Cardiology News

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

Treatment with a novel myosin-inhibiting agent may improve symptoms and hemodynamics enough in patients with obstructive hypertrophic cardiomyopathy (OHCM) so that they can avoid or at least delay septal reduction therapy (SRT), suggests a randomized trial of modest size and duration.

Of 112 patients with OHCM who were sick enough while receiving standard medications to qualify for SRT, those assigned to take mavacamten (MyoKardia) instead of placebo were far less likely to still be eligible for SRT 16 weeks later.

In other words, their OHCM had improved enough during therapy with mavacamten such that SRT, either surgical septal myectomy or transcatheter alcohol septal ablation, could no longer be recommended per guidelines.

Mavacamten, which lessens myocardial contractility by selective inhibition of cardiac myosin, is the first agent tested in prospective trials to appear as a viable medical option in patients with severe, symptomatic OHCM, observed principal investigator Milind Y. Desai, MD, MBA, of the Cleveland Clinic.

“There’s clearly an unmet need for noninvasive therapies, medical therapies, that work in OHCM,” he said in an interview. Mavacamten “adds to the armamentarium” of OHCM management options and may give patients with symptoms despite conventional medications an alternative to SRT, which is considered definitive but has drawbacks.

The goal of SRT is to alleviate obstruction of the left ventricular outflow tract (LVOT), but surgical SRT requires a sternotomy, with all the risks and recovery time that entails. Catheter-based alcohol septal ablation is a less common alternative for some patients with suitable anatomy, Dr. Desai noted.

But those procedures “are not uniformly available, and even when  available, the outcomes are fairly heterogeneous,” he said. “The guidelines recommend that you should go to a center with a mortality rate of less than 1% with these procedures. Centers like that are very few across the world,” and procedural mortality can be much higher at centers with less SRT experience.

Dr. Desai presented the results of VALOR-HCM at the annual scientific sessions of the American College of Cardiology. Of the 56 patients assigned to mavacamten, 10 (17.9%) decided to undergo SRT by the end of the trial, or otherwise still met guideline-recommended criteria for receiving SRT, the primary endpoint. In comparison, 43 of the 56 patients (76.8%) in the control group (P < .0001) met that endpoint.

More patients receiving mavacamten improved by at least one New York Heart Association (NYHA) functional class during the trial’s 16 weeks: 63% versus 21% for those assigned to placebo. And 27% and 2%, respectively, improved by at least two NYHA classes, Dr. Desai said.

Guidelines recommend that SRT be reserved for patients in NYHA class III or IV heart failure with a resting or provoked LVOT gradient of at least 50 mm Hg.

Of note, Desai said, only two patients in each group elected to undergo SRT during the study. “The primary endpoint was driven by reduction in guideline eligibility for SRT, but 95% of patients in the study chose to continue with medical therapy.”

Speaking as a panelist after Dr. Desai’s presentation, Lynne W. Stevenson, MD, lauded the phase 3 trial’s “brave design,” which featured a highly unusual subjective primary endpoint and framed it as an advantage.

That the trial showed a significant mavacamten effect for that endpoint “answered, in one step, the question of what does this actually mean to the patient – which often takes much longer,” observed Dr. Stevenson, from Vanderbilt University, Nashville, Tenn.

Even so, she added, whether patients still qualified for SRT in the trial at least had to be supported by objective measures of LVOT gradient and NT-proBNP levels.

“My perspective is that of a cardiac surgeon who performs septal myectomies,” said John Cleveland, MD, University of Colorado at Denver, Aurora, who said he was impressed at how few patients receiving mavacamten went on to undergo SRT, while the rest were able to at least defer that decision.

Current recommendations are that patients who go to SRT “should be maximally medically treated and still symptomatic,” Dr. Cleveland observed at a press conference on VALOR-HCM. Should mavacamten be added to the list of agents to use before resorting to invasive therapy? “My answer would be yes,” he said, and patients who remain symptomatic even while receiving the myosin inhibitor and other medications should proceed to SRT.

The trial’s patients had documented OHCM, severe symptoms, and a resting or provoked LVOT gradient of at least 50 mm Hg despite maximally tolerated medications – which could include disopyramide, beta-blockers, and calcium channel blockers. About half the study population was female, and 89% were White. All had been referred for SRT.

Active therapy consisted of mavacamten initiated at 5 mg/day, with up-titrations at 8 and 12 weeks as tolerated, guided by echocardiographic left ventricular ejection fraction and LVOT gradient.  

Most secondary endpoints improved significantly in patients receiving the drug, compared with placebo. They included measures of quality of life, symptom status, ventricular function, natriuretic peptides, and troponin I.

The secondary outcomes are consistent with what was observed in the EXPLORER-HCM trial, which in 2020 suggested that mavacamten could improve measures of quality of life, NYHA functional class, LVOT gradient, peak VO2, and other metrics in patients with OHCM.

Dr. Desai said mavacamten was well tolerated. “There were two patients who had a transient drop in ejection fraction to less than 50%, so the drug was temporarily discontinued, but resumed at a lower dose and they were able to complete the study.”

Dr. Stevenson commented on the “pretty quick” up-titration of mavacamten dosages in a study lasting only 4 months, which could have been a concern given the drug’s limited track record and its mechanism of action targeting contractility. “Fortunately, no serious safety signals” were observed.

Dr. Desai emphasized that mavacamten up-titrations were strictly guided by regular echocardiographic monitoring and assessment of LVOT gradients, in addition to clinical responses. And that, he said, is likely how up-titrations should be carried out if mavacamten is approved for OHCM.

VALOR-HCM was supported by MyoKardia. Dr. Desai disclosed receiving honoraria or consulting fees from Caristo Diagnostics, Medtronic, and MyoKardia. Dr. Stevenson disclosed receiving honoraria or consulting fees from Novartis; serving on a data safety monitoring board for Livanova; and other relationships with Abbott Medical, Biotronik, Boston Scientific, Bristol-Myers Squibb, Endotronic, Gore Medical, and Johnson & Johnson. Dr. Cleveland had no disclosures.

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

Treatment with a novel myosin-inhibiting agent may improve symptoms and hemodynamics enough in patients with obstructive hypertrophic cardiomyopathy (OHCM) so that they can avoid or at least delay septal reduction therapy (SRT), suggests a randomized trial of modest size and duration.

Of 112 patients with OHCM who were sick enough while receiving standard medications to qualify for SRT, those assigned to take mavacamten (MyoKardia) instead of placebo were far less likely to still be eligible for SRT 16 weeks later.

In other words, their OHCM had improved enough during therapy with mavacamten such that SRT, either surgical septal myectomy or transcatheter alcohol septal ablation, could no longer be recommended per guidelines.

Mavacamten, which lessens myocardial contractility by selective inhibition of cardiac myosin, is the first agent tested in prospective trials to appear as a viable medical option in patients with severe, symptomatic OHCM, observed principal investigator Milind Y. Desai, MD, MBA, of the Cleveland Clinic.

“There’s clearly an unmet need for noninvasive therapies, medical therapies, that work in OHCM,” he said in an interview. Mavacamten “adds to the armamentarium” of OHCM management options and may give patients with symptoms despite conventional medications an alternative to SRT, which is considered definitive but has drawbacks.

The goal of SRT is to alleviate obstruction of the left ventricular outflow tract (LVOT), but surgical SRT requires a sternotomy, with all the risks and recovery time that entails. Catheter-based alcohol septal ablation is a less common alternative for some patients with suitable anatomy, Dr. Desai noted.

But those procedures “are not uniformly available, and even when  available, the outcomes are fairly heterogeneous,” he said. “The guidelines recommend that you should go to a center with a mortality rate of less than 1% with these procedures. Centers like that are very few across the world,” and procedural mortality can be much higher at centers with less SRT experience.

Dr. Desai presented the results of VALOR-HCM at the annual scientific sessions of the American College of Cardiology. Of the 56 patients assigned to mavacamten, 10 (17.9%) decided to undergo SRT by the end of the trial, or otherwise still met guideline-recommended criteria for receiving SRT, the primary endpoint. In comparison, 43 of the 56 patients (76.8%) in the control group (P < .0001) met that endpoint.

More patients receiving mavacamten improved by at least one New York Heart Association (NYHA) functional class during the trial’s 16 weeks: 63% versus 21% for those assigned to placebo. And 27% and 2%, respectively, improved by at least two NYHA classes, Dr. Desai said.

Guidelines recommend that SRT be reserved for patients in NYHA class III or IV heart failure with a resting or provoked LVOT gradient of at least 50 mm Hg.

Of note, Desai said, only two patients in each group elected to undergo SRT during the study. “The primary endpoint was driven by reduction in guideline eligibility for SRT, but 95% of patients in the study chose to continue with medical therapy.”

Speaking as a panelist after Dr. Desai’s presentation, Lynne W. Stevenson, MD, lauded the phase 3 trial’s “brave design,” which featured a highly unusual subjective primary endpoint and framed it as an advantage.

That the trial showed a significant mavacamten effect for that endpoint “answered, in one step, the question of what does this actually mean to the patient – which often takes much longer,” observed Dr. Stevenson, from Vanderbilt University, Nashville, Tenn.

Even so, she added, whether patients still qualified for SRT in the trial at least had to be supported by objective measures of LVOT gradient and NT-proBNP levels.

“My perspective is that of a cardiac surgeon who performs septal myectomies,” said John Cleveland, MD, University of Colorado at Denver, Aurora, who said he was impressed at how few patients receiving mavacamten went on to undergo SRT, while the rest were able to at least defer that decision.

Current recommendations are that patients who go to SRT “should be maximally medically treated and still symptomatic,” Dr. Cleveland observed at a press conference on VALOR-HCM. Should mavacamten be added to the list of agents to use before resorting to invasive therapy? “My answer would be yes,” he said, and patients who remain symptomatic even while receiving the myosin inhibitor and other medications should proceed to SRT.

The trial’s patients had documented OHCM, severe symptoms, and a resting or provoked LVOT gradient of at least 50 mm Hg despite maximally tolerated medications – which could include disopyramide, beta-blockers, and calcium channel blockers. About half the study population was female, and 89% were White. All had been referred for SRT.

Active therapy consisted of mavacamten initiated at 5 mg/day, with up-titrations at 8 and 12 weeks as tolerated, guided by echocardiographic left ventricular ejection fraction and LVOT gradient.  

Most secondary endpoints improved significantly in patients receiving the drug, compared with placebo. They included measures of quality of life, symptom status, ventricular function, natriuretic peptides, and troponin I.

The secondary outcomes are consistent with what was observed in the EXPLORER-HCM trial, which in 2020 suggested that mavacamten could improve measures of quality of life, NYHA functional class, LVOT gradient, peak VO2, and other metrics in patients with OHCM.

Dr. Desai said mavacamten was well tolerated. “There were two patients who had a transient drop in ejection fraction to less than 50%, so the drug was temporarily discontinued, but resumed at a lower dose and they were able to complete the study.”

Dr. Stevenson commented on the “pretty quick” up-titration of mavacamten dosages in a study lasting only 4 months, which could have been a concern given the drug’s limited track record and its mechanism of action targeting contractility. “Fortunately, no serious safety signals” were observed.

Dr. Desai emphasized that mavacamten up-titrations were strictly guided by regular echocardiographic monitoring and assessment of LVOT gradients, in addition to clinical responses. And that, he said, is likely how up-titrations should be carried out if mavacamten is approved for OHCM.

VALOR-HCM was supported by MyoKardia. Dr. Desai disclosed receiving honoraria or consulting fees from Caristo Diagnostics, Medtronic, and MyoKardia. Dr. Stevenson disclosed receiving honoraria or consulting fees from Novartis; serving on a data safety monitoring board for Livanova; and other relationships with Abbott Medical, Biotronik, Boston Scientific, Bristol-Myers Squibb, Endotronic, Gore Medical, and Johnson & Johnson. Dr. Cleveland had no disclosures.

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

Treatment with a novel myosin-inhibiting agent may improve symptoms and hemodynamics enough in patients with obstructive hypertrophic cardiomyopathy (OHCM) so that they can avoid or at least delay septal reduction therapy (SRT), suggests a randomized trial of modest size and duration.

Of 112 patients with OHCM who were sick enough while receiving standard medications to qualify for SRT, those assigned to take mavacamten (MyoKardia) instead of placebo were far less likely to still be eligible for SRT 16 weeks later.

In other words, their OHCM had improved enough during therapy with mavacamten such that SRT, either surgical septal myectomy or transcatheter alcohol septal ablation, could no longer be recommended per guidelines.

Mavacamten, which lessens myocardial contractility by selective inhibition of cardiac myosin, is the first agent tested in prospective trials to appear as a viable medical option in patients with severe, symptomatic OHCM, observed principal investigator Milind Y. Desai, MD, MBA, of the Cleveland Clinic.

