COMMENTARY

Aug 13, 2021 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

August 13, 2021

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.

In This Week’s Podcast

For the week ending August 13, 2021, John Mandrola, MD comments on the following news and features stories.

COVID-19

The COVID situation has not changed from last week. Cases due to the Delta variant continue to rise and hot spots, such as Florida, Texas, and Louisiana seem to be driving this rise. I’ve been following our situation in Kentucky closely. Early this month we went from one ICU patient with COVID to 11 within 3 days. It was a shocker. But all week we’ve stayed steady at around eight to nine cases, and, like everywhere else, nearly all hospitalized patients with COVID have risk factors and are unvaccinated.

Adding to the stress in our city, and maybe yours, is that even before this uptick of COVID admissions, all hospitals were at capacity with non-COVID diseases. So even this modest increase in admissions has stressed the system. Local news has reported all hospitals in our area have many unfilled staff positions. Some of our statewide bed crunch is due to staffing challenges.

I would not want to be a hospital administrator these days. I saw a report that a medium size hospital in rural Kentucky, which already had staffing shortages, had a number of staff quit because of the vaccine mandates.

I am pro-vaccine. I encourage my patients to take it. The harm-benefit calculus in adults clearly favors vaccination. The main issue is getting more people to take the vaccine. Gosh it is sad to walk through the ICU and see the unnecessary suffering. The main thing I think about every week when I write this section of the podcast is how we could have done better with vaccine acceptance.

COVID-Vaccine Myocarditis

You may think it strange that myocarditis keeps making the podcast, but it’s not just me. JAMA-Cardiology has published a case series of 15 children hospitalized with myocarditis after an mRNA vaccine. Lead author Audrey Dionne and co-authors are from Boston Children’s Hospital.

The kids ranged from ages 12-18 years, median 15 years; 14 were boys, one was a girl. Symptoms began 3 days post-vaccine. All patients had chest pain as an early symptom. All patients had elevated troponin levels, and at the time of discharge, all patients still had elevated troponin levels.

By echocardiogram, three of 15 had left ventricular (LV) global hypokinesis. By cardiac magnetic resonance (CMR) imaging, three patients had LV dysfunction and findings consistent with myocarditis were seen in 13 of 15; late gadolinium enhancement (LGE) was noted in 12.

At follow-up 1 to 2 weeks post discharge:

  • Four of 15 were asymptomatic and had normal troponin and ECG.

  • Four of 15 had persistent symptoms.

  • One of 15 had persistent mild LV dysfunction.

  • Four had persistent ECG changes.

  • One had recurrence of non-sustained ventricular tachycardia (VT) at follow up.

  • Three had persistently high troponin levels.

The good news: no kid required ICU and all were discharged alive within 5 days. LV function mostly improved to normal and only one kid had VT. You may wonder about calling that good news, but this is the COVID era.

Now for the not so good news and notice the euphemisms and jargon:

  • “CMR LGE was a frequent finding at time of diagnosis. In this clinical setting, LGE reflects an increased volume of distribution of the gadolinium-based contrast agent in the affected region likely related to myocyte necrosis and/or extracellular edema.”

  • “In nonvaccine-associated myocarditis, the presence of LGE is associated with increased risk for adverse cardiovascular events during follow-up.”

Myocyte necrosis means cardiac cell death to be replaced by scar. Much of what I deal with in the electrophysiology lab is scar-related arrhythmia.

I want to be clear—LGE can resolve and CMR scans can normalize, but I agree with the authors that the long-term prognosis of these kids remains unknown. And I intensely want to push back on the characterization of any of this as mild, which I have seen in media reports. A sore arm is a mild adverse effect from a vaccine. Cardiac injury due to inflammation, enough to warrant hospitalization and cause scar formation in the heart of previously healthy kids is not mild. Even in the short run, these kids will be told not to exercise or participate in sports. Their parents will worry. Calling this stuff mild crushes public trust. The better messaging is that this is quite serious but fortunately rare.

I have an academic paper under review on this topic. I can’t say much about it, but I will say that the harm-benefit calculus of two-shot mRNA vaccinations in healthy young adolescent males is immensely different from a 50-year-old person with obesity and hypertension.

The take-home of the vaccine myocarditis tradeoff is not yes or no to vaccinate kids. It is:

  • Should we study one-shot in this group?

