Percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) does not prolong survival or improve ventricular function, compared with OMT alone, in patients with severe ischemic cardiomyopathy, according to results from the REVIVED-BCIS2 trial.

The primary composite outcome of all-cause death or heart failure hospitalization occurred in 37.2% of the PCI group and 38% of the OMT group (hazard ratio, 0.99; P = .96) over a median of 3.4 years follow-up. The treatment effect was consistent across all subgroups.

There were no significant differences in left ventricular ejection fraction (LVEF) at 6 and 12 months.

Quality of life scores favored PCI early on, but there was catch-up over time with medical therapy, and this advantage disappeared by 2 years, principal investigator Divaka Perera, MD, King’s College London, reported at the annual congress of the European Society of Cardiology.

“The takeaway is that we should not be offering PCI to patients who have stable, well-medicated left ventricular dysfunction,” Dr. Perera told this news organization. “But we should still consider revascularization in patients presenting with acute coronary syndromes or who have lots of angina, because they were not included in the trial.”

The study, published simultaneously in the New England Journal of Medicine, provides the first randomized evidence on PCI for ischemic cardiomyopathy.

Revascularization guidelines in the United States make no recommendation for PCI, whereas those in Europe recommend coronary artery bypass grafting (CABG) first for patients with multivessel disease (class 1); they have a class 2a, level of evidence C indication for PCI in select patients. U.S. and European heart failure guidelines also support guideline directed therapy and CABG in select patients with ejection fractions of 35% or less.

This guidance is based on consensus opinion and the STICH trial, in which CABG plus OMT failed to provide a mortality benefit over OMT alone at 5 years but improved survival at 10 years in the extension STICHES study.

“Medical therapy for heart failure works, and this trial’s results are another important reminder of that,” said Eric Velazquez, MD, who led STICH and was invited to comment on the findings.

Mortality will only get better with the use of SGLT2 inhibitors, he noted, which were not included in the trial. Utilization of ACE inhibitors/ARBs/ARNIs and beta-blockers was similar to STICH and excellent in REVIVED. “They did do a better job in utilization of ICD and CRTs than the STICH trial, and I think that needs to be explored further about the impact of those changes.”

Nevertheless, ischemic cardiomyopathy patients have “unacceptably high mortality,” with the observed mortality about 20% at 3 years and about 35% at 5 years, said Dr. Velazquez, with Yale University, New Haven, Conn.

In most heart failure trials, HF hospitalization drives the primary composite endpoint, but the opposite was true here and in STICH, he observed. “You had twice the risk of dying during the 3.4 years than you did of being hospitalized for heart failure, and ... that is [an important] distinction we must realize is evident in our ischemic cardiomyopathy patients.”

The findings will likely not lead to a change in the guidelines, he added. “I think we continue as status quo for now and get more data.”

Despite the lack of randomized evidence, he cautioned that PCI is increasingly performed in patients with ischemic cardiomyopathy, with registry data suggesting nearly 60% of patients received the procedure.

Reached for comment, Clyde Yancy, MD, chief of cardiology and vice dean of diversity & inclusion at Northwestern University Feinberg School of Medicine, Chicago, said, “For now, the current guidelines are correct. Best application of guideline-directed medical and device therapy is the gold standard for heart failure, and that includes heart failure due to ischemic etiologies.

Detailed results

Between August 2013 and March 2020, REVIVED-BCIS2 enrolled 700 patients at 40 U.K. centers who had an LVEF of 35% or less, extensive CAD (defined by a British Cardiovascular Intervention Society myocardial Jeopardy Score [BCIS-JS] of at least 6), and viability in at least four myocardial segments amenable to PCI. Patients were evenly randomly assigned to individually adjusted pharmacologic and device therapy for heart failure alone or with PCI.

The average age was about 70, only 12.3% women, 344 patients had 2-vessel CAD, and 281 had 3-vessel CAD. The mean LVEF was 27% and median BCIS-JS score 10.

During follow-up, which reached 8.5 years in some patients due to the long enrollment, 31.7% of patients in the PCI group and 32.6% patients in the OMT group died from any cause and 14.7% and 15.3%, respectively, were admitted for heart failure.

LVEF improved by 1.8% at 6 months and 2% at 12 months in the PCI group and by 3.4% and 1.1%, respectively, in the OMT group. The mean between-group difference was –1.6% at 6 months and 0.9% at 12 months.

With regard to quality of life, the Kansas City Cardiomyopathy Questionnaire overall summary score favored the PCI group by 6.5 points at 6 months and by 4.5 points at 12 months, but by 24 months the between-group difference was 2.6 points (95% confidence interval, –0.7 to 5.8). Scores on the EuroQol Group 5-Dimensions 5-Level Questionnaire followed a similar pattern.

Unplanned revascularization was more common in the OMT group (HR, 0.27; 95% CI, 0.13-0.53). Acute myocardial infarction rates were similar in the two groups (HR, 1.01, 95% CI, 0.64-1.60), with the PCI group having more periprocedural infarcts and slightly fewer spontaneous infarcts.

Possible reasons for the discordant results between STICH and REVIVED are the threefold excess mortality within 30 days of CABG, whereas no such early hit occurred with PCI, lead investigator Dr. Perera said in an interview. Medical therapy has also evolved over time and REVIVED enrolled a more “real-world” population, with a median age close to 70 years versus 59 in STICH.
 

‘Modest’ degree of CAD?

An accompanying editorial, however, points out that despite considerable ventricular dysfunction, about half the patients in REVIVED had only 2-vessel disease and a median of two lesions treated.

“This relatively modest degree of coronary artery disease seems unusual for patients selected to undergo revascularization with the hope of restoring or normalizing ventricular function,” writes Ajay Kirtane, MD, from Columbia University Irving Medical Center, NewYork-Presbyterian Hospital.

He said more details are needed on completeness of the revascularization, severity of stenosis, physiologic assessment of the lesion and, “most importantly, the correlation of stenosis with previous ischemic or viability testing.”

Asked about the editorial, Dr. Perera agreed that information on the type of revascularization and myocardial viability are important and said they hope to share analyses of the only recently unblinded data at the American College of Cardiology meeting next spring. Importantly, about 71% of viability testing was done by cardiac MR and the rest largely by dobutamine stress echocardiogram.

He disagreed, however, that participants had relatively modest CAD based on the 2- or 3-vessel classification and said the median score on the more granular BCIS-JS was 10, with maximum 12 indicating the entire myocardium is supplied by diseased vessels.

The trial also included almost 100 patients with left main disease, a group not included in previous medical therapy trials, including STICH and ISCHEMIA, Dr. Perera noted. “So, I think it was pretty, pretty severe coronary disease but a cohort that was better treated medically.”

George Dangas, MD, PhD, a professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said the study provides valuable information but also expressed concerns that the chronic heart failure in the trial was much more advanced than the CAD.

Copyright American Heart Association copyright American Heart Association copyright American Heart Association

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

Percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) does not prolong survival or improve ventricular function, compared with OMT alone, in patients with severe ischemic cardiomyopathy, according to results from the REVIVED-BCIS2 trial.

The primary composite outcome of all-cause death or heart failure hospitalization occurred in 37.2% of the PCI group and 38% of the OMT group (hazard ratio, 0.99; P = .96) over a median of 3.4 years follow-up. The treatment effect was consistent across all subgroups.

There were no significant differences in left ventricular ejection fraction (LVEF) at 6 and 12 months.

Quality of life scores favored PCI early on, but there was catch-up over time with medical therapy, and this advantage disappeared by 2 years, principal investigator Divaka Perera, MD, King’s College London, reported at the annual congress of the European Society of Cardiology.

“The takeaway is that we should not be offering PCI to patients who have stable, well-medicated left ventricular dysfunction,” Dr. Perera told this news organization. “But we should still consider revascularization in patients presenting with acute coronary syndromes or who have lots of angina, because they were not included in the trial.”

The study, published simultaneously in the New England Journal of Medicine, provides the first randomized evidence on PCI for ischemic cardiomyopathy.

Revascularization guidelines in the United States make no recommendation for PCI, whereas those in Europe recommend coronary artery bypass grafting (CABG) first for patients with multivessel disease (class 1); they have a class 2a, level of evidence C indication for PCI in select patients. U.S. and European heart failure guidelines also support guideline directed therapy and CABG in select patients with ejection fractions of 35% or less.

This guidance is based on consensus opinion and the STICH trial, in which CABG plus OMT failed to provide a mortality benefit over OMT alone at 5 years but improved survival at 10 years in the extension STICHES study.

“Medical therapy for heart failure works, and this trial’s results are another important reminder of that,” said Eric Velazquez, MD, who led STICH and was invited to comment on the findings.

Mortality will only get better with the use of SGLT2 inhibitors, he noted, which were not included in the trial. Utilization of ACE inhibitors/ARBs/ARNIs and beta-blockers was similar to STICH and excellent in REVIVED. “They did do a better job in utilization of ICD and CRTs than the STICH trial, and I think that needs to be explored further about the impact of those changes.”

Nevertheless, ischemic cardiomyopathy patients have “unacceptably high mortality,” with the observed mortality about 20% at 3 years and about 35% at 5 years, said Dr. Velazquez, with Yale University, New Haven, Conn.

In most heart failure trials, HF hospitalization drives the primary composite endpoint, but the opposite was true here and in STICH, he observed. “You had twice the risk of dying during the 3.4 years than you did of being hospitalized for heart failure, and ... that is [an important] distinction we must realize is evident in our ischemic cardiomyopathy patients.”

The findings will likely not lead to a change in the guidelines, he added. “I think we continue as status quo for now and get more data.”

Despite the lack of randomized evidence, he cautioned that PCI is increasingly performed in patients with ischemic cardiomyopathy, with registry data suggesting nearly 60% of patients received the procedure.

Reached for comment, Clyde Yancy, MD, chief of cardiology and vice dean of diversity & inclusion at Northwestern University Feinberg School of Medicine, Chicago, said, “For now, the current guidelines are correct. Best application of guideline-directed medical and device therapy is the gold standard for heart failure, and that includes heart failure due to ischemic etiologies.

Detailed results

Between August 2013 and March 2020, REVIVED-BCIS2 enrolled 700 patients at 40 U.K. centers who had an LVEF of 35% or less, extensive CAD (defined by a British Cardiovascular Intervention Society myocardial Jeopardy Score [BCIS-JS] of at least 6), and viability in at least four myocardial segments amenable to PCI. Patients were evenly randomly assigned to individually adjusted pharmacologic and device therapy for heart failure alone or with PCI.

The average age was about 70, only 12.3% women, 344 patients had 2-vessel CAD, and 281 had 3-vessel CAD. The mean LVEF was 27% and median BCIS-JS score 10.

During follow-up, which reached 8.5 years in some patients due to the long enrollment, 31.7% of patients in the PCI group and 32.6% patients in the OMT group died from any cause and 14.7% and 15.3%, respectively, were admitted for heart failure.

LVEF improved by 1.8% at 6 months and 2% at 12 months in the PCI group and by 3.4% and 1.1%, respectively, in the OMT group. The mean between-group difference was –1.6% at 6 months and 0.9% at 12 months.

With regard to quality of life, the Kansas City Cardiomyopathy Questionnaire overall summary score favored the PCI group by 6.5 points at 6 months and by 4.5 points at 12 months, but by 24 months the between-group difference was 2.6 points (95% confidence interval, –0.7 to 5.8). Scores on the EuroQol Group 5-Dimensions 5-Level Questionnaire followed a similar pattern.

Unplanned revascularization was more common in the OMT group (HR, 0.27; 95% CI, 0.13-0.53). Acute myocardial infarction rates were similar in the two groups (HR, 1.01, 95% CI, 0.64-1.60), with the PCI group having more periprocedural infarcts and slightly fewer spontaneous infarcts.

Possible reasons for the discordant results between STICH and REVIVED are the threefold excess mortality within 30 days of CABG, whereas no such early hit occurred with PCI, lead investigator Dr. Perera said in an interview. Medical therapy has also evolved over time and REVIVED enrolled a more “real-world” population, with a median age close to 70 years versus 59 in STICH.
 

‘Modest’ degree of CAD?

An accompanying editorial, however, points out that despite considerable ventricular dysfunction, about half the patients in REVIVED had only 2-vessel disease and a median of two lesions treated.

“This relatively modest degree of coronary artery disease seems unusual for patients selected to undergo revascularization with the hope of restoring or normalizing ventricular function,” writes Ajay Kirtane, MD, from Columbia University Irving Medical Center, NewYork-Presbyterian Hospital.

He said more details are needed on completeness of the revascularization, severity of stenosis, physiologic assessment of the lesion and, “most importantly, the correlation of stenosis with previous ischemic or viability testing.”

Asked about the editorial, Dr. Perera agreed that information on the type of revascularization and myocardial viability are important and said they hope to share analyses of the only recently unblinded data at the American College of Cardiology meeting next spring. Importantly, about 71% of viability testing was done by cardiac MR and the rest largely by dobutamine stress echocardiogram.

He disagreed, however, that participants had relatively modest CAD based on the 2- or 3-vessel classification and said the median score on the more granular BCIS-JS was 10, with maximum 12 indicating the entire myocardium is supplied by diseased vessels.

The trial also included almost 100 patients with left main disease, a group not included in previous medical therapy trials, including STICH and ISCHEMIA, Dr. Perera noted. “So, I think it was pretty, pretty severe coronary disease but a cohort that was better treated medically.”

George Dangas, MD, PhD, a professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said the study provides valuable information but also expressed concerns that the chronic heart failure in the trial was much more advanced than the CAD.

Copyright American Heart Association copyright American Heart Association copyright American Heart Association

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

Percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) does not prolong survival or improve ventricular function, compared with OMT alone, in patients with severe ischemic cardiomyopathy, according to results from the REVIVED-BCIS2 trial.

The primary composite outcome of all-cause death or heart failure hospitalization occurred in 37.2% of the PCI group and 38% of the OMT group (hazard ratio, 0.99; P = .96) over a median of 3.4 years follow-up. The treatment effect was consistent across all subgroups.

There were no significant differences in left ventricular ejection fraction (LVEF) at 6 and 12 months.

Quality of life scores favored PCI early on, but there was catch-up over time with medical therapy, and this advantage disappeared by 2 years, principal investigator Divaka Perera, MD, King’s College London, reported at the annual congress of the European Society of Cardiology.

“The takeaway is that we should not be offering PCI to patients who have stable, well-medicated left ventricular dysfunction,” Dr. Perera told this news organization. “But we should still consider revascularization in patients presenting with acute coronary syndromes or who have lots of angina, because they were not included in the trial.”

The study, published simultaneously in the New England Journal of Medicine, provides the first randomized evidence on PCI for ischemic cardiomyopathy.

Revascularization guidelines in the United States make no recommendation for PCI, whereas those in Europe recommend coronary artery bypass grafting (CABG) first for patients with multivessel disease (class 1); they have a class 2a, level of evidence C indication for PCI in select patients. U.S. and European heart failure guidelines also support guideline directed therapy and CABG in select patients with ejection fractions of 35% or less.

This guidance is based on consensus opinion and the STICH trial, in which CABG plus OMT failed to provide a mortality benefit over OMT alone at 5 years but improved survival at 10 years in the extension STICHES study.

“Medical therapy for heart failure works, and this trial’s results are another important reminder of that,” said Eric Velazquez, MD, who led STICH and was invited to comment on the findings.

Mortality will only get better with the use of SGLT2 inhibitors, he noted, which were not included in the trial. Utilization of ACE inhibitors/ARBs/ARNIs and beta-blockers was similar to STICH and excellent in REVIVED. “They did do a better job in utilization of ICD and CRTs than the STICH trial, and I think that needs to be explored further about the impact of those changes.”

Nevertheless, ischemic cardiomyopathy patients have “unacceptably high mortality,” with the observed mortality about 20% at 3 years and about 35% at 5 years, said Dr. Velazquez, with Yale University, New Haven, Conn.

