Kevin Kunzmann

This article was originally published on 

An analysis of Vaccine Adverse Event Reporting System (VAERS) data suggests risk of myocarditis following vaccination with either available messenger RNA (mRNA) vaccine for COVID-19 is significantly low, but was most apparent among persons aged 24 years and younger.

A team of investigators from the Centers for Disease Control and Prevention (CDC) reported findings from the VAERS showing that cases of the inflammatory heart event occurred 1626 times after an mRNA vaccine dose in US individuals from December 2020 to August 2021.

Contrasted against the 354,100,845 total doses of mRNA vaccine doses administered in that time frame, the prevalence of myocarditis is significantly low (.0000046%), three-fourths of the observed cases occurred in vaccinated persons younger than 30 years old, and one-third in those younger than 21 years old.

The research team, led by Matthew E. Oster, MD, MPH, of the CDC and the Emory University School of Medicine, additionally found differing rates of myocarditis risk in mRNA-vaccinated individuals dependent on gender and total doses received. They hope the findings can contribute to continued benefit-risk discussion for young adults and adolescents eligible for COVID-19 vaccination.

Oster and colleagues sought to describe the reports and confirmed cases of myocarditis available in the national passive surveillance VAERS database among individuals vaccinated with either Pfizer-BioNTech’s BNT162b2 or Moderna’s mRNA-1273, to provide estimated risks of myocarditis after vaccination based on age, sex and vaccine type.

The concept of vaccination serving as a trigger for myocarditis—a condition most commonly observed in infancy, adolescence or young adulthood—is mostly hypothesis, investigators wrote; only the smallpox vaccine has been causally linked to the cardiovascular event based on clinical reports. But the widespread and unprecedentedly expedited COVID-19 vaccination rollout implemented in December 2020 following the US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) of BNT162b2—the first ever regulated mRNA vaccine in the US—warranted monitoring of special-interest adverse events via VAERS.

“As the reports of myocarditis after COVID-19 vaccination were reported to VAERS, the Clinical Immunization Safety Assessment Project, a collaboration between the CDC and medical research centers, which includes physicians treating infectious diseases and other specialists (eg, cardiologists), consulted on several of the cases,” investigators wrote. “In addition, reports from several countries raised concerns that mRNA-based COVID-19 vaccines may be associated with acute myocarditis.”

Investigator adjudicated and summarized reports of myocarditis to VAERS for all age groups through the observed time. Rates of myocarditis were calculated and stratified by age and sex of patient. They additionally calculated rates of myocarditis by age and sex for 2017-2019 through claims data. Clinical presentation, diagnostic test results, treatment and early outcomes of patients aged ≤30 years old were conducted.

Their assessment included 192,405,448 individuals who received 354,100,845 doses of either mRNA COVID-19 vaccine. Of the 1991 reports of myocarditis in COVID-19 mRNA vaccine recipients from the observed time, 1626 met the case definition of the condition.

Median patient age for myocarditis patients was 21 years old (IQR, 16 – 31) and median time to symptom onset was 2 days (IQR, 1 -3) post-vaccine dose. Among eligible reports that included patient sex, men comprised 82% of all observed myocarditis cases.

Investigators noted that the crude reporting rates for cases of myocarditis within 7 days of COVID-19 mRNA vaccination exceeded expectation across multiple strata of age and sex. Approximately 71 per 1 million doses of BNT162b2 resulted in myocarditis among adolescent males aged 12 – 15 years old; the rate was even greater in males aged 16 – 17 years old (105.9 per 1 million). The rate remained significant for men aged 18 – 24 years old for both vaccines (BNT162b2, 52.4 per 1 million; mRNA-1273,56.3 per 1 million).

Of the 826 cases observed among adults ≤30 years old, a majority (98%) were shown to include elevated troponin levels, as well as abnormal electrocardiogram results (72%) and abnormal cardiac magnetic resonance imaging (MRI) results (72%). Nonsteroidal anti-inflammatory drugs were the most common therapy prescribed to patients (87%). “Cardiac MRI was often used for diagnostic purposes and also for possible prognostic purposes,” Oster and colleagues noted. “Supportive care was a mainstay of treatment, with specific cardiac or intensive care therapies as indicated by the patient’s clinical status.”

The cases of myocarditis reported after COVID-19 mRNA vaccination were generally diagnosed within days of patients’ vaccination—contrasted to typical viral myocarditis cases, which can often have “indolent courses with symptoms sometimes present for weeks to months after a trigger if the cause is ever identified.”

Investigators also noted that the major presenting symptoms of myocarditis in vaccinated patients seemed to resolve faster than typical viral cases: “Even though almost all individuals with cases of myocarditis were hospitalized and clinically monitored, they typically experienced symptomatic recovery after receiving only pain management.”

