Heart Failure

The COVID-19 pandemic has created unique and unprecedented challenges for the clinical research world, with potentially long-lasting consequences.

A new analysis of the extent of disruption shows that the average rate of stopped trials nearly doubled during the first 5 months of 2020, compared with the 2 previous years.

“Typically, clinical research precedes clinical practice by several years, so this disruption we’re seeing now will be felt for many years to come,” said Mario Guadino, MD, of Weill Cornell Medicine, New York.

The analysis was published online July 31 in the Journal of the American College of Cardiology.

The researchers used Python software to query meta-data from all trials reported on ClinicalTrials.gov. Of 321,218 non-COVID-19 trials queried, 28,672 (8.9%) were reported as stopped, defined as a switch in trial status from “recruiting” to “active and not recruiting,” “completed,” “suspended,” “terminated,” or “withdrawn.”

The average rate of discontinuation was 638 trials/month from January 2017 to December 2019, rising to 1,147 trials/month between January 2020 and May 2020 (P < .001 for trend).

Once stopped (as opposed to paused), restarting a trial is a tricky prospect, said Dr. Guadino. “You can’t stop and restart a trial because it creates a lot of issues, so we should expect many of these stopped trials to never be completed.”

He said these figures likely represent an underestimate of the true impact of the pandemic because there is typically a delay in the updating of the status of a trial on ClinicalTrials.gov.

“We are likely looking only at the tip of the iceberg,” he added. “My impression is that the number of trials that will be affected and even canceled will be very high.”

As for cardiology trials, one of the report’s authors, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, without naming specific trials, had this to say: “Several cardiovascular trials were paused, and some were permanently discontinued. It may be a while before we fully appreciate just how much information was lost and how much might be salvaged.”

He’s not worried, however, that upcoming cardiology meetings, which have moved online for the foreseeable future, might get a bit boring. “Fortunately, there is enough good work going on in the cardiovascular and cardiometabolic space that I believe there will still be ample randomized and observational data of high quality to present at the major meetings,” Dr. Bhatt said in an email.

The researchers found a weak correlation between the national population-adjusted numbers of COVID-19 cases and the proportion of non-COVID-19 trials stopped by country.

Even for trials that stopped recruiting for a period of time but are continuing, there are myriad issues involving compliance, data integrity, statistical interpretability, etc.

“Even if there is just a temporary disruption, that will most likely lead to reduced enrollment, missing follow-up visits, and protocol deviations, all things that would be red flags during normal times and impact the quality of the clinical trial,” said Dr. Guadino.

“And if your outcome of interest is mortality, well, how exactly do you measure that during a pandemic?” he added.
 

Stopped for lack of funding

Besides the logistical issues, another reason trials may be in jeopardy is funding. A warning early in the pandemic from the research community in Canada that funding was quickly drying up, leaving both jobs and data at risk, led to an aid package from the government to keep the lights on.

The National Institutes of Health (NIH), the Canadian Institutes of Health Research, and similar groups “have devoted large sums of money to research in COVID, which is of course very appropriate, but that clearly reduces the amount of funding that is available for other researchers,” said Dr. Guadino.

Some funding agencies around the world have canceled or put on hold all non-COVID-19 clinical trials still at the design state, Dr. Guadino said in an interview.

The NIH, he stressed, has not canceled funding and has been “extremely open and cooperative” in trying to help trialists navigate the many COVID-generated issues. They’ve even issued guidance on how to manage trials during COVID-19.

Of note, in the survey, the majority of the trials stopped (95.4%) had nongovernmental funding.

“The data are not very granular, so we’re only able to make some very simple, descriptive comments, but it does seem like the more fragile trials – those that are smaller and industry-funded – are the ones more likely to be disrupted,” said Dr. Guadino.

In some cases, he said, priorities have shifted to COVID-19. “If a small company is sponsoring a trial and they decide they want to sponsor something related to COVID, or they realize that because of the slow enrollment, the trial becomes too expensive to complete, they may opt to just abandon it,” said Dr. Guadino.

At what cost? It will take years to sort that out, he said.

This study received no funding. Dr. Guadino and Dr. Bhatt are both active trialists, participating in both industry- and government-sponsored clinical research.
 

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

The COVID-19 pandemic has created unique and unprecedented challenges for the clinical research world, with potentially long-lasting consequences.

A new analysis of the extent of disruption shows that the average rate of stopped trials nearly doubled during the first 5 months of 2020, compared with the 2 previous years.

“Typically, clinical research precedes clinical practice by several years, so this disruption we’re seeing now will be felt for many years to come,” said Mario Guadino, MD, of Weill Cornell Medicine, New York.

The analysis was published online July 31 in the Journal of the American College of Cardiology.

The researchers used Python software to query meta-data from all trials reported on ClinicalTrials.gov. Of 321,218 non-COVID-19 trials queried, 28,672 (8.9%) were reported as stopped, defined as a switch in trial status from “recruiting” to “active and not recruiting,” “completed,” “suspended,” “terminated,” or “withdrawn.”

The average rate of discontinuation was 638 trials/month from January 2017 to December 2019, rising to 1,147 trials/month between January 2020 and May 2020 (P < .001 for trend).

Once stopped (as opposed to paused), restarting a trial is a tricky prospect, said Dr. Guadino. “You can’t stop and restart a trial because it creates a lot of issues, so we should expect many of these stopped trials to never be completed.”

He said these figures likely represent an underestimate of the true impact of the pandemic because there is typically a delay in the updating of the status of a trial on ClinicalTrials.gov.

“We are likely looking only at the tip of the iceberg,” he added. “My impression is that the number of trials that will be affected and even canceled will be very high.”

As for cardiology trials, one of the report’s authors, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, without naming specific trials, had this to say: “Several cardiovascular trials were paused, and some were permanently discontinued. It may be a while before we fully appreciate just how much information was lost and how much might be salvaged.”

He’s not worried, however, that upcoming cardiology meetings, which have moved online for the foreseeable future, might get a bit boring. “Fortunately, there is enough good work going on in the cardiovascular and cardiometabolic space that I believe there will still be ample randomized and observational data of high quality to present at the major meetings,” Dr. Bhatt said in an email.

The researchers found a weak correlation between the national population-adjusted numbers of COVID-19 cases and the proportion of non-COVID-19 trials stopped by country.

Even for trials that stopped recruiting for a period of time but are continuing, there are myriad issues involving compliance, data integrity, statistical interpretability, etc.

“Even if there is just a temporary disruption, that will most likely lead to reduced enrollment, missing follow-up visits, and protocol deviations, all things that would be red flags during normal times and impact the quality of the clinical trial,” said Dr. Guadino.

“And if your outcome of interest is mortality, well, how exactly do you measure that during a pandemic?” he added.
 

Stopped for lack of funding

Besides the logistical issues, another reason trials may be in jeopardy is funding. A warning early in the pandemic from the research community in Canada that funding was quickly drying up, leaving both jobs and data at risk, led to an aid package from the government to keep the lights on.

The National Institutes of Health (NIH), the Canadian Institutes of Health Research, and similar groups “have devoted large sums of money to research in COVID, which is of course very appropriate, but that clearly reduces the amount of funding that is available for other researchers,” said Dr. Guadino.

Some funding agencies around the world have canceled or put on hold all non-COVID-19 clinical trials still at the design state, Dr. Guadino said in an interview.

The NIH, he stressed, has not canceled funding and has been “extremely open and cooperative” in trying to help trialists navigate the many COVID-generated issues. They’ve even issued guidance on how to manage trials during COVID-19.

Of note, in the survey, the majority of the trials stopped (95.4%) had nongovernmental funding.

“The data are not very granular, so we’re only able to make some very simple, descriptive comments, but it does seem like the more fragile trials – those that are smaller and industry-funded – are the ones more likely to be disrupted,” said Dr. Guadino.

In some cases, he said, priorities have shifted to COVID-19. “If a small company is sponsoring a trial and they decide they want to sponsor something related to COVID, or they realize that because of the slow enrollment, the trial becomes too expensive to complete, they may opt to just abandon it,” said Dr. Guadino.

At what cost? It will take years to sort that out, he said.

This study received no funding. Dr. Guadino and Dr. Bhatt are both active trialists, participating in both industry- and government-sponsored clinical research.
 

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

The COVID-19 pandemic has created unique and unprecedented challenges for the clinical research world, with potentially long-lasting consequences.

A new analysis of the extent of disruption shows that the average rate of stopped trials nearly doubled during the first 5 months of 2020, compared with the 2 previous years.

“Typically, clinical research precedes clinical practice by several years, so this disruption we’re seeing now will be felt for many years to come,” said Mario Guadino, MD, of Weill Cornell Medicine, New York.

The analysis was published online July 31 in the Journal of the American College of Cardiology.

The researchers used Python software to query meta-data from all trials reported on ClinicalTrials.gov. Of 321,218 non-COVID-19 trials queried, 28,672 (8.9%) were reported as stopped, defined as a switch in trial status from “recruiting” to “active and not recruiting,” “completed,” “suspended,” “terminated,” or “withdrawn.”

The average rate of discontinuation was 638 trials/month from January 2017 to December 2019, rising to 1,147 trials/month between January 2020 and May 2020 (P < .001 for trend).

Once stopped (as opposed to paused), restarting a trial is a tricky prospect, said Dr. Guadino. “You can’t stop and restart a trial because it creates a lot of issues, so we should expect many of these stopped trials to never be completed.”

He said these figures likely represent an underestimate of the true impact of the pandemic because there is typically a delay in the updating of the status of a trial on ClinicalTrials.gov.

“We are likely looking only at the tip of the iceberg,” he added. “My impression is that the number of trials that will be affected and even canceled will be very high.”

As for cardiology trials, one of the report’s authors, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, without naming specific trials, had this to say: “Several cardiovascular trials were paused, and some were permanently discontinued. It may be a while before we fully appreciate just how much information was lost and how much might be salvaged.”

He’s not worried, however, that upcoming cardiology meetings, which have moved online for the foreseeable future, might get a bit boring. “Fortunately, there is enough good work going on in the cardiovascular and cardiometabolic space that I believe there will still be ample randomized and observational data of high quality to present at the major meetings,” Dr. Bhatt said in an email.

The researchers found a weak correlation between the national population-adjusted numbers of COVID-19 cases and the proportion of non-COVID-19 trials stopped by country.

Even for trials that stopped recruiting for a period of time but are continuing, there are myriad issues involving compliance, data integrity, statistical interpretability, etc.

“Even if there is just a temporary disruption, that will most likely lead to reduced enrollment, missing follow-up visits, and protocol deviations, all things that would be red flags during normal times and impact the quality of the clinical trial,” said Dr. Guadino.

“And if your outcome of interest is mortality, well, how exactly do you measure that during a pandemic?” he added.
 

Stopped for lack of funding

Besides the logistical issues, another reason trials may be in jeopardy is funding. A warning early in the pandemic from the research community in Canada that funding was quickly drying up, leaving both jobs and data at risk, led to an aid package from the government to keep the lights on.

The National Institutes of Health (NIH), the Canadian Institutes of Health Research, and similar groups “have devoted large sums of money to research in COVID, which is of course very appropriate, but that clearly reduces the amount of funding that is available for other researchers,” said Dr. Guadino.

Some funding agencies around the world have canceled or put on hold all non-COVID-19 clinical trials still at the design state, Dr. Guadino said in an interview.

The NIH, he stressed, has not canceled funding and has been “extremely open and cooperative” in trying to help trialists navigate the many COVID-generated issues. They’ve even issued guidance on how to manage trials during COVID-19.

Of note, in the survey, the majority of the trials stopped (95.4%) had nongovernmental funding.

“The data are not very granular, so we’re only able to make some very simple, descriptive comments, but it does seem like the more fragile trials – those that are smaller and industry-funded – are the ones more likely to be disrupted,” said Dr. Guadino.

In some cases, he said, priorities have shifted to COVID-19. “If a small company is sponsoring a trial and they decide they want to sponsor something related to COVID, or they realize that because of the slow enrollment, the trial becomes too expensive to complete, they may opt to just abandon it,” said Dr. Guadino.

