The American College of Cardiology's 70th Annual Scientific Session & Expo will be held virtually May 15-17, 2021. ACC.21 will provide practice-changing research and cutting-edge education.

Coverage of the American College of Cardiology Conference Is Coming

ATS 2021 will be held virtually May 14-19, 2021. The meeting will include latest advances and discoveries in respiratory science, patient care and global respiratory health.

Coverage of the American Thoracic Society Conference Is Coming

Virtual ISPOR 2021 will be held May 17-20. This year's meeting, themed "HEOR: Evolving for Tomorrow’s Challenges," will analyze opportunities and challenges in health economics and outcomes research methods, practices, and application.

Coverage of the Virtual ISPOR 2021 Meeting Is Coming

If 2020 was dominated by the news of how COVID-19 spread across the globe, then 2021 has so far been focused on ending the pandemic through vaccine distribution.

A Timeline of COVID-19 Vaccine Developments in 2021

We interview experts on investigational treatments such as liso-cel, and ask how to bring them to community practice.

Spotlight on CAR T-Cell Therapy

The American Journal of Accountable Care® features research and commentary on new payment models.

New Members for AJAC Board

One of the things that drew me to the field of pediatric pulmonology is the fact that children are so vulnerable, said Stephanie Lovinsky-Desir, MD, MS, a pediatric pulmonologist at Columbia University Medical Center and incoming director of that program. Lovinsky-Desir's talk was presented at this year's 

American Thoracic Society's (ATS) annual conference.

Can you give an overview of your talk "Addressing Structural and Social Determinants of Health" at this year's ATS meeting?

I think that what my talk will focus a bit on are some of these societal, environmental, and structural factors that contribute to respiratory diseases in our population. I think that there's been an awakening in the last year, although many of us investigators have known about this for a period of time, a lot of factors in the social environment that influence the health of people. What opportunities [do they have]? Where do people live? Where do people have opportunities to work? Where do children have opportunities to play? All of these factors can play a role in their overall health, particularly respiratory health.

What challenges are unique to pediatric pulmonology patients when it comes to social and structural determinants of health?

I think one of the things that drew me to the field of pediatric pulmonology is the fact that children are so vulnerable. They can't choose where they live, they can't choose where they go to school, they can't choose where they have opportunities for play. It's these specific factors that they have no control over, but that influence their health, that make them so vulnerable. I feel like it's my duty as a clinician, but also as somebody who wants to have a broader reach, to really think about how do we influence public health in a way [so] that these children, obviously, don't have to think about these things, and their parents shouldn't have to think about these things, and that every child should be able to live a healthy, happy life.

What are some of the main areas in respiratory health affected by SDOH? Is it clinical trial recruitment, treatment access, disease management, or is it across the board?

I absolutely think it's across the board. There are multiple factors that influence health overall, and social determinants play a role in each one of those factors. We actually have a manuscript that was recently accepted for publication where we talk about some of the strategies for improving recruitment and retention of underrepresented minorities in clinical trials and research studies, because we know that if new interventions come on the market or become available, if they're not studied in all different populations, they may have differential effects on different people or different groups.

Another study that I'll be highlighting in my talk, during this conference, focuses on hospitals and the resources that certain hospitals have compared to others. How resourced the hospital is has a direct influence on the outcomes of the patients who go to those hospitals. Underrepresented minorities may be more likely to go to underresourced hospitals, and that might be the reason why there's poor outcomes and poor health. I think there are a multitude of factors that need to be addressed. This is something that needs to be looked at, on multiple different levels at multiple different angles.

Videos

Stephanie Lovinsky-Desir, MD, MS, discusses the importance of addressing social determinants of health (SDOH) to improve outcomes in pediatric respiratory health. 

Dr Stephanie Lovinsky-Desir Highlights the Impact of SDOH on Respiratory Health

Two leading cardiologists were divided Sunday during the 70th American College of Cardiology (ACC) Scientific Session on how to explain conflicting—and controversial—results from trials involving different formulations of omega-3 fatty acids.

In November 2018, Harvard’s Deepak L. Bhatt, MD, MPH, stunned the cardiology community 

 that showed a purified form of icosapent ethyl (EPA) had reduced cardiac events or death by 25%. The fish oil capsules, which had been sold for several years as Vascepa to treat high triglycerides, later received 

 as an add-on to statins to prevent cardiovascular events. (First quarter revenues 

 for Amarin, based on Vascepa sales, were $141.4 million.)

