Emergency Medicine

New atrial fibrillation (AFib) management guidelines from the European Society of Cardiology (ESC) call for diagnostic confirmation and structured characterization of AFib and the need to streamline integrated care with the Atrial fibrillation Better Care (ABC) pathway.

“It’s as simple as CC to ABC,” quipped one task force member during the virtual unveiling of the guidelines at the ESC Congress 2020.

The guidelines were developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) and published simultaneously August 29 in the European Heart Journal.

Acknowledging the slew of novel screening tools now available and their reported sensitivity and specificity rates, the document supports opportunistic screening for AFib by pulse taking or electrocardiogram (ECG) rhythm strip in patients at least 65 years of age, with a class 1 recommendation, evidence level B.

Systematic ECG screening should also be considered to detect AFib in individuals at least 75 years of age or in those at high risk for stroke (class IIa, level B).

Other new class I screening recommendations are to inform individuals undergoing screening about the significance and treatment implications of detecting AFib and to have a structured referral platform in place for further physician-led evaluation.

A definite diagnosis of clinical AFib is established only after confirmation by a conventional 12-lead ECG or single-lead ECG strip with at least 30 seconds of AFib.

In line with ESC’s 2016 AFib guidelines, the new iteration classifies AFib as first diagnosed, paroxysmal, persistent, long-standing persistent, and permanent. But it’s also important to classify the clinical profile of AFib, task force member Giuseppe Boriani, MD, PhD, University of Modena, Italy, said in the first of five presentations.

“So the novelty of the 2020 guidelines is related to the proposal of the 4S-AF scheme for a structured characterization of atrial fibrillation that takes into account Stroke risk, severity of Symptoms, Severity of atrial fibrillation burden, and Substrate severity,” he said.

This represents a paradigm shift from a single-domain conventional classification of AFib toward a structured characterization that streamlines assessment, informs treatment decision-making, and facilitates communication among physicians of various specialties, said Tatjana Potpara, MD, PhD, guideline co-chair and head of the Department for Intensive Arrhythmia Care, Clinical Centre of Serbia, Belgrade.

“The beauty of this approach is that, at present, the assessment of the ‘S’ components are performed using available tools, but in the future, the 4S-AF has a great potential to incorporate whatever becomes available for a more precision assessment of substrate or symptoms or arrhythmia burden and so forth,” she said.


 

ABC pathway

The guidelines advocate the previously described ABC pathway for integrated care management, which includes ‘A’ for Anticoagulation/Avoid stroke, ‘B’ for Better symptom control, and ‘C’ for Comorbidity/Cardiovascular risk factor optimization.

The document strengthens support for formal risk score–based assessment of bleeding risk in all patients, including use of the HAS-BLED score to help address modifiable bleeding risk factors and to identify patients at high bleeding risk (HAS-BLED score ≥3) for early and more frequent follow-up.

These assessments should be done regularly, given that both stroke and bleeding risk are dynamic and change over time with aging and comorbidities, Dr. Potpara stressed. In patients with AFib initially at low risk for stroke, the next assessment should be optimally performed at 4-6 months.

The guideline also targets weight loss in patients who are obese and have AFib, particularly those being evaluated for ablation, and good blood pressure control in patients with AFib and hypertension to reduce AFib recurrences and risk for stroke and bleeding (both class I, up from IIa). 

It’s particularly important that these risk factors are addressed, and that modifiable risk factors that go along with increased AFib occurrence and persistence are addressed and communicated to patients, said Gerhard Hindricks, MD, PhD, guideline cochair and medical director of the Rhythmology Department, Heart Centre Leipzig (Germany).

“I have to confess, as an interventional electrophysiologist, there has been a time where I have not appreciated these risk factors intensely enough,” he said. “But we have learned, also in the field of catheter ablation, that weight loss is an essential basis for a good procedure. If we can motivate patients to lose weight and then come to the intervention with better outcome, it’s a true benefit for the patient and addresses patient values. So I’m particularly happy we have introduced that with such intensity in the guidelines.”
 

Rate and rhythm control

The guidelines make no recommendation of one novel oral anticoagulant (NOAC) over another. However, in patients already receiving vitamin K antagonists with low time in the therapeutic range, they recommend switching to a different NOAC but ensuring good adherence and persistence with therapy (class I recommendation) or efforts to improve time in therapeutic range (class IIa).

Catheter ablation takes on a more prominent role for rhythm control and is now recommended after one antiarrhythmic drug therapy fails to improve symptoms of AF recurrence in patients with paroxysmal AFib, or persistent AFib with or without major risk factors for recurrence. The class I recommendation is based on results from the CAPTAF and CABANA trials, said task force member Carina Blomström-Lundqvist, MD, PhD, Uppsala University, Sweden.

Catheter ablation is also now a first-line therapy for patients with AFib who have a high likelihood of tachycardia-induced cardiomyopathy, independent of symptom status. “In this subset of patients, catheter ablation may offer a lot with respect to restoration of left ventricular function,” observed Dr. Hindricks.

Complete electrical isolation of the pulmonary veins is recommended during all AFib catheter ablation procedures (class I).

“Even as a medical conservative, I think it is totally reasonable to move to catheter ablation after a failed drug trial,” commented John Mandrola, MD, Baptist Health, Louisville, Ky., who was not a part of the guideline development. 

Although the chance of a second drug working after one failure is low, he noted that operators in the United States have dofetilide, which is not used much in Europe, and sometimes works surprisingly well.

“That said, the caveat is that moving to catheter ablation after drug failure is only appropriate if we have addressed all the pertinent risk factors: sleep apnea, weight loss, lack of fitness, blood pressure control, and alcohol excess,” he said. 

As for tachycardia-mediated cardiomyopathy, this too can be reasonable, Dr. Mandrola said. “I often get people ‘out of a hole’ with amiodarone plus cardioversion for a few months and then proceed to ablation.”

Notably, the 2020 iteration sharpens its recommendation that amiodarone not be used first-line for long-term rhythm control in all patients with AFib, including those with heart failure with reduced ejection fraction, given its extracardiac toxicity (class I, up from IIa).
 

Quality counts

In response to growing evidence that guideline-adherence is associated with significantly better outcomes in AFib, the 2020 ESC/EACTS guidelines explicitly included a recommendation on the need to measure quality of care to identify opportunities for improvement.

With this framework in mind, a task force with 23 people – including members from ESC and heart rhythm societies in the United States, Asia Pacific, and Latin America, along with patient representatives – was created to develop a list of quality indicators (QIs), ultimately settling on 17 main QIs and 17 secondary ones, said Elena Arbelo, MD, PhD, MSc, University of Barcelona.

The QIs are classified into six domains: patient assessment, anticoagulation, rate control, rhythm control, risk factor modification, and, importantly, outcome measures. A full list is accessible in a paper, simultaneously published in EP EuroPace.

Five patient-reported outcomes fall under the outcomes domain but only one – health-related quality of life – is a main quality indicator. The remaining outcomes are still important but are listed as secondary because of the lack of evidence to sustain or defend their systematic implementation, particularly evidence on how to measure them appropriately, Dr. Arbelo said.

“Hopefully, following the [class I] recommendation by the 2020 ESC guidelines to routinely collect patient-reported outcomes will allow us to collect further evidence and in the future have sufficient evidence to include these as a main outcome,” she said.

The QI work was driven in parallel with the guidelines and had a huge impact on its development, including inclusion of clear recommendations on how to measure quality, Dr. Hindricks said. “I believe that the whole issue of quality management in the treatment of patients with a focus on patient values cannot be overestimated.”

Disclosure information for all writing committee members is in the report. Dr. Mandrola is a writer and podcaster for Medscape.
 

A version of this article originally appeared on Medscape.com.

New atrial fibrillation (AFib) management guidelines from the European Society of Cardiology (ESC) call for diagnostic confirmation and structured characterization of AFib and the need to streamline integrated care with the Atrial fibrillation Better Care (ABC) pathway.

“It’s as simple as CC to ABC,” quipped one task force member during the virtual unveiling of the guidelines at the ESC Congress 2020.

The guidelines were developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) and published simultaneously August 29 in the European Heart Journal.

Acknowledging the slew of novel screening tools now available and their reported sensitivity and specificity rates, the document supports opportunistic screening for AFib by pulse taking or electrocardiogram (ECG) rhythm strip in patients at least 65 years of age, with a class 1 recommendation, evidence level B.

Systematic ECG screening should also be considered to detect AFib in individuals at least 75 years of age or in those at high risk for stroke (class IIa, level B).

Other new class I screening recommendations are to inform individuals undergoing screening about the significance and treatment implications of detecting AFib and to have a structured referral platform in place for further physician-led evaluation.

A definite diagnosis of clinical AFib is established only after confirmation by a conventional 12-lead ECG or single-lead ECG strip with at least 30 seconds of AFib.

In line with ESC’s 2016 AFib guidelines, the new iteration classifies AFib as first diagnosed, paroxysmal, persistent, long-standing persistent, and permanent. But it’s also important to classify the clinical profile of AFib, task force member Giuseppe Boriani, MD, PhD, University of Modena, Italy, said in the first of five presentations.

“So the novelty of the 2020 guidelines is related to the proposal of the 4S-AF scheme for a structured characterization of atrial fibrillation that takes into account Stroke risk, severity of Symptoms, Severity of atrial fibrillation burden, and Substrate severity,” he said.

This represents a paradigm shift from a single-domain conventional classification of AFib toward a structured characterization that streamlines assessment, informs treatment decision-making, and facilitates communication among physicians of various specialties, said Tatjana Potpara, MD, PhD, guideline co-chair and head of the Department for Intensive Arrhythmia Care, Clinical Centre of Serbia, Belgrade.

“The beauty of this approach is that, at present, the assessment of the ‘S’ components are performed using available tools, but in the future, the 4S-AF has a great potential to incorporate whatever becomes available for a more precision assessment of substrate or symptoms or arrhythmia burden and so forth,” she said.


 

ABC pathway

The guidelines advocate the previously described ABC pathway for integrated care management, which includes ‘A’ for Anticoagulation/Avoid stroke, ‘B’ for Better symptom control, and ‘C’ for Comorbidity/Cardiovascular risk factor optimization.

The document strengthens support for formal risk score–based assessment of bleeding risk in all patients, including use of the HAS-BLED score to help address modifiable bleeding risk factors and to identify patients at high bleeding risk (HAS-BLED score ≥3) for early and more frequent follow-up.

These assessments should be done regularly, given that both stroke and bleeding risk are dynamic and change over time with aging and comorbidities, Dr. Potpara stressed. In patients with AFib initially at low risk for stroke, the next assessment should be optimally performed at 4-6 months.

The guideline also targets weight loss in patients who are obese and have AFib, particularly those being evaluated for ablation, and good blood pressure control in patients with AFib and hypertension to reduce AFib recurrences and risk for stroke and bleeding (both class I, up from IIa). 

It’s particularly important that these risk factors are addressed, and that modifiable risk factors that go along with increased AFib occurrence and persistence are addressed and communicated to patients, said Gerhard Hindricks, MD, PhD, guideline cochair and medical director of the Rhythmology Department, Heart Centre Leipzig (Germany).

“I have to confess, as an interventional electrophysiologist, there has been a time where I have not appreciated these risk factors intensely enough,” he said. “But we have learned, also in the field of catheter ablation, that weight loss is an essential basis for a good procedure. If we can motivate patients to lose weight and then come to the intervention with better outcome, it’s a true benefit for the patient and addresses patient values. So I’m particularly happy we have introduced that with such intensity in the guidelines.”
 

Rate and rhythm control

The guidelines make no recommendation of one novel oral anticoagulant (NOAC) over another. However, in patients already receiving vitamin K antagonists with low time in the therapeutic range, they recommend switching to a different NOAC but ensuring good adherence and persistence with therapy (class I recommendation) or efforts to improve time in therapeutic range (class IIa).

Catheter ablation takes on a more prominent role for rhythm control and is now recommended after one antiarrhythmic drug therapy fails to improve symptoms of AF recurrence in patients with paroxysmal AFib, or persistent AFib with or without major risk factors for recurrence. The class I recommendation is based on results from the CAPTAF and CABANA trials, said task force member Carina Blomström-Lundqvist, MD, PhD, Uppsala University, Sweden.

Catheter ablation is also now a first-line therapy for patients with AFib who have a high likelihood of tachycardia-induced cardiomyopathy, independent of symptom status. “In this subset of patients, catheter ablation may offer a lot with respect to restoration of left ventricular function,” observed Dr. Hindricks.

Complete electrical isolation of the pulmonary veins is recommended during all AFib catheter ablation procedures (class I).

“Even as a medical conservative, I think it is totally reasonable to move to catheter ablation after a failed drug trial,” commented John Mandrola, MD, Baptist Health, Louisville, Ky., who was not a part of the guideline development. 

Although the chance of a second drug working after one failure is low, he noted that operators in the United States have dofetilide, which is not used much in Europe, and sometimes works surprisingly well.

“That said, the caveat is that moving to catheter ablation after drug failure is only appropriate if we have addressed all the pertinent risk factors: sleep apnea, weight loss, lack of fitness, blood pressure control, and alcohol excess,” he said. 

As for tachycardia-mediated cardiomyopathy, this too can be reasonable, Dr. Mandrola said. “I often get people ‘out of a hole’ with amiodarone plus cardioversion for a few months and then proceed to ablation.”

Notably, the 2020 iteration sharpens its recommendation that amiodarone not be used first-line for long-term rhythm control in all patients with AFib, including those with heart failure with reduced ejection fraction, given its extracardiac toxicity (class I, up from IIa).
 

Quality counts

In response to growing evidence that guideline-adherence is associated with significantly better outcomes in AFib, the 2020 ESC/EACTS guidelines explicitly included a recommendation on the need to measure quality of care to identify opportunities for improvement.

With this framework in mind, a task force with 23 people – including members from ESC and heart rhythm societies in the United States, Asia Pacific, and Latin America, along with patient representatives – was created to develop a list of quality indicators (QIs), ultimately settling on 17 main QIs and 17 secondary ones, said Elena Arbelo, MD, PhD, MSc, University of Barcelona.

The QIs are classified into six domains: patient assessment, anticoagulation, rate control, rhythm control, risk factor modification, and, importantly, outcome measures. A full list is accessible in a paper, simultaneously published in EP EuroPace.

Five patient-reported outcomes fall under the outcomes domain but only one – health-related quality of life – is a main quality indicator. The remaining outcomes are still important but are listed as secondary because of the lack of evidence to sustain or defend their systematic implementation, particularly evidence on how to measure them appropriately, Dr. Arbelo said.

“Hopefully, following the [class I] recommendation by the 2020 ESC guidelines to routinely collect patient-reported outcomes will allow us to collect further evidence and in the future have sufficient evidence to include these as a main outcome,” she said.

The QI work was driven in parallel with the guidelines and had a huge impact on its development, including inclusion of clear recommendations on how to measure quality, Dr. Hindricks said. “I believe that the whole issue of quality management in the treatment of patients with a focus on patient values cannot be overestimated.”

Disclosure information for all writing committee members is in the report. Dr. Mandrola is a writer and podcaster for Medscape.
 

A version of this article originally appeared on Medscape.com.

New atrial fibrillation (AFib) management guidelines from the European Society of Cardiology (ESC) call for diagnostic confirmation and structured characterization of AFib and the need to streamline integrated care with the Atrial fibrillation Better Care (ABC) pathway.

“It’s as simple as CC to ABC,” quipped one task force member during the virtual unveiling of the guidelines at the ESC Congress 2020.

The guidelines were developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) and published simultaneously August 29 in the European Heart Journal.

Acknowledging the slew of novel screening tools now available and their reported sensitivity and specificity rates, the document supports opportunistic screening for AFib by pulse taking or electrocardiogram (ECG) rhythm strip in patients at least 65 years of age, with a class 1 recommendation, evidence level B.

Systematic ECG screening should also be considered to detect AFib in individuals at least 75 years of age or in those at high risk for stroke (class IIa, level B).

Other new class I screening recommendations are to inform individuals undergoing screening about the significance and treatment implications of detecting AFib and to have a structured referral platform in place for further physician-led evaluation.

A definite diagnosis of clinical AFib is established only after confirmation by a conventional 12-lead ECG or single-lead ECG strip with at least 30 seconds of AFib.

In line with ESC’s 2016 AFib guidelines, the new iteration classifies AFib as first diagnosed, paroxysmal, persistent, long-standing persistent, and permanent. But it’s also important to classify the clinical profile of AFib, task force member Giuseppe Boriani, MD, PhD, University of Modena, Italy, said in the first of five presentations.

“So the novelty of the 2020 guidelines is related to the proposal of the 4S-AF scheme for a structured characterization of atrial fibrillation that takes into account Stroke risk, severity of Symptoms, Severity of atrial fibrillation burden, and Substrate severity,” he said.