In most heart failure trials, HF hospitalization drives the primary composite endpoint, but the opposite was true here and in STICH, he observed. “You had twice the risk of dying during the 3.4 years than you did of being hospitalized for heart failure, and ... that is [an important] distinction we must realize is evident in our ischemic cardiomyopathy patients.”

The findings will likely not lead to a change in the guidelines, he added. “I think we continue as status quo for now and get more data.”

Despite the lack of randomized evidence, he cautioned that PCI is increasingly performed in patients with ischemic cardiomyopathy, with registry data suggesting nearly 60% of patients received the procedure.

Reached for comment, Clyde Yancy, MD, chief of cardiology and vice dean of diversity & inclusion at Northwestern University Feinberg School of Medicine, Chicago, said, “For now, the current guidelines are correct. Best application of guideline-directed medical and device therapy is the gold standard for heart failure, and that includes heart failure due to ischemic etiologies.

Detailed results

Between August 2013 and March 2020, REVIVED-BCIS2 enrolled 700 patients at 40 U.K. centers who had an LVEF of 35% or less, extensive CAD (defined by a British Cardiovascular Intervention Society myocardial Jeopardy Score [BCIS-JS] of at least 6), and viability in at least four myocardial segments amenable to PCI. Patients were evenly randomly assigned to individually adjusted pharmacologic and device therapy for heart failure alone or with PCI.

The average age was about 70, only 12.3% women, 344 patients had 2-vessel CAD, and 281 had 3-vessel CAD. The mean LVEF was 27% and median BCIS-JS score 10.

During follow-up, which reached 8.5 years in some patients due to the long enrollment, 31.7% of patients in the PCI group and 32.6% patients in the OMT group died from any cause and 14.7% and 15.3%, respectively, were admitted for heart failure.

LVEF improved by 1.8% at 6 months and 2% at 12 months in the PCI group and by 3.4% and 1.1%, respectively, in the OMT group. The mean between-group difference was –1.6% at 6 months and 0.9% at 12 months.

With regard to quality of life, the Kansas City Cardiomyopathy Questionnaire overall summary score favored the PCI group by 6.5 points at 6 months and by 4.5 points at 12 months, but by 24 months the between-group difference was 2.6 points (95% confidence interval, –0.7 to 5.8). Scores on the EuroQol Group 5-Dimensions 5-Level Questionnaire followed a similar pattern.

Unplanned revascularization was more common in the OMT group (HR, 0.27; 95% CI, 0.13-0.53). Acute myocardial infarction rates were similar in the two groups (HR, 1.01, 95% CI, 0.64-1.60), with the PCI group having more periprocedural infarcts and slightly fewer spontaneous infarcts.

Possible reasons for the discordant results between STICH and REVIVED are the threefold excess mortality within 30 days of CABG, whereas no such early hit occurred with PCI, lead investigator Dr. Perera said in an interview. Medical therapy has also evolved over time and REVIVED enrolled a more “real-world” population, with a median age close to 70 years versus 59 in STICH.
 

‘Modest’ degree of CAD?

An accompanying editorial, however, points out that despite considerable ventricular dysfunction, about half the patients in REVIVED had only 2-vessel disease and a median of two lesions treated.

“This relatively modest degree of coronary artery disease seems unusual for patients selected to undergo revascularization with the hope of restoring or normalizing ventricular function,” writes Ajay Kirtane, MD, from Columbia University Irving Medical Center, NewYork-Presbyterian Hospital.

He said more details are needed on completeness of the revascularization, severity of stenosis, physiologic assessment of the lesion and, “most importantly, the correlation of stenosis with previous ischemic or viability testing.”

Asked about the editorial, Dr. Perera agreed that information on the type of revascularization and myocardial viability are important and said they hope to share analyses of the only recently unblinded data at the American College of Cardiology meeting next spring. Importantly, about 71% of viability testing was done by cardiac MR and the rest largely by dobutamine stress echocardiogram.

He disagreed, however, that participants had relatively modest CAD based on the 2- or 3-vessel classification and said the median score on the more granular BCIS-JS was 10, with maximum 12 indicating the entire myocardium is supplied by diseased vessels.

The trial also included almost 100 patients with left main disease, a group not included in previous medical therapy trials, including STICH and ISCHEMIA, Dr. Perera noted. “So, I think it was pretty, pretty severe coronary disease but a cohort that was better treated medically.”

George Dangas, MD, PhD, a professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said the study provides valuable information but also expressed concerns that the chronic heart failure in the trial was much more advanced than the CAD.

Copyright American Heart Association copyright American Heart Association copyright American Heart Association

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

Video-based artificial intelligence provided a more accurate and consistent reading of echocardiograms than did experienced sonographers in a blinded trial, a result suggesting that this technology is no longer experimental.

“We are planning to deploy this at Cedars, so this is essentially ready for use,” said David Ouyang, MD, who is affiliated with the Cedars-Sinai Medical School and is an instructor of cardiology at the University of California, both in Los Angeles.

The primary outcome of this trial, called EchoNet-RCT, was the proportion of cases in which cardiologists changed the left ventricular ejection fraction (LVEF) reading by more than 5%. They were blinded to the origin of the reports.

This endpoint was reached in 27.2% of reports generated by sonographers but just 16.8% of reports generated by AI, a mean difference of 10.5% (P < .001).

The AI tested in the trial is called EchoNet-Dynamic. It employs a video-based deep learning algorithm that permits beat-by-beat evaluation of ejection fraction. The specifics of this system were described in a study published 2 years ago in Nature. In that evaluation of the model training set, the absolute error rate was 6% in the more than 10,000 annotated echocardiogram videos.
 

Echo-Net is first blinded AI echo trial

Although AI is already being employed for image evaluation in many areas of medicine, the EchoNet-RCT study “is the first blinded trial of AI in cardiology,” Dr. Ouyang said. Indeed, he noted that no prior study has even been randomized.

After a run-in period, 3,495 echocardiograms were randomizly assigned to be read by AI or by a sonographer. The reports generated by these two approaches were then evaluated by the blinded cardiologists. The sonographers and the cardiologists participating in this study had a mean of 14.1 years and 12.7 years of experience, respectively.

Each reading by both sonographers and AI was based on a single beat, but this presumably was a relative handicap for the potential advantage of AI technology, which is capable of evaluating ejection fraction across multiple cardiac cycles. The evaluation of multiple cycles has been shown previously to improve accuracy, but it is tedious and not commonly performed in routine practice, according to Dr. Ouyang.
 

AI favored for all major endpoints

The superiority of AI was calculated after noninferiority was demonstrated. AI also showed superiority for the secondary safety outcome which involved a test-retest evaluation. Historical AI and sonographer echocardiogram reports were again blindly assessed. Although the retest variability was lower for both (6.29% vs. 7.23%), the difference was still highly significant in favor of AI (P < .001)

The relative efficiency of AI to sonographer assessment was also tested and showed meaningful reductions in work time. While AI eliminates the labor of the sonographer completely (0 vs. a median of 119 seconds, P < .001), it was also associated with a highly significant reduction in median cardiologist time spent on echo evaluation (54 vs. 64 seconds, P < .001).

Assuming that AI is integrated into the routine workflow of a busy center, AI “could be very effective at not only improving the quality of echo reading output but also increasing efficiencies in time and effort spent by sonographers and cardiologists by simplifying otherwise tedious but important tasks,” Dr. Ouyang said.

The trial enrolled a relatively typical population. The median age was 66 years, 57% were male, and comorbidities such as diabetes and chronic kidney disease were common. When AI was compared with sonographer evaluation in groups stratified by these variables as well as by race, image quality, and location of the evaluation (inpatient vs. outpatient), the advantage of AI was consistent.

Cardiologists cannot detect AI-read echos

Identifying potential limitations of this study, James D. Thomas, MD, professor of medicine, Northwestern University, Chicago, pointed out that it was a single-center trial, and he questioned a potential bias from cardiologists able to guess accurately which of the reports they were evaluating were generated by AI.

Dr. Ouyang acknowledged that this study was limited to patients at UCLA, but he pointed out that the training model was developed at Stanford (Calif.) University, so there were two sets of patients involved in testing the machine learning algorithm. He also noted that it was exceptionally large, providing a robust dataset.

As for the bias, this was evaluated as predefined endpoint.

“We asked the cardiologists to tell us [whether] they knew which reports were generated by AI,” Dr. Ouyang said. In 43% of cases, they reported they were not sure. However, when they did express confidence that the report was generated by AI, they were correct in only 32% of the cases and incorrect in 24%. Dr. Ouyang suggested these numbers argue against a substantial role for a bias affecting the trial results.

Dr. Thomas, who has an interest in the role of AI for cardiology, cautioned that there are “technical, privacy, commercial, maintenance, and regulatory barriers” that must be circumvented before AI is widely incorporated into clinical practice, but he praised this blinded trial for advancing the field. Even accounting for any limitations, he clearly shared Dr. Ouyang’s enthusiasm about the future of AI for EF assessment.

Dr. Ouyang reports financial relationships with EchoIQ, Ultromics, and InVision. Dr. Thomas reports financial relationships with Abbott, GE, egnite, EchoIQ, and Caption Health.

Video-based artificial intelligence provided a more accurate and consistent reading of echocardiograms than did experienced sonographers in a blinded trial, a result suggesting that this technology is no longer experimental.

“We are planning to deploy this at Cedars, so this is essentially ready for use,” said David Ouyang, MD, who is affiliated with the Cedars-Sinai Medical School and is an instructor of cardiology at the University of California, both in Los Angeles.

The primary outcome of this trial, called EchoNet-RCT, was the proportion of cases in which cardiologists changed the left ventricular ejection fraction (LVEF) reading by more than 5%. They were blinded to the origin of the reports.

This endpoint was reached in 27.2% of reports generated by sonographers but just 16.8% of reports generated by AI, a mean difference of 10.5% (P < .001).

The AI tested in the trial is called EchoNet-Dynamic. It employs a video-based deep learning algorithm that permits beat-by-beat evaluation of ejection fraction. The specifics of this system were described in a study published 2 years ago in Nature. In that evaluation of the model training set, the absolute error rate was 6% in the more than 10,000 annotated echocardiogram videos.
 

Echo-Net is first blinded AI echo trial

Although AI is already being employed for image evaluation in many areas of medicine, the EchoNet-RCT study “is the first blinded trial of AI in cardiology,” Dr. Ouyang said. Indeed, he noted that no prior study has even been randomized.

After a run-in period, 3,495 echocardiograms were randomizly assigned to be read by AI or by a sonographer. The reports generated by these two approaches were then evaluated by the blinded cardiologists. The sonographers and the cardiologists participating in this study had a mean of 14.1 years and 12.7 years of experience, respectively.

Each reading by both sonographers and AI was based on a single beat, but this presumably was a relative handicap for the potential advantage of AI technology, which is capable of evaluating ejection fraction across multiple cardiac cycles. The evaluation of multiple cycles has been shown previously to improve accuracy, but it is tedious and not commonly performed in routine practice, according to Dr. Ouyang.
 

AI favored for all major endpoints

The superiority of AI was calculated after noninferiority was demonstrated. AI also showed superiority for the secondary safety outcome which involved a test-retest evaluation. Historical AI and sonographer echocardiogram reports were again blindly assessed. Although the retest variability was lower for both (6.29% vs. 7.23%), the difference was still highly significant in favor of AI (P < .001)

The relative efficiency of AI to sonographer assessment was also tested and showed meaningful reductions in work time. While AI eliminates the labor of the sonographer completely (0 vs. a median of 119 seconds, P < .001), it was also associated with a highly significant reduction in median cardiologist time spent on echo evaluation (54 vs. 64 seconds, P < .001).

Assuming that AI is integrated into the routine workflow of a busy center, AI “could be very effective at not only improving the quality of echo reading output but also increasing efficiencies in time and effort spent by sonographers and cardiologists by simplifying otherwise tedious but important tasks,” Dr. Ouyang said.

The trial enrolled a relatively typical population. The median age was 66 years, 57% were male, and comorbidities such as diabetes and chronic kidney disease were common. When AI was compared with sonographer evaluation in groups stratified by these variables as well as by race, image quality, and location of the evaluation (inpatient vs. outpatient), the advantage of AI was consistent.

Cardiologists cannot detect AI-read echos

Identifying potential limitations of this study, James D. Thomas, MD, professor of medicine, Northwestern University, Chicago, pointed out that it was a single-center trial, and he questioned a potential bias from cardiologists able to guess accurately which of the reports they were evaluating were generated by AI.

Dr. Ouyang acknowledged that this study was limited to patients at UCLA, but he pointed out that the training model was developed at Stanford (Calif.) University, so there were two sets of patients involved in testing the machine learning algorithm. He also noted that it was exceptionally large, providing a robust dataset.

As for the bias, this was evaluated as predefined endpoint.

“We asked the cardiologists to tell us [whether] they knew which reports were generated by AI,” Dr. Ouyang said. In 43% of cases, they reported they were not sure. However, when they did express confidence that the report was generated by AI, they were correct in only 32% of the cases and incorrect in 24%. Dr. Ouyang suggested these numbers argue against a substantial role for a bias affecting the trial results.

Dr. Thomas, who has an interest in the role of AI for cardiology, cautioned that there are “technical, privacy, commercial, maintenance, and regulatory barriers” that must be circumvented before AI is widely incorporated into clinical practice, but he praised this blinded trial for advancing the field. Even accounting for any limitations, he clearly shared Dr. Ouyang’s enthusiasm about the future of AI for EF assessment.

Dr. Ouyang reports financial relationships with EchoIQ, Ultromics, and InVision. Dr. Thomas reports financial relationships with Abbott, GE, egnite, EchoIQ, and Caption Health.

Video-based artificial intelligence provided a more accurate and consistent reading of echocardiograms than did experienced sonographers in a blinded trial, a result suggesting that this technology is no longer experimental.

“We are planning to deploy this at Cedars, so this is essentially ready for use,” said David Ouyang, MD, who is affiliated with the Cedars-Sinai Medical School and is an instructor of cardiology at the University of California, both in Los Angeles.

The primary outcome of this trial, called EchoNet-RCT, was the proportion of cases in which cardiologists changed the left ventricular ejection fraction (LVEF) reading by more than 5%. They were blinded to the origin of the reports.

This endpoint was reached in 27.2% of reports generated by sonographers but just 16.8% of reports generated by AI, a mean difference of 10.5% (P < .001).

The AI tested in the trial is called EchoNet-Dynamic. It employs a video-based deep learning algorithm that permits beat-by-beat evaluation of ejection fraction. The specifics of this system were described in a study published 2 years ago in Nature. In that evaluation of the model training set, the absolute error rate was 6% in the more than 10,000 annotated echocardiogram videos.
 

Echo-Net is first blinded AI echo trial

Although AI is already being employed for image evaluation in many areas of medicine, the EchoNet-RCT study “is the first blinded trial of AI in cardiology,” Dr. Ouyang said. Indeed, he noted that no prior study has even been randomized.

After a run-in period, 3,495 echocardiograms were randomizly assigned to be read by AI or by a sonographer. The reports generated by these two approaches were then evaluated by the blinded cardiologists. The sonographers and the cardiologists participating in this study had a mean of 14.1 years and 12.7 years of experience, respectively.

Each reading by both sonographers and AI was based on a single beat, but this presumably was a relative handicap for the potential advantage of AI technology, which is capable of evaluating ejection fraction across multiple cardiac cycles. The evaluation of multiple cycles has been shown previously to improve accuracy, but it is tedious and not commonly performed in routine practice, according to Dr. Ouyang.
 

AI favored for all major endpoints

The superiority of AI was calculated after noninferiority was demonstrated. AI also showed superiority for the secondary safety outcome which involved a test-retest evaluation. Historical AI and sonographer echocardiogram reports were again blindly assessed. Although the retest variability was lower for both (6.29% vs. 7.23%), the difference was still highly significant in favor of AI (P < .001)

The relative efficiency of AI to sonographer assessment was also tested and showed meaningful reductions in work time. While AI eliminates the labor of the sonographer completely (0 vs. a median of 119 seconds, P < .001), it was also associated with a highly significant reduction in median cardiologist time spent on echo evaluation (54 vs. 64 seconds, P < .001).