But Vascepa has been dogged by questions that the landmark trial, called REDUCE-IT, used a placebo of mineral oil that might have interfered with statin absorption and skewed results.

Those questions flared anew last fall during the American Heart Association meeting, when Cleveland Clinic investigators represented findings from STRENGTH. That trial studied omega-3 carboxylic acid, a drug that contains both EPA and docosahexaenoic acid (DHA); the second omega-3 benefits the brain and for eyesight but can elevate low-density lipoprotein (LDL) cholesterol. More than a year ago, AstraZeneca pulled the plug on STRENGTH, after the Cleveland Clinic team found the drug had no effect on cardiovascular outcomes.


But that wasn’t all. STRENGTH used a corn oil placebo, which investigators called a “neutral comparator,” and the 

 presenting the results openly challenged the REDUCE-IT findings.

The debate continued Sunday at ACC, when Steven Nissen, MD, Cleveland Clinic’s chair of Cardiovascular Medicine, presented more results from STRENGTH during a late-breaking session that cast doubt on REDUCE-IT’s findings and ended with a call for head-to-head studies to settle the matter. Bhatt, who was taken by surprise with the November paper, served as a discussant for today’s results, which appeared in a 

“Additional research is needed, with trials designed to compare corn oil with mineral oil, and to compare purified EPA with other formulations of omega-3 fatty acids,” Nissen said.

In the post-hoc analysis, the STRENGTH researchers examined a subset of 10,382 patients enrolled in the study, of whom 5175 received omega-3 carboxylic acid and 5207 received the corn oil placebo. As with the original findings, there was no real difference in events: 11.1% among those treated with the fish oil capsule and 11% among patients on placebo. Researchers divided the group into tertiles based on EPA and DHA levels in the blood. They found:

The median plasma EPA level for patients taking fish oil was 89 (46-131) μg/mL, and 91 (71-114) μg/mL for DHA.

The top tertile levels were 151 (132-181) for EPA and 118 (102-143) for DHA (in μg/mL).

If EPA had a protective effect, and DHA a harmful one, researchers said they would have expected to see a difference in the event rates for patients with high EPA levels compared with those taking corn oil after a year, as patients’ EPA levels increased. 

But this is not what they found. Instead, after a year, the event rates for those with the highest EPA levels were comparable to those taking corn oil: 11.3% for EPA and 11% for corn oil—in line with the overall findings. 

Similarly, the event rate for patients with the top tertile of DHA levels, the event rate was 11.4%. When the investigators looked at relationship between changing EPA or DHA levels over time, they found no effect on cardiovascular outcomes. 

They did find that over time, there was an effect on atrial fibrillation—small in absolute numbers, but a 69% increase.

In his remarks after the Nissen’s presentation, Bhatt said that the absence of relationship in a negative trial “doesn’t tell us that much other than these specific drugs studied didn’t work.” 

He asked Nissen about the fact that the patients in the different tertiles had different levels of high-intensity statin use.

“If you measure enough characteristics, you’re going to see some characteristics that are a little bit different,” Nissen replied. “I don’t think that’s enough of a difference in high intensity statin use to explain the results that we saw.”

During a press conference after the session, Nissen said the uncertainty demands more research to settle the matter. “We’ve got all these trials that are neutral, and a single trial, not replicated, that shows a benefit,” he said.

Given how long Vascepa has been on the market, could claims studies offer any guidance? The answer, Nissen said in an email to 

“I don’t think observational data can answer these difficult questions,” he said. “We will need additional [randomized controlled trials] to determine whether this drug is effective at reducing cardiovascular events. Such trials must use a neutral comparator such as corn oil.”

Nissen was blunt. “Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in anyway,” Nissen said 

. “It’s a sad story for cardiology.”

Nissen SE, Lincoff AM, Wolski K, et al. Association between achieved ω-3 fatty acid levels and major adverse cardiovascular outcomes in patients with high cardiovascular risk a secondary analysis of the STRENGTH trial. 

. Published online May 16, 2021. doi:10.1001/jamacardio.2021.1157

Articles

Two top cardiologists debated evidence involving one clinical trial for omega-3 fatty acids, with implications for another, the REDUCE-IT study for icosapent ethyl (Vascepa).