This represents a paradigm shift from a single-domain conventional classification of AFib toward a structured characterization that streamlines assessment, informs treatment decision-making, and facilitates communication among physicians of various specialties, said Tatjana Potpara, MD, PhD, guideline co-chair and head of the Department for Intensive Arrhythmia Care, Clinical Centre of Serbia, Belgrade.

“The beauty of this approach is that, at present, the assessment of the ‘S’ components are performed using available tools, but in the future, the 4S-AF has a great potential to incorporate whatever becomes available for a more precision assessment of substrate or symptoms or arrhythmia burden and so forth,” she said.


 

ABC pathway

The guidelines advocate the previously described ABC pathway for integrated care management, which includes ‘A’ for Anticoagulation/Avoid stroke, ‘B’ for Better symptom control, and ‘C’ for Comorbidity/Cardiovascular risk factor optimization.

The document strengthens support for formal risk score–based assessment of bleeding risk in all patients, including use of the HAS-BLED score to help address modifiable bleeding risk factors and to identify patients at high bleeding risk (HAS-BLED score ≥3) for early and more frequent follow-up.

These assessments should be done regularly, given that both stroke and bleeding risk are dynamic and change over time with aging and comorbidities, Dr. Potpara stressed. In patients with AFib initially at low risk for stroke, the next assessment should be optimally performed at 4-6 months.

The guideline also targets weight loss in patients who are obese and have AFib, particularly those being evaluated for ablation, and good blood pressure control in patients with AFib and hypertension to reduce AFib recurrences and risk for stroke and bleeding (both class I, up from IIa). 

It’s particularly important that these risk factors are addressed, and that modifiable risk factors that go along with increased AFib occurrence and persistence are addressed and communicated to patients, said Gerhard Hindricks, MD, PhD, guideline cochair and medical director of the Rhythmology Department, Heart Centre Leipzig (Germany).

“I have to confess, as an interventional electrophysiologist, there has been a time where I have not appreciated these risk factors intensely enough,” he said. “But we have learned, also in the field of catheter ablation, that weight loss is an essential basis for a good procedure. If we can motivate patients to lose weight and then come to the intervention with better outcome, it’s a true benefit for the patient and addresses patient values. So I’m particularly happy we have introduced that with such intensity in the guidelines.”
 

Rate and rhythm control

The guidelines make no recommendation of one novel oral anticoagulant (NOAC) over another. However, in patients already receiving vitamin K antagonists with low time in the therapeutic range, they recommend switching to a different NOAC but ensuring good adherence and persistence with therapy (class I recommendation) or efforts to improve time in therapeutic range (class IIa).

Catheter ablation takes on a more prominent role for rhythm control and is now recommended after one antiarrhythmic drug therapy fails to improve symptoms of AF recurrence in patients with paroxysmal AFib, or persistent AFib with or without major risk factors for recurrence. The class I recommendation is based on results from the CAPTAF and CABANA trials, said task force member Carina Blomström-Lundqvist, MD, PhD, Uppsala University, Sweden.

Catheter ablation is also now a first-line therapy for patients with AFib who have a high likelihood of tachycardia-induced cardiomyopathy, independent of symptom status. “In this subset of patients, catheter ablation may offer a lot with respect to restoration of left ventricular function,” observed Dr. Hindricks.

Complete electrical isolation of the pulmonary veins is recommended during all AFib catheter ablation procedures (class I).

“Even as a medical conservative, I think it is totally reasonable to move to catheter ablation after a failed drug trial,” commented John Mandrola, MD, Baptist Health, Louisville, Ky., who was not a part of the guideline development. 

Although the chance of a second drug working after one failure is low, he noted that operators in the United States have dofetilide, which is not used much in Europe, and sometimes works surprisingly well.

“That said, the caveat is that moving to catheter ablation after drug failure is only appropriate if we have addressed all the pertinent risk factors: sleep apnea, weight loss, lack of fitness, blood pressure control, and alcohol excess,” he said. 

As for tachycardia-mediated cardiomyopathy, this too can be reasonable, Dr. Mandrola said. “I often get people ‘out of a hole’ with amiodarone plus cardioversion for a few months and then proceed to ablation.”

Notably, the 2020 iteration sharpens its recommendation that amiodarone not be used first-line for long-term rhythm control in all patients with AFib, including those with heart failure with reduced ejection fraction, given its extracardiac toxicity (class I, up from IIa).
 

Quality counts

In response to growing evidence that guideline-adherence is associated with significantly better outcomes in AFib, the 2020 ESC/EACTS guidelines explicitly included a recommendation on the need to measure quality of care to identify opportunities for improvement.

With this framework in mind, a task force with 23 people – including members from ESC and heart rhythm societies in the United States, Asia Pacific, and Latin America, along with patient representatives – was created to develop a list of quality indicators (QIs), ultimately settling on 17 main QIs and 17 secondary ones, said Elena Arbelo, MD, PhD, MSc, University of Barcelona.

The QIs are classified into six domains: patient assessment, anticoagulation, rate control, rhythm control, risk factor modification, and, importantly, outcome measures. A full list is accessible in a paper, simultaneously published in EP EuroPace.

Five patient-reported outcomes fall under the outcomes domain but only one – health-related quality of life – is a main quality indicator. The remaining outcomes are still important but are listed as secondary because of the lack of evidence to sustain or defend their systematic implementation, particularly evidence on how to measure them appropriately, Dr. Arbelo said.

“Hopefully, following the [class I] recommendation by the 2020 ESC guidelines to routinely collect patient-reported outcomes will allow us to collect further evidence and in the future have sufficient evidence to include these as a main outcome,” she said.

The QI work was driven in parallel with the guidelines and had a huge impact on its development, including inclusion of clear recommendations on how to measure quality, Dr. Hindricks said. “I believe that the whole issue of quality management in the treatment of patients with a focus on patient values cannot be overestimated.”

Disclosure information for all writing committee members is in the report. Dr. Mandrola is a writer and podcaster for Medscape.
 

A version of this article originally appeared on Medscape.com.

An investigational drug that targets part of the molecular machinery underlying obstructive hypertrophic cardiomyopathy (HCM) can improve both symptoms and functional status in patients with the genetic disorder, suggests a placebo-controlled phase 3 trial.

Treatment with mavacamten (MyoKardia) worked partly by alleviating high-pressure gradients in the left ventricular outflow tract (LVOT), a key characteristic of obstructive HCM. Its effects appeared consistent across a wide range of objective and patient-assessed endpoints.

Mavacamten is “the first potential medical therapy addressing the underlying biology of symptoms in hypertrophic obstructive cardiomyopathy,” observed Iacopo Olivotto, MD, Careggi University Hospital, Florence, Italy.

Patients in the EXPLORER-HCM trial who took the new drug showed improvements in “every aspect of objective performance and subjective well-being,” Dr. Olivotto said at a preview for journalists before his formal online presentation of the results during the virtual European Society of Cardiology Congress 2020, staged in lieu of the traditional annual meeting because of the COVID-19 pandemic.

Dr. Olivotto, also lead author on the study’s same-day publication in The Lancet, was exuberant about the findings. “It is really hard to convey what this actually means for a scientific and clinical community that has spent over 60 years trying to understand and cure hypertrophic cardiomyopathy.”

MyoKardia released abbreviated top-line results of EXPLORER-HCM in May, which were reported by theheart.org | Medscape Cardiology at the time.

“I think it’s pretty exciting. We certainly need more and better drugs for this patient population,” Arnon Adler, MD, who is not associated with the trial but follows HCM at the Peter Munk Cardiac Centre, Toronto General Hospital, said in an interview.

The trial compared the new drug to placebo rather than full contemporary drug therapy for obstructive HCM, Adler cautioned, and had a fairly short follow-up time. But he was impressed that mavacamten’s apparent benefits seemed consistent not only for endpoints like change in New York Heart Association (NYHA) functional class and quality of life but also for more objective measures like peak VO₂ and LVOT gradients.

“I think the results were promising across the board,” he told.
 

Unique mechanism of action

Mavacamten is described as a first-in-class, small-molecule, selective allosteric inhibitor of cardiac myosin adenosine triphosphatase that addresses the underlying pathophysiology of HCM by reducing actin–myosin cross-bridge formation. It thereby inhibits the excessive myocyte contractility that is a key mechanism of the disorder’s tell-tale hypertrophy, something the available HCM drug therapies don’t do.

Almost three-fourths of patients in the trial were initially in NYHA class 2. Such patients in practice tend to be treated pharmacologically, with more invasive but generally effective surgical myectomy and alcohol septal ablation performed more often for patients in NYHA class 3.

“In the EXPLORER-HCM trial, patients enrolled did not have any immediate indication for surgery,” although many of them in NYHA class 2 would likely progress to NYHA 3, Dr. Olivotto said in an interview.

Based on the trial, he said, it’s possible that mavacamten could lead to “earlier and broader treatment of obstruction symptoms in patients who would never have qualified for surgery in the first place because their symptoms may not be severe enough, but they are still limited.”

Notably, the published report notes, 27% of patients taking mavacamten achieved what was defined as a complete response – that is, a reduction of all LVOT gradients to less than 30 mm Hg in the total absence of symptoms.

Only 1% of patients in the placebo-treated control group met that goal, “showing that mavacamten might be capable of achieving marked relief of symptoms and LVOT obstruction,” the report states.

In the trial, “treatment with mavacamten led to clinically meaningful improvements in hemodynamic status, functional capacity, and subjective well-being in patients with obstructive hypertrophic cardiomyopathy,” agrees an editorial accompanying the EXPLORER-HCM publication.

Mavacamten might even compare favorably to surgery and ablative therapy, speculated the editorialists, Michael Papadakis, MBBS, MD, and colleagues of St. George’s University Hospitals NHS Foundation Trust, London. The drug appeared to reduce the peak LVOT gradient “to less than the guideline-based threshold for septal reduction therapy, 50 mm Hg, in 74% of patients, compared with 21% in the placebo group, indicating that mavacamten could represent a valid alternative to highly specialized invasive therapy,” they wrote.
 

Standard drug therapy

“There are approved drugs for obstructive hypertrophic cardiomyopathy, but they are ancient and were developed for other diseases,” observed Dr. Olivotto at the media briefing. Those drug options – primarily beta-blockers, nondihydropyridine calcium-channel blockers, and the sodium-channel blocker disopyramide – are often ineffective or cause onerous side effects, he said.

Notably in EXPLORER-HCM, patients in both the mavacamten and placebo groups could also be receiving beta-blockers and calcium-channel blockers, but no one in the trial could be receiving disopyramide, which can prolong the QT interval.

“By design,” mavacamten wasn’t compared to disopyramide, “a much more potent drug for lowering gradient and improving symptoms than beta-blockers or calcium-channel blockers,” said Martin S. Maron, MD, medical director at the Hypertrophic Cardiomyopathy Center and Research Institute, Tufts Medical Center, Boston.

Therefore, the trial’s results can’t be extrapolated to conclude that the new drug is superior to disopyramide “or the gold standard, surgical myectomy,” he said in an interview.

Dr. Adler agreed that observational studies suggest a benefit from disopyramide that may rival the apparent effect of mavacamten. “But of course, you can’t make direct comparisons because we never had a study like this for disopyramide.” Because it has many side effects and limitations, “it’s not a drug that I like using, but it is beneficial for some patients and I do use it quite a bit.”

What EXPLORER-HCM does seem to show, Dr. Maron said, “is that the mechanism of action of the drug does seem to play out. It lowers gradients in a pretty reliable and powerful way, and that translates into clinical improvement in many patients. So it starts to support the idea that this drug and the class of drugs, myosin inhibitors, may represent another medical therapy option for symptomatic obstructive HCM.”

And, he pointed out, about one-fifth of patients with obstructive HCM don’t respond to disopyramide with fewer symptoms, and in others the drug “starts to lose efficacy over time.” So disopyramide has limitations, and EXPLORER-HCM “provides the possibility of an additional drug option.”

EXPLORER-HCM randomly assigned 251 adults with obstructive HCM in 13 countries to receive mavacamten, titrated from a starting dosage of 5 mg/day to a possible 15 mg/day or to placebo for 30 weeks.

The patients were required to have a peak LVOT gradient at least 50 mm Hg, a left ventricular ejection fraction (LVEF) of at least 55%, and symptoms indicating NYHA class 2 or 3; ultimately, 73% started the trial in NYHA class 2.

In the intention-to-treat analysis, 36.6% of patients receiving mavacamten and 17.2% of control patients met the composite primary endpoint (P = .0005), which consisted of either a 1.5–mL/kg per minute or greater improvement in peak oxygen consumption (pVO₂) and at least a one-step reduction in NYHA functional class or at least a 3.0–mL/kg per minute pVO₂ increase without deterioration in NYHA class, by week 30.

Medscape.com

A version of this article originally appeared on Medscape.com.

An investigational drug that targets part of the molecular machinery underlying obstructive hypertrophic cardiomyopathy (HCM) can improve both symptoms and functional status in patients with the genetic disorder, suggests a placebo-controlled phase 3 trial.

Treatment with mavacamten (MyoKardia) worked partly by alleviating high-pressure gradients in the left ventricular outflow tract (LVOT), a key characteristic of obstructive HCM. Its effects appeared consistent across a wide range of objective and patient-assessed endpoints.

Mavacamten is “the first potential medical therapy addressing the underlying biology of symptoms in hypertrophic obstructive cardiomyopathy,” observed Iacopo Olivotto, MD, Careggi University Hospital, Florence, Italy.

Patients in the EXPLORER-HCM trial who took the new drug showed improvements in “every aspect of objective performance and subjective well-being,” Dr. Olivotto said at a preview for journalists before his formal online presentation of the results during the virtual European Society of Cardiology Congress 2020, staged in lieu of the traditional annual meeting because of the COVID-19 pandemic.

Dr. Olivotto, also lead author on the study’s same-day publication in The Lancet, was exuberant about the findings. “It is really hard to convey what this actually means for a scientific and clinical community that has spent over 60 years trying to understand and cure hypertrophic cardiomyopathy.”

MyoKardia released abbreviated top-line results of EXPLORER-HCM in May, which were reported by theheart.org | Medscape Cardiology at the time.

“I think it’s pretty exciting. We certainly need more and better drugs for this patient population,” Arnon Adler, MD, who is not associated with the trial but follows HCM at the Peter Munk Cardiac Centre, Toronto General Hospital, said in an interview.

The trial compared the new drug to placebo rather than full contemporary drug therapy for obstructive HCM, Adler cautioned, and had a fairly short follow-up time. But he was impressed that mavacamten’s apparent benefits seemed consistent not only for endpoints like change in New York Heart Association (NYHA) functional class and quality of life but also for more objective measures like peak VO₂ and LVOT gradients.

“I think the results were promising across the board,” he told.
 

Unique mechanism of action

Mavacamten is described as a first-in-class, small-molecule, selective allosteric inhibitor of cardiac myosin adenosine triphosphatase that addresses the underlying pathophysiology of HCM by reducing actin–myosin cross-bridge formation. It thereby inhibits the excessive myocyte contractility that is a key mechanism of the disorder’s tell-tale hypertrophy, something the available HCM drug therapies don’t do.

Almost three-fourths of patients in the trial were initially in NYHA class 2. Such patients in practice tend to be treated pharmacologically, with more invasive but generally effective surgical myectomy and alcohol septal ablation performed more often for patients in NYHA class 3.

“In the EXPLORER-HCM trial, patients enrolled did not have any immediate indication for surgery,” although many of them in NYHA class 2 would likely progress to NYHA 3, Dr. Olivotto said in an interview.

Based on the trial, he said, it’s possible that mavacamten could lead to “earlier and broader treatment of obstruction symptoms in patients who would never have qualified for surgery in the first place because their symptoms may not be severe enough, but they are still limited.”

Notably, the published report notes, 27% of patients taking mavacamten achieved what was defined as a complete response – that is, a reduction of all LVOT gradients to less than 30 mm Hg in the total absence of symptoms.

Only 1% of patients in the placebo-treated control group met that goal, “showing that mavacamten might be capable of achieving marked relief of symptoms and LVOT obstruction,” the report states.

In the trial, “treatment with mavacamten led to clinically meaningful improvements in hemodynamic status, functional capacity, and subjective well-being in patients with obstructive hypertrophic cardiomyopathy,” agrees an editorial accompanying the EXPLORER-HCM publication.

Mavacamten might even compare favorably to surgery and ablative therapy, speculated the editorialists, Michael Papadakis, MBBS, MD, and colleagues of St. George’s University Hospitals NHS Foundation Trust, London. The drug appeared to reduce the peak LVOT gradient “to less than the guideline-based threshold for septal reduction therapy, 50 mm Hg, in 74% of patients, compared with 21% in the placebo group, indicating that mavacamten could represent a valid alternative to highly specialized invasive therapy,” they wrote.
 