Assuming that AI is integrated into the routine workflow of a busy center, AI “could be very effective at not only improving the quality of echo reading output but also increasing efficiencies in time and effort spent by sonographers and cardiologists by simplifying otherwise tedious but important tasks,” Dr. Ouyang said.

The trial enrolled a relatively typical population. The median age was 66 years, 57% were male, and comorbidities such as diabetes and chronic kidney disease were common. When AI was compared with sonographer evaluation in groups stratified by these variables as well as by race, image quality, and location of the evaluation (inpatient vs. outpatient), the advantage of AI was consistent.

Cardiologists cannot detect AI-read echos

Identifying potential limitations of this study, James D. Thomas, MD, professor of medicine, Northwestern University, Chicago, pointed out that it was a single-center trial, and he questioned a potential bias from cardiologists able to guess accurately which of the reports they were evaluating were generated by AI.

Dr. Ouyang acknowledged that this study was limited to patients at UCLA, but he pointed out that the training model was developed at Stanford (Calif.) University, so there were two sets of patients involved in testing the machine learning algorithm. He also noted that it was exceptionally large, providing a robust dataset.

As for the bias, this was evaluated as predefined endpoint.

“We asked the cardiologists to tell us [whether] they knew which reports were generated by AI,” Dr. Ouyang said. In 43% of cases, they reported they were not sure. However, when they did express confidence that the report was generated by AI, they were correct in only 32% of the cases and incorrect in 24%. Dr. Ouyang suggested these numbers argue against a substantial role for a bias affecting the trial results.

Dr. Thomas, who has an interest in the role of AI for cardiology, cautioned that there are “technical, privacy, commercial, maintenance, and regulatory barriers” that must be circumvented before AI is widely incorporated into clinical practice, but he praised this blinded trial for advancing the field. Even accounting for any limitations, he clearly shared Dr. Ouyang’s enthusiasm about the future of AI for EF assessment.

Dr. Ouyang reports financial relationships with EchoIQ, Ultromics, and InVision. Dr. Thomas reports financial relationships with Abbott, GE, egnite, EchoIQ, and Caption Health.

A decades-old drug, added to standard loop diuretics, could potentially help more volume-overloaded patients with acute decompensated heart failure (ADHF) to be discharged from the hospital ‘dry,’ a randomized trial suggests.

Those who received intravenous acetazolamide, compared with placebo, on top of a usual-care IV loop diuretic in the multicenter study were 46% more likely to achieve “successful” decongestion – that is, to leave the hospital without lingering signs of volume overload.

The trial, with more than 500 patients, is the first “to unequivocally show benefit of any drug, namely acetazolamide, on major heart failure outcomes in patients with acute decompensated heart failure,” said Wilfried Mullens, MD, PhD, Hospital Oost-Limburg, Genk, Belgium, at a media briefing during the annual congress of the European Society of Cardiology, Barcelona.

The patients who received acetazolamide “also had a shorter hospital stay, having a major impact on not only quality of life, but also health care expenditures,” said Dr. Mullens, who leads the steering committee of the trial conducted in Belgium. He presented the results of Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) at ESC 2022 and is lead author on its same-day publication in the New England Journal of Medicine.
 

Complementary effects?

Current guidelines on managing volume-overloaded patients with ADHF owe a lot to the 2011 DOSE trial, which provided some of the first randomized-trial evidence in an arena led largely by clinical tradition. The advantages it saw with the high-dose furosemide strategy helped it enter into clinical practice, but even in DOSE, the strategy fell short of achieving full decongestion for many patients.

The ADVOR report describes acetazolamide as a carbonic anhydrase inhibitor that reduces sodium recovery in the proximal tubule, similar to the function of loop diuretics in the loop of Henle. Acting in different segments of the nephron, acetazolamide and loop diuretics like furosemide may potentially have complementary effects that improve diuretic “efficiency.”

The difference in decongestion effect between the acetazolamide and placebo groups grew consistently from baseline to day 3. “There was an increase in treatment effect over consecutive days,” Dr. Mullens said. “This highlights the importance of treating congestion both early and aggressively. You cannot catch up,” he said. “If you don’t treat them aggressively initially, you can never get them dry.”

Of the trial’s 519 patients, 42.2% of those assigned to acetazolamide and 30.5% of those in the control group were judged to have had successful decongestion at 3 days, the primary endpoint. Successful decongestion meant they had no remaining signs of volume overload, such as edema, pleural effusion, or ascites.

Although the trial wasn’t powered for clinical outcomes, the 3-month rates of death from any cause or rehospitalization for heart failure were similar at 29.7% in the acetazolamide group and 27.8% for the control group. All-cause mortality in an exploratory analysis was also statistically comparable at 15.2% and 12%, respectively.
 

Decongestion and clinical outcomes

The study is noteworthy “because it tests a readily available diuretic, acetazolamide, that is not used widely for ADHF,” and showed a benefit at 3 days from adding the drug to a prescribed loop diuretic regimen, Mark H. Drazner, MD, University of Texas Southwestern Medical Center, Dallas, told this news organization.

The benefit didn’t translate into improved clinical outcomes; indeed, mortality at 3 months was numerically higher in the acetazolamide group, observed Dr. Drazner, who is unaffiliated with the study.

Although ADVOR isn’t powered for mortality, he acknowledged, “one would expect the enhanced decongestion would have led to improved outcomes,” or at least a signal of such improvement.

It’s worth noting, Dr. Drazner added, “that the strategy tested was to add acetazolamide up front, on day 1, before loop diuretics were maximized.”

Indeed, the published report says all patients received IV loop diuretics at double the oral maintenance dose, given the first day in a single bolus immediately on randomization. The dose was split into two doses, given at least 6 hours apart, on day 2 and day 3. “The bolus of acetazolamide or matching placebo was administered simultaneously with the first dose of loop diuretics each day,” it states.

Although the protocol called for one loop diuretic dose on day 1, typically in practice patients would be dosed twice or three times each day, Dr. Drazner observed. Once-daily IV diuretic dosing may be less effective than a 2- or 3-times-per-day schedule, he said. As a result, acetazolamide might achieve faster decongestion after it is added to the loop diuretic, a benefit that would not otherwise be available in practice.
 

Messages for practice

Before this trial, Dr. Drazner said, he would usually add the thiazide diuretic metolazone as needed “to augment diuresis beyond maximum loop diuretics.” After ADVOR, “I’d be willing to try acetazolamide in that setting, recognizing I also don’t know the impact of metolazone on outcomes.”

Still, he would restrict either drug to patients who fail on maximal loop diuretics “rather than adding it routinely and up front, before the loop diuretics are maximized.”

More data are needed, Dr. Drazner said, including from a larger clinical-outcomes trial to confirm the strategy’s safety, before “the up-front addition of acetazolamide to submaximal loop diuretics doses” could become part of standard practice in ADHF.

Given the data so far, including those from ADVOR, “treatment with loop diuretics alone is probably sufficient for successful decongestion” among patients likely to respond to the drugs: that is, “those who are younger, those who have less severe or new-onset heart failure, and those who have normal kidney function,” states an editorial accompanying the published report.

“However, for the large group of patients who have some degree of diuretic resistance, or for those who have an inadequate initial response to loop-diuretic therapy, these data suggest the use of acetazolamide as a reasonable adjunct to achieving more rapid decongestion,” writes G. Michael Felker, MD, Duke University School of Medicine, Durham, N.C. Dr. Felker was lead author on the DOSE primary publication.

ADVOR entered volume-overloaded patients with ADHF and elevated natriuretic peptide levels who had been on oral maintenance with at least 40 mg of furosemide, or equivalent doses of other loop diuretics, for at least a month before randomization.

They were assigned to either IV acetazolamide at 500 mg once daily (n = 259) or placebo (n = 260) on top of an IV loop diuretic, at 27 centers in Belgium.

The risk ratio for the primary endpoint, successful decongestion after 3 days, was 1.46 (95% confidence interval, 1.17-1.82, P < .001) for the acetazolamide versus placebo groups.

In exploratory analyses, acetazolamide versus placebo, the RR for successful decongestion among patients who survived to discharge was increased at 1.27 (95% CI, 1.13-1.43). The hazard ratio for death from any cause at 3 months was not significant at 1.28 (95% CI, 0.78-2.05), nor was the HR for heart-failure rehospitalization at 3 months, 1.07 (95% CI, 0.71-1.59).

The role of SGLT2 inhibitors

ADVOR, understandably but maybe problematically, excluded patients taking SGLT2 inhibitors. The drugs have diuretic effects, among other useful properties, and became core therapy for a range of heart failure types after the trial was designed.

“This exclusion presents a conundrum for applying these results in contemporary clinical care,” Dr. Felker writes. For example, “the data supporting the efficacy and safety of SGLT2 inhibitors across the broad spectrum of patients with heart failure are now overwhelming, and most patients who are hospitalized for heart failure have a clear indication for these agents.”

Given that no ADVOR patients were on the drugs, his editorial states, “we can only speculate as to the efficacy of acetazolamide in patients treated with background SGLT2 inhibitors, which could potentially be additive, subadditive, or synergistic.”

The SGLT2 inhibitors will likely “be used in ADHF in the future, based on studies such as EMPULSE. It will be important to know whether SGLT2 inhibitors change the risk-benefit of also giving acetazolamide,” Dr. Drazner said when interviewed.

“I don’t think there’s any safety issue with regards to the combination of SGLT2 inhibitors and acetazolamide,” Dr. Mullens said. Their diuretic effects are likely to be additive, he proposed.

“Although SGLT2 inhibitors and acetazolamide both exert natriuretic and diuretic effects on the proximal tubules, their mode of action and potency differ substantially,” the published report states.

ADVOR is funded by the Belgian Health Care Knowledge Center. Dr. Mullens discloses receiving fees for speaking from Abbott Fund, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Medtronic, and Novartis. Disclosures for the other authors are at NEJM.org. Dr. Drazner has reported no relevant financial relationships. Dr. Felker discloses serving as a consultant for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cardionomic, Cytokinetics, Novartis, Reprieve, and Sequana.

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

A decades-old drug, added to standard loop diuretics, could potentially help more volume-overloaded patients with acute decompensated heart failure (ADHF) to be discharged from the hospital ‘dry,’ a randomized trial suggests.

Those who received intravenous acetazolamide, compared with placebo, on top of a usual-care IV loop diuretic in the multicenter study were 46% more likely to achieve “successful” decongestion – that is, to leave the hospital without lingering signs of volume overload.

The trial, with more than 500 patients, is the first “to unequivocally show benefit of any drug, namely acetazolamide, on major heart failure outcomes in patients with acute decompensated heart failure,” said Wilfried Mullens, MD, PhD, Hospital Oost-Limburg, Genk, Belgium, at a media briefing during the annual congress of the European Society of Cardiology, Barcelona.

The patients who received acetazolamide “also had a shorter hospital stay, having a major impact on not only quality of life, but also health care expenditures,” said Dr. Mullens, who leads the steering committee of the trial conducted in Belgium. He presented the results of Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) at ESC 2022 and is lead author on its same-day publication in the New England Journal of Medicine.
 

Complementary effects?

Current guidelines on managing volume-overloaded patients with ADHF owe a lot to the 2011 DOSE trial, which provided some of the first randomized-trial evidence in an arena led largely by clinical tradition. The advantages it saw with the high-dose furosemide strategy helped it enter into clinical practice, but even in DOSE, the strategy fell short of achieving full decongestion for many patients.

The ADVOR report describes acetazolamide as a carbonic anhydrase inhibitor that reduces sodium recovery in the proximal tubule, similar to the function of loop diuretics in the loop of Henle. Acting in different segments of the nephron, acetazolamide and loop diuretics like furosemide may potentially have complementary effects that improve diuretic “efficiency.”

The difference in decongestion effect between the acetazolamide and placebo groups grew consistently from baseline to day 3. “There was an increase in treatment effect over consecutive days,” Dr. Mullens said. “This highlights the importance of treating congestion both early and aggressively. You cannot catch up,” he said. “If you don’t treat them aggressively initially, you can never get them dry.”

Of the trial’s 519 patients, 42.2% of those assigned to acetazolamide and 30.5% of those in the control group were judged to have had successful decongestion at 3 days, the primary endpoint. Successful decongestion meant they had no remaining signs of volume overload, such as edema, pleural effusion, or ascites.

Although the trial wasn’t powered for clinical outcomes, the 3-month rates of death from any cause or rehospitalization for heart failure were similar at 29.7% in the acetazolamide group and 27.8% for the control group. All-cause mortality in an exploratory analysis was also statistically comparable at 15.2% and 12%, respectively.
 

Decongestion and clinical outcomes

The study is noteworthy “because it tests a readily available diuretic, acetazolamide, that is not used widely for ADHF,” and showed a benefit at 3 days from adding the drug to a prescribed loop diuretic regimen, Mark H. Drazner, MD, University of Texas Southwestern Medical Center, Dallas, told this news organization.

The benefit didn’t translate into improved clinical outcomes; indeed, mortality at 3 months was numerically higher in the acetazolamide group, observed Dr. Drazner, who is unaffiliated with the study.

Although ADVOR isn’t powered for mortality, he acknowledged, “one would expect the enhanced decongestion would have led to improved outcomes,” or at least a signal of such improvement.

It’s worth noting, Dr. Drazner added, “that the strategy tested was to add acetazolamide up front, on day 1, before loop diuretics were maximized.”

Indeed, the published report says all patients received IV loop diuretics at double the oral maintenance dose, given the first day in a single bolus immediately on randomization. The dose was split into two doses, given at least 6 hours apart, on day 2 and day 3. “The bolus of acetazolamide or matching placebo was administered simultaneously with the first dose of loop diuretics each day,” it states.

Although the protocol called for one loop diuretic dose on day 1, typically in practice patients would be dosed twice or three times each day, Dr. Drazner observed. Once-daily IV diuretic dosing may be less effective than a 2- or 3-times-per-day schedule, he said. As a result, acetazolamide might achieve faster decongestion after it is added to the loop diuretic, a benefit that would not otherwise be available in practice.
 

Messages for practice

Before this trial, Dr. Drazner said, he would usually add the thiazide diuretic metolazone as needed “to augment diuresis beyond maximum loop diuretics.” After ADVOR, “I’d be willing to try acetazolamide in that setting, recognizing I also don’t know the impact of metolazone on outcomes.”

Still, he would restrict either drug to patients who fail on maximal loop diuretics “rather than adding it routinely and up front, before the loop diuretics are maximized.”

More data are needed, Dr. Drazner said, including from a larger clinical-outcomes trial to confirm the strategy’s safety, before “the up-front addition of acetazolamide to submaximal loop diuretics doses” could become part of standard practice in ADHF.

Given the data so far, including those from ADVOR, “treatment with loop diuretics alone is probably sufficient for successful decongestion” among patients likely to respond to the drugs: that is, “those who are younger, those who have less severe or new-onset heart failure, and those who have normal kidney function,” states an editorial accompanying the published report.

“However, for the large group of patients who have some degree of diuretic resistance, or for those who have an inadequate initial response to loop-diuretic therapy, these data suggest the use of acetazolamide as a reasonable adjunct to achieving more rapid decongestion,” writes G. Michael Felker, MD, Duke University School of Medicine, Durham, N.C. Dr. Felker was lead author on the DOSE primary publication.

ADVOR entered volume-overloaded patients with ADHF and elevated natriuretic peptide levels who had been on oral maintenance with at least 40 mg of furosemide, or equivalent doses of other loop diuretics, for at least a month before randomization.

They were assigned to either IV acetazolamide at 500 mg once daily (n = 259) or placebo (n = 260) on top of an IV loop diuretic, at 27 centers in Belgium.

The risk ratio for the primary endpoint, successful decongestion after 3 days, was 1.46 (95% confidence interval, 1.17-1.82, P < .001) for the acetazolamide versus placebo groups.

