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In This Week’s Podcast
For the week ending December 3, 2021, John Mandrola, MD comments on the following news and features stories.
The aMAZE Trial and LAA Ligation
On the surface there is the mundane issue of whether doing more destruction in the left atrium (LA) improves ablation outcomes. In patients with long-standing persistent atrial fibrillation (AF), the aMAZE trial tested whether add-on LA appendage (LAA) ligation with the LARIAT device would reduce AF compared with standard AF ablation. The answer was no. There was no statistical reduction of AF with more extensive work in the LA. But aMAZE teaches us many other lessons relevant to regulatory approval, critical appraisal, and the value of a medically conservative approach.
First some specifics on aMAZE. In all, 610 patients with advanced AF were enrolled. Patients in the treatment arm underwent LARIAT LAA, and then pulmonary vein (PV) isolation 1 to 2 months later; patients in the control arm had basic PV isolation. LARIAT is a device approved via the very lax US Food and Drug Administration (FDA) 510 clearance for the approximation of soft tissue — as if it was some sort of suture device. It is not that. It is basically an epicardial clip for the LAA, the idea being that if you clip the LAA, you electrically and mechanically isolate it, which would reduce AF.
64% of the control arm had freedom from AF vs 60% of the LARIAT arm.
The difference did not get close to statistical significance.
There were some attempts to look at subgroups, but this is dubious when there is a strongly nonsignificant primary endpoint.
In addition to no efficacy, 12 patients in the LARIAT group suffered serious complications, three of which required surgical intervention.
The authors said in their presentation that the “primary safety endpoint” was met at 3.4% but they set the safety endpoint at < 10%. What we will need to see is the actual events in the two groups.
We can tell from the slides, without the paper, that this technology as an add-on to AF ablation is not effective and not especially safe either. But I mentioned other important lessons. First is regulatory. The LARIAT is a highly specific device used to perform epicardial LAA closure. That’s extremely invasive and it ought to be proven effective and safe for something, say stroke prevention or AF prevention, before being unleashed on the public.
It wasn’t adequately tested. The FDA 510(k) clearance does not require clinical testing for a specific indication; rather, clearance is predicated on the demonstration of "substantial equivalence" with existing devices used for suture placement during other types of surgery. Approving this device for the approximation of soft tissue exposes a huge loophole in regulatory function.
And I’m not sure aMAZE would have been done if not for a July 2015 JAMA-Internal Medicine paper chronicling a worrisome incidence of major complications from this device in the MAUDE database. The aMAZE trial was posted to clinicaltrials.gov 1 month after that paper.
There is another lesson relevant to the medically conservative approach to invasive new techniques like LAA isolation. In 2015, a group of prominent electrophysiologists presented the BELIEF trial which found a significant reduction in AF with electrical isolation of the LAA. I wrote a strong critical appraisal of the trial. The president of the European Heart Rhythm Association criticized it heavily at its presentation.
One of the main issues is that when you electrically isolate the LAA, it does not squeeze and thus becomes a huge nidus for clots and a major stroke risk. You create near total anticoagulation-dependence. And some have advocated for placing devices to plug it.
In the intervening 6 years, until aMAZE, there have been no further randomized controlled trials (RCTs) confirming this technique. There are observational studies and meta-analyses of observational studies, plus BELIEF. Now aMAZE comes out, with nearly 4 times more patients and finds that LAA isolation has no effect. It’s not exactly the same technique of LAA isolation, but it’s close.
The value of aMAZE is that it teaches us the important lesson that before accepting a new technique or therapy, especially one that has serious tradeoffs, we should have more than one trial. If you want to do more to people, then the onus is on proponents to show us it that it definitively works.
A New CETP Inhibitor
The number one trending story among cardiologists on theheart.org | Medscape Cardiology this week is coverage of obicetrapib, a new lipid lowering agent in a class that had been written off.
