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In This Week’s Podcast
For the week ending May 13, 2022, John Mandrola, MD comments on the following news and features stories.
Big news came from the US Food and Drug Administration (FDA) this month with their approval of the novel drug mavacamten, which I covered in the April 8 podcast. To briefly review, mavacamten is totally novel and first in its class. It is a reversible inhibitor of cardiac myosin. That is important in hypertrophic cardiomyopathy (HCM), as excess myosin-actin cross-bridge formation and dysregulation cause HCM. Mavacamten shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In short, it is a negative inotrope.
The FDA approval was based on the EXPLORER HCM trial, published first in the Lancet in August 2020. EXPLORER was a placebo-controlled randomized control trial (RCT) conducted in 13 countries. Enrolled patients had a left ventricular outflow tract (LVOT) gradient of just over 50 mmHg and class 2 or 3 New York Heart Association heart failure (HF). The trial included 251 patients.
Patients in the mavacamten arm had dose adjustments to optimize response — decrease in LVOT gradient on Valsalva and maintenance of LV ejection fraction (EF) > 50%. The primary endpoint for EXPLORER-HCM was a composite functional endpoint, assessed at 30 weeks, and was defined by objective measures of function and subjective reduction in NYHA class.
A greater proportion of patients met the primary endpoint at week 30 in the mavacamten group compared with the placebo group (37% vs 17%).
Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (−36 mm Hg, 95% confidence interval [CI] −43·2 to −28·1; p<0·0001), and improved symptom scores (Kansas City Cardiomyopathy Clinical Summary score, +9.1, CI 5.5 to 12.7; HCM Symptom Questionnaire-Shortness-of-Breath score, −1·8, CI −2.4 to −1.2;p<0·0001).
That was in 2020. At the American College of Cardiology meeting in April, EXPLORER-HCM authors reported the long-term follow-up study called MAVA-LTE, which is a dose-blinded extension study in patients who completed EXPLORER HCM.
This paper is not yet published, but we were told that:
Improvements in gradients, NT-BNP, and NYHA class were sustained at a median follow-up of 62 weeks.
There were some safety signals:
11% of patients had temporary treatment interruptions for things like QTc prolongation,
Mavacamten concentration > 1000
5% of patients had LVEF < 40%
Overall, 77% patients remained on the treatment over the long-term. (Recall that this is in a super-careful RCT.)
Neither the FDA nor the Bristol Myers Squibb press release mentioned the VALOR HCM, another study presented at ACC, which also showed positive results for the novel cardiac myosin inhibitor.
VALOR HCM enrolled patients with HCM who were referred to big centers for septal reduction therapy with either surgical myectomy or septal alcohol ablation. These patients had quite severe HCM. The primary endpoint was avoidance of septal reduction therapy.
The results strongly favored mavacamten.
18% of the mavacamten arm met the primary endpoint vs 77% of patients in the placebo arm.
The absolute risk difference was 59 percentage points.
Mavacamten also performed well in clinical and echocardiography parameters.
Improvement in one or more NYHA functional class, resting LVOT gradient, Valsalva LVOT gradient, NT-pro-BNP level, and troponin I level all favored mavacamten over placebo.
Comments: As with most new drugs, there will be a learning curve. Mavacamten looks especially challenging.
You need lots of echocardiograms, before and during, and there are dose escalations.
You should not start the drug if the LVEF is below 55% and should stop it if the EF < 50%.
There is a black box warning for the possibility of HF.
The drug-drug interactions are huge:
Use of mavacamten with cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to high mavacamten levels.
Thus, the use of mavacamten is contraindicated with moderate to strong CYP2C19 inhibitors or moderate to strong CYP3A4 inhibitors
That is a lot of drugs that will either preclude use of mavacamten or require extra caution in the use of this drug. Fortunately, mavacamten will only be available through a restricted program called the Mavacamten REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the program include:
Prescribers must be certified by enrolling in the REMS Program.
Patients must enroll in the REMS Program and comply with ongoing monitoring requirements.
Pharmacies must be certified by enrolling in the program and must only dispense to patients who are authorized to receive mavacamten.
Wholesalers and distributors must only distribute to certified pharmacies.
Maya E. Guglin, MD, professor of clinical medicine and an advanced heart failure physician at Indiana University (IU), Indianapolis said that mavacamten represents "an almost revolutionary change" for treating obstructive HCM. I think the drug holds promise but after reading that 25% of participants could not continue it in a seriously rigorous clinical trial, and the details of the prescribing information, and the lack of clinical outcomes data, I would emphasize the “almost” modifier for revolutionary change.
But it is potential progress and that is a good thing for these patients. We must keep alert for safety signals.
Dapagliflozin in HFpEF
AstraZeneca, the makers of dapagliflozin, reported, via a press release, that the topline results of the DELIVER trial were positive. Recall that dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor and is already approved for patients with chronic kidney disease (CKD), diabetes, and HF with reduced ejection fraction (EF).
DELIVER is a phase 3 RCT looking at use of dapagliflozin in patients with HF with preserved EF (HFpEF). Its primary endpoint was a composite of cardiovascular (CV) death, hospitalization for HF, or an urgent HF visit.
That’s slightly different from the EMPEROR-Preserved trial, which was empagliflozin vs placebo in HF. EMPEROR-preserved used CV death and HF hospitalization (HHF) as its primary endpoint. The press release says the positive trial will be presented at a future medical meeting.
Some comments: I don’t like these pre-meeting paper/press releases. I feel like they act as anchoring bias. As in, they prime us to already know the drug works, and we start our critical appraisal from the point of view of a positive finding—like a car salesman starting negotiations from a high price point. We should not do that.