In exploratory analyses, acetazolamide versus placebo, the RR for successful decongestion among patients who survived to discharge was increased at 1.27 (95% CI, 1.13-1.43). The hazard ratio for death from any cause at 3 months was not significant at 1.28 (95% CI, 0.78-2.05), nor was the HR for heart-failure rehospitalization at 3 months, 1.07 (95% CI, 0.71-1.59).

The role of SGLT2 inhibitors

ADVOR, understandably but maybe problematically, excluded patients taking SGLT2 inhibitors. The drugs have diuretic effects, among other useful properties, and became core therapy for a range of heart failure types after the trial was designed.

“This exclusion presents a conundrum for applying these results in contemporary clinical care,” Dr. Felker writes. For example, “the data supporting the efficacy and safety of SGLT2 inhibitors across the broad spectrum of patients with heart failure are now overwhelming, and most patients who are hospitalized for heart failure have a clear indication for these agents.”

Given that no ADVOR patients were on the drugs, his editorial states, “we can only speculate as to the efficacy of acetazolamide in patients treated with background SGLT2 inhibitors, which could potentially be additive, subadditive, or synergistic.”

The SGLT2 inhibitors will likely “be used in ADHF in the future, based on studies such as EMPULSE. It will be important to know whether SGLT2 inhibitors change the risk-benefit of also giving acetazolamide,” Dr. Drazner said when interviewed.

“I don’t think there’s any safety issue with regards to the combination of SGLT2 inhibitors and acetazolamide,” Dr. Mullens said. Their diuretic effects are likely to be additive, he proposed.

“Although SGLT2 inhibitors and acetazolamide both exert natriuretic and diuretic effects on the proximal tubules, their mode of action and potency differ substantially,” the published report states.

ADVOR is funded by the Belgian Health Care Knowledge Center. Dr. Mullens discloses receiving fees for speaking from Abbott Fund, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Medtronic, and Novartis. Disclosures for the other authors are at NEJM.org. Dr. Drazner has reported no relevant financial relationships. Dr. Felker discloses serving as a consultant for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cardionomic, Cytokinetics, Novartis, Reprieve, and Sequana.

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

A decades-old drug, added to standard loop diuretics, could potentially help more volume-overloaded patients with acute decompensated heart failure (ADHF) to be discharged from the hospital ‘dry,’ a randomized trial suggests.

Those who received intravenous acetazolamide, compared with placebo, on top of a usual-care IV loop diuretic in the multicenter study were 46% more likely to achieve “successful” decongestion – that is, to leave the hospital without lingering signs of volume overload.

The trial, with more than 500 patients, is the first “to unequivocally show benefit of any drug, namely acetazolamide, on major heart failure outcomes in patients with acute decompensated heart failure,” said Wilfried Mullens, MD, PhD, Hospital Oost-Limburg, Genk, Belgium, at a media briefing during the annual congress of the European Society of Cardiology, Barcelona.

The patients who received acetazolamide “also had a shorter hospital stay, having a major impact on not only quality of life, but also health care expenditures,” said Dr. Mullens, who leads the steering committee of the trial conducted in Belgium. He presented the results of Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) at ESC 2022 and is lead author on its same-day publication in the New England Journal of Medicine.
 

Complementary effects?

Current guidelines on managing volume-overloaded patients with ADHF owe a lot to the 2011 DOSE trial, which provided some of the first randomized-trial evidence in an arena led largely by clinical tradition. The advantages it saw with the high-dose furosemide strategy helped it enter into clinical practice, but even in DOSE, the strategy fell short of achieving full decongestion for many patients.

The ADVOR report describes acetazolamide as a carbonic anhydrase inhibitor that reduces sodium recovery in the proximal tubule, similar to the function of loop diuretics in the loop of Henle. Acting in different segments of the nephron, acetazolamide and loop diuretics like furosemide may potentially have complementary effects that improve diuretic “efficiency.”

The difference in decongestion effect between the acetazolamide and placebo groups grew consistently from baseline to day 3. “There was an increase in treatment effect over consecutive days,” Dr. Mullens said. “This highlights the importance of treating congestion both early and aggressively. You cannot catch up,” he said. “If you don’t treat them aggressively initially, you can never get them dry.”

Of the trial’s 519 patients, 42.2% of those assigned to acetazolamide and 30.5% of those in the control group were judged to have had successful decongestion at 3 days, the primary endpoint. Successful decongestion meant they had no remaining signs of volume overload, such as edema, pleural effusion, or ascites.

Although the trial wasn’t powered for clinical outcomes, the 3-month rates of death from any cause or rehospitalization for heart failure were similar at 29.7% in the acetazolamide group and 27.8% for the control group. All-cause mortality in an exploratory analysis was also statistically comparable at 15.2% and 12%, respectively.
 

Decongestion and clinical outcomes

The study is noteworthy “because it tests a readily available diuretic, acetazolamide, that is not used widely for ADHF,” and showed a benefit at 3 days from adding the drug to a prescribed loop diuretic regimen, Mark H. Drazner, MD, University of Texas Southwestern Medical Center, Dallas, told this news organization.

The benefit didn’t translate into improved clinical outcomes; indeed, mortality at 3 months was numerically higher in the acetazolamide group, observed Dr. Drazner, who is unaffiliated with the study.

Although ADVOR isn’t powered for mortality, he acknowledged, “one would expect the enhanced decongestion would have led to improved outcomes,” or at least a signal of such improvement.

It’s worth noting, Dr. Drazner added, “that the strategy tested was to add acetazolamide up front, on day 1, before loop diuretics were maximized.”

Indeed, the published report says all patients received IV loop diuretics at double the oral maintenance dose, given the first day in a single bolus immediately on randomization. The dose was split into two doses, given at least 6 hours apart, on day 2 and day 3. “The bolus of acetazolamide or matching placebo was administered simultaneously with the first dose of loop diuretics each day,” it states.

Although the protocol called for one loop diuretic dose on day 1, typically in practice patients would be dosed twice or three times each day, Dr. Drazner observed. Once-daily IV diuretic dosing may be less effective than a 2- or 3-times-per-day schedule, he said. As a result, acetazolamide might achieve faster decongestion after it is added to the loop diuretic, a benefit that would not otherwise be available in practice.
 

Messages for practice

Before this trial, Dr. Drazner said, he would usually add the thiazide diuretic metolazone as needed “to augment diuresis beyond maximum loop diuretics.” After ADVOR, “I’d be willing to try acetazolamide in that setting, recognizing I also don’t know the impact of metolazone on outcomes.”

Still, he would restrict either drug to patients who fail on maximal loop diuretics “rather than adding it routinely and up front, before the loop diuretics are maximized.”

More data are needed, Dr. Drazner said, including from a larger clinical-outcomes trial to confirm the strategy’s safety, before “the up-front addition of acetazolamide to submaximal loop diuretics doses” could become part of standard practice in ADHF.

Given the data so far, including those from ADVOR, “treatment with loop diuretics alone is probably sufficient for successful decongestion” among patients likely to respond to the drugs: that is, “those who are younger, those who have less severe or new-onset heart failure, and those who have normal kidney function,” states an editorial accompanying the published report.

“However, for the large group of patients who have some degree of diuretic resistance, or for those who have an inadequate initial response to loop-diuretic therapy, these data suggest the use of acetazolamide as a reasonable adjunct to achieving more rapid decongestion,” writes G. Michael Felker, MD, Duke University School of Medicine, Durham, N.C. Dr. Felker was lead author on the DOSE primary publication.

ADVOR entered volume-overloaded patients with ADHF and elevated natriuretic peptide levels who had been on oral maintenance with at least 40 mg of furosemide, or equivalent doses of other loop diuretics, for at least a month before randomization.

They were assigned to either IV acetazolamide at 500 mg once daily (n = 259) or placebo (n = 260) on top of an IV loop diuretic, at 27 centers in Belgium.

The risk ratio for the primary endpoint, successful decongestion after 3 days, was 1.46 (95% confidence interval, 1.17-1.82, P < .001) for the acetazolamide versus placebo groups.

In exploratory analyses, acetazolamide versus placebo, the RR for successful decongestion among patients who survived to discharge was increased at 1.27 (95% CI, 1.13-1.43). The hazard ratio for death from any cause at 3 months was not significant at 1.28 (95% CI, 0.78-2.05), nor was the HR for heart-failure rehospitalization at 3 months, 1.07 (95% CI, 0.71-1.59).

The role of SGLT2 inhibitors

ADVOR, understandably but maybe problematically, excluded patients taking SGLT2 inhibitors. The drugs have diuretic effects, among other useful properties, and became core therapy for a range of heart failure types after the trial was designed.

“This exclusion presents a conundrum for applying these results in contemporary clinical care,” Dr. Felker writes. For example, “the data supporting the efficacy and safety of SGLT2 inhibitors across the broad spectrum of patients with heart failure are now overwhelming, and most patients who are hospitalized for heart failure have a clear indication for these agents.”

Given that no ADVOR patients were on the drugs, his editorial states, “we can only speculate as to the efficacy of acetazolamide in patients treated with background SGLT2 inhibitors, which could potentially be additive, subadditive, or synergistic.”

The SGLT2 inhibitors will likely “be used in ADHF in the future, based on studies such as EMPULSE. It will be important to know whether SGLT2 inhibitors change the risk-benefit of also giving acetazolamide,” Dr. Drazner said when interviewed.

“I don’t think there’s any safety issue with regards to the combination of SGLT2 inhibitors and acetazolamide,” Dr. Mullens said. Their diuretic effects are likely to be additive, he proposed.

“Although SGLT2 inhibitors and acetazolamide both exert natriuretic and diuretic effects on the proximal tubules, their mode of action and potency differ substantially,” the published report states.

ADVOR is funded by the Belgian Health Care Knowledge Center. Dr. Mullens discloses receiving fees for speaking from Abbott Fund, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Medtronic, and Novartis. Disclosures for the other authors are at NEJM.org. Dr. Drazner has reported no relevant financial relationships. Dr. Felker discloses serving as a consultant for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cardionomic, Cytokinetics, Novartis, Reprieve, and Sequana.

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

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

Patients who received a first prescription for medicinal cannabis for chronic pain were more likely to have new onset of arrhythmia – bradyarrhythmia, tachyarrhythmia, or a conduction disorder – within 6 months than were similar nonusers, in a new case-control study.

VladK213/Getty Images

There were no between-group differences in the incidence of heart failure or acute coronary syndrome.

The researchers identified 5,071 patients in a national Danish registry who had filled at least one prescription for medicinal cannabis for chronic pain and matched each patient with five patients of the same sex, age range, and type of chronic pain who did not receive this therapy.

The relative risk for arrhythmia was 83% higher in those who used medicinal cannabis than it was in the other patients, study author Nina Nouhravesh, MD, told this news organization in an email.

However, the absolute risks for arrhythmia were slight – a 0.86% risk (95% confidence interval, 0.61%-1.1%) in medicinal cannabis users versus a 0.47% risk (95% CI, 0.38%-0.56%) in those who did not use medicinal cannabis.

“Since medical cannabis is a relatively new drug for a large market of patients with chronic pain, it is important to investigate and report serious side effects,” said Dr. Nouhravesh, from Gentofte University Hospital, Denmark.

The study results, she said, suggest that “there may be a previously unreported risk of arrhythmias following medical cannabis use.”

“Even though the absolute risk difference is small, both patients and physicians should have as much information as possible when weighing up the pros and cons of any treatment,” Dr. Nouhravesh said, adding that “the findings of this study raise concerns for both legal and illegal [cannabis] use worldwide.”

The results will be presented at the annual European Society of Cardiology (ESC) Congress 2022.
 

Too soon to tell?

However, Brian Olshansky, MD, who was not involved with this research, cautions that it is important to consider several study limitations before drawing clinical implications.

“Other data and reports have considered the possibility of arrhythmias in relationship to marijuana use, and the data go in both directions,” Dr. Olshansky, a clinical cardiac electrophysiologist and professor emeritus at University of Iowa Hospitals, Iowa City, pointed out in an email.

“Importantly, arrhythmias, by themselves, are not necessarily consequential,” he stressed. “In any case,” he added, the risks in the current study are “extraordinarily small.”

Sinus bradycardia, sinus tachycardia, and premature atrial or ventricular contractions could be totally benign, he said. On the other hand, arrhythmias may indicate the presence of atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation, which are potentially dangerous.

There may be a specific “high risk” group who can develop potentially serious arrhythmias, Dr. Olshansky suggested.

“There is no evidence that any of these patients underwent or required any treatment for their arrhythmia or that stopping or starting the cannabinoids affected the arrhythmia one way or the other,” he said. “In addition, there is no dose/arrhythmia relationship.”

More patients in the medicinal cannabis group than in the nonuser group were also taking opioids (49% vs. 30%), nonsteroidal anti-inflammatory drugs (24% vs. 19%), antiepileptics (35% vs. 23%), or tricyclic antidepressants (11% vs. 4%), he noted.

In summary, according to Dr. Olshansky, “these data pose no obvious health concern and provide no vital knowledge for physicians prescribing cannabis.”

“My concern is that the information will be overblown,” he cautioned. “If the cannabinoid actually has benefit in terms of pain reduction, its use may be mitigated based on the fear of an arrhythmia that may occur – but the risk of an arrhythmia, in any event, is very small and undefined in terms of its seriousness.”
 

Cancer, musculoskeletal, and neurologic pain

For this analysis, the researchers identified 1.8 million patients in Denmark who were diagnosed with chronic pain between 2018 and 2021.

Of those, around 5,000 patients had claimed at least one prescription of medicinal cannabis (dronabinol 29%, cannabinoids 46%, or cannabidiol 25%).

The patients had a median age of 60 years, and 63% were women.

The cannabis users had been prescribed this therapy for musculoskeletal (35%), cancer (18%), neurological (14%), or other (33%) pain, Dr. Nouhravesh said. 

The researchers and Dr. Olshansky have no relevant financial disclosures.  

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

Patients who received a first prescription for medicinal cannabis for chronic pain were more likely to have new onset of arrhythmia – bradyarrhythmia, tachyarrhythmia, or a conduction disorder – within 6 months than were similar nonusers, in a new case-control study.

VladK213/Getty Images

There were no between-group differences in the incidence of heart failure or acute coronary syndrome.

The researchers identified 5,071 patients in a national Danish registry who had filled at least one prescription for medicinal cannabis for chronic pain and matched each patient with five patients of the same sex, age range, and type of chronic pain who did not receive this therapy.

The relative risk for arrhythmia was 83% higher in those who used medicinal cannabis than it was in the other patients, study author Nina Nouhravesh, MD, told this news organization in an email.

However, the absolute risks for arrhythmia were slight – a 0.86% risk (95% confidence interval, 0.61%-1.1%) in medicinal cannabis users versus a 0.47% risk (95% CI, 0.38%-0.56%) in those who did not use medicinal cannabis.

“Since medical cannabis is a relatively new drug for a large market of patients with chronic pain, it is important to investigate and report serious side effects,” said Dr. Nouhravesh, from Gentofte University Hospital, Denmark.

The study results, she said, suggest that “there may be a previously unreported risk of arrhythmias following medical cannabis use.”

“Even though the absolute risk difference is small, both patients and physicians should have as much information as possible when weighing up the pros and cons of any treatment,” Dr. Nouhravesh said, adding that “the findings of this study raise concerns for both legal and illegal [cannabis] use worldwide.”

The results will be presented at the annual European Society of Cardiology (ESC) Congress 2022.
 

Too soon to tell?

However, Brian Olshansky, MD, who was not involved with this research, cautions that it is important to consider several study limitations before drawing clinical implications.

“Other data and reports have considered the possibility of arrhythmias in relationship to marijuana use, and the data go in both directions,” Dr. Olshansky, a clinical cardiac electrophysiologist and professor emeritus at University of Iowa Hospitals, Iowa City, pointed out in an email.

“Importantly, arrhythmias, by themselves, are not necessarily consequential,” he stressed. “In any case,” he added, the risks in the current study are “extraordinarily small.”