Though long-term effects and recovery of myocarditis cases in COVID-19 vaccinated persons is still under assessment, investigators did observe in these acute cases that 96% of patients were hospitalized and 87% had resolution of presenting symptoms by their discharge. No deaths were observed among hospitalized patients.

The CDC previously began follow-up surveillance in vaccinated adolescents and young adults in order to better interpret health and functional status, including cardiac outcomes, 3-6 months following probably and confirmed cases of myocarditis. Oster and colleagues emphasized the American Heart Association (AHA) and American College of Cardiology (ACC) guidelines advising that such patients should refrain from competitive sports for 3-6 months and that documentation of normal electrocardiogram result, ambulatory rhythm monitoring, and an exercise test should be completed prior to their resumption.

Further doses of mRNA-based COVID-19 vaccines should be deferred, but may be considered in select circumstances,” they wrote.

Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021,

Articles

An analysis of Vaccine Adverse Event Reporting System (VAERS) data suggests three-fourths of all myocarditis cases observed in the first 8 months of COVID-19 vaccination occurred in persons 30 years and younger.

Risk of mRNA COVID-19 Vaccine-Related Myocarditis Most Apparent in Young Adults, Adolescents

A new retrospective cohort study presented at the American Society of Hematology 2021 Meeting suggests patients with sickle cell disease had a greater risk of developing atrial fibrillation and having the disease present earlier in life. 

Presented by a team of Chicago-based investigators, results indicate the increased incidence among patients with the hematologic disorder may be a contributing factor to the patient population’s plateaued life expectancy, as well as their increased use of cardiovascular and nephrological medications.

Investigators, led by Chinonso Michelle Ukeje, MD, of the University of Illinois at Chicago School of Medicine, sought to determine the prevalence, incidence, and key clinical characteristics of atrial fibrillation in a cohort of patients with sickle cell disease. As they noted, the prevalence and risk factors for atrial fibrillation remains unclear in these patients.

“Life expectancy amongst individuals with sickle cell disease has plateaued, with cardiopulmonary complications now becoming a leading cause of death,” they wrote. “Indeed, sickle cell disease is associated with increased rates of pulmonary hypertension and diastolic dysfunction.”

Ukeje and colleagues conducted a retrospective, longitudinal cohort trial observing adult patients with sickle cell disease treated at the university’s care center from 2008 – 2017. Sickle cell disease was identified via automated direct chart review; atrial fibrillation was identified via manual review of approximately 17,000 available electrocardiograms of subjects assessed for the condition.

The final cohort included 763 adults with sickle cell disease; median patient age was 27.95 years old, with 59.5% being female. Approximately three-fourths (72.4%) had Hb SS or Sβ0-thalassemia genotype; another two-thirds (61.2%) were treated with hydroxyurea. Mean observation time for the cohort was 8.3 years.

Among the cohort, atrial fibrillation was identified in 30 patients (3.9%; 3.02 per 1000 patient-years). Mean age of onset was 51 years. Investigators observed no differences in gender, ethnicity, or sickle cell disease genotype between sickle cell patients with and without atrial fibrillation.

On average, patients with sickle cell disease and atrial fibrillation were older at initial care (40 vs 25 years; 

 <.0001) and follow-up visits (53 vs 35 years; 

 <.0001), and were observed for nearly 4 years longer (13.3 vs 9.5 years; 

 = .0014) than sickle cell patients without atrial fibrillation.

What’s more, patients with atrial fibrillation and sickle cell disease were more likely to carry chronic disease diagnoses:


Though hydroxyurea use was not associated with increased risk of atrial fibrillation, sickle cell patients with atrial fibrillation were more likely to receive diuretics, atrioventricular nodal blocking agents, antihypertensives, antiplatelets, and statins. Such patients were also more likely to have worse anemia and renal function.

“We showed that the prevalence and incidence of atrial fibrillation is high in patients with sickle cell disease with the median age of onset occurring 1-2 decades earlier than in the general populace,” investigators wrote.

Atrial fibrillation in patients with sickle cell disease was associated with older age, worsened renal function and anemia, and increased use of medications. Ukeje and colleagues concluded that further analysis is warranted on the basis of these findings.

“The high incidence of atrial fibrillation in patients with sickle cell disease may contribute to the plateauing of life expectancy and identifying the causative risk factors and the underlying mechanisms may not only improve life expectancy but also the quality of life,” they wrote.

The Burden of Atrial Fibrillation in Sickle Cell Disease

A retrospective analysis of data from a Chicago School of Medicine care center provides insight into the apparent increase in risk of atrial fibrillation among patients with sickle cell disease.

AFib More Common Among Patients with Sickle Cell Disease

The US Food and Drug Administration (FDA) has approved evolocumab (Repatha) injection as an adjunct to diet or other treatment for patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).