At what cost? It will take years to sort that out, he said.

This study received no funding. Dr. Guadino and Dr. Bhatt are both active trialists, participating in both industry- and government-sponsored clinical research.
 

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

Patients with sarcoidosis have an increased risk of heart failure and other adverse outcomes, including all-cause mortality, according to a decade-long nationwide study of Danish patients with the inflammatory disease.

“Although these findings are suggestive of the need for regular monitoring of cardiac manifestations in patients with sarcoidosis, it is important to emphasize that no causal relationships can be established from an observational study. Further studies are therefore needed to confirm our findings,” said first author Adelina Yafasova, MB, of Copenhagen University Hospital in Denmark, in an interview. The study was published in the Journal of the American College of Cardiology.

To determine the long-term risk of cardiac outcomes, and beyond – including incident heart failure; a composite of implantable cardioverter-defibrillator (ICD) implantation, ventricular arrhythmias or cardiac arrest; and all-cause mortality – Dr. Yafasova and her colleagues analyzed data from all Danish residents 18 years or older who were diagnosed with sarcoidosis from 1996 to 2016. Patients with any history of cardiac events were excluded. Of the 12,883 diagnosed patients, 11,834 were matched with subjects from a nationwide background population of more than 47,000 based on age, sex, and comorbidity. The median age of both populations was 42.8 (33.1-55.8) and 54.3% were men.

Median follow-up was 8.2 years for the sarcoidosis population and 8.4 years for the background population. The absolute 10-year risk of heart failure was 3.18% (95% confidence interval, 2.83%-3.57%) for sarcoidosis patients and 1.72% (95% CI, 1.58%-1.86%) for their matched controls. The 10-year risk for the composite of ICD implantation, ventricular arrhythmias and cardiac arrest was 0.96% (95% CI, 0.77%-1.18%) for sarcoidosis patients and 0.45% (95% CI, 0.38%-0.53%) for the background population.

For all-cause mortality, the 10-year risk was 10.88% (95% CI, 10.23%-11.55%) for sarcoidosis patients and 7.43% (95% CI, 7.15%-7.72%) for the background population. In a secondary analysis that compared all-cause mortality between the 364 sarcoidosis patients who developed heart failure and the 1,456 patients with heart failure without a history of sarcoidosis, the sarcoidosis group had a 35% higher rate than the nonsarcoidosis group (adjusted hazard ratio 1.35; 95% CI, 1.10-1.64).

“It’s not necessarily surprising that sarcoidosis patients would have a higher rate of heart failure,” said Melissa A. Lyle, MD, of the Mayo Clinic in Jacksonville, Fla., in an interview. “But the key takeaway is that sarcoidosis was associated with a higher rate of all-cause mortality compared to patients with heart failure and no sarcoidosis. That was more of a surprise.”

“There’s been some discrepancy in previous studies describing the cardiovascular outcomes in sarcoidosis,” Dr. Lyle added, “so I think this study provides excellent information while also highlighting the need for additional large-scale studies. We need to have further data on cardiovascular outcomes, which will allow us to refine the consensus statements and guidelines for management and the diagnosis of cardiac sarcoidosis.”

Dr. Lyle and Leslie T. Cooper Jr., MD, also of the Mayo Clinic, extrapolated on those thoughts in an editorial that accompanied the study. In it, the two authors praised the size and lengthy follow-up of the study, while noting its limitations. Specifically, they stressed that the study’s Danish population “may not be representative of other general populations” because of notable differences in ethnicity, age, and comorbidities.

That said, they reinforced that the study did feature “important takeaways” and that its findings emphasize the “need for monitoring for cardiac manifestations in patients with systemic sarcoidosis.”

In addition to the limitations noted in the editorial, the study’s authors acknowledged that the observational nature limited its “assessment of cause-effect relationships” and that the diagnosis codes for sarcoidosis had not been validated in the Danish National Patient Registry.

The authors of both the study and the editorial reported no conflicts of interest.

SOURCE: Yafasova A et al. J Am Coll Cardiol. 2020 Aug 10. doi: 10.1016/j.jacc.2020.06.038.

Patients with sarcoidosis have an increased risk of heart failure and other adverse outcomes, including all-cause mortality, according to a decade-long nationwide study of Danish patients with the inflammatory disease.

“Although these findings are suggestive of the need for regular monitoring of cardiac manifestations in patients with sarcoidosis, it is important to emphasize that no causal relationships can be established from an observational study. Further studies are therefore needed to confirm our findings,” said first author Adelina Yafasova, MB, of Copenhagen University Hospital in Denmark, in an interview. The study was published in the Journal of the American College of Cardiology.

To determine the long-term risk of cardiac outcomes, and beyond – including incident heart failure; a composite of implantable cardioverter-defibrillator (ICD) implantation, ventricular arrhythmias or cardiac arrest; and all-cause mortality – Dr. Yafasova and her colleagues analyzed data from all Danish residents 18 years or older who were diagnosed with sarcoidosis from 1996 to 2016. Patients with any history of cardiac events were excluded. Of the 12,883 diagnosed patients, 11,834 were matched with subjects from a nationwide background population of more than 47,000 based on age, sex, and comorbidity. The median age of both populations was 42.8 (33.1-55.8) and 54.3% were men.

Median follow-up was 8.2 years for the sarcoidosis population and 8.4 years for the background population. The absolute 10-year risk of heart failure was 3.18% (95% confidence interval, 2.83%-3.57%) for sarcoidosis patients and 1.72% (95% CI, 1.58%-1.86%) for their matched controls. The 10-year risk for the composite of ICD implantation, ventricular arrhythmias and cardiac arrest was 0.96% (95% CI, 0.77%-1.18%) for sarcoidosis patients and 0.45% (95% CI, 0.38%-0.53%) for the background population.

For all-cause mortality, the 10-year risk was 10.88% (95% CI, 10.23%-11.55%) for sarcoidosis patients and 7.43% (95% CI, 7.15%-7.72%) for the background population. In a secondary analysis that compared all-cause mortality between the 364 sarcoidosis patients who developed heart failure and the 1,456 patients with heart failure without a history of sarcoidosis, the sarcoidosis group had a 35% higher rate than the nonsarcoidosis group (adjusted hazard ratio 1.35; 95% CI, 1.10-1.64).

“It’s not necessarily surprising that sarcoidosis patients would have a higher rate of heart failure,” said Melissa A. Lyle, MD, of the Mayo Clinic in Jacksonville, Fla., in an interview. “But the key takeaway is that sarcoidosis was associated with a higher rate of all-cause mortality compared to patients with heart failure and no sarcoidosis. That was more of a surprise.”

“There’s been some discrepancy in previous studies describing the cardiovascular outcomes in sarcoidosis,” Dr. Lyle added, “so I think this study provides excellent information while also highlighting the need for additional large-scale studies. We need to have further data on cardiovascular outcomes, which will allow us to refine the consensus statements and guidelines for management and the diagnosis of cardiac sarcoidosis.”

Dr. Lyle and Leslie T. Cooper Jr., MD, also of the Mayo Clinic, extrapolated on those thoughts in an editorial that accompanied the study. In it, the two authors praised the size and lengthy follow-up of the study, while noting its limitations. Specifically, they stressed that the study’s Danish population “may not be representative of other general populations” because of notable differences in ethnicity, age, and comorbidities.

That said, they reinforced that the study did feature “important takeaways” and that its findings emphasize the “need for monitoring for cardiac manifestations in patients with systemic sarcoidosis.”

In addition to the limitations noted in the editorial, the study’s authors acknowledged that the observational nature limited its “assessment of cause-effect relationships” and that the diagnosis codes for sarcoidosis had not been validated in the Danish National Patient Registry.

The authors of both the study and the editorial reported no conflicts of interest.

SOURCE: Yafasova A et al. J Am Coll Cardiol. 2020 Aug 10. doi: 10.1016/j.jacc.2020.06.038.

Patients with sarcoidosis have an increased risk of heart failure and other adverse outcomes, including all-cause mortality, according to a decade-long nationwide study of Danish patients with the inflammatory disease.

“Although these findings are suggestive of the need for regular monitoring of cardiac manifestations in patients with sarcoidosis, it is important to emphasize that no causal relationships can be established from an observational study. Further studies are therefore needed to confirm our findings,” said first author Adelina Yafasova, MB, of Copenhagen University Hospital in Denmark, in an interview. The study was published in the Journal of the American College of Cardiology.

To determine the long-term risk of cardiac outcomes, and beyond – including incident heart failure; a composite of implantable cardioverter-defibrillator (ICD) implantation, ventricular arrhythmias or cardiac arrest; and all-cause mortality – Dr. Yafasova and her colleagues analyzed data from all Danish residents 18 years or older who were diagnosed with sarcoidosis from 1996 to 2016. Patients with any history of cardiac events were excluded. Of the 12,883 diagnosed patients, 11,834 were matched with subjects from a nationwide background population of more than 47,000 based on age, sex, and comorbidity. The median age of both populations was 42.8 (33.1-55.8) and 54.3% were men.

Median follow-up was 8.2 years for the sarcoidosis population and 8.4 years for the background population. The absolute 10-year risk of heart failure was 3.18% (95% confidence interval, 2.83%-3.57%) for sarcoidosis patients and 1.72% (95% CI, 1.58%-1.86%) for their matched controls. The 10-year risk for the composite of ICD implantation, ventricular arrhythmias and cardiac arrest was 0.96% (95% CI, 0.77%-1.18%) for sarcoidosis patients and 0.45% (95% CI, 0.38%-0.53%) for the background population.

For all-cause mortality, the 10-year risk was 10.88% (95% CI, 10.23%-11.55%) for sarcoidosis patients and 7.43% (95% CI, 7.15%-7.72%) for the background population. In a secondary analysis that compared all-cause mortality between the 364 sarcoidosis patients who developed heart failure and the 1,456 patients with heart failure without a history of sarcoidosis, the sarcoidosis group had a 35% higher rate than the nonsarcoidosis group (adjusted hazard ratio 1.35; 95% CI, 1.10-1.64).

“It’s not necessarily surprising that sarcoidosis patients would have a higher rate of heart failure,” said Melissa A. Lyle, MD, of the Mayo Clinic in Jacksonville, Fla., in an interview. “But the key takeaway is that sarcoidosis was associated with a higher rate of all-cause mortality compared to patients with heart failure and no sarcoidosis. That was more of a surprise.”

“There’s been some discrepancy in previous studies describing the cardiovascular outcomes in sarcoidosis,” Dr. Lyle added, “so I think this study provides excellent information while also highlighting the need for additional large-scale studies. We need to have further data on cardiovascular outcomes, which will allow us to refine the consensus statements and guidelines for management and the diagnosis of cardiac sarcoidosis.”

Dr. Lyle and Leslie T. Cooper Jr., MD, also of the Mayo Clinic, extrapolated on those thoughts in an editorial that accompanied the study. In it, the two authors praised the size and lengthy follow-up of the study, while noting its limitations. Specifically, they stressed that the study’s Danish population “may not be representative of other general populations” because of notable differences in ethnicity, age, and comorbidities.

That said, they reinforced that the study did feature “important takeaways” and that its findings emphasize the “need for monitoring for cardiac manifestations in patients with systemic sarcoidosis.”

In addition to the limitations noted in the editorial, the study’s authors acknowledged that the observational nature limited its “assessment of cause-effect relationships” and that the diagnosis codes for sarcoidosis had not been validated in the Danish National Patient Registry.

The authors of both the study and the editorial reported no conflicts of interest.

SOURCE: Yafasova A et al. J Am Coll Cardiol. 2020 Aug 10. doi: 10.1016/j.jacc.2020.06.038.

A study of patients with pulmonary hypertension suggests a reconsideration of the accepted benchmark for pulmonary vascular hypertension as a predictor of heart failure may be warranted.

An elevated pulmonary vascular resistance of 3.0 Wood units or greater has been used as a prognostic marker for death and heart failure in pulmonary hypertension subgroups. But a large, multiyear study of a veterans population suggests that shifting that threshold to 2.2 Wood units in patients with right-heart catheterization may be justified.