Sinus bradycardia, sinus tachycardia, and premature atrial or ventricular contractions could be totally benign, he said. On the other hand, arrhythmias may indicate the presence of atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation, which are potentially dangerous.

There may be a specific “high risk” group who can develop potentially serious arrhythmias, Dr. Olshansky suggested.

“There is no evidence that any of these patients underwent or required any treatment for their arrhythmia or that stopping or starting the cannabinoids affected the arrhythmia one way or the other,” he said. “In addition, there is no dose/arrhythmia relationship.”

More patients in the medicinal cannabis group than in the nonuser group were also taking opioids (49% vs. 30%), nonsteroidal anti-inflammatory drugs (24% vs. 19%), antiepileptics (35% vs. 23%), or tricyclic antidepressants (11% vs. 4%), he noted.

In summary, according to Dr. Olshansky, “these data pose no obvious health concern and provide no vital knowledge for physicians prescribing cannabis.”

“My concern is that the information will be overblown,” he cautioned. “If the cannabinoid actually has benefit in terms of pain reduction, its use may be mitigated based on the fear of an arrhythmia that may occur – but the risk of an arrhythmia, in any event, is very small and undefined in terms of its seriousness.”
 

Cancer, musculoskeletal, and neurologic pain

For this analysis, the researchers identified 1.8 million patients in Denmark who were diagnosed with chronic pain between 2018 and 2021.

Of those, around 5,000 patients had claimed at least one prescription of medicinal cannabis (dronabinol 29%, cannabinoids 46%, or cannabidiol 25%).

The patients had a median age of 60 years, and 63% were women.

The cannabis users had been prescribed this therapy for musculoskeletal (35%), cancer (18%), neurological (14%), or other (33%) pain, Dr. Nouhravesh said. 

The researchers and Dr. Olshansky have no relevant financial disclosures.  

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

Patients who received a first prescription for medicinal cannabis for chronic pain were more likely to have new onset of arrhythmia – bradyarrhythmia, tachyarrhythmia, or a conduction disorder – within 6 months than were similar nonusers, in a new case-control study.

VladK213/Getty Images

There were no between-group differences in the incidence of heart failure or acute coronary syndrome.

The researchers identified 5,071 patients in a national Danish registry who had filled at least one prescription for medicinal cannabis for chronic pain and matched each patient with five patients of the same sex, age range, and type of chronic pain who did not receive this therapy.

The relative risk for arrhythmia was 83% higher in those who used medicinal cannabis than it was in the other patients, study author Nina Nouhravesh, MD, told this news organization in an email.

However, the absolute risks for arrhythmia were slight – a 0.86% risk (95% confidence interval, 0.61%-1.1%) in medicinal cannabis users versus a 0.47% risk (95% CI, 0.38%-0.56%) in those who did not use medicinal cannabis.

“Since medical cannabis is a relatively new drug for a large market of patients with chronic pain, it is important to investigate and report serious side effects,” said Dr. Nouhravesh, from Gentofte University Hospital, Denmark.

The study results, she said, suggest that “there may be a previously unreported risk of arrhythmias following medical cannabis use.”

“Even though the absolute risk difference is small, both patients and physicians should have as much information as possible when weighing up the pros and cons of any treatment,” Dr. Nouhravesh said, adding that “the findings of this study raise concerns for both legal and illegal [cannabis] use worldwide.”

The results will be presented at the annual European Society of Cardiology (ESC) Congress 2022.
 

Too soon to tell?

However, Brian Olshansky, MD, who was not involved with this research, cautions that it is important to consider several study limitations before drawing clinical implications.

“Other data and reports have considered the possibility of arrhythmias in relationship to marijuana use, and the data go in both directions,” Dr. Olshansky, a clinical cardiac electrophysiologist and professor emeritus at University of Iowa Hospitals, Iowa City, pointed out in an email.

“Importantly, arrhythmias, by themselves, are not necessarily consequential,” he stressed. “In any case,” he added, the risks in the current study are “extraordinarily small.”

Sinus bradycardia, sinus tachycardia, and premature atrial or ventricular contractions could be totally benign, he said. On the other hand, arrhythmias may indicate the presence of atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation, which are potentially dangerous.

There may be a specific “high risk” group who can develop potentially serious arrhythmias, Dr. Olshansky suggested.

“There is no evidence that any of these patients underwent or required any treatment for their arrhythmia or that stopping or starting the cannabinoids affected the arrhythmia one way or the other,” he said. “In addition, there is no dose/arrhythmia relationship.”

More patients in the medicinal cannabis group than in the nonuser group were also taking opioids (49% vs. 30%), nonsteroidal anti-inflammatory drugs (24% vs. 19%), antiepileptics (35% vs. 23%), or tricyclic antidepressants (11% vs. 4%), he noted.

In summary, according to Dr. Olshansky, “these data pose no obvious health concern and provide no vital knowledge for physicians prescribing cannabis.”

“My concern is that the information will be overblown,” he cautioned. “If the cannabinoid actually has benefit in terms of pain reduction, its use may be mitigated based on the fear of an arrhythmia that may occur – but the risk of an arrhythmia, in any event, is very small and undefined in terms of its seriousness.”
 

Cancer, musculoskeletal, and neurologic pain

For this analysis, the researchers identified 1.8 million patients in Denmark who were diagnosed with chronic pain between 2018 and 2021.

Of those, around 5,000 patients had claimed at least one prescription of medicinal cannabis (dronabinol 29%, cannabinoids 46%, or cannabidiol 25%).

The patients had a median age of 60 years, and 63% were women.

The cannabis users had been prescribed this therapy for musculoskeletal (35%), cancer (18%), neurological (14%), or other (33%) pain, Dr. Nouhravesh said. 

The researchers and Dr. Olshansky have no relevant financial disclosures.  

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

BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.

The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology. 

MDedge News/Mitchel L. Zoler

“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).

The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.

Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.

“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.

The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.

“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said. 

Non-dippers

Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.

“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”

The study did find some differences in the blood pressure profile between the two dosing schedules.

“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said. 

“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.

The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.

TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.

The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.

The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).

What to recommend in clinical practice?

Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.

Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”

She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.

“The finding of no difference in event rate in the TIME study is therefore very intriguing.”

She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.  

“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.

Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”

The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions. 

And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”

The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.

“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.

On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”

Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”

One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.

“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.

Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.

“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.

Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”

The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.  

“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.  

“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”

Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.

“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”

She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”

The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.

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

BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.

The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology. 

MDedge News/Mitchel L. Zoler

“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).

The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.

Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.

“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.

The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.

“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said. 

Non-dippers

Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.

“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”

The study did find some differences in the blood pressure profile between the two dosing schedules.

“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said. 

“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.

The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.

TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.

The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.

The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).

What to recommend in clinical practice?

Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.

Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”

She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.

“The finding of no difference in event rate in the TIME study is therefore very intriguing.”

She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.  

“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.

Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”

The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions. 

And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”

The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.

“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.

On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”

Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”

One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.

“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.

Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.

“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.

Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”

The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.  

“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.  

“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”

Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.

“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”

She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”

The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.

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

BARCELONA – Patients with hypertension who took their antihypertensive medication in the evening or in the morning had similar rates of cardiovascular events over the following 5 years, in the much-anticipated TIME trial.

The trial, which contradicts several previous studies suggesting that evening dosing may be better, was presented at the annual congress of the European Society of Cardiology. 

MDedge News/Mitchel L. Zoler

“The key message from this study is that taking antihypertensive medication in the evening makes no difference at all from taking it in the morning for the prevention of heart attacks, strokes, and vascular deaths,” concluded TIME lead investigator Tom MacDonald, MBChB, MD, professor of clinical pharmacology & pharmacoepidemiology at the University of Dundee (Scotland).

The hazard ratio was 0.95 for the primary endpoint, a composite of hospitalization for nonfatal myocardial infarction, nonfatal stroke, or vascular death, in the intention-to-treat population.

Similar results, with a hazard ratio around 1, were seen for all the secondary outcomes and in all subgroups.

“There is nothing to see – not a smidge of a difference – in the primary outcome or any of the secondary outcomes,” Dr. MacDonald commented.

The study also showed that evening dosing was not harmful in terms of falls or other adverse effects. Dr. MacDonald explained that taking the medication at night could result in an increase in nocturnal hypotension that may translate into more dizziness and falls if patients get up to use the bathroom during the night. “But, if anything, there were more dizzy turns during the day. The rate of fractures and hospitalization for fractures were identical in the two groups,” he reported.

“Our take-home message is that patients can take their blood pressure tablets at any time they like – whenever is most convenient – as long as they take them. It’s probably best to get into a routine of taking your tablets at the same time every day. That way you are more likely to remember to take them – but it won’t matter if that is in the morning or in the evening,” he said. 

Non-dippers

Dr. MacDonald explained that the rationale for the study was that in some patients blood pressure does not drop at night, a group known as “non-dippers,” and nighttime blood pressure is the best predictor of bad outcomes. In addition, previous studies have suggested that evening dosing of antihypertensives reduces nighttime blood pressure more effectively than daytime dosing.

“We and others thought that giving medication in the evening so that its peak effect occurs during the night might be beneficial,” he said. “We did the trial because if it had turned out that taking tablets in the evening was beneficial, it would have been one of the cheapest and most cost-effective interventions known to man. It is a nice hypothesis and most people thought this would turn out with a benefit, but it actually didn’t.”

The study did find some differences in the blood pressure profile between the two dosing schedules.

“Our results show that when antihypertensive medication is taken in the morning, then blood pressure is higher in the morning and lower in the evening. With evening dosing, blood pressure is lower in the morning and higher in the evening. It’s not a huge difference – just 1-2 mm Hg – and this didn’t translate into any difference in outcomes,” Dr. MacDonald said. 

“Ideally we need medication that lowers blood pressure effectively over the whole 24-hour period. That is where the push should be,” he added.

The TIME study randomized 21,104 patients with treated hypertension to take their antihypertensive medication in the morning or in the evening. Baseline characteristics show the average age of participants was 65 years, 14% had diabetes, 4% were smokers, 13% had prior cardiovascular disease, and mean blood pressure at entry was 135/79 mmHg.

TIME was a pragmatic study, with participants recruited from primary and secondary care registering on the Internet, and information on hospitalizations and deaths obtained from participants by email and through record linkage to national databases, with further data gathered from family doctors and hospitals and independently adjudicated by a blinded committee.

The median follow-up duration was 5.2 years, but some patients were followed for over 9 years.

The primary endpoint occurred in 362 (3.4%) participants in the evening-dosing group (0.69 events per 100 patient-years) and 390 (3.7%) in the morning-dosing group (0.72 events per 100 patient-years), giving an unadjusted hazard ratio of 0.95 (95% confidence interval, 0.83-1.10; P = .53).

What to recommend in clinical practice?

Outside commentators had mixed opinions on how the TIME results should be applied to clinical practice.

Discussant of the TIME study at the ESC Hotline session, Rhian Touyz, MBBCh, University of Glasgow (Scotland), said the trial asked a “very pertinent” question and the data “are certainly provocative.”

She cited several previous studies suggesting that evening dosing improved nighttime blood pressure and reduced cardiovascular events.

“The finding of no difference in event rate in the TIME study is therefore very intriguing.”

She pointed out that other studies have shown benefit of nighttime dosing in certain patient groups such as those with sleep apnea, non-dippers, and those with nocturnal hypertension.  

“With all these previous data, we have to ask why the TIME trial has produced this unexpected result,” she said.

Dr. MacDonald replied that the study was completely neutral. “That is the result, and I believe it is definitive. I’m absolutely confident that we did the study as best we could. All events were adjudicated. Compliance was quite good at 60%. I can’t believe there is anything in our data that invalidates these results,” he said. “If we want to look at specific groups of patients then we have to do larger studies in those particular groups, but for a general population of hypertensive patients we didn’t find any difference at all in morning versus evening dosing.”

The TIME results are in direct contradiction of a previous high-profile study – the Hygia Chronotherapy Trial – published in 2020, which found a large protective effect of nocturnal dosing on cardiovascular events, and attracted much media attention. But this study has subsequently attracted criticism, with an “expression of concern” and a commentary raising several questions. 

And a systematic review from the International Society of Hypertension published earlier this month concludes that previous trials of bedtime antihypertensive dosing had “major flaws.”

The review notes that three ongoing, well-designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing.

“Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose,” it concludes.

On the new TIME results, lead author of the ISH review, George Stergiou, MD, commented: “The benefits of bedtime dosing were not confirmed – as we well expected. So, I think bedtime drug dosing should not be routinely recommended in clinical practice.”

Although the TIME trial did not show any harms with bedtime dose, Dr. Stergiou added, “I am not too happy with their conclusion that patients should do as they wish. The vast majority of well-conducted outcomes studies which we use to guide the treatment of hypertension administered all drugs in the morning.”

One of the authors of the commentary criticizing the Hygia trial, Sverre E. Kjeldsen, MD, University of Oslo, said in an interview that the TIME trial was an important study, far more reliable than the Hygia study, and the results were as expected.

“From a scientific point of view, patients have a choice as to when to take their medication, but we strongly recommend taking blood pressure meds in the morning. Adherence is proven to be worse at bedtime. However, physicians may still consider bedtime dosing in patients proven to have high night-time blood pressure,” Dr. Kjeldsen added.

Lead investigator of the Hygia study, Ramón C. Hermida, PhD, University of Vigo (Spain), told this news organization he and his coauthors are standing by their results.

“The design and conduct of the TIME trial does not comply with the quality requirements listed in the guidelines by the International Society for Chronobiology for conducting chronotherapy trials in hypertension, and the results are not in line with the reported findings of multiple clinical trials on the effects of timed hypertension treatment on blood pressure control and circadian pattern regulation, kidney function, and cardiac pathology,” Dr. Hermida said.

Chair of an ESC press conference on the TIME study, Steen Dalby Kristensen, MD, Aarhus University Hospital, Skejby, Denmark, said he thought the trial was “very well done.”

The TIME results, he said, “are quite clear, whether you take your blood pressure tablets in the morning or the evening it makes no difference for the hard outcomes that we fear in patients with hypertension.  

“I think that this solves a question that we’ve had for a long time now,” he commented. “Even though there were some changes in the blood pressure measured in the evening or in the morning it doesn’t seem to matter in terms of clinical events. This means that life might be a bit easier for patients in that they can choose when they take their medication at the time most convenient to them.  

“I don’t know why previous studies suggested such a big benefit of evening dosing,” he added. “I would say the TIME trial is a more definitive result. It is a very important trial.”

Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, agreed that the TIME study was well conducted.

“On the basis of these results I wouldn’t recommend a specific time,” she said. “That’s kind of a relief, as it can be difficult to always take medications at a set time and this gives patients more flexibility.”

She suggested a possible alternative approach for patients taking more than one drug – taking one in the morning and the other in the evening. “That might give better 24-hour coverage.”

The study was funded by the British Heart Foundation. Dr. MacDonald has reported receiving research funding from Novartis and consulting fees from Novartis and AstraZeneca.

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

Cryolipolysis accounted for a majority of noninvasive cosmetic procedures associated with adverse events, according to an analysis of data from the Manufacturer and User Facility Device Experience (MAUDE).

The number of noninvasive body-contouring procedures performed in the United States increased by fivefold from 2011 to 2019, attributed in part to a combination of improved technology and new medical devices, as well as a “cosmetically savvy consumer base heavily influenced by social media,” wrote Young Lim, MD, PhD, of the department of dermatology, Massachusetts General Hospital, Boston, and coauthors.

However, premarket evaluations of many new medical devices fail to capture rare or delayed onset complications, and consumers and providers may not be fully aware of potential adverse events, they said. The MAUDE database was created by the Food and Drug Administration in 1991 to collect information on device-related deaths, serious injuries, or malfunctions based on reports from manufacturers, patients, and health care providers.

The researchers used the MAUDE database to identify and highlight adverse events associated with noninvasive body contouring technology in order to improve patient safety and satisfaction.

