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In This Week’s Podcast
For the week ending April 8, 2022, John Mandrola, MD, comments on the following news and features stories.
In-Person ACC
First, it was nice to be at a major meeting that was held at least partially in-person. I’ve been to two smaller meetings in the last 6 months, but the American College of Cardiology (ACC) was the first major meeting.
The two American meetings in cardiology, ACC and American Heart Association (AHA), have been known for their largeness and big crowds. That was definitely not the case this year in Washington, DC. Even in the smaller convention halls, the attendance seemed sparse. You noticed this especially walking through the expo. But it is a start. There were hugs. And that is good. So good.
On to the science. I won’t get to all the key presentations this week, so we will do some next week as well.
HTN in Pregnancy
The Chronic Hypertension and Pregnancy (CHAP) Trial Consortium or CHAP trial is a very important trial presented at ACC and published in the New England Journal of Medicine (NEJM). The trial addressed the treatment of hypertension (HTN) in pregnancy.
A couple of background nuggets: chronic HTN affects about 2% of pregnancies in the United States. It disproportionally affects black women. HTN ups the odds of bad things for baby and mom – preeclampsia, placental abruption, small birth weight, and also maternal death, heart failure, stroke in mom.
Treatment is controversial. There is consensus to treat pregnant women with severe hypertension, but for women with mild chronic hypertension (<160/110 mm Hg), it is unclear whether to withhold antihypertensive medication until the increase in blood pressure is severe or to continue the patient’s previously established therapy.
CHAP looked at 2400 women with mild chronic HTN.
The active treatment arm had a goal of treatment to get the blood pressure to < 140/90. The control arm comprised no treatment unless BP was > 160/105.
Treatment arm: labetalol or nifedipine ER and then titration to goal of less than 140/90. Control arm: don’t treat unless > 160 and if treated, the BP goal was < 160/105.
Primary outcome: preeclampsia, medically indicated preterm birth < 35 weeks, abruption, and fetal or neonatal death.
The safety outcome was small-for-gestational-age (SGA) birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth.
Results:
For the primary endpoint—30.2% vs 37% favoring treatment. The hazard ratio (HR) was 0.82 with a confidence interval (CI) ranging from 0.74 to 0.92 and highly significant.
Preeclampsia was 20% lower, preterm birth was 27% lower; both were significant.
For the safety endpoint of SGA, there was no significant difference. There was also no difference in maternal complications or severe neonatal complications.
Two limitations: the study was open label, so there is always a chance for performance bias. Also they screened 12 patients to enroll one. Nonetheless, these are the clearest results of the meeting. In pregnancy, it’s best to treat mild HTN to a goal of < 140/90.
This could have massive health benefits and improve our maternal and neonate health in the United States. Congratulations to the investigators and to the National Institutes of Health (NIH) for funding such an important trial.
POISE-3
NEJM published the trial comparing tranexamic acid (TA) and placebo in non-cardiac surgery. TA is an antifibrinolytic drug and it is approved for heavy menstrual bleeding and short-term prevention in patients with hemophilia. Used off label it has been shown to reduce bleeding after C-section and cardiac surgery. Small trials have suggested benefit in orthopedic surgery. But no big trials have been done in major non-cardiac surgery.
The research group at McMasters undertook POISE-3, a large placebo-controlled trial in 114 countries on six continents. The study enrolled more than 9000 patients, average age 69 years, who were at risk for bleeding or cardiovascular (CV) complications. All sorts of surgeries were included; general, orthopedic, and vascular were the top three.
The endpoints were interesting and unusual: bleeding was the primary endpoint and was tested with superiority; myocardial injury, stroke, systemic embolism, or deep vein thrombosis (DVT) comprised the safety endpoint and it was tested with non-inferiority. This makes sense, right? You want to establish that the drug is superior in bleeding rates, but not worse than nothing in creating events caused by clotting.
The non-inferiority margin of the safety endpoint was set at 1.125. That means that if the upper bound of the CI of the rate of thrombotic events was more than 12.5%, non-inferiority would not have been met.