Bradley A. Maron, MD, of the Veterans Affairs Boston Healthcare System and Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues evaluated 40,082 veterans in the VA Clinical Assessment, Reporting and Tracking (CART) program who had right-heart catheterization (RHC) in the VA system from Oct. 1, 2007, to Sept. 30, 2016.

“To our knowledge, these data provide the first evidence-based information on the continuum of clinical risk related to PVR in patients with elevated pulmonary artery pressure,” the researchers wrote. Their report was published online in Lancet Respiratory Medicine (2020 Jul 27. doi: 10.1016/S2213-2600(20)30317-9).

The retrospective cohort study found that all-cause mortality hazard ratio (HR), when adjusted for clinical variables, and mean pulmonary artery pressure (mPAP) increased progressively beginning at around 2.0 Wood units (WU). Clinically significant mortality HR emerged at 2.2 WU, with an adjusted risk 9% greater than a PVR of 2.1 Wood units (P < .0034), which the study considered the upper limit of normal PVR in health adults of a similar age range (61.5 to 73.5 years) as the study cohort. The researchers noted that a PVR of 3.0 WU has been the standard for forecasting outcomes in pulmonary hypertension (PH) (Eur Heart J. 2010;31:2915-57).

“Overall, these results suggest that reconsidering the hemodynamic parameters that define pulmonary hypertension in patients with cardiopulmonary disease is warranted, and they identify a need for early detection strategies to capture this large and vulnerable population,” the researchers wrote.

A subsequent analysis focused on patients with an mPAP of >19 mm HG (n = 32,725) and found that all-cause death when adjusted over a wide range of clinical variables that included PVR of 2.2 WU increased to a 25% HR. “However,” the researchers added, “a median cardiac output of < 4.0 L/min, which has been shown to be independently associated with adverse outcome, was present only when PVR was more than 4.0 Wood units.”

For a PVR of 2.2-3.0 WU, the median cardiac output was 4.87 L/min; for > 3.0 WU, it was 4.13 L/min. Among the patients with PVR > 2.2 WU (n = 15,780), 13.6% (n = 2,147) had an mPAP of 19-24 mm Hg.

In all patients with mPAP > 19 mm HG, pulmonary artery wedge pressure (PAWP) became a determining risk factor, with 15 mm HG the demarcation between low and high PAWP. At PVR of 2.2 WU, low-PAWP patients had a 52% greater adjusted risk of death and high-PAWP a 23% greater risk. At 4.0 WU, those adjusted risks rose dramatically – to 272% and 58%, for the low- and high-PAWP subgroups, respectively (P < .0001).

“Stratification of patients by PAWP had a major effect on outcome estimates in our study, illustrating the limitations of using the same PVR level to define clinical risk between precapillary and postcapillary pulmonary hypertension,” the researchers wrote.

They called for further study into how these findings impact people with PH but lower levels of cardiopulmonary disease than the cohort. “Overall, these findings support reconsidering the combination of hemodynamic variables used to identify patients with pulmonary hypertension,” the researchers stated.

The analyses of the VA CART database makes this “an interesting study,” said G. Hossein Almassi, MD, FCCP, of the Medical College of Wisconsin and Zablocki VA Medical Center in Milwaukee. “Within its limitation as a retrospective cohort study, the findings of a lower PVR and a lower mean PAP of > 19 mm being associated with increased risk of all-cause mortality and HF hospitalization are significant.”

He added: “Time will tell whether this will be an impetus for the clinicians to consider earlier therapeutic interventions in addition to lifestyle modification such as smoking cessation in this group of patients.”

Dr. Maron disclosed a financial relationship with Actelion.

SOURCE: Maron BA et al. Lancet Respir Med. 2020 Jul 27. doi: 10.1016/S2213-2600(20)30317-9.

A study of patients with pulmonary hypertension suggests a reconsideration of the accepted benchmark for pulmonary vascular hypertension as a predictor of heart failure may be warranted.

An elevated pulmonary vascular resistance of 3.0 Wood units or greater has been used as a prognostic marker for death and heart failure in pulmonary hypertension subgroups. But a large, multiyear study of a veterans population suggests that shifting that threshold to 2.2 Wood units in patients with right-heart catheterization may be justified.

Bradley A. Maron, MD, of the Veterans Affairs Boston Healthcare System and Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues evaluated 40,082 veterans in the VA Clinical Assessment, Reporting and Tracking (CART) program who had right-heart catheterization (RHC) in the VA system from Oct. 1, 2007, to Sept. 30, 2016.

“To our knowledge, these data provide the first evidence-based information on the continuum of clinical risk related to PVR in patients with elevated pulmonary artery pressure,” the researchers wrote. Their report was published online in Lancet Respiratory Medicine (2020 Jul 27. doi: 10.1016/S2213-2600(20)30317-9).

The retrospective cohort study found that all-cause mortality hazard ratio (HR), when adjusted for clinical variables, and mean pulmonary artery pressure (mPAP) increased progressively beginning at around 2.0 Wood units (WU). Clinically significant mortality HR emerged at 2.2 WU, with an adjusted risk 9% greater than a PVR of 2.1 Wood units (P < .0034), which the study considered the upper limit of normal PVR in health adults of a similar age range (61.5 to 73.5 years) as the study cohort. The researchers noted that a PVR of 3.0 WU has been the standard for forecasting outcomes in pulmonary hypertension (PH) (Eur Heart J. 2010;31:2915-57).

“Overall, these results suggest that reconsidering the hemodynamic parameters that define pulmonary hypertension in patients with cardiopulmonary disease is warranted, and they identify a need for early detection strategies to capture this large and vulnerable population,” the researchers wrote.

A subsequent analysis focused on patients with an mPAP of >19 mm HG (n = 32,725) and found that all-cause death when adjusted over a wide range of clinical variables that included PVR of 2.2 WU increased to a 25% HR. “However,” the researchers added, “a median cardiac output of < 4.0 L/min, which has been shown to be independently associated with adverse outcome, was present only when PVR was more than 4.0 Wood units.”

For a PVR of 2.2-3.0 WU, the median cardiac output was 4.87 L/min; for > 3.0 WU, it was 4.13 L/min. Among the patients with PVR > 2.2 WU (n = 15,780), 13.6% (n = 2,147) had an mPAP of 19-24 mm Hg.

In all patients with mPAP > 19 mm HG, pulmonary artery wedge pressure (PAWP) became a determining risk factor, with 15 mm HG the demarcation between low and high PAWP. At PVR of 2.2 WU, low-PAWP patients had a 52% greater adjusted risk of death and high-PAWP a 23% greater risk. At 4.0 WU, those adjusted risks rose dramatically – to 272% and 58%, for the low- and high-PAWP subgroups, respectively (P < .0001).

“Stratification of patients by PAWP had a major effect on outcome estimates in our study, illustrating the limitations of using the same PVR level to define clinical risk between precapillary and postcapillary pulmonary hypertension,” the researchers wrote.

They called for further study into how these findings impact people with PH but lower levels of cardiopulmonary disease than the cohort. “Overall, these findings support reconsidering the combination of hemodynamic variables used to identify patients with pulmonary hypertension,” the researchers stated.

The analyses of the VA CART database makes this “an interesting study,” said G. Hossein Almassi, MD, FCCP, of the Medical College of Wisconsin and Zablocki VA Medical Center in Milwaukee. “Within its limitation as a retrospective cohort study, the findings of a lower PVR and a lower mean PAP of > 19 mm being associated with increased risk of all-cause mortality and HF hospitalization are significant.”

He added: “Time will tell whether this will be an impetus for the clinicians to consider earlier therapeutic interventions in addition to lifestyle modification such as smoking cessation in this group of patients.”

Dr. Maron disclosed a financial relationship with Actelion.

SOURCE: Maron BA et al. Lancet Respir Med. 2020 Jul 27. doi: 10.1016/S2213-2600(20)30317-9.

A study of patients with pulmonary hypertension suggests a reconsideration of the accepted benchmark for pulmonary vascular hypertension as a predictor of heart failure may be warranted.

An elevated pulmonary vascular resistance of 3.0 Wood units or greater has been used as a prognostic marker for death and heart failure in pulmonary hypertension subgroups. But a large, multiyear study of a veterans population suggests that shifting that threshold to 2.2 Wood units in patients with right-heart catheterization may be justified.

Bradley A. Maron, MD, of the Veterans Affairs Boston Healthcare System and Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues evaluated 40,082 veterans in the VA Clinical Assessment, Reporting and Tracking (CART) program who had right-heart catheterization (RHC) in the VA system from Oct. 1, 2007, to Sept. 30, 2016.

“To our knowledge, these data provide the first evidence-based information on the continuum of clinical risk related to PVR in patients with elevated pulmonary artery pressure,” the researchers wrote. Their report was published online in Lancet Respiratory Medicine (2020 Jul 27. doi: 10.1016/S2213-2600(20)30317-9).

The retrospective cohort study found that all-cause mortality hazard ratio (HR), when adjusted for clinical variables, and mean pulmonary artery pressure (mPAP) increased progressively beginning at around 2.0 Wood units (WU). Clinically significant mortality HR emerged at 2.2 WU, with an adjusted risk 9% greater than a PVR of 2.1 Wood units (P < .0034), which the study considered the upper limit of normal PVR in health adults of a similar age range (61.5 to 73.5 years) as the study cohort. The researchers noted that a PVR of 3.0 WU has been the standard for forecasting outcomes in pulmonary hypertension (PH) (Eur Heart J. 2010;31:2915-57).

“Overall, these results suggest that reconsidering the hemodynamic parameters that define pulmonary hypertension in patients with cardiopulmonary disease is warranted, and they identify a need for early detection strategies to capture this large and vulnerable population,” the researchers wrote.

A subsequent analysis focused on patients with an mPAP of >19 mm HG (n = 32,725) and found that all-cause death when adjusted over a wide range of clinical variables that included PVR of 2.2 WU increased to a 25% HR. “However,” the researchers added, “a median cardiac output of < 4.0 L/min, which has been shown to be independently associated with adverse outcome, was present only when PVR was more than 4.0 Wood units.”

For a PVR of 2.2-3.0 WU, the median cardiac output was 4.87 L/min; for > 3.0 WU, it was 4.13 L/min. Among the patients with PVR > 2.2 WU (n = 15,780), 13.6% (n = 2,147) had an mPAP of 19-24 mm Hg.

In all patients with mPAP > 19 mm HG, pulmonary artery wedge pressure (PAWP) became a determining risk factor, with 15 mm HG the demarcation between low and high PAWP. At PVR of 2.2 WU, low-PAWP patients had a 52% greater adjusted risk of death and high-PAWP a 23% greater risk. At 4.0 WU, those adjusted risks rose dramatically – to 272% and 58%, for the low- and high-PAWP subgroups, respectively (P < .0001).

“Stratification of patients by PAWP had a major effect on outcome estimates in our study, illustrating the limitations of using the same PVR level to define clinical risk between precapillary and postcapillary pulmonary hypertension,” the researchers wrote.

They called for further study into how these findings impact people with PH but lower levels of cardiopulmonary disease than the cohort. “Overall, these findings support reconsidering the combination of hemodynamic variables used to identify patients with pulmonary hypertension,” the researchers stated.

The analyses of the VA CART database makes this “an interesting study,” said G. Hossein Almassi, MD, FCCP, of the Medical College of Wisconsin and Zablocki VA Medical Center in Milwaukee. “Within its limitation as a retrospective cohort study, the findings of a lower PVR and a lower mean PAP of > 19 mm being associated with increased risk of all-cause mortality and HF hospitalization are significant.”

He added: “Time will tell whether this will be an impetus for the clinicians to consider earlier therapeutic interventions in addition to lifestyle modification such as smoking cessation in this group of patients.”

Dr. Maron disclosed a financial relationship with Actelion.

SOURCE: Maron BA et al. Lancet Respir Med. 2020 Jul 27. doi: 10.1016/S2213-2600(20)30317-9.

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

mzoler@mdedge.com

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

mzoler@mdedge.com

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

mzoler@mdedge.com

Because heart failure patients with recovered ejection fraction are a complex and diverse group, little consensus has emerged on how to define, diagnose, and manage this growing population.

