COMMENTARY

Oct 8, 2021 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

October 08, 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 on Apple Podcasts, Spotify, or your preferred podcast provider.

In This Week’s Podcast

For the week ending October 8, 2021, John Mandrola, MD comments on the following news and features stories.

I will be at the European Association of Cardiothoracic surgery meeting next week in Barcelona. This Week in Cardiology will return in two weeks.

NEJM Weighs in on mRNA Vaccine-Related Myocarditis

On Wednesday of this week, the New England Journal of Medicine (NEJM) published two observational studies, both from Israel, that characterized the prevalence and clinical features of post-mRNA-vaccine myocarditis.

Study One. The first paper, first author was Mevorach, retrospectively reviewed data from late December 2020 to May 31, 2021, regarding all cases of myocarditis in the Israeli health system.

Recall that Israel was a world leader in early COVID vaccination. The denominator of this study was approximately 5.1 million people who received two doses of the Pfizer-BioNTech vaccine. The authors looked at the occurrence of myocarditis in three ways:

  • They calculated the risk difference for the incidence after the first and second vaccine dose;

  • They calculated the observed-to-expected incidence of myocarditis for the 3–4-week period after the first and second doses;

  • They calculated the rate ratio 30 days after the second dose compared with unvaccinated persons.

A total of 304 myocarditis cases were reported to the Ministry of Health; 21 cases were ruled to have an alternate cause. Of the remaining 283 cases, 142 occurred in vaccinated persons within 3 weeks after the first dose or 4 weeks after the second dose.

  • The cases of myocarditis within the time window of vaccine were generally mild, with resolution of clinical symptoms, ECG changes, and troponins in a matter of days.

  • One person with fulminant myocarditis died.

  • Magnetic resonance imaging that was performed in 48 persons showed findings that were consistent with myocarditis.

  • Nineteen cases occurred after the first shot vs 117 after the second dose; 95 of 117 persons (81%) who presented after the second dose were hospitalized.

Figure 1 from the paper shows a clear predominance of myocarditis in 16 to 39 year old males. Table 3 from the paper shows the clearly higher risk of myocarditis after the second dose.

Table 4 of the paper addresses the observed vs expected incidence:

  • Among 16 to 19 year-old males, the observed vs expected incidence ratio was 13.6 times higher after the second dose.

  • Among males ages 20 to 24 years the observed vs expected ratio was 8.5 times higher after the second vaccine dose.

  • The rate ratios for females were also increased in younger age groups but the absolute numbers were small.

The final data point was rate ratio between vaccinated and unvaccinated. Again, the most prominent findings were in second doses in young males. For males ages 16 to 19 years, the rate ratio after the second vaccine, vaccinated vs unvaccinated was 9.

In their first paragraph of the discussion, the authors write that myocarditis among persons ages 16 to 19 years within 21 days after the second vaccine dose occurred in approximately 1 of 6637 male recipients and in 1 of 99,853 female recipients.

Study Two. Witberg and co-authors searched the database of the largest healthcare organization in Israel to look for the diagnosis of myocarditis in persons who had received at least one dose of the Pfizer-BioNTech vaccine. The denominator was 2.5 million vaccinated members of this healthcare organization, ages 16 years and up. Total cases of myocarditis was 54.

  • The highest incidence of myocarditis (10.69 cases per 100,000 persons) was reported in male patients between the ages of 16 and 29 years. This would be a 1 in 9300 estimate.

  • Three-quarters of the cases were described as mild; 22% as intermediate; and one case was associated with cardiogenic shock.

The lower rate of 1 in 9300 of myocarditis in young males compared with the Ministry of Health data may be explained by differing time windows. The first study looked at 30 days after the second dose whereas the second study looked at 42 days after the first dose, and it's conceivable some of the post-second dose cases were missed.

Comments. These are important publications—not so much about the specifics, because we sort of knew the (low) incidence of mRNA-vaccine myocarditis, its predilection for young males, and its increased rate post-second dose.

What's most important about these studies is that publication in the NEJM and coverage in the New York Times now allows a discussion about an adverse effect of a therapy. The fact that a therapy has adverse effects does not diminish it. Life-saving therapies, such as Insulin, antibiotics, and pacemakers all can cause harm.

Maybe I am naïve, but I see the mRNA vaccines as I do any other therapy—with harms and benefits. The benefit of these drugs in older adults is massive, amazing, and clear, and far outweighs any harms. But if you combine the logarithmic age gradient of COVID-19 severity in younger people plus the signal of vaccine myocarditis after two shots in young males, there ought to be room for a discussion about the different harm-benefit ratio in younger people. And, to me, in this discussion, one must recognize that some of these post-vaccine myocarditis cases were severe and even fatal. That matters.