With No End in Sight on Omega-3 Debate, Nissen Calls for More Trials

 since 2019 and has a BA in philosophy and journalism & professional writing from The College of New Jersey. 

American Thoracic Society (ATS) virtual conference

 focused on the feasibility and potential for precision medicine in pediatric 

 diseases, emphasizing progress made via genome-wide association studies (GWAS). However, several barriers remain when it comes to cost and early screening initiatives.

For childhood asthma in particular, Anke H Maitland-van der Zee, PharmD, PhD, a professor of precision medicine at the Academic Medical Center in Amsterdam, the Netherlands, outlined recent research attempting to identify adolescents who would most benefit from either personalized care (genotype-directed prescribing) vs standard care. In the study discussed, all participants were between ages 12 and 18.

Patients that were genotyped received montelukast while those undergoing standard care received a long-acting beta agonist (LABA). Analyses showed patients who received individualized care had a better quality of life, which was a score of 0.16 on the pediatric quality of life questionnaire. “It has to be emphasized that the clinical threshold was 0.25, so it's lower than that, but after 12 months [genotyped patients] seem to be a little bit better off,” Maitland-van der Zee said.

In patients carrying homozygous variants, this effect was more pronounced, marking a sign “it’s probably useful to determine this treatment according to [patients’] genotype,” she noted. A similar trial that will include children ages 6 to 18 aims to provide a clearer answer to this question and is slated to take place in the coming years.

In addition to GWAS, another route for potential precision medicine in this population could involve using exhaled breath to assess volatile organic compounds in patients’ lungs. One study on this subject showed “that if you use a cluster approach, it is possible to identify 5 different clusters of pediatric asthma patients by looking at their exhaled breath.”

Comparing the clinical characteristics of these patients revealed differences in age group, amount of asthma control, and quality of life. “Exhaled breath tells you something about the inflammatory phenotype or the asthma phenotype in patients,” Maitland-van der Zee explained.

Similarly, researchers in the United Kingdom, by looking at exhaled breath, were able to develop a sensor technology to identify patients that were or were not negative for a skin prick test—a 

 that checks for immediate allergic reactions to different substances. These results again illustrated the use of exhaled breath to help phenotype patients.

According to Maitland-van der Zee, future priorities in this area include better phenotyping of patients—potentially by combining biomarkers—identifying treatable traits and non-invasive biomarkers, and facilitating early detection. New developments in e-health may also help providers measure these factors remotely.

Following talks on the promise of precision medicine in this field, Ann Chen Wu, MD, MOH, an associate professor in the department of population medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute, laid out some of the cost effectiveness and ethical issues linked to 

. Chen is also the director of the Center for Healthcare Research in Pediatrics and Precision Medicine Translational Research Center at Harvard Medical School.

A joint statement issued by ATS and the National Heart, Lung, and Blood Institute several years ago concluded “precision medicine had more value in lung diseases because of the introduction of biologics,” Chen explained. Currently, 

 are directed towards 10% to 15% of patients with severe, persistent asthma among those with asthma.

However, biologics can cost between $30,000 and $40,000 per patient and have to be administered in a hospital setting. But the use of precision medicine in this field “could help allocate use of biologics to those who need it and would benefit from it the most,” Chen said.

Although precision medicine holds potential, a lack of data on minority populations with respiratory diseases precludes ensuring it is generalizable to diverse real-life populations. “Addressing questions about the impact of genetic factors on therapeutic drug response in globally diverse populations is essential for making precision medicine socially and scientifically precise,” she said.

In addition, no studies currently exist that focus exclusively on cost effectiveness of precision medicine for lung diseases. Using a general example of genomic sequencing in newborns, Chen detailed the unintended positive and negative consequences of genomic testing, including:

Diagnoses in children could lead to family member diagnoses

Earlier medical diagnoses and treatment could lead to better outcomes

Whole genome sequencing could lead to increased health-care expenditures without substantial clinical benefits, as inconclusive results may lead to additional testing and a “

Notably, “systematic reviews of psychological outcomes of single gene and multi-gene testing suggests that the test disclosure does not cause depression or anxiety, as some people have worried,” she said.

Given all the potential benefits and costs, better assessments of the value of genomic sequencing for newborns are warranted. But this will require a very large sample size, a long time horizon, and will be expensive.