To provide some clarity for identifying and treating these patients, a Journal of the American College of Cardiology scientific expert panel has issued a consensus document. Published Aug. 3 in the Journal of the American College of Cardiology, it provides a working definition of heart failure with recovered ejection fraction (HFrecEF) and recommends approaches for treatment and follow-up.
 

Defining a new class of HF

“Part of the impetus of this was to bring attention to what we think is a new class of heart failure, and it requires different treatment modalities and different ways of thinking about it,” expert panel member Douglas L. Mann, MD, cardiologist-in-chief at Barnes Jewish Hospital in St. Louis, said in an interview. “It’s a newly discovered HF biology about which we know very little and it’s very confusing to just go on the ejection fraction alone.”

The panel, led by Jane E. Wilcox, MD, of Northwestern University, Chicago, recommends three components for a working definition of HFrecEF: 1) documentation of a decreased left ventricle ejection fraction (LVEF) of less than 40% at baseline; 2) a 10% or greater absolute improvement in LVEF; and 3) a second measurement of LVEF >40%.

“We try to give it a nomenclature that clearly indicates what it is,” Dr. Mann said. “There has been a lot of confusing terminology.” Among the terms the panel calls out in the lexicon of modestly recovered EF, in addition to HFrecEF, are HF improved EF, HF with preserved EF (HFpEF), borderline HFpEF and HF with mid-range EF (HFmrEF).

The panel also recommends that guideline-based medical and device therapies for HFrecEF should continue indefinitely until there’s a better understanding of the biology and clinical epidemiology of HFrecEF, and that these patients should have close clinical follow-up because of the high risk of HF relapse.

Determining EF’s ‘trajectory’

The findings presented in the statement should help cardiologists distinguish HFrecEF from HFpEF, Dr. Mann noted. “Because EF is moving, we also have to emphasize the importance of following the trajectory of EF,” he said. “It’s not enough to know where the EF is; you have to know where it came from – if it had been from a higher number or a lower number – because that will help inform you about the patient’s disease.”

In that regard, the panel states that the level of change in LVEF – the “trajectory” – will provide clues to the nature and extent of myocardial injury, degree and duration of LV remodeling, and the type of therapy that’s indicated. Clinicians should consider HFmrEF, a description the European Society of Cardiology has endorsed, as an entity different from HFrecEF without data on LVEF trajectory.

The statement delves into the biology of HFrecEF, defining reverse LV remodeling as the restoration of some normalization to cardiac myocyte size and LV chamber geometry that results in a leftward shift toward normalization of end-diastolic pressure volume. The panel also noted that cardiac remodeling in reverse LV remodeling and recovery of LV function is bidirectional and involves multiple molecular and cellular changes that contribute to changes in the heart’s size, shape and function, and explains the role gene expression has in HF-related LV changes.

The statement explores the recovery of LV function, noting that spontaneous recovery often occurs when the cause of the myocardial dysfunction resolves. Common causes are chronic tachycardia and thyroid disease.

That panel noted that “super responders” to cardiac resynchronization therapy can provide insight into HFrecEF. Favorable responders include women, patients with nonischemic HF, very wide ECG ventricular depolarization wavelength with left-bundle branch block morphology, and dyssynchrony on ECG.

Bruce Jancin/MDedge News

The panel states that, “regardless of the definition of HFrecEF,” the evidence suggests that younger patients, women, and those with nonischemic disease, shorter disease duration, and relatively few comorbidities are more likely to recover LVEF – and their outcomes are typically better than those of patients with HF reduced EF (HFrEF) and HFpEF.

Clinicians should bear in mind, however, that patients on guideline-directed medical therapy (GDMT) who achieve complete normalization of LV structure and function are prone to recurrent LV dysfunction and HF. The panel explored the role of potential treatment for three different etiologies of HF. Little is known about Takotsubo cardiomyopathy, considered a transient form of LV dysfunction, in terms of how many of these patients will develop HFrEF or if they’ll benefit from GDMT. Alcohol-induced cardiomyopathy patients should continue on medical therapy even if they have HFrecEF, as should patients with fulminant and nonfulminant myocarditis.
 

Managing HFrecEF

Management should include assessment of jugular vein distention and signs of volume overload – “particularly concerning in HFrecEF” – the panel noted. ECG is cost effective, and signs of left-bundle branch block are predictors of low success with GDMT alone. The panel also recommended a family history going back three generations and consideration of genetic testing to determine the risk for sudden cardiac death. Two-dimensional ECG can help predict GDMT response and cardiovascular magnetic resonance imaging can provide information about myocardial substrate at the time of diagnosis of HFrEF.

The panel suggested four areas for future research: 1) improved phenotyping of HFrEF; 2) use of inception cohorts to better understand the natural history of HFrecEF; 3) clinical trials to better define those clinical care components most effective at maintaining remission; and 4) basic studies to better define the biology of HFrecEF. “The goal,” wrote Dr. Wilcox and colleagues, “is to develop new therapeutic targets that will enable patients with HFrecEF to experience a durable remission from HF.”

Dr. Wilcox reported receiving funding from the National Institutes of Health and the American Heart Association, and financial relationships with Abbott, Medtronic, and Cytokinetics. Dr. Mann has received funding from NIH and reports financial relationships with MyoKardia and Novartis. Coauthors reported funding from NIH and AHA and financial relationships with Novartis, Amgen, AstraZeneca, Thoratec Corporation (Abbott), Sanofi, Pfizer, MyoKardia and American Regent.

SOURCE: Wilcox JE et al. J Am Coll Cardiol. 2020;76:719-34.

Because heart failure patients with recovered ejection fraction are a complex and diverse group, little consensus has emerged on how to define, diagnose, and manage this growing population.

To provide some clarity for identifying and treating these patients, a Journal of the American College of Cardiology scientific expert panel has issued a consensus document. Published Aug. 3 in the Journal of the American College of Cardiology, it provides a working definition of heart failure with recovered ejection fraction (HFrecEF) and recommends approaches for treatment and follow-up.
 

Defining a new class of HF

“Part of the impetus of this was to bring attention to what we think is a new class of heart failure, and it requires different treatment modalities and different ways of thinking about it,” expert panel member Douglas L. Mann, MD, cardiologist-in-chief at Barnes Jewish Hospital in St. Louis, said in an interview. “It’s a newly discovered HF biology about which we know very little and it’s very confusing to just go on the ejection fraction alone.”

The panel, led by Jane E. Wilcox, MD, of Northwestern University, Chicago, recommends three components for a working definition of HFrecEF: 1) documentation of a decreased left ventricle ejection fraction (LVEF) of less than 40% at baseline; 2) a 10% or greater absolute improvement in LVEF; and 3) a second measurement of LVEF >40%.

“We try to give it a nomenclature that clearly indicates what it is,” Dr. Mann said. “There has been a lot of confusing terminology.” Among the terms the panel calls out in the lexicon of modestly recovered EF, in addition to HFrecEF, are HF improved EF, HF with preserved EF (HFpEF), borderline HFpEF and HF with mid-range EF (HFmrEF).

The panel also recommends that guideline-based medical and device therapies for HFrecEF should continue indefinitely until there’s a better understanding of the biology and clinical epidemiology of HFrecEF, and that these patients should have close clinical follow-up because of the high risk of HF relapse.

Determining EF’s ‘trajectory’

The findings presented in the statement should help cardiologists distinguish HFrecEF from HFpEF, Dr. Mann noted. “Because EF is moving, we also have to emphasize the importance of following the trajectory of EF,” he said. “It’s not enough to know where the EF is; you have to know where it came from – if it had been from a higher number or a lower number – because that will help inform you about the patient’s disease.”

In that regard, the panel states that the level of change in LVEF – the “trajectory” – will provide clues to the nature and extent of myocardial injury, degree and duration of LV remodeling, and the type of therapy that’s indicated. Clinicians should consider HFmrEF, a description the European Society of Cardiology has endorsed, as an entity different from HFrecEF without data on LVEF trajectory.

The statement delves into the biology of HFrecEF, defining reverse LV remodeling as the restoration of some normalization to cardiac myocyte size and LV chamber geometry that results in a leftward shift toward normalization of end-diastolic pressure volume. The panel also noted that cardiac remodeling in reverse LV remodeling and recovery of LV function is bidirectional and involves multiple molecular and cellular changes that contribute to changes in the heart’s size, shape and function, and explains the role gene expression has in HF-related LV changes.

The statement explores the recovery of LV function, noting that spontaneous recovery often occurs when the cause of the myocardial dysfunction resolves. Common causes are chronic tachycardia and thyroid disease.

That panel noted that “super responders” to cardiac resynchronization therapy can provide insight into HFrecEF. Favorable responders include women, patients with nonischemic HF, very wide ECG ventricular depolarization wavelength with left-bundle branch block morphology, and dyssynchrony on ECG.

Bruce Jancin/MDedge News

The panel states that, “regardless of the definition of HFrecEF,” the evidence suggests that younger patients, women, and those with nonischemic disease, shorter disease duration, and relatively few comorbidities are more likely to recover LVEF – and their outcomes are typically better than those of patients with HF reduced EF (HFrEF) and HFpEF.

Clinicians should bear in mind, however, that patients on guideline-directed medical therapy (GDMT) who achieve complete normalization of LV structure and function are prone to recurrent LV dysfunction and HF. The panel explored the role of potential treatment for three different etiologies of HF. Little is known about Takotsubo cardiomyopathy, considered a transient form of LV dysfunction, in terms of how many of these patients will develop HFrEF or if they’ll benefit from GDMT. Alcohol-induced cardiomyopathy patients should continue on medical therapy even if they have HFrecEF, as should patients with fulminant and nonfulminant myocarditis.
 

Managing HFrecEF

Management should include assessment of jugular vein distention and signs of volume overload – “particularly concerning in HFrecEF” – the panel noted. ECG is cost effective, and signs of left-bundle branch block are predictors of low success with GDMT alone. The panel also recommended a family history going back three generations and consideration of genetic testing to determine the risk for sudden cardiac death. Two-dimensional ECG can help predict GDMT response and cardiovascular magnetic resonance imaging can provide information about myocardial substrate at the time of diagnosis of HFrEF.

The panel suggested four areas for future research: 1) improved phenotyping of HFrEF; 2) use of inception cohorts to better understand the natural history of HFrecEF; 3) clinical trials to better define those clinical care components most effective at maintaining remission; and 4) basic studies to better define the biology of HFrecEF. “The goal,” wrote Dr. Wilcox and colleagues, “is to develop new therapeutic targets that will enable patients with HFrecEF to experience a durable remission from HF.”

Dr. Wilcox reported receiving funding from the National Institutes of Health and the American Heart Association, and financial relationships with Abbott, Medtronic, and Cytokinetics. Dr. Mann has received funding from NIH and reports financial relationships with MyoKardia and Novartis. Coauthors reported funding from NIH and AHA and financial relationships with Novartis, Amgen, AstraZeneca, Thoratec Corporation (Abbott), Sanofi, Pfizer, MyoKardia and American Regent.

SOURCE: Wilcox JE et al. J Am Coll Cardiol. 2020;76:719-34.

Because heart failure patients with recovered ejection fraction are a complex and diverse group, little consensus has emerged on how to define, diagnose, and manage this growing population.

To provide some clarity for identifying and treating these patients, a Journal of the American College of Cardiology scientific expert panel has issued a consensus document. Published Aug. 3 in the Journal of the American College of Cardiology, it provides a working definition of heart failure with recovered ejection fraction (HFrecEF) and recommends approaches for treatment and follow-up.
 

Defining a new class of HF

“Part of the impetus of this was to bring attention to what we think is a new class of heart failure, and it requires different treatment modalities and different ways of thinking about it,” expert panel member Douglas L. Mann, MD, cardiologist-in-chief at Barnes Jewish Hospital in St. Louis, said in an interview. “It’s a newly discovered HF biology about which we know very little and it’s very confusing to just go on the ejection fraction alone.”