Standard drug therapy

“There are approved drugs for obstructive hypertrophic cardiomyopathy, but they are ancient and were developed for other diseases,” observed Dr. Olivotto at the media briefing. Those drug options – primarily beta-blockers, nondihydropyridine calcium-channel blockers, and the sodium-channel blocker disopyramide – are often ineffective or cause onerous side effects, he said.

Notably in EXPLORER-HCM, patients in both the mavacamten and placebo groups could also be receiving beta-blockers and calcium-channel blockers, but no one in the trial could be receiving disopyramide, which can prolong the QT interval.

“By design,” mavacamten wasn’t compared to disopyramide, “a much more potent drug for lowering gradient and improving symptoms than beta-blockers or calcium-channel blockers,” said Martin S. Maron, MD, medical director at the Hypertrophic Cardiomyopathy Center and Research Institute, Tufts Medical Center, Boston.

Therefore, the trial’s results can’t be extrapolated to conclude that the new drug is superior to disopyramide “or the gold standard, surgical myectomy,” he said in an interview.

Dr. Adler agreed that observational studies suggest a benefit from disopyramide that may rival the apparent effect of mavacamten. “But of course, you can’t make direct comparisons because we never had a study like this for disopyramide.” Because it has many side effects and limitations, “it’s not a drug that I like using, but it is beneficial for some patients and I do use it quite a bit.”

What EXPLORER-HCM does seem to show, Dr. Maron said, “is that the mechanism of action of the drug does seem to play out. It lowers gradients in a pretty reliable and powerful way, and that translates into clinical improvement in many patients. So it starts to support the idea that this drug and the class of drugs, myosin inhibitors, may represent another medical therapy option for symptomatic obstructive HCM.”

And, he pointed out, about one-fifth of patients with obstructive HCM don’t respond to disopyramide with fewer symptoms, and in others the drug “starts to lose efficacy over time.” So disopyramide has limitations, and EXPLORER-HCM “provides the possibility of an additional drug option.”

EXPLORER-HCM randomly assigned 251 adults with obstructive HCM in 13 countries to receive mavacamten, titrated from a starting dosage of 5 mg/day to a possible 15 mg/day or to placebo for 30 weeks.

The patients were required to have a peak LVOT gradient at least 50 mm Hg, a left ventricular ejection fraction (LVEF) of at least 55%, and symptoms indicating NYHA class 2 or 3; ultimately, 73% started the trial in NYHA class 2.

In the intention-to-treat analysis, 36.6% of patients receiving mavacamten and 17.2% of control patients met the composite primary endpoint (P = .0005), which consisted of either a 1.5–mL/kg per minute or greater improvement in peak oxygen consumption (pVO₂) and at least a one-step reduction in NYHA functional class or at least a 3.0–mL/kg per minute pVO₂ increase without deterioration in NYHA class, by week 30.

Medscape.com

A version of this article originally appeared on Medscape.com.

An investigational drug that targets part of the molecular machinery underlying obstructive hypertrophic cardiomyopathy (HCM) can improve both symptoms and functional status in patients with the genetic disorder, suggests a placebo-controlled phase 3 trial.

Treatment with mavacamten (MyoKardia) worked partly by alleviating high-pressure gradients in the left ventricular outflow tract (LVOT), a key characteristic of obstructive HCM. Its effects appeared consistent across a wide range of objective and patient-assessed endpoints.

Mavacamten is “the first potential medical therapy addressing the underlying biology of symptoms in hypertrophic obstructive cardiomyopathy,” observed Iacopo Olivotto, MD, Careggi University Hospital, Florence, Italy.

Patients in the EXPLORER-HCM trial who took the new drug showed improvements in “every aspect of objective performance and subjective well-being,” Dr. Olivotto said at a preview for journalists before his formal online presentation of the results during the virtual European Society of Cardiology Congress 2020, staged in lieu of the traditional annual meeting because of the COVID-19 pandemic.

Dr. Olivotto, also lead author on the study’s same-day publication in The Lancet, was exuberant about the findings. “It is really hard to convey what this actually means for a scientific and clinical community that has spent over 60 years trying to understand and cure hypertrophic cardiomyopathy.”

MyoKardia released abbreviated top-line results of EXPLORER-HCM in May, which were reported by theheart.org | Medscape Cardiology at the time.

“I think it’s pretty exciting. We certainly need more and better drugs for this patient population,” Arnon Adler, MD, who is not associated with the trial but follows HCM at the Peter Munk Cardiac Centre, Toronto General Hospital, said in an interview.

The trial compared the new drug to placebo rather than full contemporary drug therapy for obstructive HCM, Adler cautioned, and had a fairly short follow-up time. But he was impressed that mavacamten’s apparent benefits seemed consistent not only for endpoints like change in New York Heart Association (NYHA) functional class and quality of life but also for more objective measures like peak VO₂ and LVOT gradients.

“I think the results were promising across the board,” he told.
 

Unique mechanism of action

Mavacamten is described as a first-in-class, small-molecule, selective allosteric inhibitor of cardiac myosin adenosine triphosphatase that addresses the underlying pathophysiology of HCM by reducing actin–myosin cross-bridge formation. It thereby inhibits the excessive myocyte contractility that is a key mechanism of the disorder’s tell-tale hypertrophy, something the available HCM drug therapies don’t do.

Almost three-fourths of patients in the trial were initially in NYHA class 2. Such patients in practice tend to be treated pharmacologically, with more invasive but generally effective surgical myectomy and alcohol septal ablation performed more often for patients in NYHA class 3.

“In the EXPLORER-HCM trial, patients enrolled did not have any immediate indication for surgery,” although many of them in NYHA class 2 would likely progress to NYHA 3, Dr. Olivotto said in an interview.

Based on the trial, he said, it’s possible that mavacamten could lead to “earlier and broader treatment of obstruction symptoms in patients who would never have qualified for surgery in the first place because their symptoms may not be severe enough, but they are still limited.”

Notably, the published report notes, 27% of patients taking mavacamten achieved what was defined as a complete response – that is, a reduction of all LVOT gradients to less than 30 mm Hg in the total absence of symptoms.

Only 1% of patients in the placebo-treated control group met that goal, “showing that mavacamten might be capable of achieving marked relief of symptoms and LVOT obstruction,” the report states.

In the trial, “treatment with mavacamten led to clinically meaningful improvements in hemodynamic status, functional capacity, and subjective well-being in patients with obstructive hypertrophic cardiomyopathy,” agrees an editorial accompanying the EXPLORER-HCM publication.

Mavacamten might even compare favorably to surgery and ablative therapy, speculated the editorialists, Michael Papadakis, MBBS, MD, and colleagues of St. George’s University Hospitals NHS Foundation Trust, London. The drug appeared to reduce the peak LVOT gradient “to less than the guideline-based threshold for septal reduction therapy, 50 mm Hg, in 74% of patients, compared with 21% in the placebo group, indicating that mavacamten could represent a valid alternative to highly specialized invasive therapy,” they wrote.
 

Standard drug therapy

“There are approved drugs for obstructive hypertrophic cardiomyopathy, but they are ancient and were developed for other diseases,” observed Dr. Olivotto at the media briefing. Those drug options – primarily beta-blockers, nondihydropyridine calcium-channel blockers, and the sodium-channel blocker disopyramide – are often ineffective or cause onerous side effects, he said.

Notably in EXPLORER-HCM, patients in both the mavacamten and placebo groups could also be receiving beta-blockers and calcium-channel blockers, but no one in the trial could be receiving disopyramide, which can prolong the QT interval.

“By design,” mavacamten wasn’t compared to disopyramide, “a much more potent drug for lowering gradient and improving symptoms than beta-blockers or calcium-channel blockers,” said Martin S. Maron, MD, medical director at the Hypertrophic Cardiomyopathy Center and Research Institute, Tufts Medical Center, Boston.

Therefore, the trial’s results can’t be extrapolated to conclude that the new drug is superior to disopyramide “or the gold standard, surgical myectomy,” he said in an interview.

Dr. Adler agreed that observational studies suggest a benefit from disopyramide that may rival the apparent effect of mavacamten. “But of course, you can’t make direct comparisons because we never had a study like this for disopyramide.” Because it has many side effects and limitations, “it’s not a drug that I like using, but it is beneficial for some patients and I do use it quite a bit.”

What EXPLORER-HCM does seem to show, Dr. Maron said, “is that the mechanism of action of the drug does seem to play out. It lowers gradients in a pretty reliable and powerful way, and that translates into clinical improvement in many patients. So it starts to support the idea that this drug and the class of drugs, myosin inhibitors, may represent another medical therapy option for symptomatic obstructive HCM.”

And, he pointed out, about one-fifth of patients with obstructive HCM don’t respond to disopyramide with fewer symptoms, and in others the drug “starts to lose efficacy over time.” So disopyramide has limitations, and EXPLORER-HCM “provides the possibility of an additional drug option.”

EXPLORER-HCM randomly assigned 251 adults with obstructive HCM in 13 countries to receive mavacamten, titrated from a starting dosage of 5 mg/day to a possible 15 mg/day or to placebo for 30 weeks.

The patients were required to have a peak LVOT gradient at least 50 mm Hg, a left ventricular ejection fraction (LVEF) of at least 55%, and symptoms indicating NYHA class 2 or 3; ultimately, 73% started the trial in NYHA class 2.

In the intention-to-treat analysis, 36.6% of patients receiving mavacamten and 17.2% of control patients met the composite primary endpoint (P = .0005), which consisted of either a 1.5–mL/kg per minute or greater improvement in peak oxygen consumption (pVO₂) and at least a one-step reduction in NYHA functional class or at least a 3.0–mL/kg per minute pVO₂ increase without deterioration in NYHA class, by week 30.

Medscape.com

A version of this article originally appeared on Medscape.com.

The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients with heart failure with reduced ejection fraction and no diabetes, with results from a second large, controlled trial showing clear efficacy and safety in this population.

Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) had a statistically significant 25% relative cut in their incidence of cardiovascular death or first heart failure hospitalization, compared with placebo-treated controls when added on top of standard HFrEF treatment, and this benefit was consistent regardless of whether the treated patients also had type 2 diabetes, Milton Packer, MD, reported at the virtual annual congress of the European Society of Cardiology.

This 25% drop in the primary endpoint with empagliflozin treatment in the EMPEROR-Reduced trial exactly matched the cut in incidence of cardiovascular death or heart failure hospitalization produced by treatment with a another SGLT2 inhibitor, dapagliflozin (Farxiga), in the DAPA-HF trial (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

The performance of these two SGLT2 inhibitors was “incredibly consistent” across the their respective trials run in HFrEF patients with and without type 2 diabetes, and the combined evidence base of the two trials makes for “really compelling evidence” of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment, Dr. Packer said.
 

Results plant drug class firmly as HFrEF treatment

Dr. Packer stressed in his presentation that optimal treatment of patients with HFrEF now demands use of one of these two SGLT2 inhibitors, as well as sacubitril plus valsartan (Entresto), a beta-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many HFrEF patients who also need treatment for fluid overload. He further advocated for rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives a HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less while acknowledging that optimal up-titration of the beta-blocker would likely take longer.

The order in which a patient starts these drugs shouldn’t matter, and there currently seems to be no evidence that clearly points toward using either dapagliflozin or empagliflozin over the other, Dr. Packer added.

In recognition of the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in HFrEF patients, the American College of Cardiology and American Heart Association are now drafting an “expert decision pathway” to help clinicians as they enter this new prescribing space. This interim guidance should come out before the end of 2020, prior to release of fully revised HFrEF management guidelines in 2021, said Athena Poppas, MD, president of the ACC, in an interview.

“There is clearly need for education” that can help guide physicians who care for HFrEF patients on how to introduce an SGLT2 inhibitor along with the additional, lengthy list of drug classes proven to benefit these patients, noted Dr. Poppas, who is also a professor and chief of cardiology at the Brown University in Providence, R.I. Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in HFrEF patients because recent history has shown substantial pushback from third-party payers in reimbursing for these relatively expensive drugs, Dr. Poppas noted. She added that this is a problem that may be compounded when patients should ideally get both drug classes.

Physicians who care for heart failure patients have their own history of dragging their feet when adding new drugs to the regimens HFrEF patients receive. The angiotensin converting enzyme inhibitors and beta-blockers took about 17 years each to start reaching a majority of U.S. HFrEF patients, and sacubitril plus valsartan is now used on perhaps a quarter to a third of HFrEF patients despite receiving Food and Drug Administration approval for these patients in mid 2015, noted Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Va.

Despite dapagliflozin receiving FDA approval in May 2020 for treating HFrEF in patients without diabetes, early uptake in U.S. practice has been very slow, with findings from large U.S. patient registries suggesting that perhaps 1% of suitable HFrEF patients currently get the drug, estimated Dr. O’Connor in an interview.

Given how strong the evidence now is for benefit and safety from dapagliflozin and empagliflozin, it may take as little as 5 years to reach greater than 50% penetration of one of these drugs into U.S. HFrEF patient populations, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.
 

EMPEROR-Reduced outcomes

The road to routine use of these SGLT2 inhibitor drugs should be hastened by empagliflozin’s impressive performance in EMPEROR-Reduced, in which the drug scored highly significant benefits over placebo for the prespecified primary and two major secondary endpoints, one of which was a measure of preserved renal function.

The trial randomized 3,730 patients at 520 sites in 20 countries during 2017-2019 and followed them on treatment for a median of 16 months. All patients had a left ventricular ejection fraction of 40% or less, and roughly three-quarters had New York Heart Association (NYHA) class II function, nearly one-quarter had class III function, and fewer than 1% of patients fell into the class IV category.

The primary endpoint occurred in 19% of the empagliflozin-treated patients and in 25% of those who received placebo. Among the half of patients with diabetes in the trial, the relative risk reduction by empagliflozin compared with placebo was a statistically significant 28%; among those without diabetes, it was a statistically significant 22%. Concurrently with Dr. Packer’s report, the results appeared in an article posted online (N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190).

The study also had two main prespecified secondary endpoints: the incidence of total hospitalizations for heart failure, both first and recurrent, which fell by 30% in the empagliflozin-treated patients, compared with placebo, and the rate of declining renal function during the 16 months of the study as measured by estimated glomerular filtration rate, which dropped by roughly 1 mL/min per 1.73 m² among the empagliflozin recipients and by about 4 mL/min/ per 1.73 m² in the placebo patients.

Treatment with empagliflozin also achieved a notable, statistically significant 50% drop in major adverse renal events, consistent with the performance of other drugs in the class.

“Renal protection is a big plus” of empagliflozin in this trial and from the other SGLT2 inhibitors in prior studies, noted Dr. O’Connor.

The EMPEROR-Reduced results also showed an important benefit for HFrEF patients from empagliflozin not previously seen as quickly with any other drug class, noted Dr. Packer. The SGLT2 inhibitor led to statistically a significant slowing in the progression of patients from NYHA class II function to class III, compared with placebo, and it also significantly promoted the recovery of patients from NYHA class III to class II, an effect that became apparent within the first month on treatment and a benefit that is a “big deal” for patients because it represents a “significant change in functional capacity.” This additional dimension of empagliflozin’s benefit “really impressed me,” Dr. Packer said.

EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Poppas and Dr. O’Connor had no relevant disclosures.
 

[email protected]

SOURCE: Packer M. ESC 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190.

The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients with heart failure with reduced ejection fraction and no diabetes, with results from a second large, controlled trial showing clear efficacy and safety in this population.

Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) had a statistically significant 25% relative cut in their incidence of cardiovascular death or first heart failure hospitalization, compared with placebo-treated controls when added on top of standard HFrEF treatment, and this benefit was consistent regardless of whether the treated patients also had type 2 diabetes, Milton Packer, MD, reported at the virtual annual congress of the European Society of Cardiology.

This 25% drop in the primary endpoint with empagliflozin treatment in the EMPEROR-Reduced trial exactly matched the cut in incidence of cardiovascular death or heart failure hospitalization produced by treatment with a another SGLT2 inhibitor, dapagliflozin (Farxiga), in the DAPA-HF trial (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

The performance of these two SGLT2 inhibitors was “incredibly consistent” across the their respective trials run in HFrEF patients with and without type 2 diabetes, and the combined evidence base of the two trials makes for “really compelling evidence” of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment, Dr. Packer said.
 

Results plant drug class firmly as HFrEF treatment

Dr. Packer stressed in his presentation that optimal treatment of patients with HFrEF now demands use of one of these two SGLT2 inhibitors, as well as sacubitril plus valsartan (Entresto), a beta-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many HFrEF patients who also need treatment for fluid overload. He further advocated for rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives a HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less while acknowledging that optimal up-titration of the beta-blocker would likely take longer.