“There’s clearly an unmet need for noninvasive therapies, medical therapies, that work in OHCM,” he said in an interview. Mavacamten “adds to the armamentarium” of OHCM management options and may give patients with symptoms despite conventional medications an alternative to SRT, which is considered definitive but has drawbacks.

The goal of SRT is to alleviate obstruction of the left ventricular outflow tract (LVOT), but surgical SRT requires a sternotomy, with all the risks and recovery time that entails. Catheter-based alcohol septal ablation is a less common alternative for some patients with suitable anatomy, Dr. Desai noted.

But those procedures “are not uniformly available, and even when  available, the outcomes are fairly heterogeneous,” he said. “The guidelines recommend that you should go to a center with a mortality rate of less than 1% with these procedures. Centers like that are very few across the world,” and procedural mortality can be much higher at centers with less SRT experience.

Dr. Desai presented the results of VALOR-HCM at the annual scientific sessions of the American College of Cardiology. Of the 56 patients assigned to mavacamten, 10 (17.9%) decided to undergo SRT by the end of the trial, or otherwise still met guideline-recommended criteria for receiving SRT, the primary endpoint. In comparison, 43 of the 56 patients (76.8%) in the control group (P < .0001) met that endpoint.

More patients receiving mavacamten improved by at least one New York Heart Association (NYHA) functional class during the trial’s 16 weeks: 63% versus 21% for those assigned to placebo. And 27% and 2%, respectively, improved by at least two NYHA classes, Dr. Desai said.

Guidelines recommend that SRT be reserved for patients in NYHA class III or IV heart failure with a resting or provoked LVOT gradient of at least 50 mm Hg.

Of note, Desai said, only two patients in each group elected to undergo SRT during the study. “The primary endpoint was driven by reduction in guideline eligibility for SRT, but 95% of patients in the study chose to continue with medical therapy.”

Speaking as a panelist after Dr. Desai’s presentation, Lynne W. Stevenson, MD, lauded the phase 3 trial’s “brave design,” which featured a highly unusual subjective primary endpoint and framed it as an advantage.

That the trial showed a significant mavacamten effect for that endpoint “answered, in one step, the question of what does this actually mean to the patient – which often takes much longer,” observed Dr. Stevenson, from Vanderbilt University, Nashville, Tenn.

Even so, she added, whether patients still qualified for SRT in the trial at least had to be supported by objective measures of LVOT gradient and NT-proBNP levels.

“My perspective is that of a cardiac surgeon who performs septal myectomies,” said John Cleveland, MD, University of Colorado at Denver, Aurora, who said he was impressed at how few patients receiving mavacamten went on to undergo SRT, while the rest were able to at least defer that decision.

Current recommendations are that patients who go to SRT “should be maximally medically treated and still symptomatic,” Dr. Cleveland observed at a press conference on VALOR-HCM. Should mavacamten be added to the list of agents to use before resorting to invasive therapy? “My answer would be yes,” he said, and patients who remain symptomatic even while receiving the myosin inhibitor and other medications should proceed to SRT.

The trial’s patients had documented OHCM, severe symptoms, and a resting or provoked LVOT gradient of at least 50 mm Hg despite maximally tolerated medications – which could include disopyramide, beta-blockers, and calcium channel blockers. About half the study population was female, and 89% were White. All had been referred for SRT.

Active therapy consisted of mavacamten initiated at 5 mg/day, with up-titrations at 8 and 12 weeks as tolerated, guided by echocardiographic left ventricular ejection fraction and LVOT gradient.  

Most secondary endpoints improved significantly in patients receiving the drug, compared with placebo. They included measures of quality of life, symptom status, ventricular function, natriuretic peptides, and troponin I.

The secondary outcomes are consistent with what was observed in the EXPLORER-HCM trial, which in 2020 suggested that mavacamten could improve measures of quality of life, NYHA functional class, LVOT gradient, peak VO2, and other metrics in patients with OHCM.

Dr. Desai said mavacamten was well tolerated. “There were two patients who had a transient drop in ejection fraction to less than 50%, so the drug was temporarily discontinued, but resumed at a lower dose and they were able to complete the study.”

Dr. Stevenson commented on the “pretty quick” up-titration of mavacamten dosages in a study lasting only 4 months, which could have been a concern given the drug’s limited track record and its mechanism of action targeting contractility. “Fortunately, no serious safety signals” were observed.

Dr. Desai emphasized that mavacamten up-titrations were strictly guided by regular echocardiographic monitoring and assessment of LVOT gradients, in addition to clinical responses. And that, he said, is likely how up-titrations should be carried out if mavacamten is approved for OHCM.

VALOR-HCM was supported by MyoKardia. Dr. Desai disclosed receiving honoraria or consulting fees from Caristo Diagnostics, Medtronic, and MyoKardia. Dr. Stevenson disclosed receiving honoraria or consulting fees from Novartis; serving on a data safety monitoring board for Livanova; and other relationships with Abbott Medical, Biotronik, Boston Scientific, Bristol-Myers Squibb, Endotronic, Gore Medical, and Johnson & Johnson. Dr. Cleveland had no disclosures.

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

A new subanalysis of the FAME 3 trial, which failed to show that percutaneous intervention (PCI) guided by fractional flow reserve (FFR) is noninferior to coronary artery bypass grafting (CABG) for treating three-vessel coronary artery disease, has associated PCI with early quality of life (QOL) advantages, according to findings presented at the annual scientific sessions of the American College of Cardiology.

Despite a modestly greater risk of major adverse cardiac events (MACE) at the end of 12 months’ follow-up among those treated with FFR-guided PCI, the greater QOL early after the procedure might be relevant to patients weighing these options, according to Frederik M. Zimmerman, MD, of Catharina Hospital in Eindhoven, the Netherlands.

“FFR-guided PCI results in a faster improvement in quality of life than CABG during the first year after revascularization, and it improved working status in patients younger than 65 years of age,” Dr. Zimmermann said.

The primary results of FAME 3 were presented at the 2021 Transcatheter Cardiovascular Therapeutics annual meeting by lead author William F. Fearon, MD, of Stanford (Calif.) University and published simultaneously in the New England Journal of Medicine.

Rather than confirming the hypothesis that FFR-guided PCI is comparable with CABG for the primary composite MACE outcome death from any cause, myocardial infarction, stroke, or revascularization, the incidence of MACE at 12 months was 10.6% in those randomized to PCI and 6.9% in the group assigned to CABG.

This translated into a hazard ratio for MACE of 1.5, signifying a 50% increase in risk for FFR-guided PCI relative to CABG for the primary outcome, a difference that negated the study definition of noninferiority (P = .35).

In this new health-related subanalysis, which was published simultaneously with his ACC presentation, the groups were compared over 12 months for QOL as measured with European Quality of Life–5 dimensions (EQ-5D) scale, angina as measured with the Canadian Cardiovascular Classification (CCC) system, and employment.

Outcomes data available in >85% of patients

Of the 1,500 patients enrolled and randomized in FAME 3 (757 to FFR-guided PCI and 743 to CABG), this health outcomes subanalysis was performed with complete data at 12 months from 89% of those in the PCI group and 88% of those in the CABG group.

Ultimately, the study did not show differences in any of these measures at the end of 12 months, but there were significant differences in QOL and employment at earlier time points. In particular, the significantly different (P < .001) trajectory for QOL improvement at 1 and 6 months favored FFR-guided PCI whether evaluated with the EQ-5D instrument or an EQ visual analog scale.

Rates of angina defined by as CCC class of at least 2 were low after revascularization in both arms of the study, negating any opportunity for differences, but patients aged younger than 65 years were almost twice as likely to have returned to full- or part-time work 1 month after revascularization (60.2% vs. 33.1%), and they remained at higher odds for working at 12 months (68.1% vs. 57.4%).

In patients aged older than 65 years, return-to-work rates did not differ significantly at any time point.

These results suggest potentially clinically meaningful early advantages for FFR-guided PCI, but some experts questioned the rationale for reporting positive secondary findings from a negative trial.

“This subanalysis is curious,” said Allen Jeremias, MD, director of interventional cardiology research, Saint Francis Hospital, Roslyn, N.Y. He pointed out that reporting these data is an anomaly.
 

Subanalyses uncommon in negative trials

“CABG was found to be better, so why look at QOL,” said Dr. Jeremias, who was an ACC-invited expert to discuss the results. However, he went on to say, “this could be an exception to the rule.”

The reason, according to Dr. Jeremias, is that the absolute difference at 12 months between FFR-guided PCI and CABG for the MACE events of greatest concern – death, MI, or stroke – was only about 2% greater in the FFR-guided PCI group (7.3% vs. 5.2%). The biggest contributor to the difference in MACE in FAME 3 at 12 months was the higher rate of repeat revascularization (5.9% vs. 3.9%).

Moreover, patients randomized to FFR-guided PCI had lower rates of many adverse events. This included risk of bleeding (1.6% vs. 3.8%; P = .009 as defined by type ≥3 Bleeding Academic Research Consortium , acute kidney injury (0.1% vs. 0.9%; P = .04), atrial fibrillation (2.4% vs. 14.1%; P < .001) and rehospitalization within 30 days (5.5% vs. 10.2%; P < .001).

In the context of a modest increase in risk of MACE and the lower rate of several important treatment-related adverse events, the QOL advantages identified in this subanalysis “might be a reasonable topic for patient-shared decision-making,” Dr. Jeremias suggested.
 

New data might inform patient decision-making

He granted the possibility that well-informed patients might accept the modestly increased risk of MACE for one or more of the outcomes, such as a higher likelihood of an early return to work, that favored FFR-guided PCI.

This is the point of this subanalysis, agreed Dr. Zimmermann.

“It is all about shared decision-making,” he said. Also emphasizing that the negative trial endpoint of FAME 3 “was driven largely by an increased risk of revascularization,” he believes that these new data might be a basis for discussions with patients weighing relative risks and benefits.

There are more data to come, according to Dr. Zimmermann, who said that follow-up of up to 5 years is planned. The 3-year data will be made available in 2023.

Dr. Zimmermann reported no potential conflicts of interest. Dr. Jeremias reported financial relationships with Abbott, ACIST, Boston Scientific, and Volcano. The investigator-initiated trial received research grants from Abbott Vascular and Medtronic.

A new subanalysis of the FAME 3 trial, which failed to show that percutaneous intervention (PCI) guided by fractional flow reserve (FFR) is noninferior to coronary artery bypass grafting (CABG) for treating three-vessel coronary artery disease, has associated PCI with early quality of life (QOL) advantages, according to findings presented at the annual scientific sessions of the American College of Cardiology.

Despite a modestly greater risk of major adverse cardiac events (MACE) at the end of 12 months’ follow-up among those treated with FFR-guided PCI, the greater QOL early after the procedure might be relevant to patients weighing these options, according to Frederik M. Zimmerman, MD, of Catharina Hospital in Eindhoven, the Netherlands.

“FFR-guided PCI results in a faster improvement in quality of life than CABG during the first year after revascularization, and it improved working status in patients younger than 65 years of age,” Dr. Zimmermann said.

The primary results of FAME 3 were presented at the 2021 Transcatheter Cardiovascular Therapeutics annual meeting by lead author William F. Fearon, MD, of Stanford (Calif.) University and published simultaneously in the New England Journal of Medicine.

Rather than confirming the hypothesis that FFR-guided PCI is comparable with CABG for the primary composite MACE outcome death from any cause, myocardial infarction, stroke, or revascularization, the incidence of MACE at 12 months was 10.6% in those randomized to PCI and 6.9% in the group assigned to CABG.

This translated into a hazard ratio for MACE of 1.5, signifying a 50% increase in risk for FFR-guided PCI relative to CABG for the primary outcome, a difference that negated the study definition of noninferiority (P = .35).

In this new health-related subanalysis, which was published simultaneously with his ACC presentation, the groups were compared over 12 months for QOL as measured with European Quality of Life–5 dimensions (EQ-5D) scale, angina as measured with the Canadian Cardiovascular Classification (CCC) system, and employment.

Outcomes data available in >85% of patients

Of the 1,500 patients enrolled and randomized in FAME 3 (757 to FFR-guided PCI and 743 to CABG), this health outcomes subanalysis was performed with complete data at 12 months from 89% of those in the PCI group and 88% of those in the CABG group.

Ultimately, the study did not show differences in any of these measures at the end of 12 months, but there were significant differences in QOL and employment at earlier time points. In particular, the significantly different (P < .001) trajectory for QOL improvement at 1 and 6 months favored FFR-guided PCI whether evaluated with the EQ-5D instrument or an EQ visual analog scale.