The panel, led by Jane E. Wilcox, MD, of Northwestern University, Chicago, recommends three components for a working definition of HFrecEF: 1) documentation of a decreased left ventricle ejection fraction (LVEF) of less than 40% at baseline; 2) a 10% or greater absolute improvement in LVEF; and 3) a second measurement of LVEF >40%.

“We try to give it a nomenclature that clearly indicates what it is,” Dr. Mann said. “There has been a lot of confusing terminology.” Among the terms the panel calls out in the lexicon of modestly recovered EF, in addition to HFrecEF, are HF improved EF, HF with preserved EF (HFpEF), borderline HFpEF and HF with mid-range EF (HFmrEF).

The panel also recommends that guideline-based medical and device therapies for HFrecEF should continue indefinitely until there’s a better understanding of the biology and clinical epidemiology of HFrecEF, and that these patients should have close clinical follow-up because of the high risk of HF relapse.

Determining EF’s ‘trajectory’

The findings presented in the statement should help cardiologists distinguish HFrecEF from HFpEF, Dr. Mann noted. “Because EF is moving, we also have to emphasize the importance of following the trajectory of EF,” he said. “It’s not enough to know where the EF is; you have to know where it came from – if it had been from a higher number or a lower number – because that will help inform you about the patient’s disease.”

In that regard, the panel states that the level of change in LVEF – the “trajectory” – will provide clues to the nature and extent of myocardial injury, degree and duration of LV remodeling, and the type of therapy that’s indicated. Clinicians should consider HFmrEF, a description the European Society of Cardiology has endorsed, as an entity different from HFrecEF without data on LVEF trajectory.

The statement delves into the biology of HFrecEF, defining reverse LV remodeling as the restoration of some normalization to cardiac myocyte size and LV chamber geometry that results in a leftward shift toward normalization of end-diastolic pressure volume. The panel also noted that cardiac remodeling in reverse LV remodeling and recovery of LV function is bidirectional and involves multiple molecular and cellular changes that contribute to changes in the heart’s size, shape and function, and explains the role gene expression has in HF-related LV changes.

The statement explores the recovery of LV function, noting that spontaneous recovery often occurs when the cause of the myocardial dysfunction resolves. Common causes are chronic tachycardia and thyroid disease.

That panel noted that “super responders” to cardiac resynchronization therapy can provide insight into HFrecEF. Favorable responders include women, patients with nonischemic HF, very wide ECG ventricular depolarization wavelength with left-bundle branch block morphology, and dyssynchrony on ECG.

Bruce Jancin/MDedge News

The panel states that, “regardless of the definition of HFrecEF,” the evidence suggests that younger patients, women, and those with nonischemic disease, shorter disease duration, and relatively few comorbidities are more likely to recover LVEF – and their outcomes are typically better than those of patients with HF reduced EF (HFrEF) and HFpEF.

Clinicians should bear in mind, however, that patients on guideline-directed medical therapy (GDMT) who achieve complete normalization of LV structure and function are prone to recurrent LV dysfunction and HF. The panel explored the role of potential treatment for three different etiologies of HF. Little is known about Takotsubo cardiomyopathy, considered a transient form of LV dysfunction, in terms of how many of these patients will develop HFrEF or if they’ll benefit from GDMT. Alcohol-induced cardiomyopathy patients should continue on medical therapy even if they have HFrecEF, as should patients with fulminant and nonfulminant myocarditis.
 

Managing HFrecEF

Management should include assessment of jugular vein distention and signs of volume overload – “particularly concerning in HFrecEF” – the panel noted. ECG is cost effective, and signs of left-bundle branch block are predictors of low success with GDMT alone. The panel also recommended a family history going back three generations and consideration of genetic testing to determine the risk for sudden cardiac death. Two-dimensional ECG can help predict GDMT response and cardiovascular magnetic resonance imaging can provide information about myocardial substrate at the time of diagnosis of HFrEF.

The panel suggested four areas for future research: 1) improved phenotyping of HFrEF; 2) use of inception cohorts to better understand the natural history of HFrecEF; 3) clinical trials to better define those clinical care components most effective at maintaining remission; and 4) basic studies to better define the biology of HFrecEF. “The goal,” wrote Dr. Wilcox and colleagues, “is to develop new therapeutic targets that will enable patients with HFrecEF to experience a durable remission from HF.”

Dr. Wilcox reported receiving funding from the National Institutes of Health and the American Heart Association, and financial relationships with Abbott, Medtronic, and Cytokinetics. Dr. Mann has received funding from NIH and reports financial relationships with MyoKardia and Novartis. Coauthors reported funding from NIH and AHA and financial relationships with Novartis, Amgen, AstraZeneca, Thoratec Corporation (Abbott), Sanofi, Pfizer, MyoKardia and American Regent.

SOURCE: Wilcox JE et al. J Am Coll Cardiol. 2020;76:719-34.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

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

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

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

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

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

A 10-year follow-up analysis based on one of cardiology’s most influential trials has shed further light on one of its key issues: how to sharpen selection of patients most likely to benefit from a primary prevention implantable cardioverter-defibrillator (ICD).

In a new report from SCD-HeFT, the survival advantage in patients with heart failure seen 5 years after receiving ICDs, compared with a non-ICD control group, narrowed a bit but remained significant after an additional 5 years. But not all patients with devices shared in that long-term ICD benefit. Patients with either ischemic disease or nonischemic cardiomyopathy (NICM) with devices showed a similar mortality risk reduction in the trial’s previously reported 5-year outcomes. That advantage, compared with non-ICD control patients, persisted throughout the subsequent 5 years for ischemic patients but tapered to nil for those with NICM.

The NICM patients “had what appears to be some accrual of benefit maybe out to about 6 years, and then the curves appear to come together where there’s no apparent further benefit after 6 years,” Jeanne E. Poole, MD, of the University of Washington, Seattle, said in an interview.

In both the 10-year analysis and the earlier results, ICD survival gains went preferentially to patients who enrolled with New York Heart Association (NYHA) functional class II symptoms. Patients who entered in NYHA class III “didn’t appear to have any benefit whatsoever” in either period, Dr. Poole said.

“The simple message is that the same groups of patients that benefited strongly from the ICD in the original SCD-HeFT – the NYHA class 2 patients and those with ischemic cardiomyopathy – were really the ones who benefited the greatest over the long term,” she said.

Dr. Poole is lead author on the SCD-HeFT 10-year analysis, which was published in the July 28 issue of the Journal of the American College of Cardiology.

Why the ICD survival effect disappeared midway in patients with NICM “is hard to sort out,” she said. Many in the control group were offered such devices after the trial concluded. Among those, it’s possible that disproportionately more control patients with NICM, compared with patients with ischemic disease, were fitted with ICDs that were also cardiac resynchronization therapy (CRT) devices, Dr. Poole and her colleagues speculated. That could have shifted their late outcomes to be more in line with patients who had received ICDs when the trial started.

Or “it is possible that the intermediate-term benefit of ICD therapy in NICM is overwhelmed by nonarrhythmic death in extended follow-up” given that ICDs prolong survival only by preventing arrhythmic death, noted an editorial accompanying the new SCD-HeFT publication.

Another possibility: Because NICM is a heterogeneous disorder with many potential causes, perhaps “the absence of long-term mortality benefit among SCD-HeFT participants with NICM was due to an unintended but preferential enrollment of subtypes at relatively lower risk for arrhythmic death in the longer term,” proposed Eric C. Stecker, MD, MPH, Oregon Health & Science University, Portland, and coauthors in their editorial.

“What are the take-away messages from the current analysis by Poole et al?” they asked. “These findings strongly support the clinical efficacy and cost-effectiveness of ICD therapy for the majority of patients with severe but mildly symptomatic ischemic cardiomyopathy who do not have an excessive comorbidity burden.”

But “the implications for patients with NICM are less clear,” they wrote. “Given evidence for intermediate-term benefit and the limitations inherent to assessing longer-term benefit, we do not believe it is appropriate to walk back guideline recommendations regarding ICD implantation for NICM patients.”

The findings in nonischemic patients invite comparison with the randomized DANISH trial, which entered only patients with NICM and, over more than 5 years, saw no primary-prevention ICD advantage for the end point of all-cause mortality.

But patients who received ICDs showed a reduction in arrhythmic death, a secondary end point. And mortality in the trial showed a significant interaction with patient age; survival went up sharply with ICDs for those younger than 60 years.

Also in DANISH, “the ICD treatment effect appears to vary over time, with an earlier phase showing possible survival benefit and a later phase showing attenuation of that benefit,” similar to what was seen long-term in SCD-HeFT, in which the interaction between mortality and time since implantation was significant at P = .0015, observe Dr. Poole and colleagues.

However, Dr. Poole cautioned when interviewed, patient management in DANISH, conducted exclusively in Denmark, may not have been representative of the rest of the world, complicating comparisons with other studies. For example, nearly 60% of all patients in DANISH had defibrillating CRT devices. Virtually everyone was on ACE inhibitors or angiotensin-receptor blockers, and almost 60% were taking aldosterone inhibitors.

“DANISH is an unusually high bar and probably does not reflect all patients with heart failure, and certainly does not reflect patients in the United States in terms of those high levels of guideline-directed medical therapy,” Dr. Poole said. The message from DANISH, she said, seems to be that patients with NICM who are definitely on goal-directed heart failure medications with CRT devices “probably don’t have a meaningful benefit from an ICD, on total mortality, because their sudden death rates are simply so low.”

SCD-HeFT had originally assigned 2,521 patients with heart failure of NYHA class II or III and an left ventricular ejection fraction of less than 35% to receive an ICD, amiodarone without an ICD, or an amiodarone placebo and no ICD; patients in the latter cohorts made up the non-ICD control group.

Those who received an ICD, compared with the non-ICD control patients, showed a 23% drop in all-cause mortality over a median of 45.5 months ending on October 31, 2003, Dr. Poole and colleagues noted in their current report. The trial’s primary results were unveiled 2005.

The current analysis, based on data collected in 2010 and 2011, followed the 1,855 patients alive at the trial’s official conclusion and combined outcomes before and after that time for a median follow-up of 11 years, Dr. Poole and colleagues reported.

In the ICD group, the overall hazard ratio for mortality by intention-to-treat was 0.87 (95% confidence interval, 0.76-0.98; P = .028), compared with the non-ICD control group.

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

A 10-year follow-up analysis based on one of cardiology’s most influential trials has shed further light on one of its key issues: how to sharpen selection of patients most likely to benefit from a primary prevention implantable cardioverter-defibrillator (ICD).

In a new report from SCD-HeFT, the survival advantage in patients with heart failure seen 5 years after receiving ICDs, compared with a non-ICD control group, narrowed a bit but remained significant after an additional 5 years. But not all patients with devices shared in that long-term ICD benefit. Patients with either ischemic disease or nonischemic cardiomyopathy (NICM) with devices showed a similar mortality risk reduction in the trial’s previously reported 5-year outcomes. That advantage, compared with non-ICD control patients, persisted throughout the subsequent 5 years for ischemic patients but tapered to nil for those with NICM.

The NICM patients “had what appears to be some accrual of benefit maybe out to about 6 years, and then the curves appear to come together where there’s no apparent further benefit after 6 years,” Jeanne E. Poole, MD, of the University of Washington, Seattle, said in an interview.

In both the 10-year analysis and the earlier results, ICD survival gains went preferentially to patients who enrolled with New York Heart Association (NYHA) functional class II symptoms. Patients who entered in NYHA class III “didn’t appear to have any benefit whatsoever” in either period, Dr. Poole said.

“The simple message is that the same groups of patients that benefited strongly from the ICD in the original SCD-HeFT – the NYHA class 2 patients and those with ischemic cardiomyopathy – were really the ones who benefited the greatest over the long term,” she said.

Dr. Poole is lead author on the SCD-HeFT 10-year analysis, which was published in the July 28 issue of the Journal of the American College of Cardiology.

Why the ICD survival effect disappeared midway in patients with NICM “is hard to sort out,” she said. Many in the control group were offered such devices after the trial concluded. Among those, it’s possible that disproportionately more control patients with NICM, compared with patients with ischemic disease, were fitted with ICDs that were also cardiac resynchronization therapy (CRT) devices, Dr. Poole and her colleagues speculated. That could have shifted their late outcomes to be more in line with patients who had received ICDs when the trial started.