  • Should we consider different formulations of vaccine?

  • Should we wait a bit and see what happens in the 4-6 weeks once the Delta variant passes through.

  • Will the Novavax be a better choice?

The mom of a 16-year-old star athlete asked me about it this week. She read the data from the Centers for Disease Control and Prevention, and she was concerned about both COVID and myocarditis.

Watchman

I know, you are thinking, come on Mandrola, give us something different. But JAMA-Cardiology has published an important paper from the National Cardiovascular Data Registry (NCDR). The NCDR was mandated for Medicare patients, so right off the bat, it’s going to be far better data than “voluntary” registries, in which patients are enrolled at the discretion of the clinician. Remember Dr. Bavaria’s comments: Science tells us what we can do; trials tell us what we should do; registries tell us what we are actually doing

The purpose of this study was to report on sex differences in major complications from the Watchman procedure. The study group was nearly 50,000 patients implanted from 2016 to mid-2019. The median age was about 76 years in both men and woman; surprising that 41% of the 50,000 were woman. The CHADSVASC was 5.3 in women (W) vs 4.5 in men (M). The HAS-BLED score was around 3 for both groups.

Here are the in-hospital complications. Remember, this is real-world data from a mandated registry for Medicare patients.

  • Any adverse event (AE): 6.3% W vs 3.9% M

  • Any major AE: 4.1% W vs 2.0% M

  • Hospital Stay > 1 day: 16% W vs 11.6% M

  • Death: 58 W vs 37 M

Any in-hospital major AE included death, cardiac arrest, ischemic stroke, hemorrhagic stroke, intracranial hemorrhage, systemic arterial embolism, major bleeding, major vascular complication, myocardial infarction, pericardial effusion requiring drainage, and device embolization. After adjustment, women were 64% more likely than men to have any AE, 2-fold more likely to have a major AE, and 46% more likely to require more than 1 day of hospitalization.

Here is yet another sobering report on the preventive procedure. Remember, friends, left atrial appendage closure (LAAC) is supposed to prevent something that is yet to happen. For the sake of argument, let’s forget the fact that the first trial, PROTECT AF, did not pass US Food and Drug Administration muster; the second trial, PREVAIL, missed noninferiority in its first co-primary endpoint of stroke, embolism, and CV death due to a doubling of the risk of ischemic stroke in the Watchman arm, and that major bleeding rates were similar in both warfarin and Watchman arms.

Let’s spot the proponents that there is a 1% or 2% net benefit in the future. There likely isn’t, but let’s just say there is. This data reports that a typical female Watchman patient starts the future probabilistic gamble with a 6% chance of any AE and a 4% risk of a major AE during her hospital stay. This doesn’t even count the patients who come back with a bleed, or late tamponade, or device thrombus, or stroke after a day or week or month. Men fare better but even they have a 4% risk of major AE.

So even if you bury your head in the sand and ignore the regulatory trials, and take a rosy view of future benefit, every patient starts with a very significant risk for harm. Proponents may say women do worse because of case selection. If docs were smarter, it would not be like this. I would counter that by saying that registries tell us what we are doing. This paper is a good use of registry data, and it provides very useful data to patients considering this a preventive strategy. It is what it is.

Proponents may say that most of the included cases were done at low-volume centers; here at bigshot referral center XYZ, we don’t have complications. I would counter by saying that not only did the regulatory trials and registries average out to a 6% complication rate, I can cite two real-world registries with similar or higher complication rates.

Here’s another worrisome thing: complication rates appear to be skyrocketing. In 2020, Freeman and colleagues looked at NCDR registry and reported a major adverse event rate of 1.9%. This was 663 complications in about 38,000 procedures.

The new paper, which included 11,000 more procedures and 6 more months of data, reported a combined complication rate (adding males and females) of 2.8% or 1394 complications in ≈ 48,000 patients. That’s 731 more complications in just 11,000 more procedures. So, in the last 6 months, it looks to be a 6.5% rate of major complications. I’ve sent an email to the authors to comment on this huge rise in complications, but just going by the absolute number in the last paper, a nearly 3% rate of complications is a big headwind for any patient.

Finally, 97 patients died in the hospital after this procedure, a procedure without any proven benefits.

