Sep 22, 2023 This Week in Cardiology Podcast

John M. Mandrola, MD


September 22, 2023

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In This Week’s Podcast

For the week ending September 22, 2023, John Mandrola, MD, comments on the following news and features stories: coronary artery calcium scans, cardiac arrest survival, good news in Factor Xi drug development, APCs and movement towards a new board certification in cardiology.

In This Week’s Podcast

Coronary Artery Calcium

JACC-Interventions published an observational cohort study looking at the rate of atherosclerotic cardiovascular disease (ASCVD) events in group of patients referred for Cardiac computed tomography angiography (CTA) scans.

They retrospectively made two groups – those with established ASCVD, such as prior MI, stroke or PAD and the second group were those without ASCVD events. Think of it as secondary and primary prevention groups.

All patients had CAC scores. In the primary prevention group they broke it down to 4 groups: CAC = 0, 1-99, 100-299, >300.

They then looked at the rate of future events.

The main finding was that patients with a CAC score > 300 had the same rate of events as those who had ASCVD.  From the paper

This observation, that those with CAC >300 have event rates comparable to those with established ASCVD, supplies important background for further study related to secondary prevention treatment targets in subjects without prior ASCVD with elevated CAC. Understanding the CAC scores that are associated with ASCVD risk equivalent to stable secondary prevention populations may be important for guiding the intensity of preventive approaches more broadly.


It makes sense. Perhaps a hidden message is that a certain score means you have ASCVD but I am not convinced by this paper. Let me start with the authors’ words

It must be emphasized that as an observation, prospective study, we did not have complete information on treatment and other clinical indicators of risk, which limits the conclusions.

Second statement

Furthermore, because this was a referred population for coronary CTA across many indications, caution must be taken when generalizing to the general population.

The authors don’t report the 10-year risks of the CAC groups. We have no idea what the CAC score adds to the pooled cohort equations risk assessment. The CAC>300 group had more HTN, more smoking and higher cholesterol than the lower CAC groups. So they might also have had higher risk scores and these could be used to maximize therapy.

In the first year, patients in the established CAD arm had a major adverse cardiac event rate of 3%-4%. Contrast this with the CURE study of clopidogrel + aspirin vs aspirin alone after MI. MACE rates were 9%-11% in the first year. My take is that the CONFIRM Registry CAD arm are not very high risk “established” CAD patients.

I have a problem with the whole idea of declaring a patient to have CAD vs being at risk. Guidelines say if you have established disease, you are eligible for additional LDL-C lowering drugs beyond high-intensity statins, such as PCSK9i or ezetimibe.

Go back and look at these trials. Neither drug reduces mortality or CV mortality. They both provide very small absolute risk reductions in nonfatal events.

Now let me repeat my warning about CAC. In real life CAC scans scare patients and are a major driver of angiography, PCI and bypass of asymptomatic disease.

Proponents say none of us ever wrote that CAC should be used this way. It’s not in our guidelines.

But they have done little to stop the misuse of these tests. I would propose that they start a massive publication education program. DON’T USE CAC to DRIVE DOWNSTREAM TESTING.

My view is simple: primary or secondary prevention alike. If a person wants to do everything to reduce heart disease risk: eat a great diet, exercise, don’t smoke, make sure the BP is controlled, take a high dose statin, and don’t ignore symptoms if they arise. Otherwise, stay away from medical imaging and overly enthusiastic doctors.

Cardiac Arrest

Professional Cyclists Nathan Van Hooydonck, was driving his car in Belgium when he had a cardiac arrest.

Initial reports were that he had a car crash, but it turned out that he required out of hospital resuscitation. He was transferred to a hospital and reports this week was that he has a cardiac condition requiring an ICD and he has to retire from sport.

Van Hooydonck benefited from the chain of survival of cardiac arrest.

A randomized controlled trial (RCT) presented at ESC directly studied part of this chain. The ARREST trial—which was a prospective RCT randomizing non-STEMI patients who had return of spontaneous circulation (ROSC) at the scene to a specialized cardiac arrest center or the closest standard hospital.

ARREST was carried out in London, England, first author, Tiffany Patterson, PhD. I read that there are 7 special cardiac arrest centers in London, -- with emergency out-of-hours provision for interventional cardiology, cardiac surgery, and specialist intensive-care facilities.

The primary outcome was all-cause mortality at 30 days.

This is a great unbiased endpoint. Alive or dead. Not nonfatal MI, not HF hospitalization. Not an anxiety or depression score.

Also, I love this design because I can easily imagine a group of key opinion leaders say how important it is to get these CA survivors to our special hospitals.

Well, the ARREST authors randomized about 400 pts to each group and the primary endpoint of 30-day mortality occurred in 63% of both groups. Identical! Risk ratio = 1.00; 95% CI, 0.90-1.11. Even professor of statistics Frank Harrell would probably allow me to say no difference.


The authors spent time in the discussion section saying how this data effects hospital planning and resource use.

That is true, but I also think the resuscitation/ICU space teaches us a lot about the importance of RCTs.

ARREST – says get survivors of CA to the nearest hospital. Stop worrying about special centers. The ECLS-SHOCK study found no benefit from extracorporeal life support in cardiogenic shock after MI. How about the oodles of RCTs showing no benefit to aggressive cooling—a massive reversal.

Resuscitation trials rarely bring the attention of drug or device trials, but gosh they teach us a lot.

One final comment – | Medscape cardiology has a nice conversation about cardiac arrest in famous athletes. Bob Harrington and Manesh Patel hit many of the important themes. I agree with many of their comments. Especially the caution we should have in screening.