In their report, published in Lasers in Surgery and Medicine, they analyzed 723 medical device reports (MDRs) reported between 2015 and 2021: 660 for noninvasive body contouring, 55 for cellulite treatments, and 8 for muscle stimulation.

“Notably, of the 723 total MDRs between 2015 and 2021, 515 (71.2%) were reported in 2021, with the next highest reported being 64 in 2019 (8.8%),” the researchers wrote.

Overall, paradoxical hyperplasia (PAH) accounted for the majority of adverse reactions in the noninvasive body-contouring category (73.2%). In PAH, patients develop additional adipose tissue in areas treated with cryolipolysis. In this study, all reports of PAH as well as all 47 reported cases of abdominal hernias were attributed to the CoolSculpting device.

For cellulite treatments, the most common MDRs – 11 of 55 – were scars and keloids (20%). The Cellfina subcision technique accounted for 47% (26 of 55) of the MDRs in this category, including 9 of the scar and keloid cases.

Only eight of the MDRs analyzed were in the muscle stimulation category; of these, burns were the most common adverse event and accounted for three of the reports. The other reported AEs were two cases of pain and one report each of electrical shock, urticaria, and arrhythmia.

Patients are increasingly opting for noninvasive cosmetic procedures, but adverse events may be underreported despite the existence of databases such as MAUDE, the researchers wrote in their discussion.

“PAH, first reported in 2014 as an adverse sequelae of cryolipolysis, remains without known pathophysiology, though it proportionately affects men more than women,” they noted. The incidence of PAH varies widely, and the current treatment of choice is power-assisted liposuction, they said, although surgical abdominoplasty may be needed in severe cases.

The findings were limited by several factors including the reliance of the quality of submissions, the selection biases of the MAUDE database, and the potential for underreporting, the researchers noted.

However, “by cataloging the AEs of the growing noninvasive cosmetics market, the MAUDE can educate providers and inform patients to maximize safety and efficacy,” they said.

The size of the database and volume of reports provides a picture that likely reflects overall trends occurring in clinical practice, but in order to be effective, such databases require diligence on the part of manufacturers and clinicians to provide accurate, up-to-date information, the researchers concluded.

More procedures mean more complications

“As the market for minimally and noninvasive cosmetic procedures continues to expand, clinicians will likely encounter a greater number of patients with complications from these procedures,” said Jacqueline Watchmaker, MD, a general and cosmetic dermatologist in Scottsdale, Ariz., in an interview.

“Now more than ever, it is important for providers to understand potential side effects of procedures so that they can adequately counsel patients and optimize patient safety,” and therefore the current study is important at this time, she commented.

Dr. Watchmaker, who was not involved in the study, said that, overall, she was not surprised by the findings. “The adverse events analyzed from the Manufacturer and User Facility Device Experience parallel what is seen in clinical practice,” she said. “I did find it slightly surprising that an overwhelming majority of the medical device reports (515 of 723) were from 2021.” As the authors discuss, the reasons for this increase may include such factors as more flexible pandemic work schedules, pandemic weight gain, and the rise in MedSpas in recent years, she added.

“Some patients mistakenly think that ‘noninvasive’ or ‘minimally invasive’ procedures are risk free,” said Dr. Watchmaker. “However, as this review clearly demonstrates, complications can and do occur with these procedures. It is our job as clinicians to educate our patients on potential adverse events prior to treatment,” she emphasized. Also, she added, it is important for clinicians to report all adverse events to the MAUDE database so the true risks of noninvasive procedures can be more accurately assessed.

As for additional research, “It would be interesting to repeat the same study but to look at other minimally and noninvasive cosmetic devices such as radiofrequency and ultrasound devices,” Dr. Watchmaker noted.

The study received no outside funding. Dr. Lim and his coauthors, Adam Wulkan, MD, of the Lahey Clinic, Burlington, Mass., and Mathew Avram, MD, JD, of Massachusetts General Hospital, had no financial conflicts to disclose. Dr. Watchmaker had no financial conflicts to disclose.
 

Medical device–related adverse events can be reported to the FDA’s MAUDE database here .

Cryolipolysis accounted for a majority of noninvasive cosmetic procedures associated with adverse events, according to an analysis of data from the Manufacturer and User Facility Device Experience (MAUDE).

The number of noninvasive body-contouring procedures performed in the United States increased by fivefold from 2011 to 2019, attributed in part to a combination of improved technology and new medical devices, as well as a “cosmetically savvy consumer base heavily influenced by social media,” wrote Young Lim, MD, PhD, of the department of dermatology, Massachusetts General Hospital, Boston, and coauthors.

However, premarket evaluations of many new medical devices fail to capture rare or delayed onset complications, and consumers and providers may not be fully aware of potential adverse events, they said. The MAUDE database was created by the Food and Drug Administration in 1991 to collect information on device-related deaths, serious injuries, or malfunctions based on reports from manufacturers, patients, and health care providers.

The researchers used the MAUDE database to identify and highlight adverse events associated with noninvasive body contouring technology in order to improve patient safety and satisfaction.

In their report, published in Lasers in Surgery and Medicine, they analyzed 723 medical device reports (MDRs) reported between 2015 and 2021: 660 for noninvasive body contouring, 55 for cellulite treatments, and 8 for muscle stimulation.

“Notably, of the 723 total MDRs between 2015 and 2021, 515 (71.2%) were reported in 2021, with the next highest reported being 64 in 2019 (8.8%),” the researchers wrote.

Overall, paradoxical hyperplasia (PAH) accounted for the majority of adverse reactions in the noninvasive body-contouring category (73.2%). In PAH, patients develop additional adipose tissue in areas treated with cryolipolysis. In this study, all reports of PAH as well as all 47 reported cases of abdominal hernias were attributed to the CoolSculpting device.

For cellulite treatments, the most common MDRs – 11 of 55 – were scars and keloids (20%). The Cellfina subcision technique accounted for 47% (26 of 55) of the MDRs in this category, including 9 of the scar and keloid cases.

Only eight of the MDRs analyzed were in the muscle stimulation category; of these, burns were the most common adverse event and accounted for three of the reports. The other reported AEs were two cases of pain and one report each of electrical shock, urticaria, and arrhythmia.

Patients are increasingly opting for noninvasive cosmetic procedures, but adverse events may be underreported despite the existence of databases such as MAUDE, the researchers wrote in their discussion.

“PAH, first reported in 2014 as an adverse sequelae of cryolipolysis, remains without known pathophysiology, though it proportionately affects men more than women,” they noted. The incidence of PAH varies widely, and the current treatment of choice is power-assisted liposuction, they said, although surgical abdominoplasty may be needed in severe cases.

The findings were limited by several factors including the reliance of the quality of submissions, the selection biases of the MAUDE database, and the potential for underreporting, the researchers noted.

However, “by cataloging the AEs of the growing noninvasive cosmetics market, the MAUDE can educate providers and inform patients to maximize safety and efficacy,” they said.

The size of the database and volume of reports provides a picture that likely reflects overall trends occurring in clinical practice, but in order to be effective, such databases require diligence on the part of manufacturers and clinicians to provide accurate, up-to-date information, the researchers concluded.

More procedures mean more complications

“As the market for minimally and noninvasive cosmetic procedures continues to expand, clinicians will likely encounter a greater number of patients with complications from these procedures,” said Jacqueline Watchmaker, MD, a general and cosmetic dermatologist in Scottsdale, Ariz., in an interview.

“Now more than ever, it is important for providers to understand potential side effects of procedures so that they can adequately counsel patients and optimize patient safety,” and therefore the current study is important at this time, she commented.

Dr. Watchmaker, who was not involved in the study, said that, overall, she was not surprised by the findings. “The adverse events analyzed from the Manufacturer and User Facility Device Experience parallel what is seen in clinical practice,” she said. “I did find it slightly surprising that an overwhelming majority of the medical device reports (515 of 723) were from 2021.” As the authors discuss, the reasons for this increase may include such factors as more flexible pandemic work schedules, pandemic weight gain, and the rise in MedSpas in recent years, she added.

“Some patients mistakenly think that ‘noninvasive’ or ‘minimally invasive’ procedures are risk free,” said Dr. Watchmaker. “However, as this review clearly demonstrates, complications can and do occur with these procedures. It is our job as clinicians to educate our patients on potential adverse events prior to treatment,” she emphasized. Also, she added, it is important for clinicians to report all adverse events to the MAUDE database so the true risks of noninvasive procedures can be more accurately assessed.

As for additional research, “It would be interesting to repeat the same study but to look at other minimally and noninvasive cosmetic devices such as radiofrequency and ultrasound devices,” Dr. Watchmaker noted.

The study received no outside funding. Dr. Lim and his coauthors, Adam Wulkan, MD, of the Lahey Clinic, Burlington, Mass., and Mathew Avram, MD, JD, of Massachusetts General Hospital, had no financial conflicts to disclose. Dr. Watchmaker had no financial conflicts to disclose.
 

Medical device–related adverse events can be reported to the FDA’s MAUDE database here .

Cryolipolysis accounted for a majority of noninvasive cosmetic procedures associated with adverse events, according to an analysis of data from the Manufacturer and User Facility Device Experience (MAUDE).

The number of noninvasive body-contouring procedures performed in the United States increased by fivefold from 2011 to 2019, attributed in part to a combination of improved technology and new medical devices, as well as a “cosmetically savvy consumer base heavily influenced by social media,” wrote Young Lim, MD, PhD, of the department of dermatology, Massachusetts General Hospital, Boston, and coauthors.

However, premarket evaluations of many new medical devices fail to capture rare or delayed onset complications, and consumers and providers may not be fully aware of potential adverse events, they said. The MAUDE database was created by the Food and Drug Administration in 1991 to collect information on device-related deaths, serious injuries, or malfunctions based on reports from manufacturers, patients, and health care providers.

The researchers used the MAUDE database to identify and highlight adverse events associated with noninvasive body contouring technology in order to improve patient safety and satisfaction.

In their report, published in Lasers in Surgery and Medicine, they analyzed 723 medical device reports (MDRs) reported between 2015 and 2021: 660 for noninvasive body contouring, 55 for cellulite treatments, and 8 for muscle stimulation.

“Notably, of the 723 total MDRs between 2015 and 2021, 515 (71.2%) were reported in 2021, with the next highest reported being 64 in 2019 (8.8%),” the researchers wrote.

Overall, paradoxical hyperplasia (PAH) accounted for the majority of adverse reactions in the noninvasive body-contouring category (73.2%). In PAH, patients develop additional adipose tissue in areas treated with cryolipolysis. In this study, all reports of PAH as well as all 47 reported cases of abdominal hernias were attributed to the CoolSculpting device.

For cellulite treatments, the most common MDRs – 11 of 55 – were scars and keloids (20%). The Cellfina subcision technique accounted for 47% (26 of 55) of the MDRs in this category, including 9 of the scar and keloid cases.

Only eight of the MDRs analyzed were in the muscle stimulation category; of these, burns were the most common adverse event and accounted for three of the reports. The other reported AEs were two cases of pain and one report each of electrical shock, urticaria, and arrhythmia.

Patients are increasingly opting for noninvasive cosmetic procedures, but adverse events may be underreported despite the existence of databases such as MAUDE, the researchers wrote in their discussion.

“PAH, first reported in 2014 as an adverse sequelae of cryolipolysis, remains without known pathophysiology, though it proportionately affects men more than women,” they noted. The incidence of PAH varies widely, and the current treatment of choice is power-assisted liposuction, they said, although surgical abdominoplasty may be needed in severe cases.

The findings were limited by several factors including the reliance of the quality of submissions, the selection biases of the MAUDE database, and the potential for underreporting, the researchers noted.

However, “by cataloging the AEs of the growing noninvasive cosmetics market, the MAUDE can educate providers and inform patients to maximize safety and efficacy,” they said.

The size of the database and volume of reports provides a picture that likely reflects overall trends occurring in clinical practice, but in order to be effective, such databases require diligence on the part of manufacturers and clinicians to provide accurate, up-to-date information, the researchers concluded.

More procedures mean more complications

“As the market for minimally and noninvasive cosmetic procedures continues to expand, clinicians will likely encounter a greater number of patients with complications from these procedures,” said Jacqueline Watchmaker, MD, a general and cosmetic dermatologist in Scottsdale, Ariz., in an interview.

“Now more than ever, it is important for providers to understand potential side effects of procedures so that they can adequately counsel patients and optimize patient safety,” and therefore the current study is important at this time, she commented.

Dr. Watchmaker, who was not involved in the study, said that, overall, she was not surprised by the findings. “The adverse events analyzed from the Manufacturer and User Facility Device Experience parallel what is seen in clinical practice,” she said. “I did find it slightly surprising that an overwhelming majority of the medical device reports (515 of 723) were from 2021.” As the authors discuss, the reasons for this increase may include such factors as more flexible pandemic work schedules, pandemic weight gain, and the rise in MedSpas in recent years, she added.

“Some patients mistakenly think that ‘noninvasive’ or ‘minimally invasive’ procedures are risk free,” said Dr. Watchmaker. “However, as this review clearly demonstrates, complications can and do occur with these procedures. It is our job as clinicians to educate our patients on potential adverse events prior to treatment,” she emphasized. Also, she added, it is important for clinicians to report all adverse events to the MAUDE database so the true risks of noninvasive procedures can be more accurately assessed.

As for additional research, “It would be interesting to repeat the same study but to look at other minimally and noninvasive cosmetic devices such as radiofrequency and ultrasound devices,” Dr. Watchmaker noted.

The study received no outside funding. Dr. Lim and his coauthors, Adam Wulkan, MD, of the Lahey Clinic, Burlington, Mass., and Mathew Avram, MD, JD, of Massachusetts General Hospital, had no financial conflicts to disclose. Dr. Watchmaker had no financial conflicts to disclose.
 

Medical device–related adverse events can be reported to the FDA’s MAUDE database here .

The years start coming and they don’t stop coming.

Smash Mouth, “All Star”

Dermatologists, similar to everyone else, are subject to the inevitable: aging. More than 80% of the US population develops presbyopia, an age-related reduction in visual acuity, in their lifetime. The most common cause of refractive error in adults, presbyopia can contribute to reduced professional productivity, and individuals with uncorrected presbyopia face an estimated 8-fold increase in difficulty performing demanding near-vision tasks.¹

As specialists who rely heavily on visual assessment, dermatologists likely are aware of presbyopia, seeking care as appropriate; however, visual correction is not one size fits all, and identifying effective job-specific adjustments may require considerable trial and error. To this end, if visual correction may be needed by a large majority of dermatologists at some point, why do we not have specialized recommendations to guide the corrective process according to the individual’s defect and type of practice within the specialty? Do we need resources for dermatologists concerning ophthalmologic wellness and key warning signs of visual acuity deficits and other ocular complications?

These matters are difficult to address, made more so by the lack of data examining correctable visual impairment (CVI) in dermatology. The basis for discussion is clear; however, visual skills are highly relevant to the practice of dermatology, and age-related visual changes often are inevitable. This article will provide an overview of CVI in related disciplines and the importance of understanding CVI and corrective options in dermatology.

CVI Across Medical Disciplines

Other predominantly visual medical specialties such as pathology, radiology, and surgery have initiated research evaluating the impact of CVI on their respective practices, although consistent data still are limited. Much of the work surrounding CVI in medicine can be identified in surgery and its subspecialties. A 2020 study by Tuna et al² found that uncorrected myopia with greater than 1.75 diopter, hyperopia regardless of grade, and presbyopia with greater than 1.25 diopter correlated with reduced surgical performance when using the Da Vinci robotic system. A 2002 report by Wanzel et al³ was among the first of many studies to demonstrate the importance of visuospatial ability in surgical success. In radiology, Krupinski et al⁴ demonstrated reduced accuracy in detecting pulmonary nodules that correlated with increased myopia and decreased accommodation secondary to visual strain.