As observational data and computational modeling approaches provide an alternative to such studies, Chen and other researchers developed a model to estimate the cost effectiveness of integrating various genomic sequencing strategies into clinical care.

One version of the model focused on pediatric cancer and included a panel of 11 genes. It showed that “among children with the cancer risk variant found on newborn screening, subsequent surveillance and care would reduce cancer deaths before age 20 by half, as compared with no screening or usual care.”

Chen continued “we calculated that universal screening would cost $244,000 per life year gained at a cost of $55 per test. We concluded that population-based genetic testing of newborns can reduce mortality associated with pediatric cancers and could potentially be cost effective as sequencing costs decline.”

If cost effectiveness is determined for lung diseases, policy makers and insurers can decide whether to cover the cost of the test, while as new findings of genetic variants or genes are found, their interpretation can change. “For example, one variant that was thought to be associated with a disease could have a new benign interpretation,” Chen said. This scenario poses another challenge as it is still unknown, ethnically, how much time should be allocated to communicate updated information to patients or whose job it is to inform patients of these changes in interpretation.

“Precision medicine for pediatric lung disease has great potential, but we have a long way to go,” Chen concluded. “Assessing cost effectiveness, generalizability to diverse populations, and the ethical considerations will increase likelihood of translation to clinical practice.”

Genome-wide association studies are building the potential for precision medicine for children with respiratory diseases, but the progress also comes with challenges related to cost and issues with early screening, according to speakers at the ATS 2021 International Conference.

A Look at the Potential of Precision Medicine for Pediatric Respiratory Diseases

Anthony Fauci, MD, highlighted this weekend that the real-world evidence of vaccines against SARS-CoV-2, the virus that causes COVID-19, is even better than expected.

The head of the National Institute of Allergy and Infectious Diseases and chief medical advisor to President Joe Biden also reiterated the administration’s goal of having 70% of US adults inoculated with at least 1 dose of a COVID-19 vaccine by July 4.

During a prerecorded speech to kick off the 

, Fauci recapped what researchers and clinicians have learned about the disease since it first appeared in China at the end of 2019 and early 2020, and the challenges that remain to defeat the virus.

He called it “the most devastating pandemic of a respiratory illness in the last 102 years.”

Estimates of illness and death—both globally and in the United States—are likely undercounted, he repeatedly emphasized. Worldwide, about 160 million have been infected and 3.3 million have died; US deaths are close to 580,000 and infections have surpassed 30 million.

The United States has yet to get its baseline count of infection down to a low level, as each of the 3 deadly surges over the past year left the country worse off than before. Currently, the number of daily infections has dropped to about 40,000 a day down from 60,000 a few weeks ago.

He contrasted that with Israel, which implemented a very robust vaccination program and now has few infections.

, Fauci pointed out that the scientific research that gave rise to the 3 approved vaccines in the United States began decades ago. The belief that somehow the vaccine technology is new or unproven is just one of many factors contributing to 

Clinical US trials of the Pfizer/BioNTech and Moderna vaccines showed 95% and 94.1% efficacy, he said. The Johnson & Johnson vaccine, which was tested in the United States, Brazil, and South Africa, had 66% efficacy overall and 85% efficacy against severe disease.

"Now, usually, as many of you know, the effectiveness in the real world is often not as good as the efficacy in the pristine conditions of a clinical trial," Fauci said. "We have found just the opposite with COVID-19 vaccines, where effectiveness is easily as good, if not better, in the real world setting."

He cited a study of more than 23,000 employees of the University of Texas Southwestern Medical Center in Dallas, where vaccinations began December 15, 2020. There was just a 0.05% infection rate among workers who were fully immunized, he said.

Another study looked at the efficacy of vaccines in 8 US locations of close to 4000 essential and frontline health care workers. There were just 3 polymerase chain reaction (PCR)-confirmed infections during 78,902 person-days with full immunization (0.04/1000 person-days).

Fauci also referenced a study published in 

 earlier this month looking at the impact of the Pfizer/BioNTech vaccine on infections, hospitalizations, and deaths in Israel after a nationwide vaccination campaign began on December 20, 2020. The study used national surveillance data from the first 4 months of the campaign.

The campaign began around the time of a surge in SARS-CoV-2 infections in Israel that resulted in a nationwide lockdown on December 27. Additional lockdowns were implemented on January 8, 2021. The country began a phased reopening on February 7 and February 21, 2021, and the lockdown was lifted on March 7.