Or “it is possible that the intermediate-term benefit of ICD therapy in NICM is overwhelmed by nonarrhythmic death in extended follow-up” given that ICDs prolong survival only by preventing arrhythmic death, noted an editorial accompanying the new SCD-HeFT publication.

Another possibility: Because NICM is a heterogeneous disorder with many potential causes, perhaps “the absence of long-term mortality benefit among SCD-HeFT participants with NICM was due to an unintended but preferential enrollment of subtypes at relatively lower risk for arrhythmic death in the longer term,” proposed Eric C. Stecker, MD, MPH, Oregon Health & Science University, Portland, and coauthors in their editorial.

“What are the take-away messages from the current analysis by Poole et al?” they asked. “These findings strongly support the clinical efficacy and cost-effectiveness of ICD therapy for the majority of patients with severe but mildly symptomatic ischemic cardiomyopathy who do not have an excessive comorbidity burden.”

But “the implications for patients with NICM are less clear,” they wrote. “Given evidence for intermediate-term benefit and the limitations inherent to assessing longer-term benefit, we do not believe it is appropriate to walk back guideline recommendations regarding ICD implantation for NICM patients.”

The findings in nonischemic patients invite comparison with the randomized DANISH trial, which entered only patients with NICM and, over more than 5 years, saw no primary-prevention ICD advantage for the end point of all-cause mortality.

But patients who received ICDs showed a reduction in arrhythmic death, a secondary end point. And mortality in the trial showed a significant interaction with patient age; survival went up sharply with ICDs for those younger than 60 years.

Also in DANISH, “the ICD treatment effect appears to vary over time, with an earlier phase showing possible survival benefit and a later phase showing attenuation of that benefit,” similar to what was seen long-term in SCD-HeFT, in which the interaction between mortality and time since implantation was significant at P = .0015, observe Dr. Poole and colleagues.

However, Dr. Poole cautioned when interviewed, patient management in DANISH, conducted exclusively in Denmark, may not have been representative of the rest of the world, complicating comparisons with other studies. For example, nearly 60% of all patients in DANISH had defibrillating CRT devices. Virtually everyone was on ACE inhibitors or angiotensin-receptor blockers, and almost 60% were taking aldosterone inhibitors.

“DANISH is an unusually high bar and probably does not reflect all patients with heart failure, and certainly does not reflect patients in the United States in terms of those high levels of guideline-directed medical therapy,” Dr. Poole said. The message from DANISH, she said, seems to be that patients with NICM who are definitely on goal-directed heart failure medications with CRT devices “probably don’t have a meaningful benefit from an ICD, on total mortality, because their sudden death rates are simply so low.”

SCD-HeFT had originally assigned 2,521 patients with heart failure of NYHA class II or III and an left ventricular ejection fraction of less than 35% to receive an ICD, amiodarone without an ICD, or an amiodarone placebo and no ICD; patients in the latter cohorts made up the non-ICD control group.

Those who received an ICD, compared with the non-ICD control patients, showed a 23% drop in all-cause mortality over a median of 45.5 months ending on October 31, 2003, Dr. Poole and colleagues noted in their current report. The trial’s primary results were unveiled 2005.

The current analysis, based on data collected in 2010 and 2011, followed the 1,855 patients alive at the trial’s official conclusion and combined outcomes before and after that time for a median follow-up of 11 years, Dr. Poole and colleagues reported.

In the ICD group, the overall hazard ratio for mortality by intention-to-treat was 0.87 (95% confidence interval, 0.76-0.98; P = .028), compared with the non-ICD control group.

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

A 10-year follow-up analysis based on one of cardiology’s most influential trials has shed further light on one of its key issues: how to sharpen selection of patients most likely to benefit from a primary prevention implantable cardioverter-defibrillator (ICD).

In a new report from SCD-HeFT, the survival advantage in patients with heart failure seen 5 years after receiving ICDs, compared with a non-ICD control group, narrowed a bit but remained significant after an additional 5 years. But not all patients with devices shared in that long-term ICD benefit. Patients with either ischemic disease or nonischemic cardiomyopathy (NICM) with devices showed a similar mortality risk reduction in the trial’s previously reported 5-year outcomes. That advantage, compared with non-ICD control patients, persisted throughout the subsequent 5 years for ischemic patients but tapered to nil for those with NICM.

The NICM patients “had what appears to be some accrual of benefit maybe out to about 6 years, and then the curves appear to come together where there’s no apparent further benefit after 6 years,” Jeanne E. Poole, MD, of the University of Washington, Seattle, said in an interview.

In both the 10-year analysis and the earlier results, ICD survival gains went preferentially to patients who enrolled with New York Heart Association (NYHA) functional class II symptoms. Patients who entered in NYHA class III “didn’t appear to have any benefit whatsoever” in either period, Dr. Poole said.

“The simple message is that the same groups of patients that benefited strongly from the ICD in the original SCD-HeFT – the NYHA class 2 patients and those with ischemic cardiomyopathy – were really the ones who benefited the greatest over the long term,” she said.

Dr. Poole is lead author on the SCD-HeFT 10-year analysis, which was published in the July 28 issue of the Journal of the American College of Cardiology.

Why the ICD survival effect disappeared midway in patients with NICM “is hard to sort out,” she said. Many in the control group were offered such devices after the trial concluded. Among those, it’s possible that disproportionately more control patients with NICM, compared with patients with ischemic disease, were fitted with ICDs that were also cardiac resynchronization therapy (CRT) devices, Dr. Poole and her colleagues speculated. That could have shifted their late outcomes to be more in line with patients who had received ICDs when the trial started.

Or “it is possible that the intermediate-term benefit of ICD therapy in NICM is overwhelmed by nonarrhythmic death in extended follow-up” given that ICDs prolong survival only by preventing arrhythmic death, noted an editorial accompanying the new SCD-HeFT publication.

Another possibility: Because NICM is a heterogeneous disorder with many potential causes, perhaps “the absence of long-term mortality benefit among SCD-HeFT participants with NICM was due to an unintended but preferential enrollment of subtypes at relatively lower risk for arrhythmic death in the longer term,” proposed Eric C. Stecker, MD, MPH, Oregon Health & Science University, Portland, and coauthors in their editorial.

“What are the take-away messages from the current analysis by Poole et al?” they asked. “These findings strongly support the clinical efficacy and cost-effectiveness of ICD therapy for the majority of patients with severe but mildly symptomatic ischemic cardiomyopathy who do not have an excessive comorbidity burden.”

But “the implications for patients with NICM are less clear,” they wrote. “Given evidence for intermediate-term benefit and the limitations inherent to assessing longer-term benefit, we do not believe it is appropriate to walk back guideline recommendations regarding ICD implantation for NICM patients.”

The findings in nonischemic patients invite comparison with the randomized DANISH trial, which entered only patients with NICM and, over more than 5 years, saw no primary-prevention ICD advantage for the end point of all-cause mortality.

But patients who received ICDs showed a reduction in arrhythmic death, a secondary end point. And mortality in the trial showed a significant interaction with patient age; survival went up sharply with ICDs for those younger than 60 years.

Also in DANISH, “the ICD treatment effect appears to vary over time, with an earlier phase showing possible survival benefit and a later phase showing attenuation of that benefit,” similar to what was seen long-term in SCD-HeFT, in which the interaction between mortality and time since implantation was significant at P = .0015, observe Dr. Poole and colleagues.

However, Dr. Poole cautioned when interviewed, patient management in DANISH, conducted exclusively in Denmark, may not have been representative of the rest of the world, complicating comparisons with other studies. For example, nearly 60% of all patients in DANISH had defibrillating CRT devices. Virtually everyone was on ACE inhibitors or angiotensin-receptor blockers, and almost 60% were taking aldosterone inhibitors.

“DANISH is an unusually high bar and probably does not reflect all patients with heart failure, and certainly does not reflect patients in the United States in terms of those high levels of guideline-directed medical therapy,” Dr. Poole said. The message from DANISH, she said, seems to be that patients with NICM who are definitely on goal-directed heart failure medications with CRT devices “probably don’t have a meaningful benefit from an ICD, on total mortality, because their sudden death rates are simply so low.”

SCD-HeFT had originally assigned 2,521 patients with heart failure of NYHA class II or III and an left ventricular ejection fraction of less than 35% to receive an ICD, amiodarone without an ICD, or an amiodarone placebo and no ICD; patients in the latter cohorts made up the non-ICD control group.

Those who received an ICD, compared with the non-ICD control patients, showed a 23% drop in all-cause mortality over a median of 45.5 months ending on October 31, 2003, Dr. Poole and colleagues noted in their current report. The trial’s primary results were unveiled 2005.

The current analysis, based on data collected in 2010 and 2011, followed the 1,855 patients alive at the trial’s official conclusion and combined outcomes before and after that time for a median follow-up of 11 years, Dr. Poole and colleagues reported.

In the ICD group, the overall hazard ratio for mortality by intention-to-treat was 0.87 (95% confidence interval, 0.76-0.98; P = .028), compared with the non-ICD control group.

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

Patients with psoriatic disease are known to be at increased risk of heart failure. A new cohort study suggests that part of the risk may be attributable to the disease itself, not just traditional cardiovascular risk factors like obesity and metabolic abnormalities that are common comorbidities in psoriatic disease. There may also be differences in the risk profiles of patients with ischemic and nonischemic heart failure.

Courtesy Dr. Sahil Koppikar

Previous studies have shown that heart failure risk in patients with psoriatic arthritis is 32% higher than in the general population, and with psoriasis, it is 22%-53% higher. However, those studies were based on administrative databases with no clinical information to back up the accuracy of diagnoses, Sahil Koppikar, MD, from the University of Toronto, said during a presentation of the research at the virtual annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

The finding that psoriatic disease inflammation may be a direct risk factor for heart failure might be good news for patients. “By controlling inflammation, we may be able to reduce the risk of heart failure in these patients,” Dr. Koppikar said.

During a question and answer session, discussant Deepak Jadon, MBChB, PhD, director of the rheumatology research unit and lead for psoriatic arthritis at Addenbrooke’s Hospital, Cambridge (England), noted that patients with conditions like lupus and systemic sclerosis may undergo regular echocardiograms, chest CTs, or other surveillance, and asked if Dr. Koppikar could recommend a framework for similar surveillance in psoriatic arthritis.

“With the current data we have, I don’t know if we can make recommendations. What we learned from our study is that patients that have elevated inflammatory disease, with elevated inflammatory markers for a prolonged period of time, were at higher risk than [if they had elevated markers only] just before the event. So poorly controlled patients might be something you should be more aware of, and maybe get cardiology involved. But I don’t think it’s something we should be doing right now for all patients,” Dr. Koppikar said.

The researchers analyzed data from a psoriasis cohort at the University of Toronto that began in 2006. Every 6-12 months, they were assessed by a rheumatologist and underwent imaging assessment and laboratory tests. The primary outcome of the study was the first heart failure event, which the researchers identified by linking the cohort database with provincial hospitalization and mortality databases. They verified all events by examining medical records. They also assessed the association between heart failure and disease activity over time rather than just before the event.

The analysis included 1,994 patients. A total of 64 new heart failure events occurred during a mean follow-up of 11.3 years (2.85 per 1,000 person-years), including 38 ischemic and 26 nonischemic events. A multivariate analysis found that heart failure was associated with adjusted mean (AM) tender joint count (hazard ratio, 1.51; P = .02), AM swollen joint count (HR, 1.82; P = .04), AM erythrocyte sedimentation rate (HR, 1.26; P = .009), AM C-reactive protein (HR, 1.27; P = .001), Health Assessment Questionnaire (HR, 1.95; P = .001), and minimum disease activity state (HR, 0.40; P = .04). The multivariate analysis was adjusted for sex, hypertension, diabetes mellitus, body mass index, ischemic heart disease, lipids, and smoking status.