Rates of angina defined by as CCC class of at least 2 were low after revascularization in both arms of the study, negating any opportunity for differences, but patients aged younger than 65 years were almost twice as likely to have returned to full- or part-time work 1 month after revascularization (60.2% vs. 33.1%), and they remained at higher odds for working at 12 months (68.1% vs. 57.4%).

In patients aged older than 65 years, return-to-work rates did not differ significantly at any time point.

These results suggest potentially clinically meaningful early advantages for FFR-guided PCI, but some experts questioned the rationale for reporting positive secondary findings from a negative trial.

“This subanalysis is curious,” said Allen Jeremias, MD, director of interventional cardiology research, Saint Francis Hospital, Roslyn, N.Y. He pointed out that reporting these data is an anomaly.
 

Subanalyses uncommon in negative trials

“CABG was found to be better, so why look at QOL,” said Dr. Jeremias, who was an ACC-invited expert to discuss the results. However, he went on to say, “this could be an exception to the rule.”

The reason, according to Dr. Jeremias, is that the absolute difference at 12 months between FFR-guided PCI and CABG for the MACE events of greatest concern – death, MI, or stroke – was only about 2% greater in the FFR-guided PCI group (7.3% vs. 5.2%). The biggest contributor to the difference in MACE in FAME 3 at 12 months was the higher rate of repeat revascularization (5.9% vs. 3.9%).

Moreover, patients randomized to FFR-guided PCI had lower rates of many adverse events. This included risk of bleeding (1.6% vs. 3.8%; P = .009 as defined by type ≥3 Bleeding Academic Research Consortium , acute kidney injury (0.1% vs. 0.9%; P = .04), atrial fibrillation (2.4% vs. 14.1%; P < .001) and rehospitalization within 30 days (5.5% vs. 10.2%; P < .001).

In the context of a modest increase in risk of MACE and the lower rate of several important treatment-related adverse events, the QOL advantages identified in this subanalysis “might be a reasonable topic for patient-shared decision-making,” Dr. Jeremias suggested.
 

New data might inform patient decision-making

He granted the possibility that well-informed patients might accept the modestly increased risk of MACE for one or more of the outcomes, such as a higher likelihood of an early return to work, that favored FFR-guided PCI.

This is the point of this subanalysis, agreed Dr. Zimmermann.

“It is all about shared decision-making,” he said. Also emphasizing that the negative trial endpoint of FAME 3 “was driven largely by an increased risk of revascularization,” he believes that these new data might be a basis for discussions with patients weighing relative risks and benefits.

There are more data to come, according to Dr. Zimmermann, who said that follow-up of up to 5 years is planned. The 3-year data will be made available in 2023.

Dr. Zimmermann reported no potential conflicts of interest. Dr. Jeremias reported financial relationships with Abbott, ACIST, Boston Scientific, and Volcano. The investigator-initiated trial received research grants from Abbott Vascular and Medtronic.

A new subanalysis of the FAME 3 trial, which failed to show that percutaneous intervention (PCI) guided by fractional flow reserve (FFR) is noninferior to coronary artery bypass grafting (CABG) for treating three-vessel coronary artery disease, has associated PCI with early quality of life (QOL) advantages, according to findings presented at the annual scientific sessions of the American College of Cardiology.

Despite a modestly greater risk of major adverse cardiac events (MACE) at the end of 12 months’ follow-up among those treated with FFR-guided PCI, the greater QOL early after the procedure might be relevant to patients weighing these options, according to Frederik M. Zimmerman, MD, of Catharina Hospital in Eindhoven, the Netherlands.

“FFR-guided PCI results in a faster improvement in quality of life than CABG during the first year after revascularization, and it improved working status in patients younger than 65 years of age,” Dr. Zimmermann said.

The primary results of FAME 3 were presented at the 2021 Transcatheter Cardiovascular Therapeutics annual meeting by lead author William F. Fearon, MD, of Stanford (Calif.) University and published simultaneously in the New England Journal of Medicine.

Rather than confirming the hypothesis that FFR-guided PCI is comparable with CABG for the primary composite MACE outcome death from any cause, myocardial infarction, stroke, or revascularization, the incidence of MACE at 12 months was 10.6% in those randomized to PCI and 6.9% in the group assigned to CABG.

This translated into a hazard ratio for MACE of 1.5, signifying a 50% increase in risk for FFR-guided PCI relative to CABG for the primary outcome, a difference that negated the study definition of noninferiority (P = .35).

In this new health-related subanalysis, which was published simultaneously with his ACC presentation, the groups were compared over 12 months for QOL as measured with European Quality of Life–5 dimensions (EQ-5D) scale, angina as measured with the Canadian Cardiovascular Classification (CCC) system, and employment.

Outcomes data available in >85% of patients

Of the 1,500 patients enrolled and randomized in FAME 3 (757 to FFR-guided PCI and 743 to CABG), this health outcomes subanalysis was performed with complete data at 12 months from 89% of those in the PCI group and 88% of those in the CABG group.

Ultimately, the study did not show differences in any of these measures at the end of 12 months, but there were significant differences in QOL and employment at earlier time points. In particular, the significantly different (P < .001) trajectory for QOL improvement at 1 and 6 months favored FFR-guided PCI whether evaluated with the EQ-5D instrument or an EQ visual analog scale.

Rates of angina defined by as CCC class of at least 2 were low after revascularization in both arms of the study, negating any opportunity for differences, but patients aged younger than 65 years were almost twice as likely to have returned to full- or part-time work 1 month after revascularization (60.2% vs. 33.1%), and they remained at higher odds for working at 12 months (68.1% vs. 57.4%).

In patients aged older than 65 years, return-to-work rates did not differ significantly at any time point.

These results suggest potentially clinically meaningful early advantages for FFR-guided PCI, but some experts questioned the rationale for reporting positive secondary findings from a negative trial.

“This subanalysis is curious,” said Allen Jeremias, MD, director of interventional cardiology research, Saint Francis Hospital, Roslyn, N.Y. He pointed out that reporting these data is an anomaly.
 

Subanalyses uncommon in negative trials

“CABG was found to be better, so why look at QOL,” said Dr. Jeremias, who was an ACC-invited expert to discuss the results. However, he went on to say, “this could be an exception to the rule.”

The reason, according to Dr. Jeremias, is that the absolute difference at 12 months between FFR-guided PCI and CABG for the MACE events of greatest concern – death, MI, or stroke – was only about 2% greater in the FFR-guided PCI group (7.3% vs. 5.2%). The biggest contributor to the difference in MACE in FAME 3 at 12 months was the higher rate of repeat revascularization (5.9% vs. 3.9%).

Moreover, patients randomized to FFR-guided PCI had lower rates of many adverse events. This included risk of bleeding (1.6% vs. 3.8%; P = .009 as defined by type ≥3 Bleeding Academic Research Consortium , acute kidney injury (0.1% vs. 0.9%; P = .04), atrial fibrillation (2.4% vs. 14.1%; P < .001) and rehospitalization within 30 days (5.5% vs. 10.2%; P < .001).

In the context of a modest increase in risk of MACE and the lower rate of several important treatment-related adverse events, the QOL advantages identified in this subanalysis “might be a reasonable topic for patient-shared decision-making,” Dr. Jeremias suggested.
 

New data might inform patient decision-making

He granted the possibility that well-informed patients might accept the modestly increased risk of MACE for one or more of the outcomes, such as a higher likelihood of an early return to work, that favored FFR-guided PCI.

This is the point of this subanalysis, agreed Dr. Zimmermann.

“It is all about shared decision-making,” he said. Also emphasizing that the negative trial endpoint of FAME 3 “was driven largely by an increased risk of revascularization,” he believes that these new data might be a basis for discussions with patients weighing relative risks and benefits.

There are more data to come, according to Dr. Zimmermann, who said that follow-up of up to 5 years is planned. The 3-year data will be made available in 2023.

Dr. Zimmermann reported no potential conflicts of interest. Dr. Jeremias reported financial relationships with Abbott, ACIST, Boston Scientific, and Volcano. The investigator-initiated trial received research grants from Abbott Vascular and Medtronic.

The antifibrinolytic tranexamic acid (TXA) reduced serious bleeding without a significant effect on major vascular outcomes in patients undergoing noncardiac surgery at risk for these complications in the POISE-3 trial.

TXA cut the primary efficacy outcome of life-threatening, major, and critical organ bleeding at 30 days by 24% compared with placebo (9.1% vs. 11.7%; hazard ratio [HR], 0.76; P < .0001).

The primary safety outcome of myocardial injury after noncardiac surgery (MINS), nonhemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism (VTE) at 30 days occurred in 14.2% vs.. 13.9% of patients, respectively (HR, 1.023). This failed, however, to meet the study›s threshold to prove TXA noninferior to placebo (one-sided P = .044).

There was no increased risk for death or stroke with TXA, according to results published April 2 in the New England Journal of Medicine.

Principal investigator P.J. Devereaux, MD, PhD, Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada, pointed out that there is only a 4.4% probability that the composite vascular outcome hazard ratio was above the noninferiority margin and that just 10 events separated the two groups (649 vs.. 639).

“Healthcare providers and patients will have to weigh a clear beneficial reduction in the composite bleeding outcome, which is an absolute difference of 2.7%, a result that was highly statistically significant, versus a low probability of a small increase in risk of the composite vascular endpoint, with an absolute difference of 0.3%,” a nonsignificant result, Dr. Devereaux said during the formal presentation of the results at the hybrid annual scientific sessions of the American College of Cardiology.

The findings, he said, should also be put in the context that 300 million adults have a major surgery each year worldwide and most don’t receive TXA. At the same time, there’s an annual global shortage of 30 million blood product units, and surgical bleeding accounts for up to 40% of all transfusions.

“POISE-3 identifies that use of TXA could avoid upwards of 8 million bleeding events resulting in transfusion on an annual basis, indicating potential for large public health and clinical benefit if TXA become standard practice in noncardiac surgery,” Dr. Devereaux said during the late-breaking trial session.

TXA is indicated for heavy menstrual bleeding and hemophilia and has been used in cardiac surgery, but it is increasingly being used in noncardiac surgeries. As previously reported, POISE showed that the beta-blocker metoprolol lowered the risk for myocardial infarction (MI) but increased the risk for severe stroke and overall death, whereas in POISE-2, perioperative low-dose aspirin lowered the risk for MI but was linked to more major bleeding.

The cumulative data have not shown an increased risk for thrombotic events in other settings, Dr. Devereaux told this news organization.

“I’m a cardiologist, and I think that we’ve been guilty at times of always only focusing on the thrombotic side of the equation and ignoring that bleeding is a very important aspect of the circulatory system,” he said. “And I think this shows for the first time clear unequivocal evidence that there’s a cheap, very encouraging, safe way to prevent this.”

“An important point is that if you can give tranexamic acid and prevent bleeding in your cardiac patients having noncardiac surgery, then you can prevent the delay of reinitiating their anticoagulants and their antiplatelets after surgery and getting them back on the medications that are important for them to prevent their cardiovascular event,” Dr. Devereaux added.

Discussant Michael J. Mack, MD, commented that TXA, widely used in cardiac surgery, is an old, inexpensive drug that “should be more widely used in noncardiac surgery.” Dr. Mack, from Baylor Scott & White Health, Dallas, added that he would limit it to major noncardiac surgery.

International trial

PeriOperative ISchemic Evaluation-3 (POISE-3) investigators at 114 hospitals in 22 countries (including countries in North and South America, Europe, and Africa; Russia; India; and Australia) randomly assigned 9,535 patients, aged 45 years or older, with or at risk for cardiovascular and bleeding complications to receive a TXA 1-g intravenous bolus or placebo at the start and end of inpatient noncardiac surgery.

Patients taking at least one long-term antihypertensive medication were also randomly assigned to a perioperative hypotension- or hypertension-avoidance strategy, which differ in the use of antihypertensives on the morning of surgery and the first 2 days after surgery, and in the target mean arterial pressure during surgery. Results from these cohorts will be presented in a separate session on April 4.

The study had planned to enroll 10,000 patients but was stopped early by the steering committee because of financial constraints resulting from slow enrollment during the pandemic. The decision was made without knowledge of the trial results but with knowledge that aggregate composite bleeding and vascular outcomes were higher than originally estimated, Dr. Devereaux noted.

Among all participants, the mean age was 70 years, 56% were male, almost a third had coronary artery disease, 15% had peripheral artery disease, and 8% had a prior stroke. About 80% were undergoing major surgery. Adherence to the study medications was 96.3% in both groups.