The order in which a patient starts these drugs shouldn’t matter, and there currently seems to be no evidence that clearly points toward using either dapagliflozin or empagliflozin over the other, Dr. Packer added.

In recognition of the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in HFrEF patients, the American College of Cardiology and American Heart Association are now drafting an “expert decision pathway” to help clinicians as they enter this new prescribing space. This interim guidance should come out before the end of 2020, prior to release of fully revised HFrEF management guidelines in 2021, said Athena Poppas, MD, president of the ACC, in an interview.

“There is clearly need for education” that can help guide physicians who care for HFrEF patients on how to introduce an SGLT2 inhibitor along with the additional, lengthy list of drug classes proven to benefit these patients, noted Dr. Poppas, who is also a professor and chief of cardiology at the Brown University in Providence, R.I. Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in HFrEF patients because recent history has shown substantial pushback from third-party payers in reimbursing for these relatively expensive drugs, Dr. Poppas noted. She added that this is a problem that may be compounded when patients should ideally get both drug classes.

Physicians who care for heart failure patients have their own history of dragging their feet when adding new drugs to the regimens HFrEF patients receive. The angiotensin converting enzyme inhibitors and beta-blockers took about 17 years each to start reaching a majority of U.S. HFrEF patients, and sacubitril plus valsartan is now used on perhaps a quarter to a third of HFrEF patients despite receiving Food and Drug Administration approval for these patients in mid 2015, noted Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Va.

Despite dapagliflozin receiving FDA approval in May 2020 for treating HFrEF in patients without diabetes, early uptake in U.S. practice has been very slow, with findings from large U.S. patient registries suggesting that perhaps 1% of suitable HFrEF patients currently get the drug, estimated Dr. O’Connor in an interview.

Given how strong the evidence now is for benefit and safety from dapagliflozin and empagliflozin, it may take as little as 5 years to reach greater than 50% penetration of one of these drugs into U.S. HFrEF patient populations, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.
 

EMPEROR-Reduced outcomes

The road to routine use of these SGLT2 inhibitor drugs should be hastened by empagliflozin’s impressive performance in EMPEROR-Reduced, in which the drug scored highly significant benefits over placebo for the prespecified primary and two major secondary endpoints, one of which was a measure of preserved renal function.

The trial randomized 3,730 patients at 520 sites in 20 countries during 2017-2019 and followed them on treatment for a median of 16 months. All patients had a left ventricular ejection fraction of 40% or less, and roughly three-quarters had New York Heart Association (NYHA) class II function, nearly one-quarter had class III function, and fewer than 1% of patients fell into the class IV category.

The primary endpoint occurred in 19% of the empagliflozin-treated patients and in 25% of those who received placebo. Among the half of patients with diabetes in the trial, the relative risk reduction by empagliflozin compared with placebo was a statistically significant 28%; among those without diabetes, it was a statistically significant 22%. Concurrently with Dr. Packer’s report, the results appeared in an article posted online (N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190).

The study also had two main prespecified secondary endpoints: the incidence of total hospitalizations for heart failure, both first and recurrent, which fell by 30% in the empagliflozin-treated patients, compared with placebo, and the rate of declining renal function during the 16 months of the study as measured by estimated glomerular filtration rate, which dropped by roughly 1 mL/min per 1.73 m² among the empagliflozin recipients and by about 4 mL/min/ per 1.73 m² in the placebo patients.

Treatment with empagliflozin also achieved a notable, statistically significant 50% drop in major adverse renal events, consistent with the performance of other drugs in the class.

“Renal protection is a big plus” of empagliflozin in this trial and from the other SGLT2 inhibitors in prior studies, noted Dr. O’Connor.

The EMPEROR-Reduced results also showed an important benefit for HFrEF patients from empagliflozin not previously seen as quickly with any other drug class, noted Dr. Packer. The SGLT2 inhibitor led to statistically a significant slowing in the progression of patients from NYHA class II function to class III, compared with placebo, and it also significantly promoted the recovery of patients from NYHA class III to class II, an effect that became apparent within the first month on treatment and a benefit that is a “big deal” for patients because it represents a “significant change in functional capacity.” This additional dimension of empagliflozin’s benefit “really impressed me,” Dr. Packer said.

EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Poppas and Dr. O’Connor had no relevant disclosures.
 

[email protected]

SOURCE: Packer M. ESC 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190.

The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients with heart failure with reduced ejection fraction and no diabetes, with results from a second large, controlled trial showing clear efficacy and safety in this population.

Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) had a statistically significant 25% relative cut in their incidence of cardiovascular death or first heart failure hospitalization, compared with placebo-treated controls when added on top of standard HFrEF treatment, and this benefit was consistent regardless of whether the treated patients also had type 2 diabetes, Milton Packer, MD, reported at the virtual annual congress of the European Society of Cardiology.

This 25% drop in the primary endpoint with empagliflozin treatment in the EMPEROR-Reduced trial exactly matched the cut in incidence of cardiovascular death or heart failure hospitalization produced by treatment with a another SGLT2 inhibitor, dapagliflozin (Farxiga), in the DAPA-HF trial (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

The performance of these two SGLT2 inhibitors was “incredibly consistent” across the their respective trials run in HFrEF patients with and without type 2 diabetes, and the combined evidence base of the two trials makes for “really compelling evidence” of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment, Dr. Packer said.
 

Results plant drug class firmly as HFrEF treatment

Dr. Packer stressed in his presentation that optimal treatment of patients with HFrEF now demands use of one of these two SGLT2 inhibitors, as well as sacubitril plus valsartan (Entresto), a beta-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many HFrEF patients who also need treatment for fluid overload. He further advocated for rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives a HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less while acknowledging that optimal up-titration of the beta-blocker would likely take longer.

The order in which a patient starts these drugs shouldn’t matter, and there currently seems to be no evidence that clearly points toward using either dapagliflozin or empagliflozin over the other, Dr. Packer added.

In recognition of the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in HFrEF patients, the American College of Cardiology and American Heart Association are now drafting an “expert decision pathway” to help clinicians as they enter this new prescribing space. This interim guidance should come out before the end of 2020, prior to release of fully revised HFrEF management guidelines in 2021, said Athena Poppas, MD, president of the ACC, in an interview.

“There is clearly need for education” that can help guide physicians who care for HFrEF patients on how to introduce an SGLT2 inhibitor along with the additional, lengthy list of drug classes proven to benefit these patients, noted Dr. Poppas, who is also a professor and chief of cardiology at the Brown University in Providence, R.I. Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in HFrEF patients because recent history has shown substantial pushback from third-party payers in reimbursing for these relatively expensive drugs, Dr. Poppas noted. She added that this is a problem that may be compounded when patients should ideally get both drug classes.

Physicians who care for heart failure patients have their own history of dragging their feet when adding new drugs to the regimens HFrEF patients receive. The angiotensin converting enzyme inhibitors and beta-blockers took about 17 years each to start reaching a majority of U.S. HFrEF patients, and sacubitril plus valsartan is now used on perhaps a quarter to a third of HFrEF patients despite receiving Food and Drug Administration approval for these patients in mid 2015, noted Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Va.

Despite dapagliflozin receiving FDA approval in May 2020 for treating HFrEF in patients without diabetes, early uptake in U.S. practice has been very slow, with findings from large U.S. patient registries suggesting that perhaps 1% of suitable HFrEF patients currently get the drug, estimated Dr. O’Connor in an interview.

Given how strong the evidence now is for benefit and safety from dapagliflozin and empagliflozin, it may take as little as 5 years to reach greater than 50% penetration of one of these drugs into U.S. HFrEF patient populations, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.
 

EMPEROR-Reduced outcomes

The road to routine use of these SGLT2 inhibitor drugs should be hastened by empagliflozin’s impressive performance in EMPEROR-Reduced, in which the drug scored highly significant benefits over placebo for the prespecified primary and two major secondary endpoints, one of which was a measure of preserved renal function.

The trial randomized 3,730 patients at 520 sites in 20 countries during 2017-2019 and followed them on treatment for a median of 16 months. All patients had a left ventricular ejection fraction of 40% or less, and roughly three-quarters had New York Heart Association (NYHA) class II function, nearly one-quarter had class III function, and fewer than 1% of patients fell into the class IV category.

The primary endpoint occurred in 19% of the empagliflozin-treated patients and in 25% of those who received placebo. Among the half of patients with diabetes in the trial, the relative risk reduction by empagliflozin compared with placebo was a statistically significant 28%; among those without diabetes, it was a statistically significant 22%. Concurrently with Dr. Packer’s report, the results appeared in an article posted online (N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190).

The study also had two main prespecified secondary endpoints: the incidence of total hospitalizations for heart failure, both first and recurrent, which fell by 30% in the empagliflozin-treated patients, compared with placebo, and the rate of declining renal function during the 16 months of the study as measured by estimated glomerular filtration rate, which dropped by roughly 1 mL/min per 1.73 m² among the empagliflozin recipients and by about 4 mL/min/ per 1.73 m² in the placebo patients.

Treatment with empagliflozin also achieved a notable, statistically significant 50% drop in major adverse renal events, consistent with the performance of other drugs in the class.

“Renal protection is a big plus” of empagliflozin in this trial and from the other SGLT2 inhibitors in prior studies, noted Dr. O’Connor.

The EMPEROR-Reduced results also showed an important benefit for HFrEF patients from empagliflozin not previously seen as quickly with any other drug class, noted Dr. Packer. The SGLT2 inhibitor led to statistically a significant slowing in the progression of patients from NYHA class II function to class III, compared with placebo, and it also significantly promoted the recovery of patients from NYHA class III to class II, an effect that became apparent within the first month on treatment and a benefit that is a “big deal” for patients because it represents a “significant change in functional capacity.” This additional dimension of empagliflozin’s benefit “really impressed me,” Dr. Packer said.

EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Poppas and Dr. O’Connor had no relevant disclosures.
 

[email protected]

SOURCE: Packer M. ESC 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2022190.

Initiation of rhythm control with antiarrhythmic drugs and/or ablation in patients with early, recently diagnosed atrial fibrillation (AFib) led to a significantly lower risk of major adverse cardiovascular outcomes, compared with a rate-control strategy, during more than 5 years of follow-up in the large randomized EAST-AFNET 4 trial, Paulus Kirchhof, MD, said at the virtual annual congress of the European Society of Cardiology.

Previous trials of rate versus rhythm control in AFib, such as AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), failed to show an advantage for rhythm over rate control in terms of clinical outcomes. Why was EAST-AFNET 4 different? Dr. Kirchhof offered two major reasons: The study incorporated AFib ablation as an option in the rhythm control strategy, and treatment started soon after diagnosis of the arrhythmia. Indeed, nearly 40% of patients had their first-ever AFib episode at the time of randomization, and the median time from diagnosis to randomization was just 36 days.

“Once you are in AFib for a few months, the atrium suffers severe damage, some of it irreversible, so it becomes more difficult to restore and maintain sinus rhythm when you wait longer,” explained Dr. Kirchhof, director of the department of cardiology at the University Heart and Vascular Center in Hamburg (Ger.) and professor of cardiovascular medicine at the University of Birmingham, England.

Also, epidemiologic studies show that the risk of cardiovascular complications is heightened in the first year following diagnosis of AFib. “So there’s a window of opportunity to prevent complications,” he added.

The impetus for conducting EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial ) was straightforward, according to the cardiologist: “The question of whether rhythm control is beneficial or not has been in the field for several decades. Most people, like me, always believed that maintaining sinus rhythm would help, but we didn’t have the data to show it.”
 

Early rhythm control shows sustained benefits

EAST-AFNET 4 was a prospective, open, blinded-outcome-assessement trial. It included 2,789 patients with early AFib and an average CHA₂DS₂-VASc score of 3.4 who were randomized at 135 sites in 11 European countries to early rhythm control or guideline-recommended rate control. At a median 5.1 years of follow-up, the primary outcome – a composite of cardiovascular death, stroke, acute coronary syndrome, or hospitalization for worsening heart failure – occurred at a pace of 3.9% per year in the rhythm control group and 5% per year with rate control. This translated to a statistically significant and clinically meaningful 21% relative risk reduction favoring early rhythm control.

The 28% reduction in cardiovascular death with rhythm control was statistically significant, as was the 35% reduction in stroke. However, the 19% reduction in heart failure hospitalizations and 17% decrease in hospitalizations for acute coronary syndrome were not.

The co–primary endpoint – the mean number of nights spent in the hospital per year, which served as a proxy for the cost of treatment to a health care system – didn’t differ between the two treatment arms, at roughly 5 nights per year.

The clinical benefit of early rhythm control was consistent across all 19 prespecified patient subgroups, including those who were asymptomatic and patients with or without heart failure.

Serious adverse events related to rhythm control therapy – most often drug-related bradycardia – occurred in 4.9% of patients over the course of 5.1 years, compared to a 1.4% serious event rate in patients assigned to rate control. Dr. Kirchhof called the roughly 1% per year serious event rate in the rhythm control group quite acceptable.

“To put that in perspective, the annualized rate of severe bleeds on oral anticoagulation – a very beneficial therapy used by more than 90% of participants at 2 years – is about 2%,” the cardiologist noted.

Only 8% of patients randomized to rhythm control received AFib ablation as initial therapy, consistent with current clinical practice. By 2 years, 19.4% of the rhythm control group had undergone AFib ablation. Also at that time, 15% of the rate control group was receiving rhythm control therapy to help manage AFib-related symptoms.

One of the big surprises in the study, he said, was that nearly three-quarters of patients in both groups were asymptomatic at 2 years.

“I think that shows how well we control symptoms, even without rhythm control,” he observed.
 

Results ‘move the field forward’

Dr. Kirchhof stressed that this was a trial of two different treatment strategies, and it’s not yet possible to single out any specific component of the rhythm control strategy as being responsible for the improved outcomes.

“I cannot tell you whether the outcome difference was due to AFib ablation or early treatment or the fact that we’re now better at using antiarrhythmic drugs than we were 20 years ago,” he said.

Asked if the EAST-AFNET 4 findings warrant more aggressive screening for AFib in order to detect and intervene early in the arrhythmia, Dr. Kirchhof replied with an unambiguous yes.

“My conclusion is that every patient with newly diagnosed AFib and a CHA₂DS₂-VASc score of 2 or more should not only receive anticoagulation and rate control, but should also be offered rhythm control therapy at the time of diagnosis, which also means that all of these people have to be seen by a cardiologist who has expertise in the domain of AFib management. It’s a big clinical challenge, but it leads to a 21% improvement in outcomes, and I think we have to do what’s best for our patients,” he said.

In an interview, Kalyanam Shivkumar, MD, PhD, called EAST-AFNET 4 “a very important study.”

“It moves the field forward, for sure. I think it will change clinical practice, and it should,” commented Dr. Shivkumar, who was not involved in the study.

“Now there are so many wearable technologies out there – the Apple Watch and others – which will enable rhythm abnormalities to be detected early on. This bodes well for the field,” said Dr. Shivkumar, who is editor-in-chief of JACC: Clinical Electrophysiology. He is also professor of medicine, radiology, and bioengineering at the University of California, Los Angeles, and director of the UCLA Cardiac Arrhythmia Center.

Dr. Kirchhof reported receiving research grants to conduct the EAST-AFNET 4 trial from the German Ministry of Education and Research, the German Center for Cardiovascular Research, the Atrial Fibrillation Network, the European Heart Rhythm Association, St. Jude Medical, Abbott, Sanofi, the German Heart Foundation, the European Union, the British Heart Foundation, and the Leducq Foundation.

Simultaneous with his presentation at ESC Congress 2020, the study results were published online at NEJM.org.
 

[email protected]

SOURCE: Kirchhof P. ESC Congress 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2019422.

Initiation of rhythm control with antiarrhythmic drugs and/or ablation in patients with early, recently diagnosed atrial fibrillation (AFib) led to a significantly lower risk of major adverse cardiovascular outcomes, compared with a rate-control strategy, during more than 5 years of follow-up in the large randomized EAST-AFNET 4 trial, Paulus Kirchhof, MD, said at the virtual annual congress of the European Society of Cardiology.

Previous trials of rate versus rhythm control in AFib, such as AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), failed to show an advantage for rhythm over rate control in terms of clinical outcomes. Why was EAST-AFNET 4 different? Dr. Kirchhof offered two major reasons: The study incorporated AFib ablation as an option in the rhythm control strategy, and treatment started soon after diagnosis of the arrhythmia. Indeed, nearly 40% of patients had their first-ever AFib episode at the time of randomization, and the median time from diagnosis to randomization was just 36 days.