Here are the results:
For bleeding: 9.1% in the TA group vs 11.7% in placebo; HR 0.76 with CI 0.67-0.87 and highly significant for superiority.
For safety: 14.2% in the TA group vs 13.9% in placebo; HR 1.02 with a CI 0.92+1.14. Since the upper-bound of the CI was 1.14 and that is greater than 1.125, non-inferiority was not met.
Translation: the drug reduces major bleeding but was not non-inferior to placebo in safety.
Previous cardiac surgery trials of TA have shown a higher risk of seizures. This, the authors write, was found to be a dose-dependent effect. In POISE-3, they used two doses of 1 gram of TA, and at doses ≤ 2 grams, seizures are less common. Indeed, that is what they found: 0.2% incidence of seizures in TA group vs < 0.1% in placebo — nonsignificant.
Translation and Comments: You have a clinically significant and statistically robust reduction in major bleeding balanced against a very small increase in thrombotic events. The authors suggest considering bleeding risk and have even published a bleeding risk calculator. They wrote:
Patients prefer to avoid bleeding and transfusions. Although tranexamic acid can facilitate these goals, only a small proportion of patients undergoing noncardiac surgery receive it.
There is an annual global shortage of 30 million blood-product units, and surgical bleeding accounts for up to 40% of all transfusions.
Given that 300 million surgeries occur annually worldwide, the results of the POISE-3 trial indicate the potential for large public health and clinical benefits if tranexamic acid becomes standard practice in noncardiac surgery.
I see their point. This is a tough call. I tend to agree with them. The problem is that the risk factors that make one at higher risk of bleeding often overlap with thrombotic events.
On the other hand, the rate of thrombotic events barely missed non-inferiority. And remember, non-inferiority margins are not set in stone. Had the non-inferiority margin here been just a bit higher, we’d be declaring, yep, TA is non-inferior. If any listener has more experience with this drug, and feels strongly, please leave a comment on the webpage.
Hypertrophic Cardiomyopathy
VALOR-HCM: Novel Drug May Delay, Avert Invasive Therapy in OHCM
Mavacamten in Hypertrophic Cardiomyopathy: Reasons for Both Optimism and Caution
ACC brought potential good news for patients with severe hypertrophic cardiomyopathy (HCM). The drug has funny sounding name: mavacamten. It is a myosin-inhibitor drug that decreases sarcomere power. Previous studies have shown that the drug reduces the left ventricular outflow tract (LVOT) gradient, improves functional capacity, and reduces symptoms.
The trial presented at ACC, 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. It was mavacamten vs placebo for 16 weeks.
The results strongly favored mavacamten: Only 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. The driver of the composite was no longer meeting septal reduction therapy (SRT) eligibility.
Mavacamten also performed well in clinical and echocardiography parameters.
Improvement in one or more NYHA functional class, resting LVOT gradient, Valsalva LVOT gradient, N-terminal pro–brain natriuretic peptide (NT-pro-BNP) level, and troponin I level all favored mavacamten over placebo.
Adverse effects were minimal.
Comments: HCM is not as common as coronary artery disease (CAD), heart failure with reduced ejection fraction ( HFrEF), or atrial fibrillation (AF), but it is not uncommon. When the gradient gets severe, patients have no good noninvasive options. If a pill reduces the gradient and helps patients feel better and avoid surgery, I see this as a big gain.
There are a few big caveats:
We have only about 400 patients who have been studied with this drug in quite short-duration trials. We need more safety data. Myosin inhibition is essentially a negative inotrope. Will it increase the risk of arrhythmia? We don’t really know from these sorts of studies.
Another issue is translation to practice: the trial was conducted at Centers of Excellence and the protocol required frequent echocardiograms and dose titration depending on echo parameters. I doubt this can be simulated in real-world practice.
What’s more, FDA is meeting on this drug later in the month. If it is approved there will be tremendous excitement and marketing. There will be a temptation to use it in patients with less severe disease who were not enrolled in trials.