Most reports examining CVI across medical disciplines are primarily conversational or observational, with some utilizing surveys to assess the prevalence of CVI and the opinions of physicians in the field. For example, in a survey of 93 pathologists in Turkey, 93.5% (87/93) reported at least 1 type of refractive error. Eyeglasses were the most common form of correction (64.5% [60/93]); of those, 33.3% (31/93) reported using eyeglasses during microscopy.⁵

The importance of visual ability in other highly visual specialties suggests that parallels can be drawn to similar practices in dermatology. Detection of cutaneous lesions might be affected by changes in vision, similar to detection of pulmonary lesions in radiology. Likewise, dermatologic surgeons might experience a similar reduction in surgical performance due to impaired visual acuity or visuospatial ability.

The Importance of Visual Performancein Dermatology

With presbyopia often becoming clinically apparent at approximately 40 years of age,^1,6 CVI has the potential to be present for much of a dermatologist’s career. Responsibility falls on the individual practitioner to recognize their visual deficit and seek appropriate optometric or ophthalmologic care. It should be emphasized that there are many effective avenues to correct refractive error, most of which can functionally restore an individual’s vision; however, each option prioritizes different visual attributes (eg, contrast, depth perception, clarity) that have varying degrees of importance in particular areas of dermatologic practice. For example, in addition to visual acuity, dermatologic surgeons might require optimized depth perception, whereas dermatologists performing detailed visual inspection or dermoscopy might instead require optimized contrast sensitivity and acuity. At present, the literature is silent on guiding dermatologists in selecting corrective approaches that enhance the visual characteristics most important for their practice. Lack of research and direction surrounding which visual correction techniques are best suited for individual tasks risks inaccurate and nonspecific conversations with our eye care providers. Focused educated dialogues about visual needs would streamline the process of finding appropriate correction, thereby reducing unnecessary trial and error. As each dermatologic subspecialty might require a unique subset of visual skills, the conceivable benefit of dermatology-specific visual correction resources is evident.

Additionally (although beyond the scope of this commentary), guidance on how a dermatologist should increase their awareness and approach to more serious ophthalmologic conditions—including retinal tear or detachment, age-related macular degeneration, and glaucoma—also would serve as a valuable resource. Overall, prompt identification of visual changes and educated discussions surrounding their correction would allow for optimization based on the required skill set and would improve overall outcomes.

Final Thoughts

Age-related visual changes are a highly prevalent and normal process that carry the potential to impact clinical practice. Fortunately, there are multiple corrective mechanisms that can functionally restore an individual’s eyesight. However, there are no resources to guide dermatologists in seeking specialty-specific correction centered on their daily tasks, which places the responsibility for such correction on the individual. This is a circumstance in which the task at hand is clear, yet we continue to individually reinvent the wheel. We should consider this an opportunity to work together with our optometry and ophthalmology colleagues to create centralized resources that assist dermatologists in navigating age-related visual changes.

Acknowledgments—The authors thank Delaney Stratton, DNP, FNP-BC (Tucson, Arizona); J. Daniel Twelker, OD, PhD (Tucson, Arizona); and Julia Freeman, MD (Pittsburgh, Pennsylvania), for their contributions to the manuscript, as well as Susan M. Swetter, MD (Palo Alto, California) for reviewing and providing feedback.

The years start coming and they don’t stop coming.

Smash Mouth, “All Star”

Dermatologists, similar to everyone else, are subject to the inevitable: aging. More than 80% of the US population develops presbyopia, an age-related reduction in visual acuity, in their lifetime. The most common cause of refractive error in adults, presbyopia can contribute to reduced professional productivity, and individuals with uncorrected presbyopia face an estimated 8-fold increase in difficulty performing demanding near-vision tasks.¹

As specialists who rely heavily on visual assessment, dermatologists likely are aware of presbyopia, seeking care as appropriate; however, visual correction is not one size fits all, and identifying effective job-specific adjustments may require considerable trial and error. To this end, if visual correction may be needed by a large majority of dermatologists at some point, why do we not have specialized recommendations to guide the corrective process according to the individual’s defect and type of practice within the specialty? Do we need resources for dermatologists concerning ophthalmologic wellness and key warning signs of visual acuity deficits and other ocular complications?

These matters are difficult to address, made more so by the lack of data examining correctable visual impairment (CVI) in dermatology. The basis for discussion is clear; however, visual skills are highly relevant to the practice of dermatology, and age-related visual changes often are inevitable. This article will provide an overview of CVI in related disciplines and the importance of understanding CVI and corrective options in dermatology.

CVI Across Medical Disciplines

Other predominantly visual medical specialties such as pathology, radiology, and surgery have initiated research evaluating the impact of CVI on their respective practices, although consistent data still are limited. Much of the work surrounding CVI in medicine can be identified in surgery and its subspecialties. A 2020 study by Tuna et al² found that uncorrected myopia with greater than 1.75 diopter, hyperopia regardless of grade, and presbyopia with greater than 1.25 diopter correlated with reduced surgical performance when using the Da Vinci robotic system. A 2002 report by Wanzel et al³ was among the first of many studies to demonstrate the importance of visuospatial ability in surgical success. In radiology, Krupinski et al⁴ demonstrated reduced accuracy in detecting pulmonary nodules that correlated with increased myopia and decreased accommodation secondary to visual strain.

Most reports examining CVI across medical disciplines are primarily conversational or observational, with some utilizing surveys to assess the prevalence of CVI and the opinions of physicians in the field. For example, in a survey of 93 pathologists in Turkey, 93.5% (87/93) reported at least 1 type of refractive error. Eyeglasses were the most common form of correction (64.5% [60/93]); of those, 33.3% (31/93) reported using eyeglasses during microscopy.⁵

The importance of visual ability in other highly visual specialties suggests that parallels can be drawn to similar practices in dermatology. Detection of cutaneous lesions might be affected by changes in vision, similar to detection of pulmonary lesions in radiology. Likewise, dermatologic surgeons might experience a similar reduction in surgical performance due to impaired visual acuity or visuospatial ability.

The Importance of Visual Performancein Dermatology

With presbyopia often becoming clinically apparent at approximately 40 years of age,^1,6 CVI has the potential to be present for much of a dermatologist’s career. Responsibility falls on the individual practitioner to recognize their visual deficit and seek appropriate optometric or ophthalmologic care. It should be emphasized that there are many effective avenues to correct refractive error, most of which can functionally restore an individual’s vision; however, each option prioritizes different visual attributes (eg, contrast, depth perception, clarity) that have varying degrees of importance in particular areas of dermatologic practice. For example, in addition to visual acuity, dermatologic surgeons might require optimized depth perception, whereas dermatologists performing detailed visual inspection or dermoscopy might instead require optimized contrast sensitivity and acuity. At present, the literature is silent on guiding dermatologists in selecting corrective approaches that enhance the visual characteristics most important for their practice. Lack of research and direction surrounding which visual correction techniques are best suited for individual tasks risks inaccurate and nonspecific conversations with our eye care providers. Focused educated dialogues about visual needs would streamline the process of finding appropriate correction, thereby reducing unnecessary trial and error. As each dermatologic subspecialty might require a unique subset of visual skills, the conceivable benefit of dermatology-specific visual correction resources is evident.

Additionally (although beyond the scope of this commentary), guidance on how a dermatologist should increase their awareness and approach to more serious ophthalmologic conditions—including retinal tear or detachment, age-related macular degeneration, and glaucoma—also would serve as a valuable resource. Overall, prompt identification of visual changes and educated discussions surrounding their correction would allow for optimization based on the required skill set and would improve overall outcomes.

Final Thoughts

Age-related visual changes are a highly prevalent and normal process that carry the potential to impact clinical practice. Fortunately, there are multiple corrective mechanisms that can functionally restore an individual’s eyesight. However, there are no resources to guide dermatologists in seeking specialty-specific correction centered on their daily tasks, which places the responsibility for such correction on the individual. This is a circumstance in which the task at hand is clear, yet we continue to individually reinvent the wheel. We should consider this an opportunity to work together with our optometry and ophthalmology colleagues to create centralized resources that assist dermatologists in navigating age-related visual changes.

Acknowledgments—The authors thank Delaney Stratton, DNP, FNP-BC (Tucson, Arizona); J. Daniel Twelker, OD, PhD (Tucson, Arizona); and Julia Freeman, MD (Pittsburgh, Pennsylvania), for their contributions to the manuscript, as well as Susan M. Swetter, MD (Palo Alto, California) for reviewing and providing feedback.

The years start coming and they don’t stop coming.

Smash Mouth, “All Star”

Dermatologists, similar to everyone else, are subject to the inevitable: aging. More than 80% of the US population develops presbyopia, an age-related reduction in visual acuity, in their lifetime. The most common cause of refractive error in adults, presbyopia can contribute to reduced professional productivity, and individuals with uncorrected presbyopia face an estimated 8-fold increase in difficulty performing demanding near-vision tasks.¹

As specialists who rely heavily on visual assessment, dermatologists likely are aware of presbyopia, seeking care as appropriate; however, visual correction is not one size fits all, and identifying effective job-specific adjustments may require considerable trial and error. To this end, if visual correction may be needed by a large majority of dermatologists at some point, why do we not have specialized recommendations to guide the corrective process according to the individual’s defect and type of practice within the specialty? Do we need resources for dermatologists concerning ophthalmologic wellness and key warning signs of visual acuity deficits and other ocular complications?

These matters are difficult to address, made more so by the lack of data examining correctable visual impairment (CVI) in dermatology. The basis for discussion is clear; however, visual skills are highly relevant to the practice of dermatology, and age-related visual changes often are inevitable. This article will provide an overview of CVI in related disciplines and the importance of understanding CVI and corrective options in dermatology.

CVI Across Medical Disciplines

Other predominantly visual medical specialties such as pathology, radiology, and surgery have initiated research evaluating the impact of CVI on their respective practices, although consistent data still are limited. Much of the work surrounding CVI in medicine can be identified in surgery and its subspecialties. A 2020 study by Tuna et al² found that uncorrected myopia with greater than 1.75 diopter, hyperopia regardless of grade, and presbyopia with greater than 1.25 diopter correlated with reduced surgical performance when using the Da Vinci robotic system. A 2002 report by Wanzel et al³ was among the first of many studies to demonstrate the importance of visuospatial ability in surgical success. In radiology, Krupinski et al⁴ demonstrated reduced accuracy in detecting pulmonary nodules that correlated with increased myopia and decreased accommodation secondary to visual strain.

Most reports examining CVI across medical disciplines are primarily conversational or observational, with some utilizing surveys to assess the prevalence of CVI and the opinions of physicians in the field. For example, in a survey of 93 pathologists in Turkey, 93.5% (87/93) reported at least 1 type of refractive error. Eyeglasses were the most common form of correction (64.5% [60/93]); of those, 33.3% (31/93) reported using eyeglasses during microscopy.⁵

The importance of visual ability in other highly visual specialties suggests that parallels can be drawn to similar practices in dermatology. Detection of cutaneous lesions might be affected by changes in vision, similar to detection of pulmonary lesions in radiology. Likewise, dermatologic surgeons might experience a similar reduction in surgical performance due to impaired visual acuity or visuospatial ability.

The Importance of Visual Performancein Dermatology

With presbyopia often becoming clinically apparent at approximately 40 years of age,^1,6 CVI has the potential to be present for much of a dermatologist’s career. Responsibility falls on the individual practitioner to recognize their visual deficit and seek appropriate optometric or ophthalmologic care. It should be emphasized that there are many effective avenues to correct refractive error, most of which can functionally restore an individual’s vision; however, each option prioritizes different visual attributes (eg, contrast, depth perception, clarity) that have varying degrees of importance in particular areas of dermatologic practice. For example, in addition to visual acuity, dermatologic surgeons might require optimized depth perception, whereas dermatologists performing detailed visual inspection or dermoscopy might instead require optimized contrast sensitivity and acuity. At present, the literature is silent on guiding dermatologists in selecting corrective approaches that enhance the visual characteristics most important for their practice. Lack of research and direction surrounding which visual correction techniques are best suited for individual tasks risks inaccurate and nonspecific conversations with our eye care providers. Focused educated dialogues about visual needs would streamline the process of finding appropriate correction, thereby reducing unnecessary trial and error. As each dermatologic subspecialty might require a unique subset of visual skills, the conceivable benefit of dermatology-specific visual correction resources is evident.

Additionally (although beyond the scope of this commentary), guidance on how a dermatologist should increase their awareness and approach to more serious ophthalmologic conditions—including retinal tear or detachment, age-related macular degeneration, and glaucoma—also would serve as a valuable resource. Overall, prompt identification of visual changes and educated discussions surrounding their correction would allow for optimization based on the required skill set and would improve overall outcomes.

Final Thoughts

Age-related visual changes are a highly prevalent and normal process that carry the potential to impact clinical practice. Fortunately, there are multiple corrective mechanisms that can functionally restore an individual’s eyesight. However, there are no resources to guide dermatologists in seeking specialty-specific correction centered on their daily tasks, which places the responsibility for such correction on the individual. This is a circumstance in which the task at hand is clear, yet we continue to individually reinvent the wheel. We should consider this an opportunity to work together with our optometry and ophthalmology colleagues to create centralized resources that assist dermatologists in navigating age-related visual changes.

Acknowledgments—The authors thank Delaney Stratton, DNP, FNP-BC (Tucson, Arizona); J. Daniel Twelker, OD, PhD (Tucson, Arizona); and Julia Freeman, MD (Pittsburgh, Pennsylvania), for their contributions to the manuscript, as well as Susan M. Swetter, MD (Palo Alto, California) for reviewing and providing feedback.

To the Editor:

Nail abnormalities associated with SARS-CoV-2 infection that have been reported in the medical literature include nail psoriasis,¹ Beau lines,² onychomadesis,³ heterogeneous red-white discoloration of the nail bed,⁴ transverse orange nail lesions,³ and the red half‐moon nail sign.^3,5 It has been hypothesized that these nail findings may be an indication of microvascular injury to the distal subungual arcade of the digit or may be indicative of a procoagulant state.^5,6 Currently, there is limited knowledge of the effect of COVID-19 vaccines on nail changes. We report a patient who presented with transverse leukonychia (Mees lines) and Beau lines shortly after each dose of the Pfizer-BioNTech COVID-19 messenger RNA vaccine was administered (with a total of 2 doses administered on presentation).

A 64-year-old woman with a history of rheumatoid arthritis presented with peeling of the fingernails and proximal white discoloration of several fingernails of 2 months’ duration. The patient first noticed whitening of the nails 3 weeks after she recevied the first dose of the COVID-19 vaccine. Five days after receiving the second, she presented to the dermatology clinic and exhibited transverse leukonychia in most fingernails (Figure 1).

Six weeks following the second dose of the COVID-19 vaccine, the patient returned to the dermatology clinic with Beau lines on the second and third fingernails on the right hand (Figure 2A). Subtle erythema of the proximal nail folds and distal fingers was observed in both hands. The patient also exhibited mild onychorrhexis of the left thumbnail and mottled red-brown discoloration of the third finger on the left hand (Figure 2B). Splinter hemorrhages and melanonychia of several fingernails also were observed. Our patient denied any known history of infection with SARS-CoV-2, which was confirmed by a negative COVID-19 polymerase chain reaction test result. She also denied fevers, chills, nausea, and vomiting, she and reported feeling generally well in the context of these postvaccination nail changes.

She reported no trauma or worsening of rheumatoid arthritis before or after COVID-19 vaccination. She was seronegative for rheumatoid arthritis and was being treated with hydroxychloroquine for the last year and methotrexate for the last 2 years. After each dose of the vaccine, methotrexate was withheld for 1 week and then resumed.

Subsequent follow-up examinations revealed the migration and resolution of transverse leukonychia and Beau lines. There also was interval improvement of the splinter hemorrhages. At 17 weeks following the second vaccine dose, all transverse leukonychia and Beau lines had resolved (Figure 3). The patient’s melanonychia remained unchanged.