My answer to improving survival in cardiac arrest is not from better screening—but more aggressive use of public health measures like those that saved Damar Hamlin, Christian Erikson, Bronny James and now Nathan Van Hooydonck. That is better and faster out of hospital CPR and early defibrillation.

FACTOR XI inhibition

For the prevention of thrombotic events, first there were Vitamin K antagonists. Now there are the direct acting oral anticoagulants –either Factor 10 inhibition or direct thrombin inhibitors.

Perhaps soon there will be Factor XI inhibitors.

This week, the makers of a drug called Abelacimab, an injectable monoclonal antibody Factor XI announced that a large Phase 2 study, called AZALEA-TIMI-71 study was halted because of an “overwhelming reduction” in the primary endpoint of major bleeding with abelacimab vs rivaroxaban. These were patients with AF at moderate to high risk for stroke.

Factor XI is involved in the amplification of clot formation. The hope or promise of FXI inhibition is that it may allow for preservation of normal hemostatic function to a greater extent than DOACs.

A company slide proposes the “uncoupling” of two interlinked pathways which a) suppresses the pathological thrombotic pathway while leaving the physiological hemostatic mechanisms largely intact.

AZALEA -TIMI 71 is an event-driven, randomized study comparing two blinded doses of abelacimab (90 mg or 150 mg given by subcutaneous injection once-monthly) with rivaroxaban 20 mg daily in about 2000 patients with AF. Full results of the study will be presented at an upcoming scientific congress.

In a previous proof-of-concept study published in The New England Journal of Medicine in 2021, a single IV dose of abelacimab achieved a large reduction in venous thromboembolism (VTE) vs enoxaparin in patients undergoing knee surgery.


AZALEA -TIMI 71 generated a big buzz online. It was a dramatic press release. I think optimism is warranted but it’s a cautious optimism.

Press releases give very little details. Phase 2 studies are for dose ranging and safety. Next are phase 3 outcomes trials against DOACs.

At my hospital, we are randomizing in the OCEANIC AF study of asundexian, an oral FXI inhibitor vs apixaban.

What we need to know with this group of drugs is net benefit. While there may be less bleeding, is there also less stroke prevention. The only way to know that is with OCEANIC AF type Phase 3 studies.

Abelacimab is a monthly injectable. Which may be nice for adherence. But may be less ideal for patients who need surgery or procedures. (Yet maybe the promise of uncoupling of clotting and bleeding) will allow for non-interruption.

I will close this section by noting the careful drug development process. Phase 2 studies, then large powered outcome trials. This is the right way. We have a serious confluence of interest b/w industry and clinicians and patients. The profit motive is incentivizing companies to make a better drug than DOACs which are a good standard. Companies are competing and tests will be proper trials. That is the way it should be.

I wish the device space could be this rigorous.

Advanced Practice Clinicians

The BMJ published a cross-sectional study from American authors looking at the proportion of healthcare visits delivered by nurse practitioners (NP) and physician assistants (PA) and how this has changed over time and by clinic setting, diagnosis and demographics.

  • The survey went from 2013-2019. Keep that in mind, because I think the trends are continuing in the same direction from 2019-now.

  • The proportion of outpatient visits delivered by APCs increased from 14% to 25%.

  • In 2019, diagnosis mattered – eye care 13%; HTN 20%, anxiety 37% and respiratory diseases 41%.

  • And among all patients who had at least one visit, 42%, nearly half, had one or more APC visit.


First, this is a good use of observational data. It tells us what is happening. And what is happening is remarkable. And If I had to guess, the trends for APC-delivered care are only increasing.

I also gather, from my friends in the UK, that is happening there too.

I have worked with APCs for decades, and some of them, those who have stayed in their specialty and been committed to learning, are amazing. I trust their clinical judgement as much as any physician.

I would have ZERO trouble seeing such an APC.

I have written previously that--on average – APC-delivered care will be equal to MD-delivered care. And that is because the vast majority of medical problems do not require special training.

The problem, and this is where great mentorship and focused attention comes into play is the unusual cases.

If you are an unusual case, you hope that a bell goes off in the brain of the person who sees you. Your caregiver doesn’t need to figure it out. They just need to know that something is up, and they should phone a friend or suspend the usual algorithm. That sense can be taught, it can be honed with experience. A degree, a background of years of studying the Krebs cycle doesn’t matter.

One outlier that we are seeing a lot of these days is normo-glycemic ketoacidosis from SGLT2i. It’s being missed. By lots of people with all manner of letters after their name. You don’t need a specific degree to NOT MISS this. All you need to do is not ignore a major lab abnormality as in a low bicarb. An APC could do that as well as an MD.

The rise of APCs should make MDs think about our education and licensing. If APCs can do what many MDs can do with a fraction of the training, then maybe medical educators need to think about current training programs.

I get the sense that a lot of how we are trained was based on a world before there was an Internet or Google.

Movement in Board Certification

One final note, this week, the American College of Cardiology (ACC) announced that along with Society for Cardiovascular Angiography & Interventions (SCAI), and the Heart Failure Society of America (HFSA) and the Heart Rhythm Society (HRS), they are considering forming a new board certification for CV medicine. One that moves away from maintenance of certification (MOC) and the American Board of Internal Medicine (ABIM).

The new Board requirements will de-emphasize timed, high stakes performance exams in the continuous certification process and instead will focus on learning assessments to identify gaps in current knowledge or skills, with recommendations offered on Continuing Medical Education (CME) learning resources and activities to help close the gaps. 

This just happened and I have not had time to explore exactly what it means. So stay tuned. Put me down as a bit cautious.


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