The other thing that bothers me is that VALOR-HCM had a massive effect size. Ok, the drug could be this good, but I wonder about blinding, because patients in the drug arm had more dose titrations. We know from empirical meta-studies that large effect sizes often stem from small studies and aren’t replicated in larger studies. But I am cautiously optimistic that possibly, maybe, we have devolved a new class of agents that have disease modifying properties in HCM. There is another myosin-inhibitor that looks promising in phase 2 studies.
Percutaneous LAA Occlusion
There was news on percutaneous left atrial appendage (LAA) closure from ACC. It wasn’t encouraging.
Before I start, a word on the modifier “percutaneous” before LAA occlusion (LAAO). It’s important to distinguish between percutaneous appendage closure and surgical closure. Percutaneous closure is what cardiologists are doing and it entails placing a foreign body in the inside of the left atrium. Surgical closure is done epicardially by surgeons. Percutaneous closure has dubious data; surgical closure at the time of surgery for something else has strong data (from LAAOS-3 trial). Back to ACC and percutaneous closure.
A group led by the Mayo clinic team queried the mandated NCDR-LAAO US registry and identified more than 55,000 patients who had Watchman implanted over a 3-year period.
Based on transesophageal echocardiograms at 45 days, they identified three groups: those with no leak, small leaks (< 5 mm), or large leaks (≥ 5 mm).
Get this—pause for a second—they found that 1 in 4 patients (more than 13,000) had small peri-device leaks.
These leaks were associated with statistically significant, 15% higher rate of stroke, transient ischemic attack, or systemic embolism, and an 11% higher rate of major bleeding.
Two other posters at ACC addressed the issue of who is getting this procedure in the United States. One poster, which I was a co-author on, led by groups at the University of Florida and Penn State, used Medicare claims to compare the baseline characteristics of patients who had Watchman in the real-world vs those in the PROTECT and PREVAIL regulatory trials. Another poster, from the Beth Israel (BI) Boston group, led by Robert Yeh, used Medicare data to assess the frailty scores of patients who get percutaneous closure in the United States.
Both posters found extremely sobering data:
Patients getting Watchman now are older and have many more co-morbid conditions than those enrolled in the pivotal trials.
The BI group found that nearly half of all Watchman implants are done in patients with some degree of frailty.
These two posters are scary because older sicker patients are least likely to benefit from percutaneous closure: a) because they have oodles of competing causes of stroke, and b) they will have a higher procedural risk, which studies have shown is already in the 6%-10% range.
In sum, percutaneous closure struggles to actually occlude the appendage, which is terrible because small leaks can increase thrombotic risk, and American doctors are increasingly doing these procedures in patients least likely to benefit. I remain extremely negative on this procedure. I think it may be the biggest mistake cardiology makes in a generation.
Salt Restriction for HF
Low-Sodium Diet Did Not Cut Clinical Events in Heart Failure Trial
Sodium Restriction in Heart Failure: Another Dogma Felled by Randomization
For my entire career, I’ve seen patients with heart failure (HF) be told to eat a low-salt diet. Many clinicians get extremely aggressive with this recommendation. At ACC, Justin Ezekowitz, from the University of Alberta, presented results of the SODIUM-HF trial, which put this common recommendation to the test of randomization. The Lancet simultaneously published the study.
I did not know this but before SODIUM-HF, there was little to no supportive evidence for strict sodium restriction. Studies were small and when taken together, failed to show any signal of benefit. Yet the dogma persisted. Until now.
SODIUM-HF is a pragmatic, randomized controlled trial that tested general advice on dietary sodium against a low-sodium diet of 1500 mg daily. It was done at 26 sites in six countries. An important note on the trial arms: SODIUM HF did not study a willy-nilly typical American high-salt diet vs a salt restriction. It studied general advice on avoiding salt vs a specific diet designed to get down to 1500 mg daily.
A word on pragmatic trials: Unlike drug trials, which can strictly control active and treatment arms in a relatively optimal setting, pragmatic trials test interventions in the real world. This difference influences how we interpret and apply the trial results.