When the researchers separated the analysis into ischemic and nonischemic heart failure, some interesting associations popped out. Nonischemic heart failure was associated with AM tender joint count (HR, 1.83; P = .004), but ischemic heart failure was not. Other factors associated with nonischemic but not ischemic heart failure included AM swollen joint count (HR, 3.56; P = .0003), damaged joint count (HR, 1.29; P = .04), and pain score (HR, 1.22; P = .047). Minimum disease activity had the opposite result: It was associated with only ischemic heart failure (HR, 0.40; P = .04).

The study cohort more closely resembles a rheumatology cohort than a dermatology cohort, and it suggests that patients with psoriatic arthritis have different cardiovascular comorbidities than those with pure psoriasis, according to Diamant Thaçi, MD, PhD, professor and chairman of the department of dermatology at the University of Lübeck (Germany). “It shows how it important it is to look for comorbidity in the rheumatologic setting,” Dr. Thaçi said in an interview.

The study was supported by the Arthritis Society. Dr. Koppikar and Dr. Thaçi have no relevant financial disclosures.

SOURCE: Koppikar S et al. GRAPPA 2020 Virtual Annual Meeting.

Patients with psoriatic disease are known to be at increased risk of heart failure. A new cohort study suggests that part of the risk may be attributable to the disease itself, not just traditional cardiovascular risk factors like obesity and metabolic abnormalities that are common comorbidities in psoriatic disease. There may also be differences in the risk profiles of patients with ischemic and nonischemic heart failure.

Courtesy Dr. Sahil Koppikar

Previous studies have shown that heart failure risk in patients with psoriatic arthritis is 32% higher than in the general population, and with psoriasis, it is 22%-53% higher. However, those studies were based on administrative databases with no clinical information to back up the accuracy of diagnoses, Sahil Koppikar, MD, from the University of Toronto, said during a presentation of the research at the virtual annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

The finding that psoriatic disease inflammation may be a direct risk factor for heart failure might be good news for patients. “By controlling inflammation, we may be able to reduce the risk of heart failure in these patients,” Dr. Koppikar said.

During a question and answer session, discussant Deepak Jadon, MBChB, PhD, director of the rheumatology research unit and lead for psoriatic arthritis at Addenbrooke’s Hospital, Cambridge (England), noted that patients with conditions like lupus and systemic sclerosis may undergo regular echocardiograms, chest CTs, or other surveillance, and asked if Dr. Koppikar could recommend a framework for similar surveillance in psoriatic arthritis.

“With the current data we have, I don’t know if we can make recommendations. What we learned from our study is that patients that have elevated inflammatory disease, with elevated inflammatory markers for a prolonged period of time, were at higher risk than [if they had elevated markers only] just before the event. So poorly controlled patients might be something you should be more aware of, and maybe get cardiology involved. But I don’t think it’s something we should be doing right now for all patients,” Dr. Koppikar said.

The researchers analyzed data from a psoriasis cohort at the University of Toronto that began in 2006. Every 6-12 months, they were assessed by a rheumatologist and underwent imaging assessment and laboratory tests. The primary outcome of the study was the first heart failure event, which the researchers identified by linking the cohort database with provincial hospitalization and mortality databases. They verified all events by examining medical records. They also assessed the association between heart failure and disease activity over time rather than just before the event.

The analysis included 1,994 patients. A total of 64 new heart failure events occurred during a mean follow-up of 11.3 years (2.85 per 1,000 person-years), including 38 ischemic and 26 nonischemic events. A multivariate analysis found that heart failure was associated with adjusted mean (AM) tender joint count (hazard ratio, 1.51; P = .02), AM swollen joint count (HR, 1.82; P = .04), AM erythrocyte sedimentation rate (HR, 1.26; P = .009), AM C-reactive protein (HR, 1.27; P = .001), Health Assessment Questionnaire (HR, 1.95; P = .001), and minimum disease activity state (HR, 0.40; P = .04). The multivariate analysis was adjusted for sex, hypertension, diabetes mellitus, body mass index, ischemic heart disease, lipids, and smoking status.

When the researchers separated the analysis into ischemic and nonischemic heart failure, some interesting associations popped out. Nonischemic heart failure was associated with AM tender joint count (HR, 1.83; P = .004), but ischemic heart failure was not. Other factors associated with nonischemic but not ischemic heart failure included AM swollen joint count (HR, 3.56; P = .0003), damaged joint count (HR, 1.29; P = .04), and pain score (HR, 1.22; P = .047). Minimum disease activity had the opposite result: It was associated with only ischemic heart failure (HR, 0.40; P = .04).

The study cohort more closely resembles a rheumatology cohort than a dermatology cohort, and it suggests that patients with psoriatic arthritis have different cardiovascular comorbidities than those with pure psoriasis, according to Diamant Thaçi, MD, PhD, professor and chairman of the department of dermatology at the University of Lübeck (Germany). “It shows how it important it is to look for comorbidity in the rheumatologic setting,” Dr. Thaçi said in an interview.

The study was supported by the Arthritis Society. Dr. Koppikar and Dr. Thaçi have no relevant financial disclosures.

SOURCE: Koppikar S et al. GRAPPA 2020 Virtual Annual Meeting.

Patients with psoriatic disease are known to be at increased risk of heart failure. A new cohort study suggests that part of the risk may be attributable to the disease itself, not just traditional cardiovascular risk factors like obesity and metabolic abnormalities that are common comorbidities in psoriatic disease. There may also be differences in the risk profiles of patients with ischemic and nonischemic heart failure.

Courtesy Dr. Sahil Koppikar

Previous studies have shown that heart failure risk in patients with psoriatic arthritis is 32% higher than in the general population, and with psoriasis, it is 22%-53% higher. However, those studies were based on administrative databases with no clinical information to back up the accuracy of diagnoses, Sahil Koppikar, MD, from the University of Toronto, said during a presentation of the research at the virtual annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

The finding that psoriatic disease inflammation may be a direct risk factor for heart failure might be good news for patients. “By controlling inflammation, we may be able to reduce the risk of heart failure in these patients,” Dr. Koppikar said.

During a question and answer session, discussant Deepak Jadon, MBChB, PhD, director of the rheumatology research unit and lead for psoriatic arthritis at Addenbrooke’s Hospital, Cambridge (England), noted that patients with conditions like lupus and systemic sclerosis may undergo regular echocardiograms, chest CTs, or other surveillance, and asked if Dr. Koppikar could recommend a framework for similar surveillance in psoriatic arthritis.

“With the current data we have, I don’t know if we can make recommendations. What we learned from our study is that patients that have elevated inflammatory disease, with elevated inflammatory markers for a prolonged period of time, were at higher risk than [if they had elevated markers only] just before the event. So poorly controlled patients might be something you should be more aware of, and maybe get cardiology involved. But I don’t think it’s something we should be doing right now for all patients,” Dr. Koppikar said.

The researchers analyzed data from a psoriasis cohort at the University of Toronto that began in 2006. Every 6-12 months, they were assessed by a rheumatologist and underwent imaging assessment and laboratory tests. The primary outcome of the study was the first heart failure event, which the researchers identified by linking the cohort database with provincial hospitalization and mortality databases. They verified all events by examining medical records. They also assessed the association between heart failure and disease activity over time rather than just before the event.

The analysis included 1,994 patients. A total of 64 new heart failure events occurred during a mean follow-up of 11.3 years (2.85 per 1,000 person-years), including 38 ischemic and 26 nonischemic events. A multivariate analysis found that heart failure was associated with adjusted mean (AM) tender joint count (hazard ratio, 1.51; P = .02), AM swollen joint count (HR, 1.82; P = .04), AM erythrocyte sedimentation rate (HR, 1.26; P = .009), AM C-reactive protein (HR, 1.27; P = .001), Health Assessment Questionnaire (HR, 1.95; P = .001), and minimum disease activity state (HR, 0.40; P = .04). The multivariate analysis was adjusted for sex, hypertension, diabetes mellitus, body mass index, ischemic heart disease, lipids, and smoking status.

When the researchers separated the analysis into ischemic and nonischemic heart failure, some interesting associations popped out. Nonischemic heart failure was associated with AM tender joint count (HR, 1.83; P = .004), but ischemic heart failure was not. Other factors associated with nonischemic but not ischemic heart failure included AM swollen joint count (HR, 3.56; P = .0003), damaged joint count (HR, 1.29; P = .04), and pain score (HR, 1.22; P = .047). Minimum disease activity had the opposite result: It was associated with only ischemic heart failure (HR, 0.40; P = .04).

The study cohort more closely resembles a rheumatology cohort than a dermatology cohort, and it suggests that patients with psoriatic arthritis have different cardiovascular comorbidities than those with pure psoriasis, according to Diamant Thaçi, MD, PhD, professor and chairman of the department of dermatology at the University of Lübeck (Germany). “It shows how it important it is to look for comorbidity in the rheumatologic setting,” Dr. Thaçi said in an interview.

The study was supported by the Arthritis Society. Dr. Koppikar and Dr. Thaçi have no relevant financial disclosures.

SOURCE: Koppikar S et al. GRAPPA 2020 Virtual Annual Meeting.

Empagliflozin showed favorable effects on diuretic use and congestion symptoms in patients with heart failure with reduced ejection fraction (HFrEF), but the oral sodium glucose cotransporter 2 (SGLT2) inhibitor did not improve the primary endpoint of improved exercise capacity in the EMPERIAL-Reduced trial, investigators reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

In the matching EMPERIAL-Preserved trial, conducted in patients with heart failure with preserved ejection fraction (HFpEF), empagliflozin (Jardiance) produced modest improvements in diuretic use, as well as a reduction in unscheduled outpatient visits, compared with placebo-treated controls, although these trends failed to achieve statistical significance. And as in the EMPERIAL-Reduced trial, the SGLT2 inhibitor didn’t move the needle at all on the primary endpoint of improved exercise capacity as measured by 6-minute hall walk distance.

EMPERIAL-Reduced and -Preserved were identically designed, concurrent, phase 3, double-blind, 12-week randomized trials of empagliflozin versus placebo in 312 patients with HFrEF and 315 with HFpEF, defined in EMPERIAL-preserved as a left ventricular ejection fraction above 40%. The majority of participants had type 2 diabetes.

From a baseline median 6-minute walk distance of about 300 meters, the 6-minute walk distance at week 12 was actually 4.0 meters worse in the empagliflozin-treated HFrEF patients than it was in controls and a mere 4.0 meters better than with placebo in empagliflozin-treated patients with HFpEF, reported William T. Abraham, MD, professor of medicine, director of the division of cardiovascular medicine, and associate dean at Ohio State University, Columbus.

He indicated that the audience shouldn’t make too much of the failure to achieve the primary endpoint in the two trials in light of the studies’ major limitations: namely, their relatively small size for purposes of evaluating clinical outcomes and the relatively short 12-week duration.

“In many ways, I would say it’s remarkable that we can observe a positive signal, a favorable signal, in outcomes around congestion. In the case of HFrEF it’s statistically significant, and in HFpEF it’s a trend towards improvement. Of course, there are larger trials ongoing that may confirm these observations. Hopefully the EMPERIAL trials predict a good outcome for those ongoing trials,” Dr. Abraham said.

Piotr Ponikowski, MD, presented the study results for the secondary outcomes of congestion symptoms, diuretic use, and utilization of health care resources. In EMPERIAL-Reduced, intensification of diuretic therapy – often a prelude to acute decompensation and a trip to the hospital – occurred at a rate of 4.5% with empagliflozin and 16.1% with placebo, for a highly significant 73% relative risk reduction. Intensification of loop diuretics occurred in 2.6% of the empagliflozin group and 14.2% of controls, for a 82% risk reduction.

“That’s a pretty significant effect,” observed Dr. Ponikowski, professor of cardiology and head of the department of heart diseases at the Medical University of Wroclaw (Poland).

Moreover, a congestion symptoms score comprising a summary of orthopnea, jugular veinous distention, and edema improved by 47% after 12 weeks on empagliflozin, a statistically significant and clinically meaningful improvement that grew in magnitude over time and at 12 weeks was twice as large, compared with the reduction in placebo group, he added.