, the new approval expands the indicated use of evolocumab, which was previously approved as an add-on therapy for reducing LDL-C in adults with HeFH and patients with HoFH.

The approval granted to Amgen was based on findings from a pair of pediatric clinical trials. The first, involving patients aged 10-17 years with HeFH, assessed 420 mg monthly subcutaneous injection for 24 weeks; patients reported a mean 38% reduction in LDL-C versus placebo.

In the second trial, patients aged 11-17 years old with HoFH received the same evolocumab dose regimen for 80 weeks, and reported a mean 14% reduction in LDL-C compared to baseline.

Evolocumab previously received orphan drug designation from the FDA in 2013 to treat HoFH. It is not indicated for use in patients with serious hypersensitivity, either by clinical diagnosis or emerging signs or symptoms.

Approximately 1 in 250,000 individuals are diagnosed with HoFH, while HeFH is prevalent in 1 in every 250 individuals. The conditions are rare and life-threatening, characterized by gene mutations that influence the body’s clearance of cholesterol including LDL-C.

Announced on September 24, the approval is for use as an adjunct to diet and other LDL-C-lowering therapies for reducing LDL-C in patients aged 10 years and older with heterozygous familial hypercholesterolemia.



Evolocumab Approved for Pediatric Patients with Heterozygous Familial Hypercholesterolemia

One of the most prominent discussions occurring at The Metabolic Institute of America’s (TMIOA) 2021 5th Heart in Diabetes sessions in New York, NY, centered around subpar uptake of newer medications, among endocrinologists, cardiologists, and other providers. 

Much of this discussion was related to advancing role of SGLT2 inhibitors and GLP-1 receptor agonists in the treatment of patients with diabetes and other cardiometabolic conditions, such as chronic kidney disease and heart failure.

This role, Matthew Budoff, MD, explained, is one that is being stalled by regulatory processes. In the second segment of an interview with our sister publication 

 at the meeting, Budoff, professor of medicine at David Geffen School of Medicine at UCLA, explained why the real-world uptake of newer cardiometabolic agents lags behind despite proven efficacy in clinical trials.

In this interview, Budoff explained, the US operates on a “general rule” that findings from 2 randomized trials may constitute a class I indication for a drug class. For example, he said, the DAPA-HF and EMPEROR trials supported the use of SGLT2 inhibitors for the reduced risk of heart failure in patients with and without diabetes. Budoff cited the CANVAS and EMPA-REG trials as supporting the drug class’ benefit in reducing composite cardiovascular death in patients with diabetes and atherosclerotic cardiovascular disease. Budoff went on to cite a trio of randomized clinical trials support GLP-1 receptor agonists for the reduction of composite coronary events, stroke, and all-cause death, he said.

For more on this topic, check out the video interview below:


Videos

Matthew Budoff, MD, discusses what he views as hurdles to achieving optimal prescription of newer agents in the treatment of cardiometabolic conditions, including diabetes, heart failure, dyslipidemia, and more. 

Matthew Budoff, MD: Need for Greater Uptake of Newer Medications


The US Food and Drug Administration (FDA) has approved treprostinil (Tyvaso) Inhalation Solution for the treatment of patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) to help improve exercise ability.

The indication is the second granted by the FDA for the United Therapeutics drug, following its approval as a pulmonary arterial hypertension (PAH) therapy in July 2009.

This supplemental New Drug Application (sNDA) for treprostinil was supported by data from the INCREASE trial, currently considered the largest and most comprehensive completed study of adult patients with PH-ILD.

The randomized, double-blind, placebo-controlled, parallel-group, 16-week trial involved 326 patients from multiple care centers. Investigators reported outcomes including significant improvement in PH-ILD adult patient six-minute walk distance (6MWD) when treated with treprostinil, as well as improvements among patients with differing PH-ILD etiology, disease severity, age, gender, baseline hemodynamics, and dose differences for treatment.

Investigators also reported significant patient improvements in secondary endpoints including reduction in NT-proBNP, time to first clinical worsening event, change in peak 6MWD at week 12, and change in trough 6MWD at week 15.

Patients additionally benefitted in placebo-corrected forced vital capacity (FVC) improvements, and reported significantly fewer underlying lung disease exacerbations. A treoprostinil dose of 12 breaths per session, 4 times daily, was well-tolerated and associated with a safety profile consistent in previous trials.

Pulmonary hypertension is estimated to affect at least 15% of patients with early-stage ILD, which is characterized as scarring in the lungs from a series of varied diseases. There are approximately 30,000 PH-ILD patients in the US.

As Aaron Waxman, MD, PhD, Director of the Pulmonary Vascular Disease Program at Brigham and Women's Hospital and the chair of the INCREASE Study Steering Committee, said in a 

, adults living with PH-ILD generally experience a poorer quality of life, increased shortness of breath, poor exercise tolerance, and higher risk of mortality.