Secondary bleeding outcomes were lower in the TXA and placebo groups, including bleeding independently associated with mortality after surgery (8.7% vs. 11.3%), life-threatening bleeding (1.6% vs. 1.7%), major bleeding (7.6% vs. 10.4%), and critical organ bleeding (0.3% vs. 0.4%).

Importantly, the TXA group had significantly lower rates of International Society on Thrombosis and Haemostasis major bleeding (6.6% vs. 8.7%; P = .0001) and the need for transfusion of 1 or more units of packed red blood cells (9.4% vs. 12.0%; P <.0001), Dr. Devereaux noted.

In terms of secondary vascular outcomes, there were no significant differences between the TXA and placebo groups in rates of MINS (12.8% vs. 12.6%), MINS not fulfilling definition of MI (both 11.5%), MI (1.4% vs. 1.1%), and the net risk-benefit outcome (a composite of vascular death and nonfatal life-threatening, major, or critical organ bleeding, MINS, stroke, peripheral arterial thrombosis, and symptomatic proximal VTE; 20.7% vs. 21.9%).

The two groups had similar rates of all-cause (1.1% vs. 1.2%) and vascular (0.5% vs. 0.6%) mortality.

There also were no significant differences in other tertiary outcomes, such as acute kidney injury (14.1% vs. 13.7%), rehospitalization for vascular reasons (1.8% vs. 1.6%), or seizures (0.2% vs. <0.1%). The latter has been a concern, with the risk reported to increase with higher doses.

Subgroup analyses

Preplanned subgroup analyses showed a benefit for TXA over placebo for the primary efficacy outcome in orthopedic and nonorthopedic surgery and in patients with hemoglobin level below 120 g/L or 120 g/L or higher, with an estimated glomerular filtration rate less than 45 mL/min/1.73 m ²  or 45 mL/min/1.73 m ²  or higher, or with an N-terminal pro– B-type natriuretic peptide level below 200 ng/L or 200 ng/L or higher.

For the primary safety outcome, the benefit favored placebo but the interaction was not statistically significant for any of the four subgroups.

A post hoc subgroup analysis also showed similar results across the major categories of surgery, including general, vascular, urologic, and gynecologic, Dr. Devereaux told this news organization.

Although TXA is commonly used in orthopedic procedures, Dr. Devereaux noted, in other types of surgeries, “it’s not used at all.” But because TXA “is so cheap, and we can apply it to a broad population, even at an economic level it looks like it’s a winner to give to almost all patients having noncardiac surgery.”

The team also recently published a risk prediction tool that can help estimate a patient’s baseline risk for bleeding.

“So just using a model, which will bring together the patient’s type of surgery and their risk factors, you can look to see, okay, this is enough risk of bleeding, I’m just going to give tranexamic acid,” he said. “We will also be doing economic analyses because blood is also not cheap.”

The study was funded by the Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and the Research Grant Council (Hong Kong). Dr. Devereaux reports research/research grants from Abbott Diagnostics, Philips Healthcare, Roche Diagnostics, and Siemens. Dr. Mack reports receiving research grants from Abbott Vascular, Edwards Lifesciences, and Medtronic.

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

The antifibrinolytic tranexamic acid (TXA) reduced serious bleeding without a significant effect on major vascular outcomes in patients undergoing noncardiac surgery at risk for these complications in the POISE-3 trial.

TXA cut the primary efficacy outcome of life-threatening, major, and critical organ bleeding at 30 days by 24% compared with placebo (9.1% vs. 11.7%; hazard ratio [HR], 0.76; P < .0001).

The primary safety outcome of myocardial injury after noncardiac surgery (MINS), nonhemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism (VTE) at 30 days occurred in 14.2% vs.. 13.9% of patients, respectively (HR, 1.023). This failed, however, to meet the study›s threshold to prove TXA noninferior to placebo (one-sided P = .044).

There was no increased risk for death or stroke with TXA, according to results published April 2 in the New England Journal of Medicine.

Principal investigator P.J. Devereaux, MD, PhD, Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada, pointed out that there is only a 4.4% probability that the composite vascular outcome hazard ratio was above the noninferiority margin and that just 10 events separated the two groups (649 vs.. 639).

“Healthcare providers and patients will have to weigh a clear beneficial reduction in the composite bleeding outcome, which is an absolute difference of 2.7%, a result that was highly statistically significant, versus a low probability of a small increase in risk of the composite vascular endpoint, with an absolute difference of 0.3%,” a nonsignificant result, Dr. Devereaux said during the formal presentation of the results at the hybrid annual scientific sessions of the American College of Cardiology.

The findings, he said, should also be put in the context that 300 million adults have a major surgery each year worldwide and most don’t receive TXA. At the same time, there’s an annual global shortage of 30 million blood product units, and surgical bleeding accounts for up to 40% of all transfusions.

“POISE-3 identifies that use of TXA could avoid upwards of 8 million bleeding events resulting in transfusion on an annual basis, indicating potential for large public health and clinical benefit if TXA become standard practice in noncardiac surgery,” Dr. Devereaux said during the late-breaking trial session.

TXA is indicated for heavy menstrual bleeding and hemophilia and has been used in cardiac surgery, but it is increasingly being used in noncardiac surgeries. As previously reported, POISE showed that the beta-blocker metoprolol lowered the risk for myocardial infarction (MI) but increased the risk for severe stroke and overall death, whereas in POISE-2, perioperative low-dose aspirin lowered the risk for MI but was linked to more major bleeding.

The cumulative data have not shown an increased risk for thrombotic events in other settings, Dr. Devereaux told this news organization.

“I’m a cardiologist, and I think that we’ve been guilty at times of always only focusing on the thrombotic side of the equation and ignoring that bleeding is a very important aspect of the circulatory system,” he said. “And I think this shows for the first time clear unequivocal evidence that there’s a cheap, very encouraging, safe way to prevent this.”

“An important point is that if you can give tranexamic acid and prevent bleeding in your cardiac patients having noncardiac surgery, then you can prevent the delay of reinitiating their anticoagulants and their antiplatelets after surgery and getting them back on the medications that are important for them to prevent their cardiovascular event,” Dr. Devereaux added.

Discussant Michael J. Mack, MD, commented that TXA, widely used in cardiac surgery, is an old, inexpensive drug that “should be more widely used in noncardiac surgery.” Dr. Mack, from Baylor Scott & White Health, Dallas, added that he would limit it to major noncardiac surgery.

International trial

PeriOperative ISchemic Evaluation-3 (POISE-3) investigators at 114 hospitals in 22 countries (including countries in North and South America, Europe, and Africa; Russia; India; and Australia) randomly assigned 9,535 patients, aged 45 years or older, with or at risk for cardiovascular and bleeding complications to receive a TXA 1-g intravenous bolus or placebo at the start and end of inpatient noncardiac surgery.

Patients taking at least one long-term antihypertensive medication were also randomly assigned to a perioperative hypotension- or hypertension-avoidance strategy, which differ in the use of antihypertensives on the morning of surgery and the first 2 days after surgery, and in the target mean arterial pressure during surgery. Results from these cohorts will be presented in a separate session on April 4.

The study had planned to enroll 10,000 patients but was stopped early by the steering committee because of financial constraints resulting from slow enrollment during the pandemic. The decision was made without knowledge of the trial results but with knowledge that aggregate composite bleeding and vascular outcomes were higher than originally estimated, Dr. Devereaux noted.

Among all participants, the mean age was 70 years, 56% were male, almost a third had coronary artery disease, 15% had peripheral artery disease, and 8% had a prior stroke. About 80% were undergoing major surgery. Adherence to the study medications was 96.3% in both groups.

Secondary bleeding outcomes were lower in the TXA and placebo groups, including bleeding independently associated with mortality after surgery (8.7% vs. 11.3%), life-threatening bleeding (1.6% vs. 1.7%), major bleeding (7.6% vs. 10.4%), and critical organ bleeding (0.3% vs. 0.4%).

Importantly, the TXA group had significantly lower rates of International Society on Thrombosis and Haemostasis major bleeding (6.6% vs. 8.7%; P = .0001) and the need for transfusion of 1 or more units of packed red blood cells (9.4% vs. 12.0%; P <.0001), Dr. Devereaux noted.

In terms of secondary vascular outcomes, there were no significant differences between the TXA and placebo groups in rates of MINS (12.8% vs. 12.6%), MINS not fulfilling definition of MI (both 11.5%), MI (1.4% vs. 1.1%), and the net risk-benefit outcome (a composite of vascular death and nonfatal life-threatening, major, or critical organ bleeding, MINS, stroke, peripheral arterial thrombosis, and symptomatic proximal VTE; 20.7% vs. 21.9%).

The two groups had similar rates of all-cause (1.1% vs. 1.2%) and vascular (0.5% vs. 0.6%) mortality.

There also were no significant differences in other tertiary outcomes, such as acute kidney injury (14.1% vs. 13.7%), rehospitalization for vascular reasons (1.8% vs. 1.6%), or seizures (0.2% vs. <0.1%). The latter has been a concern, with the risk reported to increase with higher doses.

Subgroup analyses

Preplanned subgroup analyses showed a benefit for TXA over placebo for the primary efficacy outcome in orthopedic and nonorthopedic surgery and in patients with hemoglobin level below 120 g/L or 120 g/L or higher, with an estimated glomerular filtration rate less than 45 mL/min/1.73 m ²  or 45 mL/min/1.73 m ²  or higher, or with an N-terminal pro– B-type natriuretic peptide level below 200 ng/L or 200 ng/L or higher.

For the primary safety outcome, the benefit favored placebo but the interaction was not statistically significant for any of the four subgroups.

A post hoc subgroup analysis also showed similar results across the major categories of surgery, including general, vascular, urologic, and gynecologic, Dr. Devereaux told this news organization.

Although TXA is commonly used in orthopedic procedures, Dr. Devereaux noted, in other types of surgeries, “it’s not used at all.” But because TXA “is so cheap, and we can apply it to a broad population, even at an economic level it looks like it’s a winner to give to almost all patients having noncardiac surgery.”

The team also recently published a risk prediction tool that can help estimate a patient’s baseline risk for bleeding.

“So just using a model, which will bring together the patient’s type of surgery and their risk factors, you can look to see, okay, this is enough risk of bleeding, I’m just going to give tranexamic acid,” he said. “We will also be doing economic analyses because blood is also not cheap.”

The study was funded by the Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and the Research Grant Council (Hong Kong). Dr. Devereaux reports research/research grants from Abbott Diagnostics, Philips Healthcare, Roche Diagnostics, and Siemens. Dr. Mack reports receiving research grants from Abbott Vascular, Edwards Lifesciences, and Medtronic.

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

The antifibrinolytic tranexamic acid (TXA) reduced serious bleeding without a significant effect on major vascular outcomes in patients undergoing noncardiac surgery at risk for these complications in the POISE-3 trial.

TXA cut the primary efficacy outcome of life-threatening, major, and critical organ bleeding at 30 days by 24% compared with placebo (9.1% vs. 11.7%; hazard ratio [HR], 0.76; P < .0001).

The primary safety outcome of myocardial injury after noncardiac surgery (MINS), nonhemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism (VTE) at 30 days occurred in 14.2% vs.. 13.9% of patients, respectively (HR, 1.023). This failed, however, to meet the study›s threshold to prove TXA noninferior to placebo (one-sided P = .044).

There was no increased risk for death or stroke with TXA, according to results published April 2 in the New England Journal of Medicine.

Principal investigator P.J. Devereaux, MD, PhD, Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada, pointed out that there is only a 4.4% probability that the composite vascular outcome hazard ratio was above the noninferiority margin and that just 10 events separated the two groups (649 vs.. 639).

“Healthcare providers and patients will have to weigh a clear beneficial reduction in the composite bleeding outcome, which is an absolute difference of 2.7%, a result that was highly statistically significant, versus a low probability of a small increase in risk of the composite vascular endpoint, with an absolute difference of 0.3%,” a nonsignificant result, Dr. Devereaux said during the formal presentation of the results at the hybrid annual scientific sessions of the American College of Cardiology.

The findings, he said, should also be put in the context that 300 million adults have a major surgery each year worldwide and most don’t receive TXA. At the same time, there’s an annual global shortage of 30 million blood product units, and surgical bleeding accounts for up to 40% of all transfusions.

“POISE-3 identifies that use of TXA could avoid upwards of 8 million bleeding events resulting in transfusion on an annual basis, indicating potential for large public health and clinical benefit if TXA become standard practice in noncardiac surgery,” Dr. Devereaux said during the late-breaking trial session.

TXA is indicated for heavy menstrual bleeding and hemophilia and has been used in cardiac surgery, but it is increasingly being used in noncardiac surgeries. As previously reported, POISE showed that the beta-blocker metoprolol lowered the risk for myocardial infarction (MI) but increased the risk for severe stroke and overall death, whereas in POISE-2, perioperative low-dose aspirin lowered the risk for MI but was linked to more major bleeding.