The cholesteryl ester transfer protein (CETP) inhibitor class, known mostly for its ability to raise HDL cholesterol, has been abandoned primarily because of inefficacy of outcomes and off-target effects. Sue Hughes superb story recounts that obicetrapib was destined for the trash heap too, as Amgen decided to discontinue its development in 2017. But a group of academics believed in it and set up a new company that acquired the rights to the new drug.
What we know from the presentation at the 2021 American Heart Association (AHA) meeting is rudimentary and pre-clinical. We know the drug is a more potent LDL reducer compared with others in the class and it does not have torcetrapib-like side effects (such as increase in blood pressure (BP), decrease in potassium, and increased cardiovascular (CV) outcomes).The ROSE study, presented at AHA, included 120 patients who had been on high-intensity statins. The primary endpoint (PEP) was change in LDL.
Obicetrapib showed a robust 51% reduction in LDL with 10 mg dose and 42% reduction with 5 mg.
ApoB also went down 30%
Lipoprotein (a) went down 56%
HDL went up 165%.
These are big reductions and this is an oral pill. Right now, there is a race to find an oral replacement for PCSK9 inhibitor drugs. Obviously, the next step for obicetrapib is to show reductions of clinical outcomes with safety. That’s the hard part, because remember, high intensity statins drive event rates quite low.
Speaking of Oral PCSK9 Inhibitors
Steve Stiles has coverage of a phase 1 trial of a Merck drug called MK-0616, an oral PCSK9 inhibitor that lowers LDL cholesterol on top of statins. The drug was generally well tolerated at up to and including single doses of 300 mg, "the maximum tested in the studies.” MK-0616 is a cyclic peptide that is "about one-hundredth the size of a monoclonal antibody, but we're able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”
Phase 1 studies are done to evaluate the safety of a new drug candidate before it proceeds to further studies. It is a very long road from phase 1 to success in phase 3 clinical trials. But you have to run a 10k before you finish a marathon, so success early allows moving on to phase 2, which are generally dosing trials. The point here is that there is a race to get an oral add-on drug to statins.
EHR Alerts and Heart Failure Prognosis
I’ve said on this podcast that heart failure (HF) care can be heartless. Everyone is focused on getting patients on meds and clicking the boxes. Due to HF’s broad presentation and frequent co-morbid conditions, there can be over-treatment at the expense of palliation. But there can also be undertreatment of things like rhythm issues, such as left bundle branch block or AF with rapid rate.
Researchers at Yale asked, what if we gave clinicians electronic health record (EHR) alerts about their patient’s prognosis? Would this knowledge lead to better treatment decisions and better outcomes? They answered the question the best possible way: with an RCT. Patients with HF who were hospitalized were randomly assigned to receive an alert on the 1-year prognosis when clinicians entered orders, or to usual care. The prediction score used an amalgam of clinical risk factors.
The group described the discrimination and calibration of this score in their rationale paper. The calibration (observed vs predicted risk) was lower in the trial population; the authors speculate that this was due to excess mortality during the pandemic. About 1500 patients were in each arm; age 67 on average.
There was no difference in composite clinical outcomes, 1-year mortality, or 30-day readmissions.
There was no difference in guideline directed medical therapy use, or palliative care referrals.
I highlight this study because we learn from it. Mortality estimates during standard workflow did not change treatment or outcomes. Whether this is due to alert fatigue or the fact that care was already pretty good, or that clinicians intrinsically take into account the prognosis, matters less than the simple fact that it didn’t work. So we learn the specific lesson that this sort of message doesn’t work. But the larger message is that pragmatic, system-level policy things can be studied. Imagine if every EHR alert was studied like this. We’d probably see fewer alerts, and that might mean the ones that we did see had an effect.
I love new care models. Listeners know one of my favorite studies of all time was the late Ron Victor’s Black Barbershop study. Well, a group at Massachusetts General Hospital and Brigham presented a nice paper on a digital care transformation in management of hypertension and lipids. It’s a new model not only because it involves digitally recruiting and digitally measuring and transmitting BPs, but also because it uses non-MDs as primary care givers.