The number of infections plummeted as vaccinations became widespread, and the authors of the study attributed the decline to the campaign, rather than the lockdown. Indeed, Fauci noted that the number of cases kept falling even as the country reopened. 

The variant in Israel, B.1.1.7, is now the dominant variant here, he said. The efficacy of the vaccine stretches across age groups and is 97.5% effective at preventing severe or critical illness and 96.7% effective at preventing COVID-19 deaths.

Fauci also used the example of Qatar, where the vaccine was 100% effective at preventing death from the South African B.1.351 variant, according to another study.

This all boils down to a "race" between the virus and the vaccines, Fauci said. 

"If we vaccinate the overwhelming proportion of our population, we will without a doubt be able to crush the outbreak in the same way as we have done with other viral-borne diseases like measles, smallpox, and polio. So the message is, get vaccinated."

Anthony Fauci, MD, told attendees at the ATS 2021 International Conference that the real-world evidence of vaccines against SARS-CoV-2, the virus that causes COVID-19, is even better than expected.









Efficacy of COVID-19 Vaccines in Real-World Settings Even Better Than Expected, Fauci Says

Heart failure is clearly syndromic, with several phenotypes—cardiopulmonary, cardiorenal, cardiometabolic—so it will remain challenging to reconcile patient to therapy until we can begin to study these unique phenotypes and a priori identify them, stated Clyde W. Yancy, MD, MSc, professor of medicine, chief of cardiology, and vice dean for diversity and inclusion at Northwestern University’s Feinberg School of Medicine.

Yancy presented “Evolving Understanding & Therapeutic Role of SGLT2i and ARNI in 3 Heart Failure Phenotypes: HFrEF, HFiEF & HFpEF” on day 1 of 

Why have treatments for heart failure with preserved ejection fraction been so elusive?

Because as you begin to think about the most important new therapies for heart failure—the ARNI [angiotensin receptor neprilysin inhibitor] compound and the SGLT2 [sodium-glucose cotransporter-2] inhibitor—we can exercise the opportunity to position these new drugs in which of those 3 phenotypes where there might be evidence of benefit.

Let's start with the ARNI compound. We know for certain, let me emphasize for certain, the ARNI compound is appropriate for reduced ejection fraction heart failure. Well, we also have a very intriguing piece of data and a very important prespecified secondary analysis from PARAGON-HF. The investigators brought forth very important information.

For those patients with symptomatic heart failure with an ejection fraction less than 57%, there was clear evidence of the benefit from the ARNI compound. Now, this was not a prospectively powered subgroup. It was a prespecified analysis, so it is at least suggestive of benefit and gives us kind of a fill-in-the-blank for that intermediate-range ejection fraction.

Now to extend the response as to why we’ve had difficulty finding agents for heart failure with preserved ejection fraction—understanding that we cannot yet place the ARNI compound in that space because the clinical trial was neutral—the reason we've had difficulties is that we know that heart failure with preserved ejection fraction is not one disease, it’s not one syndrome, because heart failure clearly is syndromic. It’s probably several different phenotypes. One is cardiopulmonary, one is cardiorenal, one that we typically see often in the office is cardiometabolic. And so until we can begin to study the unique phenotypes and have a way of a priori identifying the phenotypes, it will continue to be a challenge to reconcile how best patients will respond to individual therapies.

So we're still on the elusive search for that agent that is, without question, effective in all-comers with heart failure with preserved ejection fraction. Previously, I would have said I didn't think was possible. But given the traction we've seen what the sodium-glucose cotransporter-2 inhibitors and knowing that a trial is ongoing, looking at the use of the SGLT2 inhibitor in heart failure with preserved ejection fraction, it might happen. And importantly, the answer to that question using empagliflozin will be available later in calendar year 2021. That could be a breakthrough if that’s positive.

Heart failure is clearly syndromic, with several phenotypes, so it will remain challenging to reconcile patient to therapy until these unique phenotypes can be studied, stated Clyde W. Yancy, MD, MSc, of Northwestern University’s Feinberg School of Medicine.