The cumulative data have not shown an increased risk for thrombotic events in other settings, Dr. Devereaux told this news organization.

“I’m a cardiologist, and I think that we’ve been guilty at times of always only focusing on the thrombotic side of the equation and ignoring that bleeding is a very important aspect of the circulatory system,” he said. “And I think this shows for the first time clear unequivocal evidence that there’s a cheap, very encouraging, safe way to prevent this.”

“An important point is that if you can give tranexamic acid and prevent bleeding in your cardiac patients having noncardiac surgery, then you can prevent the delay of reinitiating their anticoagulants and their antiplatelets after surgery and getting them back on the medications that are important for them to prevent their cardiovascular event,” Dr. Devereaux added.

Discussant Michael J. Mack, MD, commented that TXA, widely used in cardiac surgery, is an old, inexpensive drug that “should be more widely used in noncardiac surgery.” Dr. Mack, from Baylor Scott & White Health, Dallas, added that he would limit it to major noncardiac surgery.

International trial

PeriOperative ISchemic Evaluation-3 (POISE-3) investigators at 114 hospitals in 22 countries (including countries in North and South America, Europe, and Africa; Russia; India; and Australia) randomly assigned 9,535 patients, aged 45 years or older, with or at risk for cardiovascular and bleeding complications to receive a TXA 1-g intravenous bolus or placebo at the start and end of inpatient noncardiac surgery.

Patients taking at least one long-term antihypertensive medication were also randomly assigned to a perioperative hypotension- or hypertension-avoidance strategy, which differ in the use of antihypertensives on the morning of surgery and the first 2 days after surgery, and in the target mean arterial pressure during surgery. Results from these cohorts will be presented in a separate session on April 4.

The study had planned to enroll 10,000 patients but was stopped early by the steering committee because of financial constraints resulting from slow enrollment during the pandemic. The decision was made without knowledge of the trial results but with knowledge that aggregate composite bleeding and vascular outcomes were higher than originally estimated, Dr. Devereaux noted.

Among all participants, the mean age was 70 years, 56% were male, almost a third had coronary artery disease, 15% had peripheral artery disease, and 8% had a prior stroke. About 80% were undergoing major surgery. Adherence to the study medications was 96.3% in both groups.

Secondary bleeding outcomes were lower in the TXA and placebo groups, including bleeding independently associated with mortality after surgery (8.7% vs. 11.3%), life-threatening bleeding (1.6% vs. 1.7%), major bleeding (7.6% vs. 10.4%), and critical organ bleeding (0.3% vs. 0.4%).

Importantly, the TXA group had significantly lower rates of International Society on Thrombosis and Haemostasis major bleeding (6.6% vs. 8.7%; P = .0001) and the need for transfusion of 1 or more units of packed red blood cells (9.4% vs. 12.0%; P <.0001), Dr. Devereaux noted.

In terms of secondary vascular outcomes, there were no significant differences between the TXA and placebo groups in rates of MINS (12.8% vs. 12.6%), MINS not fulfilling definition of MI (both 11.5%), MI (1.4% vs. 1.1%), and the net risk-benefit outcome (a composite of vascular death and nonfatal life-threatening, major, or critical organ bleeding, MINS, stroke, peripheral arterial thrombosis, and symptomatic proximal VTE; 20.7% vs. 21.9%).

The two groups had similar rates of all-cause (1.1% vs. 1.2%) and vascular (0.5% vs. 0.6%) mortality.

There also were no significant differences in other tertiary outcomes, such as acute kidney injury (14.1% vs. 13.7%), rehospitalization for vascular reasons (1.8% vs. 1.6%), or seizures (0.2% vs. <0.1%). The latter has been a concern, with the risk reported to increase with higher doses.

Subgroup analyses

Preplanned subgroup analyses showed a benefit for TXA over placebo for the primary efficacy outcome in orthopedic and nonorthopedic surgery and in patients with hemoglobin level below 120 g/L or 120 g/L or higher, with an estimated glomerular filtration rate less than 45 mL/min/1.73 m ²  or 45 mL/min/1.73 m ²  or higher, or with an N-terminal pro– B-type natriuretic peptide level below 200 ng/L or 200 ng/L or higher.

For the primary safety outcome, the benefit favored placebo but the interaction was not statistically significant for any of the four subgroups.

A post hoc subgroup analysis also showed similar results across the major categories of surgery, including general, vascular, urologic, and gynecologic, Dr. Devereaux told this news organization.

Although TXA is commonly used in orthopedic procedures, Dr. Devereaux noted, in other types of surgeries, “it’s not used at all.” But because TXA “is so cheap, and we can apply it to a broad population, even at an economic level it looks like it’s a winner to give to almost all patients having noncardiac surgery.”

The team also recently published a risk prediction tool that can help estimate a patient’s baseline risk for bleeding.

“So just using a model, which will bring together the patient’s type of surgery and their risk factors, you can look to see, okay, this is enough risk of bleeding, I’m just going to give tranexamic acid,” he said. “We will also be doing economic analyses because blood is also not cheap.”

The study was funded by the Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and the Research Grant Council (Hong Kong). Dr. Devereaux reports research/research grants from Abbott Diagnostics, Philips Healthcare, Roche Diagnostics, and Siemens. Dr. Mack reports receiving research grants from Abbott Vascular, Edwards Lifesciences, and Medtronic.

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

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

Pregnant women with even mild hypertension should receive blood pressure–lowering medications to reduce the likelihood of adverse outcomes for the mother and the child, according to a large, open-label, randomized trial.

“Treating to the blood pressure goal in this study reduced the risk of adverse events associated with pregnancy but did not impair fetal growth,” Alan T. Tita, MD, PhD, associate dean for Global and Women’s Health, University of Alabama, Birmingham, reported at the annual scientific sessions of the American College of Cardiology.

The question of whether to treat chronic hypertension during pregnancy has been “an international controversy for decades,” said Dr. Tita, who led the investigator-initiated Chronic Hypertension and Pregnancy (CHAP) trial.

For the composite primary outcome of severe preeclampsia, medically indicated preterm birth at less than 35 weeks of gestation, placental abruption, or fetal/neonatal death, the treatment of hypertension versus no treatment showed a relative risk reduction of 18% (30.2% vs. 37%, (hazard ratio, 0.82; P < .001).
 

Small for gestational age is primary safety endpoint

An increase in preeclampsia risk in women whose fetus was small for gestational age (SGA), a theoretical consequence of reductions in arterial pressure, was not seen. The rate of SGA, defined as below the 10^th percentile, was slightly higher in the treatment group (11.2% vs. 10.4%), but the difference did not approach significance (P = 0.76).

By answering this long-pending question, the CHAP data are “practice changing,” declared an ACC-invited commentator, Athena Poppas, MD, chief of cardiology and director of the Lifespan Cardiovascular Institute, Providence, R.I. She agreed that the need for treatment of mild chronic hypertension has been a dilemma for clinicians that is now acceptably resolved.

In this trial, 2,408 pregnant women with chronic mild hypertension defined as a blood pressure of 160/90 mm Hg were randomized to treatment with a goal blood pressure of less than 140/90 mm Hg or no treatment unless the blood pressure rose to at least 160/105. All women had singleton pregnancies. Enrollment before 23 weeks of gestation was required. Severe hypertension (at least 160/105 mm Hg) was an exclusion criterion, as were several comorbidities, such as kidney disease.
 

Combination therapy accepted for <140/90 mm Hg goal

The beta-blocker labetalol or the calcium channel blocker nifedipine as single agents were the preferred antihypertensive medications in the protocol, but other medications were permitted. To reach the blood pressure goal, the single-agent therapy was titrated to the maximum dose before starting a second agent.

After randomization the systolic and diastolic blood pressures fell in both groups, but they fell more and remained consistently lower in the active treatment group, particularly during the first 20 weeks after randomization, according to graphs displayed by Dr. Tita. Over the course of the study, the mean diastolic blood pressures were 129.5 and 132.6 mm Hg in the active treatment and control groups, respectively, while the systolic pressures were 79.1 vs. 81.5 mm Hg.

When the components of the primary outcome were evaluated separately, the greatest advantage of treatment was the reduction in the rate of severe eclampsia (23.3% vs. 29.1%; HR, 0.80: 95% confidence interval, 0.70-0.92) and preterm birth (12.2% vs. 16.7%; HR, 0.73: 95% CI, 0.60-0.89).

Across a large array of subgroups, including those with or without diabetes and those treated before or after 14 weeks of gestation, there was a consistent advantage for treatment, even if not statistically different. It is notable that 48% of patients were Black and 35% had a body mass index of at least 40. The active treatment was favored across all groups stratified by these characteristics.

Although the incidences of placental abruption (1.7% on treatment vs. 1.9% without) and fetal or neonatal death (3.5% vs. 4.3%) were lower in the active treatment group, they were uncommon events in both arms of the study. The differences did not reach statistical significance.
 

Maternal morbidity rates lower on treatment

Severe SGA, which was defined as below the 5^th percentile, was also numerically but not significantly higher in the control arm than in the group receiving treatment (5.1% vs. 5.5%), but the incidence of composite adverse maternal events was numerically lower (2.1% vs. 2.8%). The incidences of all components of maternal morbidity, such as maternal death (0.1% vs. 0.2%) pulmonary edema (0.4% vs. 0.9%), heart failure (0.1% vs. 0.1%), and acute kidney injury (0.8% vs. 1.2%), were either lower or the same on active treatment versus no treatment.

According to Dr. Tita, who called CHAP one of the largest and most diverse studies to address the value of treating mild hypertension in pregnancy, the American College of Obstetricians and Gynecologists (ACOG) is evaluating these data for changing their current guidelines for managing hypertension during pregnancy.

“The rate of chronic hypertension during pregnancy has been rising in the United States due to the increase in the average age of pregnant women and the rising rates of obesity,” Dr. Tita commented.

“We definitely needed these data,” said Mary Norine Walsh, MD, medical director, Ascension Saint Vincent Cardiovascular Research Institute, Indianapolis. Not only has the value of treating mild hypertension been unresolved, but Dr. Walsh pointed out that the rates of maternal mortality in the United States are rising and now generally exceed those of many other developed countries.

There are several features in the design of this trial that make the results even more salient to clinical practice, according to Dr. Walsh. This includes the fact that about half of patients enrolled were on Medicaid. As a result, the study confirmed benefit in what Dr. Walsh characterized as a “vulnerable” population.

“We will be busy now to make sure that our [pregnant] patients are achieving these target blood pressures,” Dr. Walsh said. She indicated that CHAP validates the treatment target of 140/90 mm Hg as a standard of care.

The results were published in the New England Journal of Medicine simultaneously with its ACC presentation.

The trial was funded by the National Heart, Lung, and Blood Institute. Dr. Tita reports research grants from Pfizer. Dr. Walsh reports a financial relationship with EBR Systems. Dr. Poppas reports no potential conflicts of interest.

Pregnant women with even mild hypertension should receive blood pressure–lowering medications to reduce the likelihood of adverse outcomes for the mother and the child, according to a large, open-label, randomized trial.

“Treating to the blood pressure goal in this study reduced the risk of adverse events associated with pregnancy but did not impair fetal growth,” Alan T. Tita, MD, PhD, associate dean for Global and Women’s Health, University of Alabama, Birmingham, reported at the annual scientific sessions of the American College of Cardiology.

The question of whether to treat chronic hypertension during pregnancy has been “an international controversy for decades,” said Dr. Tita, who led the investigator-initiated Chronic Hypertension and Pregnancy (CHAP) trial.

For the composite primary outcome of severe preeclampsia, medically indicated preterm birth at less than 35 weeks of gestation, placental abruption, or fetal/neonatal death, the treatment of hypertension versus no treatment showed a relative risk reduction of 18% (30.2% vs. 37%, (hazard ratio, 0.82; P < .001).
 

Small for gestational age is primary safety endpoint

An increase in preeclampsia risk in women whose fetus was small for gestational age (SGA), a theoretical consequence of reductions in arterial pressure, was not seen. The rate of SGA, defined as below the 10^th percentile, was slightly higher in the treatment group (11.2% vs. 10.4%), but the difference did not approach significance (P = 0.76).

By answering this long-pending question, the CHAP data are “practice changing,” declared an ACC-invited commentator, Athena Poppas, MD, chief of cardiology and director of the Lifespan Cardiovascular Institute, Providence, R.I. She agreed that the need for treatment of mild chronic hypertension has been a dilemma for clinicians that is now acceptably resolved.