There was a trend for fewer unscheduled outpatient visits in the empagliflozin arm of EMPERIAL-Reduced with a rate of 10.4%, compared with 25.8% in controls; however, this 26% reduction in relative risk did not achieve statistical significance.

Intensification of loop diuretics occurred in 9% of EMPERIAL-Preserved participants on empagliflozin and 13.5% on placebo, but this 34% reduction in risk didn’t reach significance.

Adverse events in the EMPERIAL trials were similar across the active treatment and placebo arms. The benign safety profile was similar to what was seen in the earlier major clinical trials of empagliflozin for treatment of type 2 diabetes.

Session chair Stephane Heymans, MD, PhD, of the University of Maastricht (the Netherlands) noted that a substantial minority of patients in EMPERIAL-Reduced were on the combined neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan (Entresto), whereas far fewer were in EMPERIAL-Preserved. He wondered if this greater use of background sacubitril/valsartan could explain empagliflozin’s greater efficacy in EMPERIAL-Reduced.

Highly unlikely, according to the investigators.

“It looks like, as is the case with most of our heart failure therapies, that we do see incremental value here. If you met the criteria for these trials, it appears you derived benefit from empagliflozin regardless of whether you were on an angiotensin receptor neprilysin inhibitor or not. I think that speaks to the incremental benefit of SGLT2 inhibitors on top of current guideline-directed medical therapy,” Dr. Abraham said.

Dr. Ponikowski observed that the same point was underscored in the DAPA-HF trial of the SGLT2 inhibitor dapagliflozin (Farxiga) in patients with heart failure (DAPA-HF: N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

“You’ll see that the mortality and morbidity and quality-of-life benefit is in those treated with dapagliflozin with or without angiotensin receptor neprilysin inhibition; so, regardless of background therapy. And the effect is especially clear in patients on both therapies,” the cardiologist said.

The EMPERIAL trials were sponsored by Boehringer Ingelheim. Dr. Abraham and Dr. Ponikowksi reported receiving consultant fees from the company for serving on the trials’ executive committee.

bjancin@mdedge.com

Empagliflozin showed favorable effects on diuretic use and congestion symptoms in patients with heart failure with reduced ejection fraction (HFrEF), but the oral sodium glucose cotransporter 2 (SGLT2) inhibitor did not improve the primary endpoint of improved exercise capacity in the EMPERIAL-Reduced trial, investigators reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

In the matching EMPERIAL-Preserved trial, conducted in patients with heart failure with preserved ejection fraction (HFpEF), empagliflozin (Jardiance) produced modest improvements in diuretic use, as well as a reduction in unscheduled outpatient visits, compared with placebo-treated controls, although these trends failed to achieve statistical significance. And as in the EMPERIAL-Reduced trial, the SGLT2 inhibitor didn’t move the needle at all on the primary endpoint of improved exercise capacity as measured by 6-minute hall walk distance.

EMPERIAL-Reduced and -Preserved were identically designed, concurrent, phase 3, double-blind, 12-week randomized trials of empagliflozin versus placebo in 312 patients with HFrEF and 315 with HFpEF, defined in EMPERIAL-preserved as a left ventricular ejection fraction above 40%. The majority of participants had type 2 diabetes.

From a baseline median 6-minute walk distance of about 300 meters, the 6-minute walk distance at week 12 was actually 4.0 meters worse in the empagliflozin-treated HFrEF patients than it was in controls and a mere 4.0 meters better than with placebo in empagliflozin-treated patients with HFpEF, reported William T. Abraham, MD, professor of medicine, director of the division of cardiovascular medicine, and associate dean at Ohio State University, Columbus.

He indicated that the audience shouldn’t make too much of the failure to achieve the primary endpoint in the two trials in light of the studies’ major limitations: namely, their relatively small size for purposes of evaluating clinical outcomes and the relatively short 12-week duration.

“In many ways, I would say it’s remarkable that we can observe a positive signal, a favorable signal, in outcomes around congestion. In the case of HFrEF it’s statistically significant, and in HFpEF it’s a trend towards improvement. Of course, there are larger trials ongoing that may confirm these observations. Hopefully the EMPERIAL trials predict a good outcome for those ongoing trials,” Dr. Abraham said.

Piotr Ponikowski, MD, presented the study results for the secondary outcomes of congestion symptoms, diuretic use, and utilization of health care resources. In EMPERIAL-Reduced, intensification of diuretic therapy – often a prelude to acute decompensation and a trip to the hospital – occurred at a rate of 4.5% with empagliflozin and 16.1% with placebo, for a highly significant 73% relative risk reduction. Intensification of loop diuretics occurred in 2.6% of the empagliflozin group and 14.2% of controls, for a 82% risk reduction.

“That’s a pretty significant effect,” observed Dr. Ponikowski, professor of cardiology and head of the department of heart diseases at the Medical University of Wroclaw (Poland).

Moreover, a congestion symptoms score comprising a summary of orthopnea, jugular veinous distention, and edema improved by 47% after 12 weeks on empagliflozin, a statistically significant and clinically meaningful improvement that grew in magnitude over time and at 12 weeks was twice as large, compared with the reduction in placebo group, he added.

There was a trend for fewer unscheduled outpatient visits in the empagliflozin arm of EMPERIAL-Reduced with a rate of 10.4%, compared with 25.8% in controls; however, this 26% reduction in relative risk did not achieve statistical significance.

Intensification of loop diuretics occurred in 9% of EMPERIAL-Preserved participants on empagliflozin and 13.5% on placebo, but this 34% reduction in risk didn’t reach significance.

Adverse events in the EMPERIAL trials were similar across the active treatment and placebo arms. The benign safety profile was similar to what was seen in the earlier major clinical trials of empagliflozin for treatment of type 2 diabetes.

Session chair Stephane Heymans, MD, PhD, of the University of Maastricht (the Netherlands) noted that a substantial minority of patients in EMPERIAL-Reduced were on the combined neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan (Entresto), whereas far fewer were in EMPERIAL-Preserved. He wondered if this greater use of background sacubitril/valsartan could explain empagliflozin’s greater efficacy in EMPERIAL-Reduced.

Highly unlikely, according to the investigators.

“It looks like, as is the case with most of our heart failure therapies, that we do see incremental value here. If you met the criteria for these trials, it appears you derived benefit from empagliflozin regardless of whether you were on an angiotensin receptor neprilysin inhibitor or not. I think that speaks to the incremental benefit of SGLT2 inhibitors on top of current guideline-directed medical therapy,” Dr. Abraham said.

Dr. Ponikowski observed that the same point was underscored in the DAPA-HF trial of the SGLT2 inhibitor dapagliflozin (Farxiga) in patients with heart failure (DAPA-HF: N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

“You’ll see that the mortality and morbidity and quality-of-life benefit is in those treated with dapagliflozin with or without angiotensin receptor neprilysin inhibition; so, regardless of background therapy. And the effect is especially clear in patients on both therapies,” the cardiologist said.

The EMPERIAL trials were sponsored by Boehringer Ingelheim. Dr. Abraham and Dr. Ponikowksi reported receiving consultant fees from the company for serving on the trials’ executive committee.

bjancin@mdedge.com

Empagliflozin showed favorable effects on diuretic use and congestion symptoms in patients with heart failure with reduced ejection fraction (HFrEF), but the oral sodium glucose cotransporter 2 (SGLT2) inhibitor did not improve the primary endpoint of improved exercise capacity in the EMPERIAL-Reduced trial, investigators reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

In the matching EMPERIAL-Preserved trial, conducted in patients with heart failure with preserved ejection fraction (HFpEF), empagliflozin (Jardiance) produced modest improvements in diuretic use, as well as a reduction in unscheduled outpatient visits, compared with placebo-treated controls, although these trends failed to achieve statistical significance. And as in the EMPERIAL-Reduced trial, the SGLT2 inhibitor didn’t move the needle at all on the primary endpoint of improved exercise capacity as measured by 6-minute hall walk distance.

EMPERIAL-Reduced and -Preserved were identically designed, concurrent, phase 3, double-blind, 12-week randomized trials of empagliflozin versus placebo in 312 patients with HFrEF and 315 with HFpEF, defined in EMPERIAL-preserved as a left ventricular ejection fraction above 40%. The majority of participants had type 2 diabetes.

From a baseline median 6-minute walk distance of about 300 meters, the 6-minute walk distance at week 12 was actually 4.0 meters worse in the empagliflozin-treated HFrEF patients than it was in controls and a mere 4.0 meters better than with placebo in empagliflozin-treated patients with HFpEF, reported William T. Abraham, MD, professor of medicine, director of the division of cardiovascular medicine, and associate dean at Ohio State University, Columbus.

He indicated that the audience shouldn’t make too much of the failure to achieve the primary endpoint in the two trials in light of the studies’ major limitations: namely, their relatively small size for purposes of evaluating clinical outcomes and the relatively short 12-week duration.

“In many ways, I would say it’s remarkable that we can observe a positive signal, a favorable signal, in outcomes around congestion. In the case of HFrEF it’s statistically significant, and in HFpEF it’s a trend towards improvement. Of course, there are larger trials ongoing that may confirm these observations. Hopefully the EMPERIAL trials predict a good outcome for those ongoing trials,” Dr. Abraham said.

Piotr Ponikowski, MD, presented the study results for the secondary outcomes of congestion symptoms, diuretic use, and utilization of health care resources. In EMPERIAL-Reduced, intensification of diuretic therapy – often a prelude to acute decompensation and a trip to the hospital – occurred at a rate of 4.5% with empagliflozin and 16.1% with placebo, for a highly significant 73% relative risk reduction. Intensification of loop diuretics occurred in 2.6% of the empagliflozin group and 14.2% of controls, for a 82% risk reduction.

“That’s a pretty significant effect,” observed Dr. Ponikowski, professor of cardiology and head of the department of heart diseases at the Medical University of Wroclaw (Poland).

Moreover, a congestion symptoms score comprising a summary of orthopnea, jugular veinous distention, and edema improved by 47% after 12 weeks on empagliflozin, a statistically significant and clinically meaningful improvement that grew in magnitude over time and at 12 weeks was twice as large, compared with the reduction in placebo group, he added.

There was a trend for fewer unscheduled outpatient visits in the empagliflozin arm of EMPERIAL-Reduced with a rate of 10.4%, compared with 25.8% in controls; however, this 26% reduction in relative risk did not achieve statistical significance.

Intensification of loop diuretics occurred in 9% of EMPERIAL-Preserved participants on empagliflozin and 13.5% on placebo, but this 34% reduction in risk didn’t reach significance.

Adverse events in the EMPERIAL trials were similar across the active treatment and placebo arms. The benign safety profile was similar to what was seen in the earlier major clinical trials of empagliflozin for treatment of type 2 diabetes.

Session chair Stephane Heymans, MD, PhD, of the University of Maastricht (the Netherlands) noted that a substantial minority of patients in EMPERIAL-Reduced were on the combined neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan (Entresto), whereas far fewer were in EMPERIAL-Preserved. He wondered if this greater use of background sacubitril/valsartan could explain empagliflozin’s greater efficacy in EMPERIAL-Reduced.

Highly unlikely, according to the investigators.

“It looks like, as is the case with most of our heart failure therapies, that we do see incremental value here. If you met the criteria for these trials, it appears you derived benefit from empagliflozin regardless of whether you were on an angiotensin receptor neprilysin inhibitor or not. I think that speaks to the incremental benefit of SGLT2 inhibitors on top of current guideline-directed medical therapy,” Dr. Abraham said.

Dr. Ponikowski observed that the same point was underscored in the DAPA-HF trial of the SGLT2 inhibitor dapagliflozin (Farxiga) in patients with heart failure (DAPA-HF: N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

“You’ll see that the mortality and morbidity and quality-of-life benefit is in those treated with dapagliflozin with or without angiotensin receptor neprilysin inhibition; so, regardless of background therapy. And the effect is especially clear in patients on both therapies,” the cardiologist said.

The EMPERIAL trials were sponsored by Boehringer Ingelheim. Dr. Abraham and Dr. Ponikowksi reported receiving consultant fees from the company for serving on the trials’ executive committee.

bjancin@mdedge.com