rate adaptive atrial pacing set to increase HR during exercise) vs no pacing. And then—after a month washout period patients crossed over to no pacing vs rate-adaptive pacing.

The primary endpoint was oxygen consumption (V̇O2) at anaerobic threshold (V̇O2,AT)

They first showed –in the pacing off group—that HR during exercise did correlate with performance. They then showed that compared to no pacing, patients randomized to the rate-adaptive pacing had slightly higher rates during submax and peak exercise.

And the main results – not a shred of difference. Also no diff in BNP, KCCQ.

And 6 patients had adverse events from the pacer. Effusion requiring drainage, lead induced TR, local skin reactions etc.

They obviously concluded that In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events.

The editorialists took an even more negative view of pacing in HFpEF. And you should read their editorial—first author Dalane Kitzman

They make 5 major points:

  • Exercise limitations in HFpEF are complicated and have as much to do with peripheral oxygen uptake as cardiac dysfunction.

  • HFpEF is a “quintessential systemic multiorgan disorder” which neatly explains why cardiac drugs have generally failed.

  • The lack of benefit of RAPID HF is credible and they mention other pacing trials that have been negative.

  • They were swayed by the reduction of stroke volume with higher paced rates.

  • Since exercise performance depends so much on peripheral oxygen uptake at the skeletal muscle, they favor exercise programs as a way to help these patients.

My Synthesis:

These studies are apples and oranges. The patients and interventions were entirely different.

My excitement about HR revelations in HFpEF remains. A) We should not implant pacers for chronotropic incompetence Exercise performance, as outlined nicely in the editorial, is far more complex than a few more heart beats; B) the myPACE conclusions that avoiding extremely low heart rates continues to be a really fruitful strategy; C) The corollary to that is that beta-blocker withdrawal should be favored; and D) if pacing is used, it needs to be under the direction of an EP who is facile in modern pacing techniques.

I also remain enthusiastic about exercise as a potential therapy. The editorialists’ comments that “a single bout of exercise in sedentary individuals evokes a nearly immediate, large increase in skeletal muscle gene transcription” has enticing plausibility and while early studies of exercise show promise, we need more data in the pragmatic setting.

Oral PCSK9i

Last week I discussed CLEAR Outcomes, a trial of the non-statin cholesterol-lowering drug Bempedoic acid.

ACC featured another non-statin cholesterol lowering agent. It is MK-0616, an oral PCSK9i inhibitor. JACC published the phase 2 dose-ranging RCT .

PCSK inhibitors are already approved for LDL-C in high-risk patients. But these require a shot.

There is a race to develop oral PCSK9i. Merck is early with this orally bioavailable, renally-excreted, macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight."

Nearly 400 patients were randomized to one of either 4 doses of the oral drug or placebo. The primary endpoints were percent change in LDL-C at week 8 and proportion with adverse events.

The drug resulted in statistically significant and large reductions in LDL-C. There was a graded dose response. And no signal of adverse events.


Phase 2 studies are mostly for finding dosages to use in Phase 3 studies wherein the drug is assessed for reducing CV outcomes.

This is promising. The LDL-C reductions are substantial. But it has to show reductions in clinical outcomes. (it likely will).

Other companies are also developing oral PCSK9i. Merck, obviously, has a good start.


I don’t treat patients with pulmonary arterial hypertension (PAH). But ACC brought pretty amazing news about a new drug, called sotatercept. A potentially major breakthrough in an uncommon but tragic disease.

Kudos to journalist Mitchel Zoler who has a wonderful explanatory news column.

PAH is a disease that involves proliferative remodeling of the small pulmonary arteries that leads to progressive narrowing and resultant right heart failure.

From my reading, there is altered signal signal transduction of the growth factors—which is way above my pay scale.

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient's blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

NEJM published results of the STELLAR trial, an RCT of 163 patients with PAH. The PEP was change in 6 min walk test. And it was highly positive for S.

The first eight secondary end points were significantly improved with sotatercept as compared with placebo,

Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.

FDA has rendered this a "Breakthrough Therapy" designation and "Orphan Drug

The editorialists were excited, but also raised several cautions and concerns.

They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH.

The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

I mention this story in much the same vein as the oral PCSK9i. It’s early, yes, and surely the drug will be incredibly costly, 3-4 in a 100,000k with this terrible condition, there may be disease modifying options. Emphasis on may be.

I am told by people in the know in the drug development space that Sotatercept is this first wave; there will be more therapies targeting this pathway.

ACCESS Trial -- Free Medicines and Outcomes

A research team in the province of Alberta Canada have published a very important paper about medical adherence.