In this trial, 2,408 pregnant women with chronic mild hypertension defined as a blood pressure of 160/90 mm Hg were randomized to treatment with a goal blood pressure of less than 140/90 mm Hg or no treatment unless the blood pressure rose to at least 160/105. All women had singleton pregnancies. Enrollment before 23 weeks of gestation was required. Severe hypertension (at least 160/105 mm Hg) was an exclusion criterion, as were several comorbidities, such as kidney disease.
 

Combination therapy accepted for <140/90 mm Hg goal

The beta-blocker labetalol or the calcium channel blocker nifedipine as single agents were the preferred antihypertensive medications in the protocol, but other medications were permitted. To reach the blood pressure goal, the single-agent therapy was titrated to the maximum dose before starting a second agent.

After randomization the systolic and diastolic blood pressures fell in both groups, but they fell more and remained consistently lower in the active treatment group, particularly during the first 20 weeks after randomization, according to graphs displayed by Dr. Tita. Over the course of the study, the mean diastolic blood pressures were 129.5 and 132.6 mm Hg in the active treatment and control groups, respectively, while the systolic pressures were 79.1 vs. 81.5 mm Hg.

When the components of the primary outcome were evaluated separately, the greatest advantage of treatment was the reduction in the rate of severe eclampsia (23.3% vs. 29.1%; HR, 0.80: 95% confidence interval, 0.70-0.92) and preterm birth (12.2% vs. 16.7%; HR, 0.73: 95% CI, 0.60-0.89).

Across a large array of subgroups, including those with or without diabetes and those treated before or after 14 weeks of gestation, there was a consistent advantage for treatment, even if not statistically different. It is notable that 48% of patients were Black and 35% had a body mass index of at least 40. The active treatment was favored across all groups stratified by these characteristics.

Although the incidences of placental abruption (1.7% on treatment vs. 1.9% without) and fetal or neonatal death (3.5% vs. 4.3%) were lower in the active treatment group, they were uncommon events in both arms of the study. The differences did not reach statistical significance.
 

Maternal morbidity rates lower on treatment

Severe SGA, which was defined as below the 5^th percentile, was also numerically but not significantly higher in the control arm than in the group receiving treatment (5.1% vs. 5.5%), but the incidence of composite adverse maternal events was numerically lower (2.1% vs. 2.8%). The incidences of all components of maternal morbidity, such as maternal death (0.1% vs. 0.2%) pulmonary edema (0.4% vs. 0.9%), heart failure (0.1% vs. 0.1%), and acute kidney injury (0.8% vs. 1.2%), were either lower or the same on active treatment versus no treatment.

According to Dr. Tita, who called CHAP one of the largest and most diverse studies to address the value of treating mild hypertension in pregnancy, the American College of Obstetricians and Gynecologists (ACOG) is evaluating these data for changing their current guidelines for managing hypertension during pregnancy.

“The rate of chronic hypertension during pregnancy has been rising in the United States due to the increase in the average age of pregnant women and the rising rates of obesity,” Dr. Tita commented.

“We definitely needed these data,” said Mary Norine Walsh, MD, medical director, Ascension Saint Vincent Cardiovascular Research Institute, Indianapolis. Not only has the value of treating mild hypertension been unresolved, but Dr. Walsh pointed out that the rates of maternal mortality in the United States are rising and now generally exceed those of many other developed countries.

There are several features in the design of this trial that make the results even more salient to clinical practice, according to Dr. Walsh. This includes the fact that about half of patients enrolled were on Medicaid. As a result, the study confirmed benefit in what Dr. Walsh characterized as a “vulnerable” population.

“We will be busy now to make sure that our [pregnant] patients are achieving these target blood pressures,” Dr. Walsh said. She indicated that CHAP validates the treatment target of 140/90 mm Hg as a standard of care.

The results were published in the New England Journal of Medicine simultaneously with its ACC presentation.

The trial was funded by the National Heart, Lung, and Blood Institute. Dr. Tita reports research grants from Pfizer. Dr. Walsh reports a financial relationship with EBR Systems. Dr. Poppas reports no potential conflicts of interest.

Pregnant women with even mild hypertension should receive blood pressure–lowering medications to reduce the likelihood of adverse outcomes for the mother and the child, according to a large, open-label, randomized trial.

“Treating to the blood pressure goal in this study reduced the risk of adverse events associated with pregnancy but did not impair fetal growth,” Alan T. Tita, MD, PhD, associate dean for Global and Women’s Health, University of Alabama, Birmingham, reported at the annual scientific sessions of the American College of Cardiology.

The question of whether to treat chronic hypertension during pregnancy has been “an international controversy for decades,” said Dr. Tita, who led the investigator-initiated Chronic Hypertension and Pregnancy (CHAP) trial.

For the composite primary outcome of severe preeclampsia, medically indicated preterm birth at less than 35 weeks of gestation, placental abruption, or fetal/neonatal death, the treatment of hypertension versus no treatment showed a relative risk reduction of 18% (30.2% vs. 37%, (hazard ratio, 0.82; P < .001).
 

Small for gestational age is primary safety endpoint

An increase in preeclampsia risk in women whose fetus was small for gestational age (SGA), a theoretical consequence of reductions in arterial pressure, was not seen. The rate of SGA, defined as below the 10^th percentile, was slightly higher in the treatment group (11.2% vs. 10.4%), but the difference did not approach significance (P = 0.76).

By answering this long-pending question, the CHAP data are “practice changing,” declared an ACC-invited commentator, Athena Poppas, MD, chief of cardiology and director of the Lifespan Cardiovascular Institute, Providence, R.I. She agreed that the need for treatment of mild chronic hypertension has been a dilemma for clinicians that is now acceptably resolved.

In this trial, 2,408 pregnant women with chronic mild hypertension defined as a blood pressure of 160/90 mm Hg were randomized to treatment with a goal blood pressure of less than 140/90 mm Hg or no treatment unless the blood pressure rose to at least 160/105. All women had singleton pregnancies. Enrollment before 23 weeks of gestation was required. Severe hypertension (at least 160/105 mm Hg) was an exclusion criterion, as were several comorbidities, such as kidney disease.
 

Combination therapy accepted for <140/90 mm Hg goal

The beta-blocker labetalol or the calcium channel blocker nifedipine as single agents were the preferred antihypertensive medications in the protocol, but other medications were permitted. To reach the blood pressure goal, the single-agent therapy was titrated to the maximum dose before starting a second agent.

After randomization the systolic and diastolic blood pressures fell in both groups, but they fell more and remained consistently lower in the active treatment group, particularly during the first 20 weeks after randomization, according to graphs displayed by Dr. Tita. Over the course of the study, the mean diastolic blood pressures were 129.5 and 132.6 mm Hg in the active treatment and control groups, respectively, while the systolic pressures were 79.1 vs. 81.5 mm Hg.

When the components of the primary outcome were evaluated separately, the greatest advantage of treatment was the reduction in the rate of severe eclampsia (23.3% vs. 29.1%; HR, 0.80: 95% confidence interval, 0.70-0.92) and preterm birth (12.2% vs. 16.7%; HR, 0.73: 95% CI, 0.60-0.89).

Across a large array of subgroups, including those with or without diabetes and those treated before or after 14 weeks of gestation, there was a consistent advantage for treatment, even if not statistically different. It is notable that 48% of patients were Black and 35% had a body mass index of at least 40. The active treatment was favored across all groups stratified by these characteristics.

Although the incidences of placental abruption (1.7% on treatment vs. 1.9% without) and fetal or neonatal death (3.5% vs. 4.3%) were lower in the active treatment group, they were uncommon events in both arms of the study. The differences did not reach statistical significance.
 

Maternal morbidity rates lower on treatment

Severe SGA, which was defined as below the 5^th percentile, was also numerically but not significantly higher in the control arm than in the group receiving treatment (5.1% vs. 5.5%), but the incidence of composite adverse maternal events was numerically lower (2.1% vs. 2.8%). The incidences of all components of maternal morbidity, such as maternal death (0.1% vs. 0.2%) pulmonary edema (0.4% vs. 0.9%), heart failure (0.1% vs. 0.1%), and acute kidney injury (0.8% vs. 1.2%), were either lower or the same on active treatment versus no treatment.

According to Dr. Tita, who called CHAP one of the largest and most diverse studies to address the value of treating mild hypertension in pregnancy, the American College of Obstetricians and Gynecologists (ACOG) is evaluating these data for changing their current guidelines for managing hypertension during pregnancy.

“The rate of chronic hypertension during pregnancy has been rising in the United States due to the increase in the average age of pregnant women and the rising rates of obesity,” Dr. Tita commented.

“We definitely needed these data,” said Mary Norine Walsh, MD, medical director, Ascension Saint Vincent Cardiovascular Research Institute, Indianapolis. Not only has the value of treating mild hypertension been unresolved, but Dr. Walsh pointed out that the rates of maternal mortality in the United States are rising and now generally exceed those of many other developed countries.

There are several features in the design of this trial that make the results even more salient to clinical practice, according to Dr. Walsh. This includes the fact that about half of patients enrolled were on Medicaid. As a result, the study confirmed benefit in what Dr. Walsh characterized as a “vulnerable” population.

“We will be busy now to make sure that our [pregnant] patients are achieving these target blood pressures,” Dr. Walsh said. She indicated that CHAP validates the treatment target of 140/90 mm Hg as a standard of care.

The results were published in the New England Journal of Medicine simultaneously with its ACC presentation.

The trial was funded by the National Heart, Lung, and Blood Institute. Dr. Tita reports research grants from Pfizer. Dr. Walsh reports a financial relationship with EBR Systems. Dr. Poppas reports no potential conflicts of interest.

A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.

“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.

SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1,500 mg/day). Patients with a baseline sodium intake of less than 1,500 mg/day were excluded.

In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.

Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.

Dr. Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.

“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.

Results showed that between baseline and 12 months, the median sodium intake decreased from 2,286 mg/day to 1,658 mg/day in the low-sodium group and from 2,119 mg/day to 2,073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.

By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 - 1.26]; P = .53).

All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).

The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.

Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).

There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.

NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).

No safety events related to the study treatment were reported in either group.

Dr. Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.

Questions on food recall and blinding

Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, congratulated Dr. Ezekowitz on conducting this trial.

“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.

But Dr. Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.

Dr. Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.

Dr. Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.

To this point, Dr. Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.

Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.

“I think we can safely tell patients that if they slip up a bit they may not end up in hospital,” she added.

This study was funded by the Canadian Institutes of Health Research and the University Hospital Foundation (Edmonton, Alberta, Canada) and the Health Research Council of New Zealand. Dr. Ezekowitz reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier.

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

A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.

“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.

SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1,500 mg/day). Patients with a baseline sodium intake of less than 1,500 mg/day were excluded.

In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.

Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.

Dr. Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.

“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.

Results showed that between baseline and 12 months, the median sodium intake decreased from 2,286 mg/day to 1,658 mg/day in the low-sodium group and from 2,119 mg/day to 2,073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.

By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 - 1.26]; P = .53).

All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).

The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.

Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).

There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.

NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).

No safety events related to the study treatment were reported in either group.

Dr. Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.

Questions on food recall and blinding

Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, congratulated Dr. Ezekowitz on conducting this trial.

“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.

But Dr. Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.

Dr. Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.

Dr. Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.

To this point, Dr. Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.

Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.

“I think we can safely tell patients that if they slip up a bit they may not end up in hospital,” she added.

This study was funded by the Canadian Institutes of Health Research and the University Hospital Foundation (Edmonton, Alberta, Canada) and the Health Research Council of New Zealand. Dr. Ezekowitz reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier.

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

A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.

“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.

SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1,500 mg/day). Patients with a baseline sodium intake of less than 1,500 mg/day were excluded.

In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.

Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.

Dr. Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.

“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.

Results showed that between baseline and 12 months, the median sodium intake decreased from 2,286 mg/day to 1,658 mg/day in the low-sodium group and from 2,119 mg/day to 2,073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.

By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 - 1.26]; P = .53).

All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).

The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.

Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).

There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.

NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).

No safety events related to the study treatment were reported in either group.

Dr. Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.

Questions on food recall and blinding

Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, congratulated Dr. Ezekowitz on conducting this trial.

“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.

But Dr. Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.

Dr. Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.

Dr. Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.

To this point, Dr. Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.

Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.

“I think we can safely tell patients that if they slip up a bit they may not end up in hospital,” she added.

This study was funded by the Canadian Institutes of Health Research and the University Hospital Foundation (Edmonton, Alberta, Canada) and the Health Research Council of New Zealand. Dr. Ezekowitz reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier.

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

Ivermectin, an antiparasitic drug that became popular as an alternative treatment for COVID-19, showed no signs of quelling the disease or reducing patients’ risk of hospitalization, according to results from a large clinical trial published in the New England Journal of Medicine.

The findings pretty much rule out the drug as a treatment for COVID-19, the study authors wrote.