Patients in SODIUM-HF had NYHA class II-III HF and average age of 66 years, average left ventricular ejection fraction of 36%, and were receiving good medical therapy.
The average sodium intake, as measured by 3-day food records, was approximately 2000 mg/day in the control group and about 1600 mg/day in the low sodium arm.
A primary outcome (death, CV hospitalizations, and CV emergency department visits) occurred in 15% of the low-sodium arm vs 17% of the control arm, which did not meet statistical significance (HR, 0.89; 95% CI, 0.69 - 1.26; P = .53).
Patients in the low-sodium arm scored significantly better on the Kansas City Cardiomyopathy Questionnaire, which measures a person's perception of their health.
The authors concluded with just one spin-free sentence: "In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events."
Comments: I love this trial. The authors did not spin the non-significant primary outcome. There was no language designed to detract to from the primary. There was no pre-COVID analysis or, hey, look at how great this subgroup did shenanigans. So, I have to admit that my highly positive interpretation may have been driven by the scientific humility of the research team.
The biggest criticism of the trial was that the control group did not eat a lot of salt and thus the difference in salt intake was only 400+ mg, the thinking being that this isn’t enough to drive lower CV events, such as HF admissions. Had the control group eaten the typical American high-salt diet, then it would have worked. My counter to that goes back to the study arms—SODIUM HF did not test no advice vs a severely restricted sodium diet. It tested “normal” advice to avoid high-salt foods to a strict diet.
The translation of this is that we don’t have to waste time getting patients down to a super-low salt diet. That is huge because one of the core challenges of caring for HF patients is to decrease their work of being a HF patient. As I wrote in my column, patients have an adherence bank. If you limit the low-value stuff they have to do, they are more apt to do the important stuff like take their meds and perhaps exercise.
Flu vaccine and HF
The IVVE trial studied flu vaccine vs placebo in patients with HF in Asia, the Middle East and Africa over three influenza seasons.
There was no significant difference in the primary outcome of CV death, myocardial infarction (MI), stroke, or HF hospitalization.
Some secondary analyses were positive: for instance, flu vaccine reduced CV outcomes during peak influenza period, and it reduced pneumonia admissions. But you know how I feel about secondary outcomes when the primary is negative. Spin gives me a rash.
This is different from the positive IAMI trial, which studied flu vaccine in early post-acute MI patients and found a significant reduction in CV events in the vaccine arm. Maybe HF patients aren’t quite as tenuous as post-MI patients. Maybe many placebo patients took the vaccine outside the trial.
Here’s the thing: I am not sure we need any more trials looking at flu shots in older patients with co-morbid conditions. It doesn’t matter if it reduces CV outcomes. If it reduces flu severity, or pneumonia or hospitalization, that seems like enough to me. Older and vulnerable patients have oodles to gain from vaccination against a common and serious respiratory virus. We should encourage our vulnerable patients to get their flu shot.
Factor XI Inhibitor Look Promising
Manesh Patel from Duke presented early data on a new antithrombotic drug that may someday replace direct oral anticoagulants (DOACs). It was called the PACIFIC AF study and it was a phase 2 studyof a drug called asundexian. It is an oral small-molecule inhibitor of activated factor XI.
A key paragraph from the amazing Sue Hughes: “Activated factor XI is thought to contribute to clot progression, but, in contrast to other clotting factors, activated factor XI has only a minor effect on clot consolidation during hemostasis.”
I will say no more, because it is too early to say anymore. Just know that we might someday have a better DOAC (but worry not, it won’t likely diminish enthusiasm for putting things in the LA).
I will continue with ACC presentations next week. Also, the European Heart Rhythm Association meeting happened at the same time as ACC. I will take a look at some of the studies there. And the US Food and Drug Administration approved another leadless pacer, from Abbott. This one has a screw-in mechanism rather than tines. We shall see if it is any better than the current version.
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Cite this: Apr 8, 2022 This Week in Cardiology Podcast - Medscape - Apr 08, 2022.
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