“Once you are in AFib for a few months, the atrium suffers severe damage, some of it irreversible, so it becomes more difficult to restore and maintain sinus rhythm when you wait longer,” explained Dr. Kirchhof, director of the department of cardiology at the University Heart and Vascular Center in Hamburg (Ger.) and professor of cardiovascular medicine at the University of Birmingham, England.

Also, epidemiologic studies show that the risk of cardiovascular complications is heightened in the first year following diagnosis of AFib. “So there’s a window of opportunity to prevent complications,” he added.

The impetus for conducting EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial ) was straightforward, according to the cardiologist: “The question of whether rhythm control is beneficial or not has been in the field for several decades. Most people, like me, always believed that maintaining sinus rhythm would help, but we didn’t have the data to show it.”
 

Early rhythm control shows sustained benefits

EAST-AFNET 4 was a prospective, open, blinded-outcome-assessement trial. It included 2,789 patients with early AFib and an average CHA₂DS₂-VASc score of 3.4 who were randomized at 135 sites in 11 European countries to early rhythm control or guideline-recommended rate control. At a median 5.1 years of follow-up, the primary outcome – a composite of cardiovascular death, stroke, acute coronary syndrome, or hospitalization for worsening heart failure – occurred at a pace of 3.9% per year in the rhythm control group and 5% per year with rate control. This translated to a statistically significant and clinically meaningful 21% relative risk reduction favoring early rhythm control.

The 28% reduction in cardiovascular death with rhythm control was statistically significant, as was the 35% reduction in stroke. However, the 19% reduction in heart failure hospitalizations and 17% decrease in hospitalizations for acute coronary syndrome were not.

The co–primary endpoint – the mean number of nights spent in the hospital per year, which served as a proxy for the cost of treatment to a health care system – didn’t differ between the two treatment arms, at roughly 5 nights per year.

The clinical benefit of early rhythm control was consistent across all 19 prespecified patient subgroups, including those who were asymptomatic and patients with or without heart failure.

Serious adverse events related to rhythm control therapy – most often drug-related bradycardia – occurred in 4.9% of patients over the course of 5.1 years, compared to a 1.4% serious event rate in patients assigned to rate control. Dr. Kirchhof called the roughly 1% per year serious event rate in the rhythm control group quite acceptable.

“To put that in perspective, the annualized rate of severe bleeds on oral anticoagulation – a very beneficial therapy used by more than 90% of participants at 2 years – is about 2%,” the cardiologist noted.

Only 8% of patients randomized to rhythm control received AFib ablation as initial therapy, consistent with current clinical practice. By 2 years, 19.4% of the rhythm control group had undergone AFib ablation. Also at that time, 15% of the rate control group was receiving rhythm control therapy to help manage AFib-related symptoms.

One of the big surprises in the study, he said, was that nearly three-quarters of patients in both groups were asymptomatic at 2 years.

“I think that shows how well we control symptoms, even without rhythm control,” he observed.
 

Results ‘move the field forward’

Dr. Kirchhof stressed that this was a trial of two different treatment strategies, and it’s not yet possible to single out any specific component of the rhythm control strategy as being responsible for the improved outcomes.

“I cannot tell you whether the outcome difference was due to AFib ablation or early treatment or the fact that we’re now better at using antiarrhythmic drugs than we were 20 years ago,” he said.

Asked if the EAST-AFNET 4 findings warrant more aggressive screening for AFib in order to detect and intervene early in the arrhythmia, Dr. Kirchhof replied with an unambiguous yes.

“My conclusion is that every patient with newly diagnosed AFib and a CHA₂DS₂-VASc score of 2 or more should not only receive anticoagulation and rate control, but should also be offered rhythm control therapy at the time of diagnosis, which also means that all of these people have to be seen by a cardiologist who has expertise in the domain of AFib management. It’s a big clinical challenge, but it leads to a 21% improvement in outcomes, and I think we have to do what’s best for our patients,” he said.

In an interview, Kalyanam Shivkumar, MD, PhD, called EAST-AFNET 4 “a very important study.”

“It moves the field forward, for sure. I think it will change clinical practice, and it should,” commented Dr. Shivkumar, who was not involved in the study.

“Now there are so many wearable technologies out there – the Apple Watch and others – which will enable rhythm abnormalities to be detected early on. This bodes well for the field,” said Dr. Shivkumar, who is editor-in-chief of JACC: Clinical Electrophysiology. He is also professor of medicine, radiology, and bioengineering at the University of California, Los Angeles, and director of the UCLA Cardiac Arrhythmia Center.

Dr. Kirchhof reported receiving research grants to conduct the EAST-AFNET 4 trial from the German Ministry of Education and Research, the German Center for Cardiovascular Research, the Atrial Fibrillation Network, the European Heart Rhythm Association, St. Jude Medical, Abbott, Sanofi, the German Heart Foundation, the European Union, the British Heart Foundation, and the Leducq Foundation.

Simultaneous with his presentation at ESC Congress 2020, the study results were published online at NEJM.org.
 

[email protected]

SOURCE: Kirchhof P. ESC Congress 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2019422.

Initiation of rhythm control with antiarrhythmic drugs and/or ablation in patients with early, recently diagnosed atrial fibrillation (AFib) led to a significantly lower risk of major adverse cardiovascular outcomes, compared with a rate-control strategy, during more than 5 years of follow-up in the large randomized EAST-AFNET 4 trial, Paulus Kirchhof, MD, said at the virtual annual congress of the European Society of Cardiology.

Previous trials of rate versus rhythm control in AFib, such as AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), failed to show an advantage for rhythm over rate control in terms of clinical outcomes. Why was EAST-AFNET 4 different? Dr. Kirchhof offered two major reasons: The study incorporated AFib ablation as an option in the rhythm control strategy, and treatment started soon after diagnosis of the arrhythmia. Indeed, nearly 40% of patients had their first-ever AFib episode at the time of randomization, and the median time from diagnosis to randomization was just 36 days.

“Once you are in AFib for a few months, the atrium suffers severe damage, some of it irreversible, so it becomes more difficult to restore and maintain sinus rhythm when you wait longer,” explained Dr. Kirchhof, director of the department of cardiology at the University Heart and Vascular Center in Hamburg (Ger.) and professor of cardiovascular medicine at the University of Birmingham, England.

Also, epidemiologic studies show that the risk of cardiovascular complications is heightened in the first year following diagnosis of AFib. “So there’s a window of opportunity to prevent complications,” he added.

The impetus for conducting EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial ) was straightforward, according to the cardiologist: “The question of whether rhythm control is beneficial or not has been in the field for several decades. Most people, like me, always believed that maintaining sinus rhythm would help, but we didn’t have the data to show it.”
 

Early rhythm control shows sustained benefits

EAST-AFNET 4 was a prospective, open, blinded-outcome-assessement trial. It included 2,789 patients with early AFib and an average CHA₂DS₂-VASc score of 3.4 who were randomized at 135 sites in 11 European countries to early rhythm control or guideline-recommended rate control. At a median 5.1 years of follow-up, the primary outcome – a composite of cardiovascular death, stroke, acute coronary syndrome, or hospitalization for worsening heart failure – occurred at a pace of 3.9% per year in the rhythm control group and 5% per year with rate control. This translated to a statistically significant and clinically meaningful 21% relative risk reduction favoring early rhythm control.

The 28% reduction in cardiovascular death with rhythm control was statistically significant, as was the 35% reduction in stroke. However, the 19% reduction in heart failure hospitalizations and 17% decrease in hospitalizations for acute coronary syndrome were not.

The co–primary endpoint – the mean number of nights spent in the hospital per year, which served as a proxy for the cost of treatment to a health care system – didn’t differ between the two treatment arms, at roughly 5 nights per year.

The clinical benefit of early rhythm control was consistent across all 19 prespecified patient subgroups, including those who were asymptomatic and patients with or without heart failure.

Serious adverse events related to rhythm control therapy – most often drug-related bradycardia – occurred in 4.9% of patients over the course of 5.1 years, compared to a 1.4% serious event rate in patients assigned to rate control. Dr. Kirchhof called the roughly 1% per year serious event rate in the rhythm control group quite acceptable.

“To put that in perspective, the annualized rate of severe bleeds on oral anticoagulation – a very beneficial therapy used by more than 90% of participants at 2 years – is about 2%,” the cardiologist noted.

Only 8% of patients randomized to rhythm control received AFib ablation as initial therapy, consistent with current clinical practice. By 2 years, 19.4% of the rhythm control group had undergone AFib ablation. Also at that time, 15% of the rate control group was receiving rhythm control therapy to help manage AFib-related symptoms.

One of the big surprises in the study, he said, was that nearly three-quarters of patients in both groups were asymptomatic at 2 years.

“I think that shows how well we control symptoms, even without rhythm control,” he observed.
 

Results ‘move the field forward’

Dr. Kirchhof stressed that this was a trial of two different treatment strategies, and it’s not yet possible to single out any specific component of the rhythm control strategy as being responsible for the improved outcomes.

“I cannot tell you whether the outcome difference was due to AFib ablation or early treatment or the fact that we’re now better at using antiarrhythmic drugs than we were 20 years ago,” he said.

Asked if the EAST-AFNET 4 findings warrant more aggressive screening for AFib in order to detect and intervene early in the arrhythmia, Dr. Kirchhof replied with an unambiguous yes.

“My conclusion is that every patient with newly diagnosed AFib and a CHA₂DS₂-VASc score of 2 or more should not only receive anticoagulation and rate control, but should also be offered rhythm control therapy at the time of diagnosis, which also means that all of these people have to be seen by a cardiologist who has expertise in the domain of AFib management. It’s a big clinical challenge, but it leads to a 21% improvement in outcomes, and I think we have to do what’s best for our patients,” he said.

In an interview, Kalyanam Shivkumar, MD, PhD, called EAST-AFNET 4 “a very important study.”

“It moves the field forward, for sure. I think it will change clinical practice, and it should,” commented Dr. Shivkumar, who was not involved in the study.

“Now there are so many wearable technologies out there – the Apple Watch and others – which will enable rhythm abnormalities to be detected early on. This bodes well for the field,” said Dr. Shivkumar, who is editor-in-chief of JACC: Clinical Electrophysiology. He is also professor of medicine, radiology, and bioengineering at the University of California, Los Angeles, and director of the UCLA Cardiac Arrhythmia Center.

Dr. Kirchhof reported receiving research grants to conduct the EAST-AFNET 4 trial from the German Ministry of Education and Research, the German Center for Cardiovascular Research, the Atrial Fibrillation Network, the European Heart Rhythm Association, St. Jude Medical, Abbott, Sanofi, the German Heart Foundation, the European Union, the British Heart Foundation, and the Leducq Foundation.

Simultaneous with his presentation at ESC Congress 2020, the study results were published online at NEJM.org.
 

[email protected]

SOURCE: Kirchhof P. ESC Congress 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2019422.

The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.

The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.

In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.

In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.

“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.

The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”

The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”

The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.

Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.

The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.

In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.

In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.

“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.

The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”

The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”

The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.

Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has removed the boxed warning about the risk of leg and foot amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes, the agency announced Aug. 26.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

As previously reported by Medscape Medical News, the FDA added the boxed warning to the canagliflozin label in May 2017, after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during two trials.

The FDA said the decision to remove the boxed warning was made following a review of new data from three clinical trials, which demonstrated additional heart- and kidney-related benefits and led to additional approved uses for canagliflozin.

In 2018, canagliflozin was approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease.

In 2019, canagliflozin was approved to reduce the risk of end-stage kidney disease, worsening of kidney function, cardiovascular death, and heart failure hospitalization, in adults with type 2 diabetes and diabetic kidney disease.

“Collectively, these newly identified effects of canagliflozin on heart and kidney disease show significantly enhanced benefit of this medicine,” the FDA said.

The safety information from these trials, the FDA said, suggests that the risk of amputation, “while still increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.”

The agency added: “Based upon these considerations, FDA concluded that the boxed warning should be removed.”

The FDA announcement said clinicians and patients should continue to be aware of the importance of preventive foot care and to monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to amputation should be considered when choosing antidiabetic medicines.

Health care professionals are encouraged to report adverse reactions with canagliflozin to the FDA’s MedWatch program.
 

A version of this article originally appeared on Medscape.com.

The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”

“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.

Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.

The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.

Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.

To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.

Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.

“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”

Hot Line Sessions 1-3, Saturday (14:00 CEST)

The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.

Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).

Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.

As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”

Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.

Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.

“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.

Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.

Hot Line Sessions 4-6, Sunday (14:00 CEST)

Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.

Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).

“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”

Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.

Hot Line Sessions 7-9, Monday (14:00 CEST)

The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.

Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.

Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.

Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.


Tuesday Hot Line Sessions 10-12 (14:00 CEST)

The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.

Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.

“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.

COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.

Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
 

This article first appeared on Medscape.com.

The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”

“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.

Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.

The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.

Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.

To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.

Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.

“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”

Hot Line Sessions 1-3, Saturday (14:00 CEST)

The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.

Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).

Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.

As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”

Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.

Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.

“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.

Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.

Hot Line Sessions 4-6, Sunday (14:00 CEST)

Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.

Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).

“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”

Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.

Hot Line Sessions 7-9, Monday (14:00 CEST)

The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.

Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.

Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.

Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.


Tuesday Hot Line Sessions 10-12 (14:00 CEST)

The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.

Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.

“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.

COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.

Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
 

This article first appeared on Medscape.com.

The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”

“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.

Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.

The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.

Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.

To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.

Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.

“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”

Hot Line Sessions 1-3, Saturday (14:00 CEST)

The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.

Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).

Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.

As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”

Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.

Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.

“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.

Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.

Hot Line Sessions 4-6, Sunday (14:00 CEST)

Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.

Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).

“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”

Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.

Hot Line Sessions 7-9, Monday (14:00 CEST)

The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.

Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.

Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.

Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.


Tuesday Hot Line Sessions 10-12 (14:00 CEST)

The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.

Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.

“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.

COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.

Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
 

This article first appeared on Medscape.com.

SARS-CoV-2 has been found in cardiac tissue of a child from Brazil with multisystem inflammatory syndrome (MIS-C) related to COVID-19 who presented with myocarditis and died of heart failure.

It’s believed to be the first evidence of direct infection of heart muscle cells by the virus; viral particles were identified in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells.

The case was described in a report published online August 20 in The Lancet Child & Adolescent Health.

“The presence of the virus in various cell types of cardiac tissue, as evidenced by electron microscopy, shows that myocarditis in this case is likely a direct inflammatory response to the virus infection in the heart,” first author Marisa Dolhnikoff, MD, department of pathology, University of São Paulo, said in an interview.

There have been previous reports in adults with COVID-19 of both SARS-CoV-2 RNA by reverse transcription–polymerase chain reaction (RT-PCR) and viral particles by electron microscopy in cardiac tissue from endomyocardial specimens, the researchers noted. One of these reports, published in April by Tavazzi and colleagues, “detected viral particles in cardiac macrophages in an adult patient with acute cardiac injury associated with COVID-19; no viral particles were seen in cardiomyocytes or endothelial cells.

“Our case report is the first to our knowledge to document the presence of viral particles in the cardiac tissue of a child affected by MIS-C,” they added. “Moreover, viral particles were identified in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells.”
 

‘Concerning’ case report

“This is a concerning report as it shows for the first time that the virus can actually invade the heart muscle cells themselves,” C. Michael Gibson, MD, CEO of the Baim Institute for Clinical Research in Boston, said in an interview.

“Previous reports of COVID-19 and the heart found that the virus was in the area outside the heart muscle cells. We do not know yet the relative contribution of the inflammatory cells invading the heart, the release of blood-borne inflammatory mediators, and the virus inside the heart muscle cells themselves to heart damage,” Dr. Gibson said.

The patient was a previously healthy 11-year-old girl of African descent with MIS-C related to COVID-19. She developed cardiac failure and died after 1 day in the hospital, despite aggressive treatment.

SARS-CoV-2 RNA was detected on a postmortem nasopharyngeal swab and in cardiac and pulmonary tissues by RT-PCR.

Postmortem ultrasound examination of the heart showed a “hyperechogenic and diffusely thickened endocardium (mean thickness, 10 mm), a thickened myocardium (18 mm thick in the left ventricle), and a small pericardial effusion,” Dr. Dolhnikoff and colleagues reported.

Histopathologic exam revealed myocarditis, pericarditis, and endocarditis characterized by infiltration of inflammatory cells. Inflammation was mainly interstitial and perivascular, associated with foci of cardiomyocyte necrosis and was mainly composed of CD68+ macrophages, a few CD45+ lymphocytes, and a few neutrophils and eosinophils.

Electron microscopy of cardiac tissue revealed spherical viral particles in shape and size consistent with the Coronaviridae family in the extracellular compartment and within cardiomyocytes, capillary endothelial cells, endocardium endothelial cells, macrophages, neutrophils, and fibroblasts.