“There’s really no sign of any benefit,” David Boulware, MD, one of the coauthors and an infectious disease specialist at the University of Minnesota, Minneapolis, told the New York Times.

The researchers shared a summary of the results in August 2021 during an online presentation hosted by the National Institutes of Health. The full data hadn’t been published until now.

“Now that people can dive into the details and the data, hopefully that will steer the majority of doctors away from ivermectin toward other therapies,” Dr. Boulware said.

In the trial, the research team compared more than 1,350 people infected with the coronavirus in Brazil who received either ivermectin or a placebo as treatment.

Between March and August 2021, 679 patients received a daily dose of ivermectin over the course of 3 days. The researchers found that ivermectin didn’t reduce the risk that people with COVID-19 would be hospitalized or go to an ED within 28 days after treatment.

In addition, the researchers looked at particular groups to understand if some patients benefited for some reason, such as taking ivermectin sooner after testing positive for COVID-19. But those who took the drug during the first 3 days after a positive coronavirus test ended up doing worse than those in the placebo group. The drug also didn’t help patients recover sooner.

The researchers found “no important effects” of treatment with ivermectin on the number of days people spent in the hospital, the number of days hospitalized people needed mechanical ventilation, or the risk of death.

Ivermectin has become a controversial focal point during the pandemic.

For decades, the drug has been widely used to treat parasitic infections. At the beginning of the pandemic, researchers checked thousands of existing drugs against the coronavirus to determine if a potential treatment already existed. Laboratory experiments on cells suggested that ivermectin might work, the New York Times reported.

But some researchers noted that the experiments worked because a high concentration of ivermectin was used, a much higher dose than would be safe for people. Despite the concerns, some doctors began prescribing ivermectin to patients. After receiving reports of people who needed medical attention, particularly after using formulations intended for livestock, the Food and Drug Administration issued a warning that the drug wasn’t approved to be used for COVID-19.

Researchers around the world have done small clinical trials to understand whether ivermectin treats COVID-19, the newspaper reported. At the end of 2020, Andrew Hill, MD, a virologist at the University of Liverpool in England, reviewed the results from 23 trials and concluded that the drug could lower the risk of death from COVID-19. He published the results in July 2021, but later reports found that many of the studies were flawed, and at least one was fraudulent.

Dr. Hill retracted his original study and began another analysis, which was published in January 2022. In this review, he and his colleagues focused on studies that were least likely to be biased. They found that ivermectin was not helpful.

Recently, Dr. Hill and associates ran another analysis using the new data from the Brazil trial, and once again they saw no benefit.

Several clinical trials are still testing ivermectin as a treatment, the New York Times reported, with results expected in upcoming months. After reviewing the data from the Brazil trial, which tested ivermectin and a variety of other drugs against COVID-19, some infectious disease experts say they’ll likely see more of the same – that ivermectin doesn’t help people with COVID-19.

“I welcome the results of the other clinical trials and will view them with an open mind,” Paul Sax, MD, an infectious disease expert at Brigham and Women’s Hospital, Boston, who has been watching the data on the drug throughout the pandemic, told the New York Times.

“But at some point, it will become a waste of resources to continue studying an unpromising approach,” he said.

A version of this article first appeared on WebMD.com.

Ivermectin, an antiparasitic drug that became popular as an alternative treatment for COVID-19, showed no signs of quelling the disease or reducing patients’ risk of hospitalization, according to results from a large clinical trial published in the New England Journal of Medicine.

The findings pretty much rule out the drug as a treatment for COVID-19, the study authors wrote.

“There’s really no sign of any benefit,” David Boulware, MD, one of the coauthors and an infectious disease specialist at the University of Minnesota, Minneapolis, told the New York Times.

The researchers shared a summary of the results in August 2021 during an online presentation hosted by the National Institutes of Health. The full data hadn’t been published until now.

“Now that people can dive into the details and the data, hopefully that will steer the majority of doctors away from ivermectin toward other therapies,” Dr. Boulware said.

In the trial, the research team compared more than 1,350 people infected with the coronavirus in Brazil who received either ivermectin or a placebo as treatment.

Between March and August 2021, 679 patients received a daily dose of ivermectin over the course of 3 days. The researchers found that ivermectin didn’t reduce the risk that people with COVID-19 would be hospitalized or go to an ED within 28 days after treatment.

In addition, the researchers looked at particular groups to understand if some patients benefited for some reason, such as taking ivermectin sooner after testing positive for COVID-19. But those who took the drug during the first 3 days after a positive coronavirus test ended up doing worse than those in the placebo group. The drug also didn’t help patients recover sooner.

The researchers found “no important effects” of treatment with ivermectin on the number of days people spent in the hospital, the number of days hospitalized people needed mechanical ventilation, or the risk of death.

Ivermectin has become a controversial focal point during the pandemic.

For decades, the drug has been widely used to treat parasitic infections. At the beginning of the pandemic, researchers checked thousands of existing drugs against the coronavirus to determine if a potential treatment already existed. Laboratory experiments on cells suggested that ivermectin might work, the New York Times reported.

But some researchers noted that the experiments worked because a high concentration of ivermectin was used, a much higher dose than would be safe for people. Despite the concerns, some doctors began prescribing ivermectin to patients. After receiving reports of people who needed medical attention, particularly after using formulations intended for livestock, the Food and Drug Administration issued a warning that the drug wasn’t approved to be used for COVID-19.

Researchers around the world have done small clinical trials to understand whether ivermectin treats COVID-19, the newspaper reported. At the end of 2020, Andrew Hill, MD, a virologist at the University of Liverpool in England, reviewed the results from 23 trials and concluded that the drug could lower the risk of death from COVID-19. He published the results in July 2021, but later reports found that many of the studies were flawed, and at least one was fraudulent.

Dr. Hill retracted his original study and began another analysis, which was published in January 2022. In this review, he and his colleagues focused on studies that were least likely to be biased. They found that ivermectin was not helpful.

Recently, Dr. Hill and associates ran another analysis using the new data from the Brazil trial, and once again they saw no benefit.

Several clinical trials are still testing ivermectin as a treatment, the New York Times reported, with results expected in upcoming months. After reviewing the data from the Brazil trial, which tested ivermectin and a variety of other drugs against COVID-19, some infectious disease experts say they’ll likely see more of the same – that ivermectin doesn’t help people with COVID-19.

“I welcome the results of the other clinical trials and will view them with an open mind,” Paul Sax, MD, an infectious disease expert at Brigham and Women’s Hospital, Boston, who has been watching the data on the drug throughout the pandemic, told the New York Times.

“But at some point, it will become a waste of resources to continue studying an unpromising approach,” he said.

A version of this article first appeared on WebMD.com.

Ivermectin, an antiparasitic drug that became popular as an alternative treatment for COVID-19, showed no signs of quelling the disease or reducing patients’ risk of hospitalization, according to results from a large clinical trial published in the New England Journal of Medicine.

The findings pretty much rule out the drug as a treatment for COVID-19, the study authors wrote.

“There’s really no sign of any benefit,” David Boulware, MD, one of the coauthors and an infectious disease specialist at the University of Minnesota, Minneapolis, told the New York Times.

The researchers shared a summary of the results in August 2021 during an online presentation hosted by the National Institutes of Health. The full data hadn’t been published until now.

“Now that people can dive into the details and the data, hopefully that will steer the majority of doctors away from ivermectin toward other therapies,” Dr. Boulware said.

In the trial, the research team compared more than 1,350 people infected with the coronavirus in Brazil who received either ivermectin or a placebo as treatment.

Between March and August 2021, 679 patients received a daily dose of ivermectin over the course of 3 days. The researchers found that ivermectin didn’t reduce the risk that people with COVID-19 would be hospitalized or go to an ED within 28 days after treatment.

In addition, the researchers looked at particular groups to understand if some patients benefited for some reason, such as taking ivermectin sooner after testing positive for COVID-19. But those who took the drug during the first 3 days after a positive coronavirus test ended up doing worse than those in the placebo group. The drug also didn’t help patients recover sooner.

The researchers found “no important effects” of treatment with ivermectin on the number of days people spent in the hospital, the number of days hospitalized people needed mechanical ventilation, or the risk of death.

Ivermectin has become a controversial focal point during the pandemic.

For decades, the drug has been widely used to treat parasitic infections. At the beginning of the pandemic, researchers checked thousands of existing drugs against the coronavirus to determine if a potential treatment already existed. Laboratory experiments on cells suggested that ivermectin might work, the New York Times reported.

But some researchers noted that the experiments worked because a high concentration of ivermectin was used, a much higher dose than would be safe for people. Despite the concerns, some doctors began prescribing ivermectin to patients. After receiving reports of people who needed medical attention, particularly after using formulations intended for livestock, the Food and Drug Administration issued a warning that the drug wasn’t approved to be used for COVID-19.

Researchers around the world have done small clinical trials to understand whether ivermectin treats COVID-19, the newspaper reported. At the end of 2020, Andrew Hill, MD, a virologist at the University of Liverpool in England, reviewed the results from 23 trials and concluded that the drug could lower the risk of death from COVID-19. He published the results in July 2021, but later reports found that many of the studies were flawed, and at least one was fraudulent.

Dr. Hill retracted his original study and began another analysis, which was published in January 2022. In this review, he and his colleagues focused on studies that were least likely to be biased. They found that ivermectin was not helpful.

Recently, Dr. Hill and associates ran another analysis using the new data from the Brazil trial, and once again they saw no benefit.

Several clinical trials are still testing ivermectin as a treatment, the New York Times reported, with results expected in upcoming months. After reviewing the data from the Brazil trial, which tested ivermectin and a variety of other drugs against COVID-19, some infectious disease experts say they’ll likely see more of the same – that ivermectin doesn’t help people with COVID-19.

“I welcome the results of the other clinical trials and will view them with an open mind,” Paul Sax, MD, an infectious disease expert at Brigham and Women’s Hospital, Boston, who has been watching the data on the drug throughout the pandemic, told the New York Times.

“But at some point, it will become a waste of resources to continue studying an unpromising approach,” he said.

A version of this article first appeared on WebMD.com.

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

Pointing a finger at COVID-19

The battle against COVID-19 is seemingly never ending. It’s been 2 years and still we struggle against the virus. But now, a new hero rises against the eternal menace, a powerful weapon against this scourge of humanity. And that weapon? Finger length.

Before you break out the sad trombone, hear us out. One of the big questions around COVID-19 is the role testosterone plays in its severity: Does low testosterone increase or decrease the odds of contracting severe COVID-19? To help answer that question, English researchers have published a study analyzing finger length ratios in both COVID-19 patients and a healthy control group. That seems random, but high testosterone in the womb leads to longer ring fingers in adulthood, while high estrogen leads to longer index fingers.

PxHere

According to the researchers, those who had significant left hand–right hand differences in the ratio between the second and fourth digits, as well as the third and fifth digits, were significantly more likely to have severe COVID-19 compared with those with more even ratios. Those with “feminized” short little fingers were also at risk. Those large ratio differences indicate low testosterone and high estrogen, which may explain why elderly men are at such high risk for severe COVID-19. Testosterone naturally falls off as men get older.

The results add credence to clinical trials looking to use testosterone-boosting drugs against COVID-19, the researchers said. It also gives credence to LOTME’s brand-new 12-step finger strength fitness routine and our branded finger weights. Now just $19.95! It’s the bargain of the century! Boost your testosterone naturally and protect yourself from COVID-19! We promise it’s not a scam.
 

Some emergencies need a superhero

Last week, we learned about the most boring person in the world. This week just happens to be opposite week, so we’re looking at a candidate for the most interesting person. Someone who can swoop down from the sky to save the injured and helpless. Someone who can go where helicopters fear to tread. Someone with jet engines for arms. Superhero-type stuff.

Richard Browning/Gravity Industries

The Great North Air Ambulance Service (GNAAS), a charitable organization located in the United Kingdom, recently announced that one of its members has completed training on the Gravity Industries Jet Suit. The suit “has two engines on each arm and a larger engine on the back [that] provide up to 317 pounds of thrust,” Interesting Engineering explained.

GNAAS is putting the suit into operation in England’s Lake District National Park, which includes mountainous terrain that is not very hospitable to helicopter landings. A paramedic using the suit can reach hikers stranded on mountainsides much faster than rescuers who have to run or hike from the nearest helicopter landing site.

“Everyone looks at the wow factor and the fact we are the world’s first jet suit paramedics, but for us, it’s about delivering patient care,” GNAAS’ Andy Mawson told Interesting Engineering. Sounds like superhero-speak to us.

So if you’re in the Lake District and have taken a bit of a tumble, you can call a superhero on your cell phone or you can use this to summon one.
 