Laboratory evaluations drawn 1 month following the first dose of the COVID-19 vaccine, including comprehensive metabolic panel; erythrocyte sedimentation rate; C-reactive protein; and vitamin B₁₂, ferritin, and iron levels were within reference range. The complete blood cell count only showed a mildly decreased white blood cell count (3.55×10³/µL [reference range, 4.16–9.95×10³/µL]) and mildly elevated mean corpuscular volume (101.9 fL [reference range, 79.3–98.6 fL), both near the patient’s baseline values prior to vaccination.

Documented cutaneous manifestations of SARS‐CoV‐2 infection have included perniolike lesions (known as COVID toes) and vesicular, urticarial, petechial, livedoid, or retiform purpura eruptions. Less frequently, nail findings in patients infected with COVID-19 have been reported, including Beau lines,² onychomadesis,³ transverse leukonychia,^3,7 and the red half‐moon nail sign.^3,5 Single or multiple nails may be affected. Although the pathogenesis of nail manifestations related to COVID-19 remains unclear, complement-mediated microvascular injury and thrombosis as well as the procoagulant state, which have been associated with COVID-19, may offer possible explanations.^5,6 The presence of microvascular abnormalities was observed in a nail fold video capillaroscopy study of the nails of 82 patients with COVID-19, revealing pericapillary edema, capillary ectasia, sludge flow, meandering capillaries and microvascular derangement, and low capillary density.⁸

Our patient exhibited transverse leukonychia of the fingernails, which is thought to result from abnormal keratinization of the nail plate due to systemic disorders that induce a temporary dysfunction of nail growth.⁹ Fernandez-Nieto et al⁷ reported transverse leukonychia in a patient with COVID-19 that was hypothesized to be due to a transitory nail matrix injury.

Beau lines and onychomadesis, which represent nail matrix arrest, commonly are seen with systemic drug treatments such as chemotherapy and in infectious diseases that precipitate systemic illness, such as hand, foot, and mouth disease. Although histologic examination was not performed in our patient due to cosmetic concerns, we believe that inflammation induced by the vaccine response also can trigger nail abnormalities such as transverse leukonychia and Beau lines. Both SARS-CoV-2 infections and the COVID-19 messenger RNA vaccines can induce systemic inflammation largely due a T_H1-dominant response, and they also can trigger other inflammatory conditions. Reports of lichen planus and psoriasis triggered by vaccination—the hepatitis B vaccine,¹⁰ influenza vaccine,¹¹ and even COVID-19 vaccines^1,12—have been reported. Beau lines have been observed to spontaneously resolve in a self-limiting manner in asymptomatic patients with COVID-19.

Interestingly, our patient only showed 2 nails with Beau lines. We hypothesize that the immune response triggered by vaccination was more subdued than that caused by SARS-CoV-2 infection. Additionally, our patient was already being treated with immunosuppressants, which may have been associated with a reduced immune response despite being withheld right before vaccination. One may debate whether the nail abnormalities observed in our patient constituted an isolated finding from COVID-19 vaccination or were caused by reactivation of rheumatoid arthritis. We favor the former, as the rheumatoid arthritis remained stable before and after COVID-19 vaccination. Laboratory evaluations and physical examination revealed no evidence of flares, and our patient was otherwise healthy. Although the splinter hemorrhages also improved, it is difficult to comment as to whether they were caused by the vaccine or had existed prior to vaccination. However, we believe the melanonychia observed in the nails was unrelated to the vaccine and was likely a chronic manifestation due to long-term hydroxychloroquine and/or methotrexate use.

Given accelerated global vaccination efforts to control the COVID-19 pandemic, more cases of adverse nail manifestations associated with COVID-19 vaccines are expected. Dermatologists should be aware of and use the reported nail findings to educate patients and reassure them that ungual abnormalities are potential adverse effects of COVID-19 vaccines, but they should not discourage vaccination because they usually are temporary and self-resolving.

To the Editor:

Nail abnormalities associated with SARS-CoV-2 infection that have been reported in the medical literature include nail psoriasis,¹ Beau lines,² onychomadesis,³ heterogeneous red-white discoloration of the nail bed,⁴ transverse orange nail lesions,³ and the red half‐moon nail sign.^3,5 It has been hypothesized that these nail findings may be an indication of microvascular injury to the distal subungual arcade of the digit or may be indicative of a procoagulant state.^5,6 Currently, there is limited knowledge of the effect of COVID-19 vaccines on nail changes. We report a patient who presented with transverse leukonychia (Mees lines) and Beau lines shortly after each dose of the Pfizer-BioNTech COVID-19 messenger RNA vaccine was administered (with a total of 2 doses administered on presentation).

A 64-year-old woman with a history of rheumatoid arthritis presented with peeling of the fingernails and proximal white discoloration of several fingernails of 2 months’ duration. The patient first noticed whitening of the nails 3 weeks after she recevied the first dose of the COVID-19 vaccine. Five days after receiving the second, she presented to the dermatology clinic and exhibited transverse leukonychia in most fingernails (Figure 1).

Six weeks following the second dose of the COVID-19 vaccine, the patient returned to the dermatology clinic with Beau lines on the second and third fingernails on the right hand (Figure 2A). Subtle erythema of the proximal nail folds and distal fingers was observed in both hands. The patient also exhibited mild onychorrhexis of the left thumbnail and mottled red-brown discoloration of the third finger on the left hand (Figure 2B). Splinter hemorrhages and melanonychia of several fingernails also were observed. Our patient denied any known history of infection with SARS-CoV-2, which was confirmed by a negative COVID-19 polymerase chain reaction test result. She also denied fevers, chills, nausea, and vomiting, she and reported feeling generally well in the context of these postvaccination nail changes.

She reported no trauma or worsening of rheumatoid arthritis before or after COVID-19 vaccination. She was seronegative for rheumatoid arthritis and was being treated with hydroxychloroquine for the last year and methotrexate for the last 2 years. After each dose of the vaccine, methotrexate was withheld for 1 week and then resumed.

Subsequent follow-up examinations revealed the migration and resolution of transverse leukonychia and Beau lines. There also was interval improvement of the splinter hemorrhages. At 17 weeks following the second vaccine dose, all transverse leukonychia and Beau lines had resolved (Figure 3). The patient’s melanonychia remained unchanged.

Laboratory evaluations drawn 1 month following the first dose of the COVID-19 vaccine, including comprehensive metabolic panel; erythrocyte sedimentation rate; C-reactive protein; and vitamin B₁₂, ferritin, and iron levels were within reference range. The complete blood cell count only showed a mildly decreased white blood cell count (3.55×10³/µL [reference range, 4.16–9.95×10³/µL]) and mildly elevated mean corpuscular volume (101.9 fL [reference range, 79.3–98.6 fL), both near the patient’s baseline values prior to vaccination.

Documented cutaneous manifestations of SARS‐CoV‐2 infection have included perniolike lesions (known as COVID toes) and vesicular, urticarial, petechial, livedoid, or retiform purpura eruptions. Less frequently, nail findings in patients infected with COVID-19 have been reported, including Beau lines,² onychomadesis,³ transverse leukonychia,^3,7 and the red half‐moon nail sign.^3,5 Single or multiple nails may be affected. Although the pathogenesis of nail manifestations related to COVID-19 remains unclear, complement-mediated microvascular injury and thrombosis as well as the procoagulant state, which have been associated with COVID-19, may offer possible explanations.^5,6 The presence of microvascular abnormalities was observed in a nail fold video capillaroscopy study of the nails of 82 patients with COVID-19, revealing pericapillary edema, capillary ectasia, sludge flow, meandering capillaries and microvascular derangement, and low capillary density.⁸

Our patient exhibited transverse leukonychia of the fingernails, which is thought to result from abnormal keratinization of the nail plate due to systemic disorders that induce a temporary dysfunction of nail growth.⁹ Fernandez-Nieto et al⁷ reported transverse leukonychia in a patient with COVID-19 that was hypothesized to be due to a transitory nail matrix injury.

Beau lines and onychomadesis, which represent nail matrix arrest, commonly are seen with systemic drug treatments such as chemotherapy and in infectious diseases that precipitate systemic illness, such as hand, foot, and mouth disease. Although histologic examination was not performed in our patient due to cosmetic concerns, we believe that inflammation induced by the vaccine response also can trigger nail abnormalities such as transverse leukonychia and Beau lines. Both SARS-CoV-2 infections and the COVID-19 messenger RNA vaccines can induce systemic inflammation largely due a T_H1-dominant response, and they also can trigger other inflammatory conditions. Reports of lichen planus and psoriasis triggered by vaccination—the hepatitis B vaccine,¹⁰ influenza vaccine,¹¹ and even COVID-19 vaccines^1,12—have been reported. Beau lines have been observed to spontaneously resolve in a self-limiting manner in asymptomatic patients with COVID-19.

Interestingly, our patient only showed 2 nails with Beau lines. We hypothesize that the immune response triggered by vaccination was more subdued than that caused by SARS-CoV-2 infection. Additionally, our patient was already being treated with immunosuppressants, which may have been associated with a reduced immune response despite being withheld right before vaccination. One may debate whether the nail abnormalities observed in our patient constituted an isolated finding from COVID-19 vaccination or were caused by reactivation of rheumatoid arthritis. We favor the former, as the rheumatoid arthritis remained stable before and after COVID-19 vaccination. Laboratory evaluations and physical examination revealed no evidence of flares, and our patient was otherwise healthy. Although the splinter hemorrhages also improved, it is difficult to comment as to whether they were caused by the vaccine or had existed prior to vaccination. However, we believe the melanonychia observed in the nails was unrelated to the vaccine and was likely a chronic manifestation due to long-term hydroxychloroquine and/or methotrexate use.

Given accelerated global vaccination efforts to control the COVID-19 pandemic, more cases of adverse nail manifestations associated with COVID-19 vaccines are expected. Dermatologists should be aware of and use the reported nail findings to educate patients and reassure them that ungual abnormalities are potential adverse effects of COVID-19 vaccines, but they should not discourage vaccination because they usually are temporary and self-resolving.

To the Editor:

Nail abnormalities associated with SARS-CoV-2 infection that have been reported in the medical literature include nail psoriasis,¹ Beau lines,² onychomadesis,³ heterogeneous red-white discoloration of the nail bed,⁴ transverse orange nail lesions,³ and the red half‐moon nail sign.^3,5 It has been hypothesized that these nail findings may be an indication of microvascular injury to the distal subungual arcade of the digit or may be indicative of a procoagulant state.^5,6 Currently, there is limited knowledge of the effect of COVID-19 vaccines on nail changes. We report a patient who presented with transverse leukonychia (Mees lines) and Beau lines shortly after each dose of the Pfizer-BioNTech COVID-19 messenger RNA vaccine was administered (with a total of 2 doses administered on presentation).

A 64-year-old woman with a history of rheumatoid arthritis presented with peeling of the fingernails and proximal white discoloration of several fingernails of 2 months’ duration. The patient first noticed whitening of the nails 3 weeks after she recevied the first dose of the COVID-19 vaccine. Five days after receiving the second, she presented to the dermatology clinic and exhibited transverse leukonychia in most fingernails (Figure 1).

Six weeks following the second dose of the COVID-19 vaccine, the patient returned to the dermatology clinic with Beau lines on the second and third fingernails on the right hand (Figure 2A). Subtle erythema of the proximal nail folds and distal fingers was observed in both hands. The patient also exhibited mild onychorrhexis of the left thumbnail and mottled red-brown discoloration of the third finger on the left hand (Figure 2B). Splinter hemorrhages and melanonychia of several fingernails also were observed. Our patient denied any known history of infection with SARS-CoV-2, which was confirmed by a negative COVID-19 polymerase chain reaction test result. She also denied fevers, chills, nausea, and vomiting, she and reported feeling generally well in the context of these postvaccination nail changes.

She reported no trauma or worsening of rheumatoid arthritis before or after COVID-19 vaccination. She was seronegative for rheumatoid arthritis and was being treated with hydroxychloroquine for the last year and methotrexate for the last 2 years. After each dose of the vaccine, methotrexate was withheld for 1 week and then resumed.

Subsequent follow-up examinations revealed the migration and resolution of transverse leukonychia and Beau lines. There also was interval improvement of the splinter hemorrhages. At 17 weeks following the second vaccine dose, all transverse leukonychia and Beau lines had resolved (Figure 3). The patient’s melanonychia remained unchanged.

Laboratory evaluations drawn 1 month following the first dose of the COVID-19 vaccine, including comprehensive metabolic panel; erythrocyte sedimentation rate; C-reactive protein; and vitamin B₁₂, ferritin, and iron levels were within reference range. The complete blood cell count only showed a mildly decreased white blood cell count (3.55×10³/µL [reference range, 4.16–9.95×10³/µL]) and mildly elevated mean corpuscular volume (101.9 fL [reference range, 79.3–98.6 fL), both near the patient’s baseline values prior to vaccination.

Documented cutaneous manifestations of SARS‐CoV‐2 infection have included perniolike lesions (known as COVID toes) and vesicular, urticarial, petechial, livedoid, or retiform purpura eruptions. Less frequently, nail findings in patients infected with COVID-19 have been reported, including Beau lines,² onychomadesis,³ transverse leukonychia,^3,7 and the red half‐moon nail sign.^3,5 Single or multiple nails may be affected. Although the pathogenesis of nail manifestations related to COVID-19 remains unclear, complement-mediated microvascular injury and thrombosis as well as the procoagulant state, which have been associated with COVID-19, may offer possible explanations.^5,6 The presence of microvascular abnormalities was observed in a nail fold video capillaroscopy study of the nails of 82 patients with COVID-19, revealing pericapillary edema, capillary ectasia, sludge flow, meandering capillaries and microvascular derangement, and low capillary density.⁸

Our patient exhibited transverse leukonychia of the fingernails, which is thought to result from abnormal keratinization of the nail plate due to systemic disorders that induce a temporary dysfunction of nail growth.⁹ Fernandez-Nieto et al⁷ reported transverse leukonychia in a patient with COVID-19 that was hypothesized to be due to a transitory nail matrix injury.

Beau lines and onychomadesis, which represent nail matrix arrest, commonly are seen with systemic drug treatments such as chemotherapy and in infectious diseases that precipitate systemic illness, such as hand, foot, and mouth disease. Although histologic examination was not performed in our patient due to cosmetic concerns, we believe that inflammation induced by the vaccine response also can trigger nail abnormalities such as transverse leukonychia and Beau lines. Both SARS-CoV-2 infections and the COVID-19 messenger RNA vaccines can induce systemic inflammation largely due a T_H1-dominant response, and they also can trigger other inflammatory conditions. Reports of lichen planus and psoriasis triggered by vaccination—the hepatitis B vaccine,¹⁰ influenza vaccine,¹¹ and even COVID-19 vaccines^1,12—have been reported. Beau lines have been observed to spontaneously resolve in a self-limiting manner in asymptomatic patients with COVID-19.

Interestingly, our patient only showed 2 nails with Beau lines. We hypothesize that the immune response triggered by vaccination was more subdued than that caused by SARS-CoV-2 infection. Additionally, our patient was already being treated with immunosuppressants, which may have been associated with a reduced immune response despite being withheld right before vaccination. One may debate whether the nail abnormalities observed in our patient constituted an isolated finding from COVID-19 vaccination or were caused by reactivation of rheumatoid arthritis. We favor the former, as the rheumatoid arthritis remained stable before and after COVID-19 vaccination. Laboratory evaluations and physical examination revealed no evidence of flares, and our patient was otherwise healthy. Although the splinter hemorrhages also improved, it is difficult to comment as to whether they were caused by the vaccine or had existed prior to vaccination. However, we believe the melanonychia observed in the nails was unrelated to the vaccine and was likely a chronic manifestation due to long-term hydroxychloroquine and/or methotrexate use.

Given accelerated global vaccination efforts to control the COVID-19 pandemic, more cases of adverse nail manifestations associated with COVID-19 vaccines are expected. Dermatologists should be aware of and use the reported nail findings to educate patients and reassure them that ungual abnormalities are potential adverse effects of COVID-19 vaccines, but they should not discourage vaccination because they usually are temporary and self-resolving.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.