Before I tell you about how this works and what they achieved, let’s agree that vast swaths of Americans have poor control of CV risk factors like BP and cholesterol. Just asking people to run the gauntlet of traditional care models and interact with an ever-decreasing supply of increasingly distracted MDs isn’t going to work.
What’s more, it’s often people with fewer resources who live in rural and urban settings who have the most to gain from better BP and lipid control. Sadly, though, the most needed areas often have the least supply of clinicians.
The group at Harvard identified, from an HER, patients who were not at goal and provided them with digitally connected BP devices. They then used non-licensed patient navigators (AKA regular people) as primary contacts with patients. These regular people provided education and gathered data. Then pharmacists had the power to independently prescribe and titrate meds and do lab studies according to guidelines. Physicians functioned in a consultative role as needed. The glue that holds this model together is a remote care delivery program.
They have reported the results of the first 5000 patients previously as a research letter in Circulation. At AHA, they reported results of the first 10,000 patients.
The raw data was pretty staggering, involving 100,000 phone calls, and more than 400,000 BP values. The results were significant.
Patients who completed the program saw big drops in systolic BP and LDL.
For LDL, the average of enrolled patients was a 45 md/dL drop, which is huge because this includes all patients, not just the ones who completed the program.
They also noted equivalent degrees of LDL reduction in Black, Hispanic, and non-English-speaking groups.
In sum: Remote, algorithm-driven, pharmacist-led, program using regular people as navigators produced impressive reductions in BP and LDL. And it did so in groups of patients who have traditionally had less access to care.
This is the future. The role of physicians will change and transition to supervisory. The naysayers of this model will point to the fact that 24,000 patients were screened, 18,000 were contacted, and 10,000 were enrolled, but less than half were maintained in the program. They will also say that a place as endowed with dollars and motivated people like Harvard can pull this off, Let’s see it work in Detroit, or Louisiana, or rural West Virginia.
Another critique – one that may come out in the paper — surrounds the question of harm. For example, were there complications of more aggressive BP control? I get that criticism, but I see this as proof-of-concept effort. We need better ways to deliver the same guideline directed care that wealthy insured Americans get to all people. The young Alexander Blood is the first author and he did an excellent presentation. Congratulations and I look forward to reading the paper.
JAMA published a short research letter that delivered shocking results regarding the health of young adults aged 18 to 25 years. Recall that this age group is at the pinnacle of one’s health. My eye doctor taught me that. One time in my late 20s, he told me there was a change in my prescription. I replied with foolish optimism: it’s got better. He pushed the refraction gadget aside and said something that is burned into my brain: “No John, you are past your peak. Everything now is downhill.” He was speaking about the eyes, but the point remains that 18 to 25 years are our best years physically.
The paper was from researchers using the longitudinal National Health and Nutrition Examination Survey (NHANES) data base and reported trends in obesity prevalence in this young adult age group. The outcome of interest was body mass index (BMI) and they divided the population into four groups: underweight, normal, overweight, and obese (> 30 BMI).
The prevalence of normal weight plummeted to 37.5% between 1976-1980 and 2017-2018.
The rate of obesity sharply increased to 33% during that time.
The first author, Dr Iejandra Ellison-Barnes said: “While we were not surprised by the general trend, given what is known about the increasing prevalence of obesity in both children and adults, we were surprised by the magnitude of the increase in prevalence and that the mean BMI in this age group now falls in the overweight range.” The average 18 to 25-year-old in America is now overweight. In 1980 the percent of 18 to 25-year-olds who were obese was 6%. Now it is nearly one in three. The authors write this utterly under-assuming sentence: “Emerging adulthood may be a key period for preventing and treating obesity, given that habits formed during this period often persist through the remainder of the life course.”
I obviously don’t have the answer to obesity, but the fact that this many adults in the prime of their lives are obese seems like a public health crisis. This will surely lead to higher rates of diabetes, stroke, myocardial infarction, and of course worse bone and joint outcomes.
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Cite this: Dec 3, 2021 This Week in Cardiology Podcast - Medscape - Dec 03, 2021.