Microthrombi in the pulmonary arterioles and renal glomerular capillaries were also seen at autopsy. SARS-CoV-2–associated pneumonia was mild.

Lymphoid depletion and signs of hemophagocytosis were observed in the spleen and lymph nodes. Acute tubular necrosis in the kidneys and hepatic centrilobular necrosis, secondary to shock, were also seen. Brain tissue showed microglial reactivity.

“Fortunately, MIS-C is a rare event and, although it can be severe and life threatening, most children recover,” Dr. Dolhnikoff commented.

“This case report comes at a time when the scientific community around the world calls attention to MIS-C and the need for it to be quickly recognized and treated by the pediatric community. Evidence of a direct relation between the virus and myocarditis confirms that MIS-C is one of the possible forms of presentation of COVID-19 and that the heart may be the target organ. It also alerts clinicians to possible cardiac sequelae in these children,” she added.

Experts weigh in

Scott Aydin, MD, medical director of pediatric cardiac intensive care, Mount Sinai Kravis Children’s Hospital in New York City, said that this case report is “unfortunately not all that surprising.

“Since the initial presentations of MIS-C several months ago, we have suspected mechanisms of direct and indirect injury to the myocardium. This important work is just the next step in further understanding the mechanisms of how COVID-19 creates havoc in the human body and the choices of possible therapies we have to treat children with COVID-19 and MIS-C,” said Dr. Aydin, who was not involved with the case report.

Anish Koka, MD, a cardiologist in private practice in Philadelphia, noted that, in these cases, endomyocardial biopsy is “rarely done because it is fairly invasive, but even when it has been done, the pathologic findings are of widespread inflammation rather than virus-induced cell necrosis.”

“While reports like this are sure to spawn viral tweets, it’s vital to understand that it’s not unusual to find widespread organ dissemination of virus in very sick patients. This does not mean that the virus is causing dysfunction of the organ it happens to be found in,” Dr. Koka said in an interview.

He noted that, in the case of the young girl who died, it took high PCR-cycle threshold values to isolate virus from the lung and heart samples.

“This means there was a low viral load in both organs, supporting the theory of SARS-CoV-2 as a potential trigger of a widespread inflammatory response that results in organ damage, rather than the virus itself infecting and destroying organs,” said Dr. Koka, who was also not associated with the case report.

This research had no specific funding. The authors declared no competing interests. Dr. Aydin disclosed no relevant financial relationships. Dr. Koka disclosed financial relationships with Boehringer Ingelheim and Jardiance.

This article first appeared on Medscape.com.

SARS-CoV-2 has been found in cardiac tissue of a child from Brazil with multisystem inflammatory syndrome (MIS-C) related to COVID-19 who presented with myocarditis and died of heart failure.

It’s believed to be the first evidence of direct infection of heart muscle cells by the virus; viral particles were identified in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells.

The case was described in a report published online August 20 in The Lancet Child & Adolescent Health.

“The presence of the virus in various cell types of cardiac tissue, as evidenced by electron microscopy, shows that myocarditis in this case is likely a direct inflammatory response to the virus infection in the heart,” first author Marisa Dolhnikoff, MD, department of pathology, University of São Paulo, said in an interview.

There have been previous reports in adults with COVID-19 of both SARS-CoV-2 RNA by reverse transcription–polymerase chain reaction (RT-PCR) and viral particles by electron microscopy in cardiac tissue from endomyocardial specimens, the researchers noted. One of these reports, published in April by Tavazzi and colleagues, “detected viral particles in cardiac macrophages in an adult patient with acute cardiac injury associated with COVID-19; no viral particles were seen in cardiomyocytes or endothelial cells.

“Our case report is the first to our knowledge to document the presence of viral particles in the cardiac tissue of a child affected by MIS-C,” they added. “Moreover, viral particles were identified in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells.”
 

‘Concerning’ case report

“This is a concerning report as it shows for the first time that the virus can actually invade the heart muscle cells themselves,” C. Michael Gibson, MD, CEO of the Baim Institute for Clinical Research in Boston, said in an interview.

“Previous reports of COVID-19 and the heart found that the virus was in the area outside the heart muscle cells. We do not know yet the relative contribution of the inflammatory cells invading the heart, the release of blood-borne inflammatory mediators, and the virus inside the heart muscle cells themselves to heart damage,” Dr. Gibson said.

The patient was a previously healthy 11-year-old girl of African descent with MIS-C related to COVID-19. She developed cardiac failure and died after 1 day in the hospital, despite aggressive treatment.

SARS-CoV-2 RNA was detected on a postmortem nasopharyngeal swab and in cardiac and pulmonary tissues by RT-PCR.

Postmortem ultrasound examination of the heart showed a “hyperechogenic and diffusely thickened endocardium (mean thickness, 10 mm), a thickened myocardium (18 mm thick in the left ventricle), and a small pericardial effusion,” Dr. Dolhnikoff and colleagues reported.

Histopathologic exam revealed myocarditis, pericarditis, and endocarditis characterized by infiltration of inflammatory cells. Inflammation was mainly interstitial and perivascular, associated with foci of cardiomyocyte necrosis and was mainly composed of CD68+ macrophages, a few CD45+ lymphocytes, and a few neutrophils and eosinophils.

Electron microscopy of cardiac tissue revealed spherical viral particles in shape and size consistent with the Coronaviridae family in the extracellular compartment and within cardiomyocytes, capillary endothelial cells, endocardium endothelial cells, macrophages, neutrophils, and fibroblasts.

Microthrombi in the pulmonary arterioles and renal glomerular capillaries were also seen at autopsy. SARS-CoV-2–associated pneumonia was mild.

Lymphoid depletion and signs of hemophagocytosis were observed in the spleen and lymph nodes. Acute tubular necrosis in the kidneys and hepatic centrilobular necrosis, secondary to shock, were also seen. Brain tissue showed microglial reactivity.

“Fortunately, MIS-C is a rare event and, although it can be severe and life threatening, most children recover,” Dr. Dolhnikoff commented.

“This case report comes at a time when the scientific community around the world calls attention to MIS-C and the need for it to be quickly recognized and treated by the pediatric community. Evidence of a direct relation between the virus and myocarditis confirms that MIS-C is one of the possible forms of presentation of COVID-19 and that the heart may be the target organ. It also alerts clinicians to possible cardiac sequelae in these children,” she added.

Experts weigh in

Scott Aydin, MD, medical director of pediatric cardiac intensive care, Mount Sinai Kravis Children’s Hospital in New York City, said that this case report is “unfortunately not all that surprising.

“Since the initial presentations of MIS-C several months ago, we have suspected mechanisms of direct and indirect injury to the myocardium. This important work is just the next step in further understanding the mechanisms of how COVID-19 creates havoc in the human body and the choices of possible therapies we have to treat children with COVID-19 and MIS-C,” said Dr. Aydin, who was not involved with the case report.

Anish Koka, MD, a cardiologist in private practice in Philadelphia, noted that, in these cases, endomyocardial biopsy is “rarely done because it is fairly invasive, but even when it has been done, the pathologic findings are of widespread inflammation rather than virus-induced cell necrosis.”

“While reports like this are sure to spawn viral tweets, it’s vital to understand that it’s not unusual to find widespread organ dissemination of virus in very sick patients. This does not mean that the virus is causing dysfunction of the organ it happens to be found in,” Dr. Koka said in an interview.

He noted that, in the case of the young girl who died, it took high PCR-cycle threshold values to isolate virus from the lung and heart samples.

“This means there was a low viral load in both organs, supporting the theory of SARS-CoV-2 as a potential trigger of a widespread inflammatory response that results in organ damage, rather than the virus itself infecting and destroying organs,” said Dr. Koka, who was also not associated with the case report.

This research had no specific funding. The authors declared no competing interests. Dr. Aydin disclosed no relevant financial relationships. Dr. Koka disclosed financial relationships with Boehringer Ingelheim and Jardiance.

This article first appeared on Medscape.com.

SARS-CoV-2 has been found in cardiac tissue of a child from Brazil with multisystem inflammatory syndrome (MIS-C) related to COVID-19 who presented with myocarditis and died of heart failure.

It’s believed to be the first evidence of direct infection of heart muscle cells by the virus; viral particles were identified in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells.

The case was described in a report published online August 20 in The Lancet Child & Adolescent Health.

“The presence of the virus in various cell types of cardiac tissue, as evidenced by electron microscopy, shows that myocarditis in this case is likely a direct inflammatory response to the virus infection in the heart,” first author Marisa Dolhnikoff, MD, department of pathology, University of São Paulo, said in an interview.

There have been previous reports in adults with COVID-19 of both SARS-CoV-2 RNA by reverse transcription–polymerase chain reaction (RT-PCR) and viral particles by electron microscopy in cardiac tissue from endomyocardial specimens, the researchers noted. One of these reports, published in April by Tavazzi and colleagues, “detected viral particles in cardiac macrophages in an adult patient with acute cardiac injury associated with COVID-19; no viral particles were seen in cardiomyocytes or endothelial cells.

“Our case report is the first to our knowledge to document the presence of viral particles in the cardiac tissue of a child affected by MIS-C,” they added. “Moreover, viral particles were identified in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells.”
 

‘Concerning’ case report

“This is a concerning report as it shows for the first time that the virus can actually invade the heart muscle cells themselves,” C. Michael Gibson, MD, CEO of the Baim Institute for Clinical Research in Boston, said in an interview.

“Previous reports of COVID-19 and the heart found that the virus was in the area outside the heart muscle cells. We do not know yet the relative contribution of the inflammatory cells invading the heart, the release of blood-borne inflammatory mediators, and the virus inside the heart muscle cells themselves to heart damage,” Dr. Gibson said.

The patient was a previously healthy 11-year-old girl of African descent with MIS-C related to COVID-19. She developed cardiac failure and died after 1 day in the hospital, despite aggressive treatment.

SARS-CoV-2 RNA was detected on a postmortem nasopharyngeal swab and in cardiac and pulmonary tissues by RT-PCR.

Postmortem ultrasound examination of the heart showed a “hyperechogenic and diffusely thickened endocardium (mean thickness, 10 mm), a thickened myocardium (18 mm thick in the left ventricle), and a small pericardial effusion,” Dr. Dolhnikoff and colleagues reported.

Histopathologic exam revealed myocarditis, pericarditis, and endocarditis characterized by infiltration of inflammatory cells. Inflammation was mainly interstitial and perivascular, associated with foci of cardiomyocyte necrosis and was mainly composed of CD68+ macrophages, a few CD45+ lymphocytes, and a few neutrophils and eosinophils.

Electron microscopy of cardiac tissue revealed spherical viral particles in shape and size consistent with the Coronaviridae family in the extracellular compartment and within cardiomyocytes, capillary endothelial cells, endocardium endothelial cells, macrophages, neutrophils, and fibroblasts.

Microthrombi in the pulmonary arterioles and renal glomerular capillaries were also seen at autopsy. SARS-CoV-2–associated pneumonia was mild.

Lymphoid depletion and signs of hemophagocytosis were observed in the spleen and lymph nodes. Acute tubular necrosis in the kidneys and hepatic centrilobular necrosis, secondary to shock, were also seen. Brain tissue showed microglial reactivity.

“Fortunately, MIS-C is a rare event and, although it can be severe and life threatening, most children recover,” Dr. Dolhnikoff commented.

“This case report comes at a time when the scientific community around the world calls attention to MIS-C and the need for it to be quickly recognized and treated by the pediatric community. Evidence of a direct relation between the virus and myocarditis confirms that MIS-C is one of the possible forms of presentation of COVID-19 and that the heart may be the target organ. It also alerts clinicians to possible cardiac sequelae in these children,” she added.

Experts weigh in

Scott Aydin, MD, medical director of pediatric cardiac intensive care, Mount Sinai Kravis Children’s Hospital in New York City, said that this case report is “unfortunately not all that surprising.

“Since the initial presentations of MIS-C several months ago, we have suspected mechanisms of direct and indirect injury to the myocardium. This important work is just the next step in further understanding the mechanisms of how COVID-19 creates havoc in the human body and the choices of possible therapies we have to treat children with COVID-19 and MIS-C,” said Dr. Aydin, who was not involved with the case report.

Anish Koka, MD, a cardiologist in private practice in Philadelphia, noted that, in these cases, endomyocardial biopsy is “rarely done because it is fairly invasive, but even when it has been done, the pathologic findings are of widespread inflammation rather than virus-induced cell necrosis.”

“While reports like this are sure to spawn viral tweets, it’s vital to understand that it’s not unusual to find widespread organ dissemination of virus in very sick patients. This does not mean that the virus is causing dysfunction of the organ it happens to be found in,” Dr. Koka said in an interview.

He noted that, in the case of the young girl who died, it took high PCR-cycle threshold values to isolate virus from the lung and heart samples.

“This means there was a low viral load in both organs, supporting the theory of SARS-CoV-2 as a potential trigger of a widespread inflammatory response that results in organ damage, rather than the virus itself infecting and destroying organs,” said Dr. Koka, who was also not associated with the case report.

This research had no specific funding. The authors declared no competing interests. Dr. Aydin disclosed no relevant financial relationships. Dr. Koka disclosed financial relationships with Boehringer Ingelheim and Jardiance.

This article first appeared on Medscape.com.

The beneficial effect on all-cause mortality of coronary artery bypass grafting surgery observed at 4 and 5 years in women with complex coronary disease seen in the SYNTAX trial is gone at 10 years.

If anything, the results suggest a mortality benefit for coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) mainly for men (adjusted hazard ratio, 0.76; 95% confidence interval, 0.56-1.02) and not for women (adjusted HR, 0.90; 95% CI, 0.54-1.51) in the SYNTAX Extended Survival (SYNTAXES) study.

The sex-treatment interaction for all-cause mortality was significant at 5 years (P = .025) but not at 10 years (P = .952).

“I’m becoming very humble with trials because I’m not expecting the convergence of the curve. I was expecting like a surge, a further divergence,” senior author Patrick Serruys, MD, PhD, National University of Ireland, Galway, said in an interview. “You could say, at the end of the day, everybody dies. And that’s the life expectancy factor.”

Although female patients had slightly lower anatomic SYNTAX scores at randomization (27.0 vs. 29.2), they were on average 4 years older than men (mean age, 68 years) and had higher prevalence rates of diabetes, hypertension, and chronic kidney disease, he noted. “The other explanation is that we know that the bypass graft, the saphenous bypass graft, became vulnerable around 7 years; that’s probably the half-life.”

Overall, mortality in both men and women tended to be lower after CABG than after PCI, although the differences were not statistically significant, the authors reported August 17 in the Journal of the American College of Cardiology.

The 1,800-patient SYNTAX trial showed no difference in all-cause mortality at 5 years between CABG and PCI, although CABG was associated with fewer major adverse cardiac and cerebrovascular events (MACCE) and more favorable results among those with complex, three-vessel disease.

The findings were confirmed in 10-year follow-up reported last year from SYNTAXES, which analyzed only all-cause mortality.

Female sex, however, was an independent predictor of mortality with PCI at 4-years follow-up (HR, 2.87) in SYNTAX and led to sex being incorporated into the SYNTAX II score to help guide revascularization decisions. Notably, this interaction for all-cause mortality has not been seen in other studies.

Treatment effect by sex

In the new prespecified subgroup analysis, women had a higher crude rate of all-cause mortality at 10 years than men (32.8% vs. 24.7%; log-rank P = .002). This held true whether women were in the PCI group (33.0% vs. 27.0%; log-rank P = .053) or the CABG group (32.5% vs. 22.5%; log-rank P = .017).

In women, the mortality rate was significantly higher with PCI than with CABG at 5 years, but was no longer different at 10 years (33.0% vs. 32.5%; log-rank P = .601). This was largely caused by an uptick in deaths between 5 and 10 years in those treated with CABG, compared with PCI.

In men, the mortality rate was similar between PCI and CABG at 5 years, but tended to be higher with PCI at 10 years (27.0% vs. 22.5%; log-rank P = .082).

Asked about the possible late benefit for CABG in men, Dr. Serruys replied: “Of course, everyone had made a hypothesis – ‘let’s look at the use of internal mammary arteries in these patients, etc.’ – but I must be honest, we don’t have an explanation so far.”

Roxana Mehran, MD, Mount Sinai School of Medicine, New York City, said with just 402 women and using a no-longer-available, first-generation (Taxus) stent, the findings are, unfortunately, not informative.

“For me, it would be important for these investigators to share their data for women so we can do a patient-based analysis to better figure out the differential between first-generation stents and how well we’re doing,” Dr. Mehran said.