Yes, it is accurate to say most vaccine-myocarditis cases were mild, but medicine is frequently practiced in the tails of probability distributions. For example, we turn ourselves inside out to never miss a single ST-segment elevation myocardial infarction (STEMI) or pulmonary embolism. We lose sleep over the rare complication we caused. We hardly feel satisfied saying most of our patients didn't have a complication or we picked up most STEMIs.

Tail events matter to us and to our patients. And yes, tail events also occur with SARS CoV-2 infection as well. Young people can get very sick from the virus. That's part of the calculus that individuals should be allowed to make along with their clinician.

Finally, the myocarditis signal does not argue for not vaccinating younger people, it argues for a way to do it most safely. Numerous countries in Europe are modifying mRNA vaccination regimens based on these myocarditis signals. Why should the United States be any different?

Stroke and AF

JAMA-Cardiology has published an interesting paper looking at the temporal association of atrial fibrillation (AF) and stroke. You might ask: why is that interesting? We know being in AF causes stroke because of stasis, left atrial thrombus formation, and embolism. But, actually, the causal relationship of a single AF episode to stroke is not so clear. AF episodes may instead be a risk marker for stroke.

The TRENDS observational study showed that the time-correlation of AF episodes and stroke is weak. Most strokes in patients with AF did not have an AF episode anywhere near the time of their stroke.

Here's another important issue: a person with a relatively low stroke risk has an episode of AF lasting 10 hours. One episode but their CHADSVASC score is 2 now so boom they are put on anticoagulants (AC), sometimes for years, decades, or life. That always bothers me. This problem is getting worse with the advent of wearables. What do we do with a 58-year-old woman on 5 mg of lisinopril who has one 6-hour episode of AF on her Apple Watch? AC for life? Really?

Singer and colleagues used a case-crossover design in which each patient acted as his or her own case and control. Here's how it went. A large national database was linked to a single-vendor pacer/ICD (implantable cardioverter-defibrillator) database. They found patients with a device capable of AF monitoring—most all nowadays—who had an ischemic stroke and who also had 120 days of monitoring before the stroke.

The case period was the 30 days right before the stroke: Day -30 to day 0. The control period was day -120 to day -90. The exposure was a 5.5-hour episode of AF on any given day during the 30 days before the stroke or the 30 days from day 120 to day 90. The main outcome was the relative risk or odds ratio of AF that occurs immediately before the stroke vs that which occurs 120 days before the stroke.

In this database of nearly a half of million patients, about 900 patients with a device had a stroke and had 120 days of monitoring pre-stroke. These were older (age 76, mostly male patients).

To get a ratio of risk, you need discordance of AF in the case and control period. If there is AF in neither or in both you can't tell the difference in stroke risk.

  • More than three-quarters of these 900 patients (76%) with stroke had no AF of more than 5.5 hours in both the case and control periods.

  • 16% had AF of more than 5.5 hours in both periods.

  • A total of 66 of 900 patients had informative, discordant arrhythmic states.

  • More patients had AF during the case period: 52 vs 14 in the control period.

  • Stroke risk was increased most in days 1 to 5 following an AF episode.

AF episodes were not associated with increased stroke risk in patients taking anticoagulants; this is consistent with the stroke-suppressing effect of anticoagulants on AF-related stroke

Comments. My friend, Stanford electrophysiologist, Mintu Turakhia has an excellent editorial on the paper. It's worth a read. In his lead in, he nicely lays out the extremely weak stroke prediction models we currently use. The CHADSVASC score, for example, was derived from roughly 1000 untreated patients, with only 1-year follow-up and 25 total thromboembolic events. Further, the CHADVASC score similarly predicts stroke in populations without AF.

We forget the massive uncertainty of using this simple integer score to commit people to AC for years or decades, or to withhold AC in seemingly low risk, high burden patients. So, any effort to discriminate patients who may benefit more or less from AC is welcome. The digital revolution will increasingly allow better characterization of AF duration and frequency and it seems that it ought to be able to be used to tailor risk.

But this paper mustn't be misinterpreted. I want to echo the authors' conclusion: “It would be premature to base anticoagulation decisions in patients with [subclinical]AF on our results.”

There are two main limitations of this analysis:

  • Crossover studies in 66 of 891 patients with stroke may hint at AF being directly causal for stroke in these patients but the vast majority of patients with stroke had no AF.

  • This study speaks in relative risk increases of stroke. The absolute risk of stroke in these patients is crucial. If the absolute stroke rate is high enough, it doesn't matter if there is an increased risk right after a 6-hour episode of AF. If someone with AF has a 1.5% or greater annual risk of stroke, there is likely a net benefit of continuous AC.

The authors argue that this data supports a trial comparing time-delimited anticoagulation covering only multi-hour AF episodes vs continuous anticoagulation in patients with infrequent paroxysmal AF. But I'm trying to figure how to do such a trial. To ethically randomize patients with AF to noncontinuous AC, you'd have to enroll low stroke-risk patients, so the event rates will be very low. And this means a bunch of patients would have to be enrolled to show a difference in hard outcomes. Also, you'd have to have near perfect AF detection from the wearable, and I am not sure we are yet.