Dapagliflozin

The European Union announced that it has approved dapagliflozin to treat adults with chronic kidney disease who do not have diabetes. This is based on the results from the DAPA-CKD phase 3 trial, which randomly assigned about 4300 patients who had an estimated glomerular filtration rate (eGFR) of 25-75 and an abnormal urinary albumin-to-creatinine ratio to either dapagliflozin or placebo. The primary endpoint was a combined renal and cardiovascular (CV) composite and it was reduced by 39%. Moreover, there was a 29% reduction in CV death/heart failure hospitalization, and a 30% reduction in all-cause death.

At least once a week I am sending notes out to referring docs asking them to start an SGLT2 inhibitor. The biggest headwind for these drugs in the United States is cost. Recently a patient sent me a note saying it was going to cost $500 for a 90-day supply of dapagliflozin. That was impossible for her.

These are long past being thought of as a diabetic drug. Renal preservation, heart failure with reduced ejection fraction (HFrEF), and in couple of weeks we will hear at European Society of Cardiology meeting how much they improve outcomes in HF with preserved EF. That’s right a successful drug in HFpEF!

Old School Pressors no Worse

I don’t know how it is at your place, but at mine, people look at me like a relic when I ask: what about good old dobutamine in this patient with cardiogenic shock? Come on Mandrola. Everyone knows milrinone is better especially in patients with pulmonary hypertension.

Recall that the drugs differ in mechanism of action. Milrinone is a phosphodiesterase-3 inhibitor that increases cardiac inotropy, lusitropy, and peripheral vasodilatation. By contrast, dobutamine is a synthetic catecholamine that acts as a beta-1- and beta-2-receptor agonist and improves blood pressure by increasing cardiac output.

Well, this week, the NEJM published the DOREMI trial, which found absolutely no difference between milrinone and dobutamine. In all, 192 patients were randomly assigned to either milrinone or dobutamine. The primary endpoint was a composite of death, cardiac arrest, transplant, or mechanical circulatory support, MI, transient ischemic attack or stroke, or dialysis. The mean age of patients was about 69 years, one-third were women, median EF of 25%; two-thirds were ischemic and one-third were nonischemic. Pulmonary artery catheters were used in less than a quarter of patients.

The results:

  • The primary outcome occurred in 49% of patients in the milrinone vs 54% in the dobutamine arm. Hazard ratio (HR) 0.90, confidence interval (CI) 0.69-1.19, P = 0.47; not even close to significant.

  • All the secondary outcomes, death, cardiac arrest, transplant or mechanical circulatory support, stroke, dialysis, did not differ.

  • ICU length of stay was not different.

  • Normalization of lactate, no difference.

  • Arrhythmias, no difference, which is a surprise because dobutamine carries the worry about worsening VT.

Once again, the story is familiar. Milrinone had become the agent of choice based on plausibility, weak observational studies, and one RCT of just 36 patients. Yet DOREMI found no differences in any major clinical outcome. With a P-value of 0.47, If there were no differences in the two drugs, the chance of seeing this data or something more extreme was a coin flip.

But there is a major caveat: The biggest issue and the reason I would hedge is that the trial was powered to detect a large, 20% absolute reduction in the primary endpoint with milrinone. Remember, to detect large effect sizes you don’t need as many patients, and the cost/burden of the trial is lower. That is good for investigators.

The problem is that if you underestimate the effect size and recruit fewer patients, you could end up with wider confidence intervals and the possibility of not detecting a smaller but still clinically important difference. For instance, the CI of the HR of the primary endpoint went from 0.69 to 1.19. That means milrinone may have been 31% better or 19% worse than dobutamine. We say the trial was underpowered.

If you were skeptical that milrinone was better than dobutamine, you stay skeptical of milrinone. You say this trial makes it unlikely that there was a large benefit from milrinone. If you were enthusiastic about milrinone, you could make an argument that the lower bound of the HR went to 0.69 and a bigger trial may have shown a difference.

My take would be that dobutamine is the less costly drug, and given these results, in patients like those in this trial, it makes sense to choose dobutamine. Or, at least, we ought to change the prevailing prior dogma that milrinone is the obvious best choice.

And finally, we don’t even know whether inotropes do anything vs placebo in cardiogenic shock. The investigators plan a follow-up DOREMI-2 trial of inotropes vs placebo.

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