Soft thinking is such a problem in medicine today. We underestimate complexity far too often. Not considering the externalities of the punitive hospital readmissions reduction program is a shining example of soft thinking.

Canadian researchers tested the idea that eliminating copayments for high-value medications among low-income older adults who were at high CV risk would improve clinical outcomes.

Disparities in outcomes among low and high SEC is frequently discussed. High costs are seen as causal. Low-income adults would be most at risk for poor outcomes for not taking statins or other preventive meds.

Heck, higher use of preventive meds was held up as causal in the 40% reduction in CVD/MI in the SCOT-HEART trial wherein patients in CTA arm had higher use of these meds.

ACCESS was actually a 2x2 factorial trial testing both the waiving of copayments of high value meds and a self-management education and support program.

This paper –presented at ACC and published in Circulation considered only the free meds.

Their primary outcome is notable: it was not use of medicines, it was actual outcomes: a composite of death, MI, stroke, coronary revasc, CV-related hospitalization over 3 years. I want to emphasize how important and notable this choice was. Many similar implementation science papers measured medicine adherence as an outcome. That, in my opinion, is a weak surrogate.

They enrolled nearly 5000 patients and followed them for 3 years. The rate of the primary outcome was not reduced in the group that had no copayments. 521 vs 533 events.

None of the components varied. Nor did changes in QoL or health care costs.

Statin adherence hardly budged. (0.72 vs 0.68). There was no difference in ACE-ARB adherence.

Authors Conclusion: In low-income adults at high cardiovascular risk, eliminating copayments (average $35 a month) did not improve clinical outcomes or reduce healthcare costs, despite a modest improvement in adherence to medications.


First let’s talk about patients. These were older patients. Mean income low. (No one was over $50K Canadian per year, which is like$ 38K per year in US dollars). Most were lower income. So even a minimal co-pay would be something. More than half had diabetes and established CAD. More than 80% had high blood pressure and high cholesterol.

I have long said that more healthcare often does not lead to more health. You have the insurance studies: RAND, the OREGON Health Insurance Experiment, and the Karnataka India experiment which all found that giving more preventive care did not significantly improve outcomes. You have the recent JAMA paper showing that states that expanded Medicaid did not lead to better CV care.

Journals, meetings, Twitter, are full up of association studies showing that patients who adhere to more GDMT do better. Low-income people do worse, because they don’t adhere to meds as well, goes the thinking.

The problem is that prevention is far more complex than simply adhering to guidelines. Why have so few thought to say that the mere ability to adhere to 4 HF meds may be a marker for a healthier patient and it those other factors that lead to better outcomes.

Has it ever dawned on people to look at how small the absolute risk reductions are in some of these anointed therapies. Even statins, you are looking at 1-2% ARR. That’s fine, but people are complex, if you had a group that 100% took these meds and 0% did not, you could show differences.

But in the real world, where people have stressful lives, they are taking care of children, grandchildren, sick elders, difficult marriages or jobs, the idea of taking meds for a 1-2% ARR of a nonfatal event over the next decade isn’t high priority.

Victor Montori from MAYO rings in my ear. He’s called for doctors to understand the work of being a patient and focus on minimally disruptive care. Pick the highest value thing a patient can do. Dinking around with a SBP of 145 might pale in comparison to helping a patient eat less salty snacks, or helping her carve out 15 min per day for a walk.

In retrospect... I think ACCESS may have been one of the best studies from ACC. Congratulations to David Campbell et al.

Metabolically Healthy Obese

JAMA Network Open has published a survey of NHANES data from 1999-2018 looking at the prevalence of metabolically healthy obese patients.

This was defined as a BMI greater than 30, but no metabolic disorders, such as hypertension, blood glucose, or lipid issues.

Their cross-sectional study suggests that the age-standardized proportion of metabolically healthy obesity increased among US adults from 1999 to 2018.

Absolute numbers went from 10.6 to 15% in 2015-2018.

Here is my problem with this: I don’t think the words healthy and obese belong in the same category. The mean age of these patients were mid 40s.

What do you think will happen to these patients in their mid-50s or mid 60s.

This is what I tell patients who are overweight. You may be skirting issues now, but to preserve quality of life in the future, not just cardiac health, but bone and joint health (mobility), we should work on strategies now.

I think we do a great disservice to patients with high BMIs, by declaring them “metabolically healthy”.

I always start my discussion by saying I am not a preacher, and I worship at the altar of liberty, and I recoil against all forms of coercion, but as your health adviser, I would encourage you to consider these strategies. Because, regardless, of your labs, having a BMI of 33 puts you at risk for future problems.


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