Why we’re rejecting food as medicine

Humans have been using food to treat ailments much longer than we’ve had the advances of modern medicine. So why have we rejected its worth in our treatment processes? And what can be done to change that? The Center for Food as Medicine and the Hunter College NYC Food Policy Center just released a 335-page report that answers those questions.

phototake/ThinkStock

First, the why: Meals in health care settings are not medically designed to help with the specific needs of the patient. Produce-prescription and nutrition-incentive programs don’t have the government funds to fully support them. And a lot of medical schools don’t even require students to take a basic nutrition course. So there’s a lack of knowledge and a disconnect between health care providers and food as a resource.

Then there’s a lack of trust in the food industry and their validity. Social media uses food as a means of promoting “pseudoscientific alternative medicine” or spreading false info, pushing away legitimate providers. The food industry has had its fingers in food science studies and an almost mafia-esque chokehold on American dietary guidelines. No wonder food for medicine is getting the boot!

To change the situation, the report offers 10 key recommendations on how to advance the idea of incorporating food into medicine for treatment and prevention. They include boosting the funding for research, making hospitals more food-as-medicine focused, expanding federal programs, and improving public awareness on the role nutrition can play in medical treatment or prevention.

So maybe instead of rejecting food outright, we should be looking a little deeper at how we can use it to our advantage. Just a thought: Ice cream as an antidepressant.
 

Being rude is a good thing, apparently

If you’ve ever been called argumentative, stubborn, or unpleasant, then this LOTME is for you. Researchers at the University of Geneva have found that people who are more stubborn and hate to conform have brains that are more protected against Alzheimer’s disease. That type of personality seems to preserve the part of the brain that usually deteriorates as we grow older.

Piqsels

The original hypothesis that personality may have a protective effect against brain degeneration led the investigators to conduct cognitive and personality assessments of 65 elderly participants over a 5-year period. Researchers have been attempting to create vaccines to protect against Alzheimer’s disease, but these new findings offer a nonbiological way to help.

“For a long time, the brain is able to compensate by activating alternative networks; when the first clinical signs appear, however, it is unfortunately often too late. The identification of early biomarkers is therefore essential for … effective disease management,” lead author Panteleimon Giannakopoulos, MD, said in a Study Finds report.

You may be wondering how people with more agreeable and less confrontational personalities can seek help. Well, researchers are working on that, too. It’s a complex situation, but as always, we’re rooting for you, science!

At least now you can take solace in the fact that your elderly next-door neighbor who yells at you for stepping on his lawn is probably more protected against Alzheimer’s disease.

Pointing a finger at COVID-19

The battle against COVID-19 is seemingly never ending. It’s been 2 years and still we struggle against the virus. But now, a new hero rises against the eternal menace, a powerful weapon against this scourge of humanity. And that weapon? Finger length.

Before you break out the sad trombone, hear us out. One of the big questions around COVID-19 is the role testosterone plays in its severity: Does low testosterone increase or decrease the odds of contracting severe COVID-19? To help answer that question, English researchers have published a study analyzing finger length ratios in both COVID-19 patients and a healthy control group. That seems random, but high testosterone in the womb leads to longer ring fingers in adulthood, while high estrogen leads to longer index fingers.

PxHere

According to the researchers, those who had significant left hand–right hand differences in the ratio between the second and fourth digits, as well as the third and fifth digits, were significantly more likely to have severe COVID-19 compared with those with more even ratios. Those with “feminized” short little fingers were also at risk. Those large ratio differences indicate low testosterone and high estrogen, which may explain why elderly men are at such high risk for severe COVID-19. Testosterone naturally falls off as men get older.

The results add credence to clinical trials looking to use testosterone-boosting drugs against COVID-19, the researchers said. It also gives credence to LOTME’s brand-new 12-step finger strength fitness routine and our branded finger weights. Now just $19.95! It’s the bargain of the century! Boost your testosterone naturally and protect yourself from COVID-19! We promise it’s not a scam.
 

Some emergencies need a superhero

Last week, we learned about the most boring person in the world. This week just happens to be opposite week, so we’re looking at a candidate for the most interesting person. Someone who can swoop down from the sky to save the injured and helpless. Someone who can go where helicopters fear to tread. Someone with jet engines for arms. Superhero-type stuff.

Richard Browning/Gravity Industries

The Great North Air Ambulance Service (GNAAS), a charitable organization located in the United Kingdom, recently announced that one of its members has completed training on the Gravity Industries Jet Suit. The suit “has two engines on each arm and a larger engine on the back [that] provide up to 317 pounds of thrust,” Interesting Engineering explained.

GNAAS is putting the suit into operation in England’s Lake District National Park, which includes mountainous terrain that is not very hospitable to helicopter landings. A paramedic using the suit can reach hikers stranded on mountainsides much faster than rescuers who have to run or hike from the nearest helicopter landing site.

“Everyone looks at the wow factor and the fact we are the world’s first jet suit paramedics, but for us, it’s about delivering patient care,” GNAAS’ Andy Mawson told Interesting Engineering. Sounds like superhero-speak to us.

So if you’re in the Lake District and have taken a bit of a tumble, you can call a superhero on your cell phone or you can use this to summon one.
 

Why we’re rejecting food as medicine

Humans have been using food to treat ailments much longer than we’ve had the advances of modern medicine. So why have we rejected its worth in our treatment processes? And what can be done to change that? The Center for Food as Medicine and the Hunter College NYC Food Policy Center just released a 335-page report that answers those questions.

phototake/ThinkStock

First, the why: Meals in health care settings are not medically designed to help with the specific needs of the patient. Produce-prescription and nutrition-incentive programs don’t have the government funds to fully support them. And a lot of medical schools don’t even require students to take a basic nutrition course. So there’s a lack of knowledge and a disconnect between health care providers and food as a resource.

Then there’s a lack of trust in the food industry and their validity. Social media uses food as a means of promoting “pseudoscientific alternative medicine” or spreading false info, pushing away legitimate providers. The food industry has had its fingers in food science studies and an almost mafia-esque chokehold on American dietary guidelines. No wonder food for medicine is getting the boot!

To change the situation, the report offers 10 key recommendations on how to advance the idea of incorporating food into medicine for treatment and prevention. They include boosting the funding for research, making hospitals more food-as-medicine focused, expanding federal programs, and improving public awareness on the role nutrition can play in medical treatment or prevention.

So maybe instead of rejecting food outright, we should be looking a little deeper at how we can use it to our advantage. Just a thought: Ice cream as an antidepressant.
 

Being rude is a good thing, apparently

If you’ve ever been called argumentative, stubborn, or unpleasant, then this LOTME is for you. Researchers at the University of Geneva have found that people who are more stubborn and hate to conform have brains that are more protected against Alzheimer’s disease. That type of personality seems to preserve the part of the brain that usually deteriorates as we grow older.

Piqsels

The original hypothesis that personality may have a protective effect against brain degeneration led the investigators to conduct cognitive and personality assessments of 65 elderly participants over a 5-year period. Researchers have been attempting to create vaccines to protect against Alzheimer’s disease, but these new findings offer a nonbiological way to help.

“For a long time, the brain is able to compensate by activating alternative networks; when the first clinical signs appear, however, it is unfortunately often too late. The identification of early biomarkers is therefore essential for … effective disease management,” lead author Panteleimon Giannakopoulos, MD, said in a Study Finds report.

You may be wondering how people with more agreeable and less confrontational personalities can seek help. Well, researchers are working on that, too. It’s a complex situation, but as always, we’re rooting for you, science!

At least now you can take solace in the fact that your elderly next-door neighbor who yells at you for stepping on his lawn is probably more protected against Alzheimer’s disease.

Pointing a finger at COVID-19

The battle against COVID-19 is seemingly never ending. It’s been 2 years and still we struggle against the virus. But now, a new hero rises against the eternal menace, a powerful weapon against this scourge of humanity. And that weapon? Finger length.

Before you break out the sad trombone, hear us out. One of the big questions around COVID-19 is the role testosterone plays in its severity: Does low testosterone increase or decrease the odds of contracting severe COVID-19? To help answer that question, English researchers have published a study analyzing finger length ratios in both COVID-19 patients and a healthy control group. That seems random, but high testosterone in the womb leads to longer ring fingers in adulthood, while high estrogen leads to longer index fingers.

PxHere

According to the researchers, those who had significant left hand–right hand differences in the ratio between the second and fourth digits, as well as the third and fifth digits, were significantly more likely to have severe COVID-19 compared with those with more even ratios. Those with “feminized” short little fingers were also at risk. Those large ratio differences indicate low testosterone and high estrogen, which may explain why elderly men are at such high risk for severe COVID-19. Testosterone naturally falls off as men get older.

The results add credence to clinical trials looking to use testosterone-boosting drugs against COVID-19, the researchers said. It also gives credence to LOTME’s brand-new 12-step finger strength fitness routine and our branded finger weights. Now just $19.95! It’s the bargain of the century! Boost your testosterone naturally and protect yourself from COVID-19! We promise it’s not a scam.
 

Some emergencies need a superhero

Last week, we learned about the most boring person in the world. This week just happens to be opposite week, so we’re looking at a candidate for the most interesting person. Someone who can swoop down from the sky to save the injured and helpless. Someone who can go where helicopters fear to tread. Someone with jet engines for arms. Superhero-type stuff.

Richard Browning/Gravity Industries

The Great North Air Ambulance Service (GNAAS), a charitable organization located in the United Kingdom, recently announced that one of its members has completed training on the Gravity Industries Jet Suit. The suit “has two engines on each arm and a larger engine on the back [that] provide up to 317 pounds of thrust,” Interesting Engineering explained.

GNAAS is putting the suit into operation in England’s Lake District National Park, which includes mountainous terrain that is not very hospitable to helicopter landings. A paramedic using the suit can reach hikers stranded on mountainsides much faster than rescuers who have to run or hike from the nearest helicopter landing site.

“Everyone looks at the wow factor and the fact we are the world’s first jet suit paramedics, but for us, it’s about delivering patient care,” GNAAS’ Andy Mawson told Interesting Engineering. Sounds like superhero-speak to us.

So if you’re in the Lake District and have taken a bit of a tumble, you can call a superhero on your cell phone or you can use this to summon one.
 

Why we’re rejecting food as medicine

Humans have been using food to treat ailments much longer than we’ve had the advances of modern medicine. So why have we rejected its worth in our treatment processes? And what can be done to change that? The Center for Food as Medicine and the Hunter College NYC Food Policy Center just released a 335-page report that answers those questions.

phototake/ThinkStock

First, the why: Meals in health care settings are not medically designed to help with the specific needs of the patient. Produce-prescription and nutrition-incentive programs don’t have the government funds to fully support them. And a lot of medical schools don’t even require students to take a basic nutrition course. So there’s a lack of knowledge and a disconnect between health care providers and food as a resource.

Then there’s a lack of trust in the food industry and their validity. Social media uses food as a means of promoting “pseudoscientific alternative medicine” or spreading false info, pushing away legitimate providers. The food industry has had its fingers in food science studies and an almost mafia-esque chokehold on American dietary guidelines. No wonder food for medicine is getting the boot!

To change the situation, the report offers 10 key recommendations on how to advance the idea of incorporating food into medicine for treatment and prevention. They include boosting the funding for research, making hospitals more food-as-medicine focused, expanding federal programs, and improving public awareness on the role nutrition can play in medical treatment or prevention.

So maybe instead of rejecting food outright, we should be looking a little deeper at how we can use it to our advantage. Just a thought: Ice cream as an antidepressant.
 

Being rude is a good thing, apparently

If you’ve ever been called argumentative, stubborn, or unpleasant, then this LOTME is for you. Researchers at the University of Geneva have found that people who are more stubborn and hate to conform have brains that are more protected against Alzheimer’s disease. That type of personality seems to preserve the part of the brain that usually deteriorates as we grow older.

Piqsels

The original hypothesis that personality may have a protective effect against brain degeneration led the investigators to conduct cognitive and personality assessments of 65 elderly participants over a 5-year period. Researchers have been attempting to create vaccines to protect against Alzheimer’s disease, but these new findings offer a nonbiological way to help.

“For a long time, the brain is able to compensate by activating alternative networks; when the first clinical signs appear, however, it is unfortunately often too late. The identification of early biomarkers is therefore essential for … effective disease management,” lead author Panteleimon Giannakopoulos, MD, said in a Study Finds report.

You may be wondering how people with more agreeable and less confrontational personalities can seek help. Well, researchers are working on that, too. It’s a complex situation, but as always, we’re rooting for you, science!

At least now you can take solace in the fact that your elderly next-door neighbor who yells at you for stepping on his lawn is probably more protected against Alzheimer’s disease.