“Until now, clinicians treating these patients did not have any approved treatment options," Waxman said. "The regulatory approval of Tyvaso, an inhaled treatment, is exciting news both for patients with PH-ILD and the physicians who treat adults living with this serious, life-threatening disease. This will change the way we manage these patients."

Martine Rothblatt, PhD, chairperson and chief executive officer of United Therapeutics, called the sNDA approval a “landmark treatment advancement” for the PH-ILD population.

"It also underscores our commitment to driving innovation in the field of pulmonary hypertension and expanding the number of patients who can achieve a clinical benefit from Tyvaso,” Rothblatt said. “We plan to tap into our experience and expanded infrastructure to bring this safe and effective inhaled therapy to the many patients living with PH-ILD in the United States."

The US FDA has granted a second approval to treprostinil (Tyvaso) inhalation solution, this time for the treatment of patients pulmonary hypertension associated with interstitial lung disease (PH-ILD) to help improve exercise ability.

Treprostinil (Tyvaso) Receives FDA Approval  for Pulmonary Hypertension Linked to Interstitial Lung Disease

Findings from a new study suggest placement of an inferior vena cava (IVC) filter was linked to significant decreases in mortality and pulmonary embolism risk among cancer patients with 


A population-based cohort analysis conducted by a team of Texas-based investigators, results indicated IVC filter placement could help mitigate the increased risk of fatal pulmonary embolism in patients with cancer.

Investigators, led by Samyuktha Balabhadra, MD, of the Department of Radiology at the University of Texas Health McGovern School of Medicine, sought to understand the appropriate use of IVC filters in patients with cancer by evaluating associations between the devices and pulmonary embolism development among cancer patients with DVT.

“This knowledge gap in IVC filter utility and outcomes is even more pronounced for patients with cancer because very few studies have investigated this patient population, to our knowledge,” they wrote. “Defining the appropriate use of IVC filters in patients with cancer remains a substantially unmet clinical need.”

Their assessment included administrative data on 88,585 patients from state inpatient databases for California and Florida, ranging in years from 2005-2014.

Balabhadra and colleagues identified patients with cancer and acute lower extremity DVT through diagnostic and procedure codes. The team evaluated subsequent hospital visits among eligible patients for the placement of an IVC filter, new embolism development, new DVT development, and in-hospital mortality.

Pulmonary embolism-free survival was measured from initial DVT diagnosis date until the development of pulmonary embolism. In the event that a patient received a pulmonary embolism diagnosis at the same time as their initial DVT diagnosis, they were considered to not have developed a new pulmonary embolism.

Median patient age was 71 years old, with half (50.8%) being male. Patients were analyzed across 534,623 inpatient encounters, with a median follow-up time of 479 days.

Of the cohort, 33,740 patients (38.1%) underwent IVC filter placement—most (80.4%) occurring within 30 days of initial DVT diagnosis. Patients with comorbid risk factors including upper gastrointestinal bleeding, intracranial hemorrhage, and coagulopathy were at 32%, 21%, and 9% greater odds of receiving a filter, respectively.

A new pulmonary embolism developed in 5.1% of IVC filter-recipient patients after their initial DVT diagnosis.

Investigators observed a 31% improvement in pulmonary embolism-free survival among these patients than those who did not receive an IVC filter—even after propensity score matching and competing risk analysis (HR, 0.69; 95% CI, 0.64-0.75; 

 <.001).

IVC filter placement additionally reduced pulmonary embolism development risk among patients with very high-risk, high-risk, and low-risk malignant neoplasms.

Despite previous analyses, investigators did not observe an association between IVC filter placement and increased new DVT development risk, with account for patient anticoagulation use and imbalanced risk factors.

That said, Balabhadra and colleagues stressed the potential risk of IVC filter placement, as per communications from the US Food and Drug Administration (FDA) in 2014 and 2010 on their link to device migration, penetration, and embolization.

“The most common complication associated with IVC filters, however, is an increased incidence of DVT,” investigators wrote. “As the devices themselves represent foreign material within a blood vessel, they are to some extent thrombogenic and can lead to thrombus formation and propagation.”

Nonetheless, the team concluded that, when accounting for death as a competing risk and comorbidities by propensity score matching, IVC filter placement in cancer patients with DVT was linked to significantly reduced new pulmonary embolism.

“These data suggest that IVC filter use in patients with cancer is of potential benefit in appropriately selected patients, and that further investigations into the appropriate use of these devices is warranted,” they wrote.

The study, “

Association of Inferior Vena Cava Filter Placement With Rates of Pulmonary Embolism in Patients With Cancer and Acute Lower Extremity Deep Venous Thrombosis

New research suggests IVC filter placement could attenuate the risk of pulmonary embolism in patients with cancer-related DVT. 