“What’s really important is to have a study where you actually collect female-specific risk factors that are never, ever looked at, [such as] age at menopause or having had pregnancy-related complications, that predispose these women to more of an atherosclerotic risk. And, even so, to better understand their anatomy and what suits them better,” she said. “I just don’t think we know enough or have put enough effort into understanding the biology that is sex specific and different for men and women.”
 

Revising SYNTAX II score

Given the lack of a sex-treatment interaction in the analysis, Dr. Serruys and colleagues suggest that the SYNTAX II score “should be reevaluated for the prediction of all-cause mortality at 10 years.”

Lending further support to this is the fact that SYNTAX II score was similar between women who died at 5-10 years and those who died in the first 5 years after CABG (31.8 vs. 31.6).

“The authors rightfully ask whether the SYNTAX II score should be revised to remove female sex, and given the current study result this appears warranted,” Arnold H. Seto, MD, MPA, Long Beach (Calif.) Veterans Administration Hospital, said in a related editorial.

He pointed out that women in SYNTAXES treated with CABG tended to have a survival time 0.51 years longer than women treated with PCI (P = .07). Nonetheless, the lack of confirmation for a sex-specific treatment interaction in any other study – EXCEL, FREEDOM, BEST, PRECOMBAT, BARI, or MASS – strongly suggests that the interaction seen in SYNTAX is likely a “type 1 error.”

Rather than focusing on early mortality, which may represent relatively rare events that are susceptible to chance, Dr. Seto suggested “other endpoints such years of life saved, quality adjusted life-years, and MACE may better capture the benefits of different revascularization decisions, even if they have a higher risk for bias.”

A new risk model, SYNTAX score 2020, has been developed and will be published imminently, Dr. Serruys said in an interview.

The SYNTAX Extended Survival study was supported by the German Foundation of Heart Research. The SYNTAX trial, during 0- to 5-years of follow-up, was funded by Boston Scientific. Both sponsors had no role in study design or data collection, analyses, and interpretation, nor were they involved in the decision to publish the final manuscript. Dr. Serruys has received personal fees from Biosensors, Micel Technologies, Sinomedical Sciences Technology, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Seto reported research grants from Philips and Acist, and honoraria from Terumo, Getinge, Boston Scientific, General Electric, and Janssen.

A version of this article originally appeared on Medscape.com.

The beneficial effect on all-cause mortality of coronary artery bypass grafting surgery observed at 4 and 5 years in women with complex coronary disease seen in the SYNTAX trial is gone at 10 years.

If anything, the results suggest a mortality benefit for coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) mainly for men (adjusted hazard ratio, 0.76; 95% confidence interval, 0.56-1.02) and not for women (adjusted HR, 0.90; 95% CI, 0.54-1.51) in the SYNTAX Extended Survival (SYNTAXES) study.

The sex-treatment interaction for all-cause mortality was significant at 5 years (P = .025) but not at 10 years (P = .952).

“I’m becoming very humble with trials because I’m not expecting the convergence of the curve. I was expecting like a surge, a further divergence,” senior author Patrick Serruys, MD, PhD, National University of Ireland, Galway, said in an interview. “You could say, at the end of the day, everybody dies. And that’s the life expectancy factor.”

Although female patients had slightly lower anatomic SYNTAX scores at randomization (27.0 vs. 29.2), they were on average 4 years older than men (mean age, 68 years) and had higher prevalence rates of diabetes, hypertension, and chronic kidney disease, he noted. “The other explanation is that we know that the bypass graft, the saphenous bypass graft, became vulnerable around 7 years; that’s probably the half-life.”

Overall, mortality in both men and women tended to be lower after CABG than after PCI, although the differences were not statistically significant, the authors reported August 17 in the Journal of the American College of Cardiology.

The 1,800-patient SYNTAX trial showed no difference in all-cause mortality at 5 years between CABG and PCI, although CABG was associated with fewer major adverse cardiac and cerebrovascular events (MACCE) and more favorable results among those with complex, three-vessel disease.

The findings were confirmed in 10-year follow-up reported last year from SYNTAXES, which analyzed only all-cause mortality.

Female sex, however, was an independent predictor of mortality with PCI at 4-years follow-up (HR, 2.87) in SYNTAX and led to sex being incorporated into the SYNTAX II score to help guide revascularization decisions. Notably, this interaction for all-cause mortality has not been seen in other studies.

Treatment effect by sex

In the new prespecified subgroup analysis, women had a higher crude rate of all-cause mortality at 10 years than men (32.8% vs. 24.7%; log-rank P = .002). This held true whether women were in the PCI group (33.0% vs. 27.0%; log-rank P = .053) or the CABG group (32.5% vs. 22.5%; log-rank P = .017).

In women, the mortality rate was significantly higher with PCI than with CABG at 5 years, but was no longer different at 10 years (33.0% vs. 32.5%; log-rank P = .601). This was largely caused by an uptick in deaths between 5 and 10 years in those treated with CABG, compared with PCI.

In men, the mortality rate was similar between PCI and CABG at 5 years, but tended to be higher with PCI at 10 years (27.0% vs. 22.5%; log-rank P = .082).

Asked about the possible late benefit for CABG in men, Dr. Serruys replied: “Of course, everyone had made a hypothesis – ‘let’s look at the use of internal mammary arteries in these patients, etc.’ – but I must be honest, we don’t have an explanation so far.”

Roxana Mehran, MD, Mount Sinai School of Medicine, New York City, said with just 402 women and using a no-longer-available, first-generation (Taxus) stent, the findings are, unfortunately, not informative.

“For me, it would be important for these investigators to share their data for women so we can do a patient-based analysis to better figure out the differential between first-generation stents and how well we’re doing,” Dr. Mehran said.

“What’s really important is to have a study where you actually collect female-specific risk factors that are never, ever looked at, [such as] age at menopause or having had pregnancy-related complications, that predispose these women to more of an atherosclerotic risk. And, even so, to better understand their anatomy and what suits them better,” she said. “I just don’t think we know enough or have put enough effort into understanding the biology that is sex specific and different for men and women.”
 

Revising SYNTAX II score

Given the lack of a sex-treatment interaction in the analysis, Dr. Serruys and colleagues suggest that the SYNTAX II score “should be reevaluated for the prediction of all-cause mortality at 10 years.”

Lending further support to this is the fact that SYNTAX II score was similar between women who died at 5-10 years and those who died in the first 5 years after CABG (31.8 vs. 31.6).

“The authors rightfully ask whether the SYNTAX II score should be revised to remove female sex, and given the current study result this appears warranted,” Arnold H. Seto, MD, MPA, Long Beach (Calif.) Veterans Administration Hospital, said in a related editorial.

He pointed out that women in SYNTAXES treated with CABG tended to have a survival time 0.51 years longer than women treated with PCI (P = .07). Nonetheless, the lack of confirmation for a sex-specific treatment interaction in any other study – EXCEL, FREEDOM, BEST, PRECOMBAT, BARI, or MASS – strongly suggests that the interaction seen in SYNTAX is likely a “type 1 error.”

Rather than focusing on early mortality, which may represent relatively rare events that are susceptible to chance, Dr. Seto suggested “other endpoints such years of life saved, quality adjusted life-years, and MACE may better capture the benefits of different revascularization decisions, even if they have a higher risk for bias.”

A new risk model, SYNTAX score 2020, has been developed and will be published imminently, Dr. Serruys said in an interview.

The SYNTAX Extended Survival study was supported by the German Foundation of Heart Research. The SYNTAX trial, during 0- to 5-years of follow-up, was funded by Boston Scientific. Both sponsors had no role in study design or data collection, analyses, and interpretation, nor were they involved in the decision to publish the final manuscript. Dr. Serruys has received personal fees from Biosensors, Micel Technologies, Sinomedical Sciences Technology, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Seto reported research grants from Philips and Acist, and honoraria from Terumo, Getinge, Boston Scientific, General Electric, and Janssen.

A version of this article originally appeared on Medscape.com.

The beneficial effect on all-cause mortality of coronary artery bypass grafting surgery observed at 4 and 5 years in women with complex coronary disease seen in the SYNTAX trial is gone at 10 years.

If anything, the results suggest a mortality benefit for coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) mainly for men (adjusted hazard ratio, 0.76; 95% confidence interval, 0.56-1.02) and not for women (adjusted HR, 0.90; 95% CI, 0.54-1.51) in the SYNTAX Extended Survival (SYNTAXES) study.

The sex-treatment interaction for all-cause mortality was significant at 5 years (P = .025) but not at 10 years (P = .952).

“I’m becoming very humble with trials because I’m not expecting the convergence of the curve. I was expecting like a surge, a further divergence,” senior author Patrick Serruys, MD, PhD, National University of Ireland, Galway, said in an interview. “You could say, at the end of the day, everybody dies. And that’s the life expectancy factor.”

Although female patients had slightly lower anatomic SYNTAX scores at randomization (27.0 vs. 29.2), they were on average 4 years older than men (mean age, 68 years) and had higher prevalence rates of diabetes, hypertension, and chronic kidney disease, he noted. “The other explanation is that we know that the bypass graft, the saphenous bypass graft, became vulnerable around 7 years; that’s probably the half-life.”

Overall, mortality in both men and women tended to be lower after CABG than after PCI, although the differences were not statistically significant, the authors reported August 17 in the Journal of the American College of Cardiology.

The 1,800-patient SYNTAX trial showed no difference in all-cause mortality at 5 years between CABG and PCI, although CABG was associated with fewer major adverse cardiac and cerebrovascular events (MACCE) and more favorable results among those with complex, three-vessel disease.

The findings were confirmed in 10-year follow-up reported last year from SYNTAXES, which analyzed only all-cause mortality.

Female sex, however, was an independent predictor of mortality with PCI at 4-years follow-up (HR, 2.87) in SYNTAX and led to sex being incorporated into the SYNTAX II score to help guide revascularization decisions. Notably, this interaction for all-cause mortality has not been seen in other studies.

Treatment effect by sex

In the new prespecified subgroup analysis, women had a higher crude rate of all-cause mortality at 10 years than men (32.8% vs. 24.7%; log-rank P = .002). This held true whether women were in the PCI group (33.0% vs. 27.0%; log-rank P = .053) or the CABG group (32.5% vs. 22.5%; log-rank P = .017).

In women, the mortality rate was significantly higher with PCI than with CABG at 5 years, but was no longer different at 10 years (33.0% vs. 32.5%; log-rank P = .601). This was largely caused by an uptick in deaths between 5 and 10 years in those treated with CABG, compared with PCI.

In men, the mortality rate was similar between PCI and CABG at 5 years, but tended to be higher with PCI at 10 years (27.0% vs. 22.5%; log-rank P = .082).

Asked about the possible late benefit for CABG in men, Dr. Serruys replied: “Of course, everyone had made a hypothesis – ‘let’s look at the use of internal mammary arteries in these patients, etc.’ – but I must be honest, we don’t have an explanation so far.”

Roxana Mehran, MD, Mount Sinai School of Medicine, New York City, said with just 402 women and using a no-longer-available, first-generation (Taxus) stent, the findings are, unfortunately, not informative.

“For me, it would be important for these investigators to share their data for women so we can do a patient-based analysis to better figure out the differential between first-generation stents and how well we’re doing,” Dr. Mehran said.

“What’s really important is to have a study where you actually collect female-specific risk factors that are never, ever looked at, [such as] age at menopause or having had pregnancy-related complications, that predispose these women to more of an atherosclerotic risk. And, even so, to better understand their anatomy and what suits them better,” she said. “I just don’t think we know enough or have put enough effort into understanding the biology that is sex specific and different for men and women.”
 

Revising SYNTAX II score

Given the lack of a sex-treatment interaction in the analysis, Dr. Serruys and colleagues suggest that the SYNTAX II score “should be reevaluated for the prediction of all-cause mortality at 10 years.”

Lending further support to this is the fact that SYNTAX II score was similar between women who died at 5-10 years and those who died in the first 5 years after CABG (31.8 vs. 31.6).

“The authors rightfully ask whether the SYNTAX II score should be revised to remove female sex, and given the current study result this appears warranted,” Arnold H. Seto, MD, MPA, Long Beach (Calif.) Veterans Administration Hospital, said in a related editorial.

He pointed out that women in SYNTAXES treated with CABG tended to have a survival time 0.51 years longer than women treated with PCI (P = .07). Nonetheless, the lack of confirmation for a sex-specific treatment interaction in any other study – EXCEL, FREEDOM, BEST, PRECOMBAT, BARI, or MASS – strongly suggests that the interaction seen in SYNTAX is likely a “type 1 error.”

Rather than focusing on early mortality, which may represent relatively rare events that are susceptible to chance, Dr. Seto suggested “other endpoints such years of life saved, quality adjusted life-years, and MACE may better capture the benefits of different revascularization decisions, even if they have a higher risk for bias.”

A new risk model, SYNTAX score 2020, has been developed and will be published imminently, Dr. Serruys said in an interview.

The SYNTAX Extended Survival study was supported by the German Foundation of Heart Research. The SYNTAX trial, during 0- to 5-years of follow-up, was funded by Boston Scientific. Both sponsors had no role in study design or data collection, analyses, and interpretation, nor were they involved in the decision to publish the final manuscript. Dr. Serruys has received personal fees from Biosensors, Micel Technologies, Sinomedical Sciences Technology, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Seto reported research grants from Philips and Acist, and honoraria from Terumo, Getinge, Boston Scientific, General Electric, and Janssen.

A version of this article originally appeared on Medscape.com.

A machine-learning model that uses readily available clinical and electrocardiography data may have the potential to identify left ventricular (LV) diastolic dysfunction, a key biomarker in predicting heart failure, without echocardiography, but a workable clinical platform is still far off, a team of North American researchers reported.

“This cost-effective strategy may be a valuable first clinical step for assessing the presence of LV dysfunction and may potentially aid in the early diagnosis and management of heart failure patients,” Nobuyuki Kagiyama, MD, PhD, of West Virginia University, Morgantown, and colleagues, wrote in the Journal of the American Academy of Cardiology.

The researchers reported on a multicenter, prospective study that evaluated 1,202 patients from three centers in the United States and one in Canada. To develop machine-learning models, the study pooled 814 patients from the U.S. institutions as an internal cohort. They were then randomly divided into a training set and an internal test set on an 80:20 basis (651 and 163). The 388 Canadian patients were reserved as an external set to test the model.

All patients had 12-lead ECG and simultaneous body surface signal-processed ECG (spECG) along with comprehensive two-dimensional Doppler ECG on the same day.
 

How the model works

The machine-learning model estimated echocardiographic LV relaxation velocities (e’) values using traditional ECG and spECG features. The model also took into account 10 basic clinical features: age; sex; systolic and diastolic blood pressure; and comorbid conditions such as cerebrovascular and cardiovascular disease, diabetes, hypertension, dyslipidemia, and chronic kidney disease.

Patient characteristics were starkly different between the internal (United States) and external (Canadian) cohorts, with the latter being 10 years older on average (65 vs. 44; P < .001), predominantly male (58.2% vs. 47.3%; P < .001) and with significantly lower rates of coronary artery disease (1.8% vs. 21.1%; P < .001), although average blood pressure was similar between the two groups.

The study used area under the curve (AUC) to calculate the predictability of the machine-learning estimated e’ values versus the guideline-based reduced e’, finding close correlation between the internal (AUC, 0.83; sensitivity, 78%; specificity, 77%; negative predictive value, 73%; and positive predictive value, 82%) and external test sets (AUC, 0.84; sensitivity, 90%; specificity, 61%; NPV, 81%; and PPV, 77%).

Similar variations between the two cohorts were reported for global LV diastolic dysfunction and reduced LV ejection fraction.

The final model used 18 features in all, including 3 clinical features (age, dyslipidemia, and hypertension), 7 scores from spECG features, and 8 from traditional ECG features.
 

Interpreting the results

Dr. Kagiyama and colleagues noted that, because impaired myocardial relaxation is an early sign of cardiac tissue deterioration, screening for it can aid in early detection of subclinical LVDD and earlier treatment for hypertension and diabetes. But they acknowledged that further studies are needed.

In an invited editorial, Khurram Nasir, MD, MPH, MSc, of Houston Methodist DeBakey Heart and Vascular Center and Rohan Khera, MD, MS, of Yale University, New Haven, Conn., wrote that the machine-learning model has a way to go.

They noted that the 73%-77% accuracy of the model in identifying diastolic dysfunction impedes its imminent use. “Although we are excited about the prospects of such developments, we hold out for better evidence for their actual use,” they wrote, adding that the algorithms have limited use in the clinic because most patients already get “definitive testing” if they need it.

Developing a machine-learning model that obviates the need for ECG for evaluating LV diastolic dysfunction seems dubious at this time, said Luigi Di Biase, MD, PhD, section head of electrophysiology and director of arrhythmia services at Montefiore Medical Center and professor at Albert Einstein College of Medicine, both in New York. “The echo is not a difficult test. It’s the most proven usable tool that we have in cardiology because it’s easy to reproduce, low cost, and noninvasive – so we have all that we want in medicine.”