Recall that empagliflozin in EMPEROR Preserved did not reduce CV death and had only a 3% reduction in HHF, which was “statistically” significant, but HHF represented less than 15% of total hospitalizations.
Total hospitalizations in these 71-year-old adults with HFpEF was no different. This is a classic example of findings that are statistically significant but not clinically significant nor high in value.
The question in the analysis of DELIVER is whether we see the same pattern. HHF is only an important endpoint if it represents a majority of hospitalizations and/or if it reduces total hospitalizations.
I appreciate the SGLT2 inhibitor class and use them often. But they are costly and as with any costly therapy, we should use them when they have a proven, clinically significant benefit.
A paper published in the journal Mathematical Biosciences looked at the all-too-common triple whammy of renin-angiotensin-system (RAS) inhibitors, diuretics, and non-steroidal anti-inflammatory drugs (NSAIDs) and risks of acute kidney injury (AKI). Obviously, this is a huge problem because RAS inhibition and diuretics are used in patients with HF and hypertension, and a lot of people have those conditions. Well, guess what other common condition often co-exists in older patients with these two problems: pain due to arthritis. Since NSAIDs are over the counter, many vulnerable patients think that if a pill is over the counter, it is safe. But volume depletion (from diuretics) plus RAS inhibitors, plus NSAIDs is a frequent cause of AKI.
I am not going into the details of the paper because it’s too technical; it doesn’t matter what the mechanisms are, we know the combination is bad; and I remember learning the NSAID/RAS inhibitor lessons while at IU decades ago.
Kidney specialists can correct me but I seem to remember that this combination is horrible because it reduces glomerular blood flow, perhaps via NSAID-induced vasoconstriction of the afferent arteriole, and RAS-induced vasodilation of the efferent arteriole. The reason I make note of this is that avoiding this combination is a seriously high-value way to avoid AKI.
My views on NSAIDs have evolved over the years. I used to be strongly opposed to the use of the drugs in vulnerable patients. No negotiation. Not only patients on RAS inhibitors and at risk for AKI but also patients with atrial fibrillation who were taking oral anticoagulants and at risk for bleeding.
But then someone reminded me that chronic pain and immobility is also a bad thing, and if NSAIDs help improve functioning, there may be an acceptable risk tradeoff.
My approach is to use acetaminophen first and refer to orthopedics to see if they can help with injections or joint replacement, and then to compromise in some patients to try and get them to take fewer NSAIDs.
Espresso and TC
The journal Open Heart published a nutritional epidemiology observational study on different types of coffee and their association with total cholesterol. I have several observations.
We have enough coffee, blueberry, chocolate, raspberry, etc studies. I’ve written about this before.
This world has a lot of health problems we need solved. These sorts of studies do not move the needle.
Because of huge amounts of confounding plus recall bias of food questionnaires, studies like this that look at one macronutrient with observational methods is simply not going to advance our knowledge base. It’s not worth the effort.
In a beautiful paper from 2013, two authors identified 50 common ingredients from random recipes in a cookbook and reported that they could find studies that showed each of these ingredients could be associated with an increase or decrease in cancer risk. Macronutrient research is fraught.
It doesn’t matter what health outcome espresso is associated with: I love it too much to give up. Especially before a big bike ride.
Medscape news has nice coverage of a very topical discussion at the American Telemedicine Association annual meeting. First, who knew there was such a Congress? The discussion centered broadly on clinician (nurse and doctor) burnout, which is a growing and costly problem in the United States. More specifically, the panelists addressed one of the main contributors of burnout: our many bureaucratic tasks.
One of the panelists, Peter Yellowlees, professor of psychiatry and chief wellness officer at the University of California, Davis, discussed his efforts to address burnout before it occurs. One of his tricks, one that caught my eye, because I have embraced it full on, is the clinical notes. In training at IU, I prided myself on my exhaustive notes. The moment I joined a private practice, observing master clinicians changed my point of view. Many of my older partners could go into a room and in seconds, come up with the right therapy. They would then go to the paper chart and write: “A: CHF. P: diuretics and BP control”. Period. Next patient.
This taught me, quickly, that I was foolish to think good medicine was about writing long notes. Well, Prof Yellowlees, now two decades on, is working on retraining physicians who for many years have been trained to be defensive in their documentation — to write absurd amounts to justify billing,
He noted that studies have found that US physician notes were three to five times longer than the notes of the Australian or UK physicians.
He has worked in all three countries, and there's no difference in the quality of the doctors across those places.
I could not agree more with this philosophy. I have learned to type very short notes that have the key phrases that coders need. I almost never cut and paste. I have a very rudimentary template. I write one or two things about the person so that when I read it in the future, I will remember. Mr Smith is a retired math professor who toiled for years helping seventh graders at school X.
You would be shocked how much you can get into a short note. I have passed my coding inquisitions every time I am tested. Coders do not care about quantity. They just need the right content. For example: The new-onset, moderate-intensity, near daily palpitations occurred in the left chest, lasting minutes, and were brought on by coffee, and relieved by deep breathing.
Boom. there is your content. No one would ever write or talk like this, but it works pragmatically. I am not advocating for not putting important material in the note. Yes, of course, but learning how to write short allows you to spend more time with the patient and your family. And no one cares about grammar and form in a medical note.
Writing is like a learning a procedure; it takes effort and practice. I do this drill a lot: write a passage of say 400-500 words. Then practice writing the same thing in 200 words. It’s one of reasons I like Twitter. I write out a thought and it’s almost always too long, then you work to eliminate unnecessary words. Try it. I can’t reiterate enough how valuable it is to minimize your time with the nonsense of Medicine so you can focus on helping people—which is what makes this job so great.
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Cite this: May 13, 2022 This Week in Cardiology Podcast - Medscape - May 13, 2022.