Intensifying BP Control

This comes up often. A patient on one or two blood pressure (BP) meds has high readings and you want to improve BP control. Do you add a new medicine or increase the dose of a current med? A group from the University of Michigan, first author Dr. Carole Aubert, studied the two approaches in a retrospective cohort study in veterans. The patients had to have a systolic BP above 130 on at least one BP medication at less than maximum dose. Two intensification approaches were followed: adding a new medication, defined as a total dose increase with new medication, or maximizing the dose, defined as a total dose increase without adding a new medication. They used inverse probability weighting to assess the efficacy of the intensification approach on a) sustainability of intensified treatment and b) follow up BP at 3 and 12 months.

The three main results were:

  • Increasing doses was more common—75% vs 25%.

  • Adding a new med, compared with increasing the dose, was associated with less sustainability of the intensified treatment.

  • Adding a new med resulted in a slightly larger reduction in SBP.

I like this study. It addresses an important tradeoff that practicing docs face often. Yes, a new medication may be more efficient at systolic BP reduction, but the pragmatic effects of an extra pill cannot be ignored. These pragmatic effects are less of a factor in trials, because in trials, you are enrolling motivated patients, well enough to comply with trial protocols, and trial support staff who look after the patients with greater rigor than typically possible. In the real world, a new pill means getting a new prescription at the pharmacy, higher costs, organizing the pill containers, etc. That extra work of being a patient should not be discounted.

Yes, increasing a BP pill may produce a slightly less potent effect but the gains in sustainability may win out over effect size. The authors write that a trial would be needed to sort this out, and I think it could be done. Perhaps as a pragmatic simple trial embedded into the electronic health record. It would be an interesting study.

Troponin-Guided CTA After MI Ruled Out

Most efforts in patients in the emergency department (ED) is to rule in or rule out MI. Patients who rule in are easy⟶ admit and treat. The advent of high sensitivity (hs)-troponin and computed tomography angiography (CTA) may be able to further risk-stratify and improve outcomes in those patients who are ruled out.

The Nick Mills group in Edinburgh Scotland, have published a prospective cohort study of patients in the ED who came because of suspected acute coronary syndrome (ACS). Patients were recruited in a 2:1 fashion, stratified by peak hs-troponin concentration above and below the risk stratification threshold of 5 ng/L. All patients underwent coronary CTA (CCTA) after hospital discharge. The total sample included 250 patients; median age 61 years; 31% female.

  • Those with intermediate hs-troponin (above 5 but less than the cutoff) were more 3.3 times more likely to have coronary artery disease (CAD) on CTA than those with troponin < 5; 72% vs 43%.

  • There was no association between angina symptoms and CAD.

  • Most patients with CAD diagnosed did not have a previous diagnosis and half of them were not on statins or aspirin.

The authors concluded that, even in patients who were ruled out for MI by hs-troponin, CAD was 3 times more likely in those with intermediate hs-troponin concentrations compared with low hs-troponin. Thus, CCTA might help identify those with occult CAD by targeting preventive therapies, and this may improve clinical outcomes.

Comments. I am drawn to this because we know that hs-troponin levels are a continuous risk marker. Very low levels portend low risk and allow rapid discharge, but those with intermediate levels of hs-troponin have a higher future risk. And the observation that they are more likely to have CAD on CCTA could explain that increased risk. Of course, we know from ISCHEMIA and COURAGE that early revascularization does not improve outcomes over medical therapy, so the advantage of discovering this likely incidental disease is to get more of these patients on preventive therapy—lifestyle, statins, and aspirin.

The problem is that once CAD is established and known, I wonder if patients, especially here in the United States, will then be more apt to present with more symptoms, like the FAME-2 effect, whereas having disease without a stent creates subtraction anxiety.

Another interesting finding from this paper was that angina did not predict disease at CTA. Right now, guidelines recommend the use of clinical judgement to select patients for invasive or non-invasive imaging after MI is ruled out. Well, if angina was not predictive of CAD, that creates a problem, because currently typical angina certainly carries a lot of weight in the minds of clinicians.

A question I'd have for the authors is, you've diagnosed CAD in many patients who have not had the diagnosis. More patients are on preventive therapies. But of these patients, how many would have qualified for statin therapies based simply on 10-year risk with a simple pooled cohort equation risk calculator?

We must remember that even atherosclerosis seen on a CTA is a surrogate marker. The events we care about are MI, stroke, death. We need to know whether the extra imaging and risk stratification leads to fewer events. Fortunately the authors are enrolling these patients now in an outcomes trial called TARGET-CTCA .

Comments

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