But machine learning does have potential, added Dr. Di Biase, who’s also a member of the American College of Cardiology’s Electrophysiology Section Leadership Council. “If this application could predict the people that would develop diastolic dysfunction that leads to heart failure – because an echo at that time may be negative but there may be other features that tell me this patient will develop disease – then it would have a much different clinical impact.”

The National Science Foundation provided funding for the study. Heart Test Laboratories, doing business as Heart Sciences, provided funding and spECG devices. Dr. Kagiyama reported receiving a research grant from Hitachi Healthcare. A coauthor disclosed financial relationships with Heart Sciences, Ultronics, and Kencor Health.

Dr. Nasir, Dr. Khera, and Dr. Di Biase have no relevant financial relationships to disclose.

SOURCE: Kagiyama N et al. J Am Coll Cardiol. 2020;76:930-41.

A machine-learning model that uses readily available clinical and electrocardiography data may have the potential to identify left ventricular (LV) diastolic dysfunction, a key biomarker in predicting heart failure, without echocardiography, but a workable clinical platform is still far off, a team of North American researchers reported.

“This cost-effective strategy may be a valuable first clinical step for assessing the presence of LV dysfunction and may potentially aid in the early diagnosis and management of heart failure patients,” Nobuyuki Kagiyama, MD, PhD, of West Virginia University, Morgantown, and colleagues, wrote in the Journal of the American Academy of Cardiology.

The researchers reported on a multicenter, prospective study that evaluated 1,202 patients from three centers in the United States and one in Canada. To develop machine-learning models, the study pooled 814 patients from the U.S. institutions as an internal cohort. They were then randomly divided into a training set and an internal test set on an 80:20 basis (651 and 163). The 388 Canadian patients were reserved as an external set to test the model.

All patients had 12-lead ECG and simultaneous body surface signal-processed ECG (spECG) along with comprehensive two-dimensional Doppler ECG on the same day.
 

How the model works

The machine-learning model estimated echocardiographic LV relaxation velocities (e’) values using traditional ECG and spECG features. The model also took into account 10 basic clinical features: age; sex; systolic and diastolic blood pressure; and comorbid conditions such as cerebrovascular and cardiovascular disease, diabetes, hypertension, dyslipidemia, and chronic kidney disease.

Patient characteristics were starkly different between the internal (United States) and external (Canadian) cohorts, with the latter being 10 years older on average (65 vs. 44; P < .001), predominantly male (58.2% vs. 47.3%; P < .001) and with significantly lower rates of coronary artery disease (1.8% vs. 21.1%; P < .001), although average blood pressure was similar between the two groups.

The study used area under the curve (AUC) to calculate the predictability of the machine-learning estimated e’ values versus the guideline-based reduced e’, finding close correlation between the internal (AUC, 0.83; sensitivity, 78%; specificity, 77%; negative predictive value, 73%; and positive predictive value, 82%) and external test sets (AUC, 0.84; sensitivity, 90%; specificity, 61%; NPV, 81%; and PPV, 77%).

Similar variations between the two cohorts were reported for global LV diastolic dysfunction and reduced LV ejection fraction.

The final model used 18 features in all, including 3 clinical features (age, dyslipidemia, and hypertension), 7 scores from spECG features, and 8 from traditional ECG features.
 

Interpreting the results

Dr. Kagiyama and colleagues noted that, because impaired myocardial relaxation is an early sign of cardiac tissue deterioration, screening for it can aid in early detection of subclinical LVDD and earlier treatment for hypertension and diabetes. But they acknowledged that further studies are needed.

In an invited editorial, Khurram Nasir, MD, MPH, MSc, of Houston Methodist DeBakey Heart and Vascular Center and Rohan Khera, MD, MS, of Yale University, New Haven, Conn., wrote that the machine-learning model has a way to go.

They noted that the 73%-77% accuracy of the model in identifying diastolic dysfunction impedes its imminent use. “Although we are excited about the prospects of such developments, we hold out for better evidence for their actual use,” they wrote, adding that the algorithms have limited use in the clinic because most patients already get “definitive testing” if they need it.

Developing a machine-learning model that obviates the need for ECG for evaluating LV diastolic dysfunction seems dubious at this time, said Luigi Di Biase, MD, PhD, section head of electrophysiology and director of arrhythmia services at Montefiore Medical Center and professor at Albert Einstein College of Medicine, both in New York. “The echo is not a difficult test. It’s the most proven usable tool that we have in cardiology because it’s easy to reproduce, low cost, and noninvasive – so we have all that we want in medicine.”

But machine learning does have potential, added Dr. Di Biase, who’s also a member of the American College of Cardiology’s Electrophysiology Section Leadership Council. “If this application could predict the people that would develop diastolic dysfunction that leads to heart failure – because an echo at that time may be negative but there may be other features that tell me this patient will develop disease – then it would have a much different clinical impact.”

The National Science Foundation provided funding for the study. Heart Test Laboratories, doing business as Heart Sciences, provided funding and spECG devices. Dr. Kagiyama reported receiving a research grant from Hitachi Healthcare. A coauthor disclosed financial relationships with Heart Sciences, Ultronics, and Kencor Health.

Dr. Nasir, Dr. Khera, and Dr. Di Biase have no relevant financial relationships to disclose.

SOURCE: Kagiyama N et al. J Am Coll Cardiol. 2020;76:930-41.

A machine-learning model that uses readily available clinical and electrocardiography data may have the potential to identify left ventricular (LV) diastolic dysfunction, a key biomarker in predicting heart failure, without echocardiography, but a workable clinical platform is still far off, a team of North American researchers reported.

“This cost-effective strategy may be a valuable first clinical step for assessing the presence of LV dysfunction and may potentially aid in the early diagnosis and management of heart failure patients,” Nobuyuki Kagiyama, MD, PhD, of West Virginia University, Morgantown, and colleagues, wrote in the Journal of the American Academy of Cardiology.

The researchers reported on a multicenter, prospective study that evaluated 1,202 patients from three centers in the United States and one in Canada. To develop machine-learning models, the study pooled 814 patients from the U.S. institutions as an internal cohort. They were then randomly divided into a training set and an internal test set on an 80:20 basis (651 and 163). The 388 Canadian patients were reserved as an external set to test the model.

All patients had 12-lead ECG and simultaneous body surface signal-processed ECG (spECG) along with comprehensive two-dimensional Doppler ECG on the same day.
 

How the model works

The machine-learning model estimated echocardiographic LV relaxation velocities (e’) values using traditional ECG and spECG features. The model also took into account 10 basic clinical features: age; sex; systolic and diastolic blood pressure; and comorbid conditions such as cerebrovascular and cardiovascular disease, diabetes, hypertension, dyslipidemia, and chronic kidney disease.

Patient characteristics were starkly different between the internal (United States) and external (Canadian) cohorts, with the latter being 10 years older on average (65 vs. 44; P < .001), predominantly male (58.2% vs. 47.3%; P < .001) and with significantly lower rates of coronary artery disease (1.8% vs. 21.1%; P < .001), although average blood pressure was similar between the two groups.

The study used area under the curve (AUC) to calculate the predictability of the machine-learning estimated e’ values versus the guideline-based reduced e’, finding close correlation between the internal (AUC, 0.83; sensitivity, 78%; specificity, 77%; negative predictive value, 73%; and positive predictive value, 82%) and external test sets (AUC, 0.84; sensitivity, 90%; specificity, 61%; NPV, 81%; and PPV, 77%).

Similar variations between the two cohorts were reported for global LV diastolic dysfunction and reduced LV ejection fraction.

The final model used 18 features in all, including 3 clinical features (age, dyslipidemia, and hypertension), 7 scores from spECG features, and 8 from traditional ECG features.
 

Interpreting the results

Dr. Kagiyama and colleagues noted that, because impaired myocardial relaxation is an early sign of cardiac tissue deterioration, screening for it can aid in early detection of subclinical LVDD and earlier treatment for hypertension and diabetes. But they acknowledged that further studies are needed.

In an invited editorial, Khurram Nasir, MD, MPH, MSc, of Houston Methodist DeBakey Heart and Vascular Center and Rohan Khera, MD, MS, of Yale University, New Haven, Conn., wrote that the machine-learning model has a way to go.

They noted that the 73%-77% accuracy of the model in identifying diastolic dysfunction impedes its imminent use. “Although we are excited about the prospects of such developments, we hold out for better evidence for their actual use,” they wrote, adding that the algorithms have limited use in the clinic because most patients already get “definitive testing” if they need it.

Developing a machine-learning model that obviates the need for ECG for evaluating LV diastolic dysfunction seems dubious at this time, said Luigi Di Biase, MD, PhD, section head of electrophysiology and director of arrhythmia services at Montefiore Medical Center and professor at Albert Einstein College of Medicine, both in New York. “The echo is not a difficult test. It’s the most proven usable tool that we have in cardiology because it’s easy to reproduce, low cost, and noninvasive – so we have all that we want in medicine.”

But machine learning does have potential, added Dr. Di Biase, who’s also a member of the American College of Cardiology’s Electrophysiology Section Leadership Council. “If this application could predict the people that would develop diastolic dysfunction that leads to heart failure – because an echo at that time may be negative but there may be other features that tell me this patient will develop disease – then it would have a much different clinical impact.”

The National Science Foundation provided funding for the study. Heart Test Laboratories, doing business as Heart Sciences, provided funding and spECG devices. Dr. Kagiyama reported receiving a research grant from Hitachi Healthcare. A coauthor disclosed financial relationships with Heart Sciences, Ultronics, and Kencor Health.

Dr. Nasir, Dr. Khera, and Dr. Di Biase have no relevant financial relationships to disclose.

SOURCE: Kagiyama N et al. J Am Coll Cardiol. 2020;76:930-41.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.

Rates of thyrotoxicosis are significantly higher among patients who are critically ill with COVID-19 than among patients who are critically ill but who do not not have COVID-19, suggesting an atypical form of thyroiditis related to the novel coronavirus infection, according to new research.

“We suggest routine assessment of thyroid function in patients with COVID-19 requiring high-intensity care because they frequently present with thyrotoxicosis due to a form of subacute thyroiditis related to SARS-CoV-2,” the authors wrote in correspondence published online in The Lancet Diabetes and Endocrinology.

However, notably, the study – which compared critically ill ICU patients who had COVID-19 with those who did not have COVID-19 or who had milder cases of COVID-19 – indicates that thyroid disorders do not appear to increase the risk of developing COVID-19, first author Ilaria Muller, MD, PhD, of the department of endocrinology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, said in an interview.

“It is important to highlight that we did not find an increased prevalence of preexisting thyroid disorders in COVID-19 patients (contrary to early media reports),” she said. “So far, clinical observations do not support this fear, and we need to reassure people with thyroid disorders, since such disorders are very common among the general population.”

Yet the findings add to emerging evidence of a COVID-19/thyroid relationship, Angela M. Leung, MD, said in an interview.

“Given the health care impacts of the current COVID-19 pandemic worldwide, this study provides some insight on the potential systemic inflammation, as well as thyroid-specific inflammation, of the SARS-Cov-2 virus that is described in some emerging reports,” she said.

“This study joins at least six others that have reported a clinical presentation resembling subacute thyroiditis in critically ill patients with COVID-19,” noted Dr. Leung, of the division of endocrinology, diabetes, and metabolism in the department of medicine at the University of California, Los Angeles.
 

Thyroid function analysis in those with severe COVID-19

Dr. Muller explained that preliminary data from her institution showed thyroid abnormalities in patients who were severely ill with COVID-19. She and her team extended the evaluation to include thyroid data and other data on 93 patients with COVID-19 who were admitted to high-intensity care units (HICUs) in Italy during the 2020 pandemic.

Those data were compared with data on 101 critically ill patients admitted to the same HICUs in 2019 who did not have COVID-19. A third group of 52 patients with COVID-19 who were admitted to low-intensity care units (LICUs) in Italy in 2020 were also included in the analysis.

The mean age of the patients in the HICU 2020 group was 65.3 years; in the HICU 2019 group, it was 73 years; and in the LICU group, it was 70 years (P = .001). In addition, the HICU 2020 group included more men than the other two groups (69% vs. 56% and 48%; P = .03).

Of note, only 9% of patients in the HICU 2020 group had preexisting thyroid disorders, compared with 21% in the LICU group and 23% in the HICU 2019 group (P = .017).

These findings suggest that “such conditions are not a risk factor for SARS-CoV-2 infection or severity of COVID-19,” the authors wrote.

The patients with the preexisting thyroid conditions were excluded from the thyroid function analysis.

A significantly higher proportion of patients in the HICU 2020 group (13; 15%) were thyrotoxic upon admission, compared with just 1 (1%) of 78 patients in the HICU 2019 group (P = .002) and one (2%) of 41 patients in the LICU group (P = .025).

Among the 14 patients in the two COVID-19 groups who had thyrotoxicosis, the majority were male (9; 64%)

Among those in the HICU 2020 group, serum thyroid-stimulating hormone concentrations were lower than in either of the other two groups (P = .018), and serum free thyroxine (free T4) concentrations were higher than in the LICU group (P = .016) but not the HICU 2019 group.
 

Differences compared with other infection-related thyroiditis

Although thyrotoxicosis relating to subacute viral thyroiditis can result from a wide variety of viral infections, there are some key differences with COVID-19, Dr. Muller said.

“Thyroid dysfunction related to SARS-CoV-2 seems to be milder than that of classic subacute thyroiditis due to other viruses,” she explained. Furthermore, thyroid dysfunction associated with other viral infections is more common in women, whereas there were more male patients with the COVID-19–related atypical thyroiditis.

In addition, the thyroid effects developed early with COVID-19, whereas they usually emerge after the infections by other viruses.

Patients did not demonstrate the neck pain that is common with classic viral thyroiditis, and the thyroid abnormalities appear to correlate with the severity of COVID-19, whereas they are seen even in patients with mild symptoms when other viral infections are the cause.

In addition to the risk for subacute viral thyroiditis, critically ill patients in general are at risk of developing nonthyroidal illness syndrome, with alterations in thyroid function. However, thyroid hormone measures in the patients severely ill with COVID-19 were not consistent with that syndrome.

A subanalysis of eight HICU 2020 patients with thyroid dysfunction who were followed for 55 days after discharge showed that two experienced hyperthyroidism but likely not from COVID-19; in the remaining six, thyroid function normalized.

Muller speculated that, when ill with COVID-19, the patients likely had a combination of SARS-CoV-2–related atypical thyroiditis and nonthyroidal illness syndrome, known as T4 toxicosis.
 

Will there be any long-term effects?

Importantly, it remains unknown whether the novel coronavirus has longer-term effects on the thyroid, Dr. Muller said.

“We cannot predict what will be the long-lasting thyroid effects after COVID-19,” she said.

With classic subacute viral thyroiditis, “After a few years ... 5%-20% of patients develop permanent hypothyroidism, [and] the same might happen in COVID-19 patients,” she hypothesized. “We will follow our patients long term to answer this question – this study is already ongoing.”

In the meantime, diagnosis of thyroid dysfunction in patients with COVID-19 is important, inasmuch as it could worsen the already critical conditions of patients, Muller stressed.

“The gold-standard treatment for thyroiditis is steroids, so the presence of thyroid dysfunction might represent an additional indication to such treatment in COVID-19 patients, to be verified in properly designed clinical trials,” she advised.
 

ACE2 cell receptors highly expressed in thyroid

Dr. Muller and colleagues also noted recent research showing that ACE2 – demonstrated to be a key host-cell entry receptor for both SARS-CoV and SARS-CoV-2 – is expressed in even higher levels in the thyroid than the lungs, where it causes COVID-19’s notorious pulmonary effects.

Dr. Muller said the implications of ACE2 expression in the thyroid remain to be elucidated.

“If ACE2 is confirmed to be expressed at higher levels, compared with the lungs in the thyroid gland and other tissues, i.e., small intestine, testis, kidney, heart, etc, dedicated studies will be needed to correlate ACE2 expression with the organs’ susceptibility to SARS-CoV-2 reflected by clinical presentation,” she said.

Dr. Leung added that, as a take-home message from these and the other thyroid/COVID-19 studies, “data are starting to show us that COVID-19 infection may cause thyrotoxicosis that is possibly related to thyroid and systemic inflammation. However, the serum thyroid function test abnormalities seen in COVID-19 patients with subacute thyroiditis are also likely exacerbated to a substantial extent by nonthyroidal illness physiology.”

The authors have disclosed no relevant financial relationships. Dr. Leung is on the advisory board of Medscape Diabetes and Endocrinology.

A version of this article originally appeared on Medscape.com.