Dr Clyde Yancy: Heart Failure With Preserved Ejection Fraction Is Not One Disease 

Previous trials of sodium glucose co-transporter 2inhibitors have shown dapagliflozin’s protective effects in the chronic care setting. We looked at its benefits in the acute illness setting, specifically organ protection, noted Mikhail N. Kosiborod, MD,cardiologist, vice president of Research at Saint Luke's Health System, director of Cardiometabolic Research and co-director of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence at Saint Luke's Mid America Heart Institute, and professor of medicine at the University of Missouri-Kansas City.

Kosiborod’s session, “Effects of Dapagliflozin on Prevention of Major Clinical Events and Recovery in Patients With Respiratory Failure Due to COVID-19 - Main Results From the DARE-19 Randomized Trial,” was presented on day 2 of ACC.21.

Can you discuss the purpose of the DARE-19 trial and the main outcomes?

 is a trial that's evaluating dapagliflozin as a potential treatment for patients hospitalized with COVID-19 who have cardiometabolic risk factors. We realized very early in the course of the pandemic that patients that have cardiometabolic comorbidities—like type 2 diabetes, for example; heart failure, atherosclerotic cardiovascular disease; chronic kidney disease—are also the patients that have the highest risk of developing complications, or even dying, from COVID-19 in case they're infected.

We knew once the pandemic started about a year ago that if you are admitted to a hospital, if you are sick enough to be in the hospital with COVID-19 and you have one of these risk factors, your outcomes tend to be much worse than if you don't have to be hospitalized or even if you're hospitalized but don't have those risk factors. We also knew from previous trials of SGLT2 [sodium glucose co-transporter 2] inhibitors, including dapagliflozin, that these medications can provide organ protection in other chronic care settings and chronic conditions, like heart failure and diabetes, atherosclerotic cardiovascular disease, and chronic kidney disease.

And we realized also during the early part of the pandemic that COVID-19 is not just a respiratory illness, but it's actually an illness that is systemic—it affects multiple organ systems, including the heart and kidneys—so because of the cardio and natural protection we observed with SGLT2 inhibitors in previous clinical trials under more chronic stable conditions, we hypothesized that it may actually provide organ protection also in the setting of acute illness, like COVID-19. It's a lot of mechanistic data also suggesting that some of the key pathophysiologic processes that are dysregulated in the setting of COVID-19 are also the same processes that SGLT2 inhibitors might have a favorable impact on.

So that ultimately led us to propose that dapagliflozin, which is an SGLT2 inhibitor, may provide organ protection and prevent the risk of organ failure or death, or improve time to clinical recovery, in patients that have those cardiometabolic conditions and are hospitalized with COVID-19.

What are the risks and benefits of dapagliflozin in COVID-19 long-haulers?

The DARE-19 trial evaluated dapagliflozin over a treatment period of 30 days. Now, we did build in an additional 60-day observational period after discontinuation of study medication at 30 days, so the total duration was actually 90 days. But the data that have we presented to the American College of Cardiology is the prespecified primary analysis for both efficacy and safety, which is the data during the 30-day treatment period. We do not yet have data available for this observational, additional 60-day follow-up after discontinuation of study medication. Those data will be available at a later time point.

With that acknowledged, I think it's difficult to say whether SGLT2 inhibitors at this point in time would have an effect on longer-term symptoms of COVID-19. It's certainly possible that if you have an agent that's efficacious in preventing acute complications, that may have a longer-term effect. While we had numerically fewer events of organ failure or death in the dapagliflozin group as compared to the placebo group, this did not reach statistical significance. It's a more of a hypothesis-generating trial in such regards, rather than hypothesis-proving trial, so I don't think we're going to get definitive answers on the potential role of SGLT2 inhibitors on long-term COVID effects after the acute phase of the illness has resolved, unless we do dedicated studies to specifically address that question.

The study looked at dapagliflozin's benefits in the acute illness setting, specifically organ protection, according to Mikhail N. Kosiborod, MD, vice president of Research at Saint Luke's Health System.

Dr Mikhail N. Kosiborod Discusses DARE-19 Trial Findings on Dapagliflozin 

Dapagliflozin, the sodium-glucose cotransporter 2 (SGLT2) inhibitor with indications in type 2 diabetes (T2D), heart failure, and most recently chronic kidney disease (CKD), did not significantly reduce the risk of death or organ failure or hasten recovery in patients who were hospitalized with COVID-19 during the early months of the pandemic, according to results presented today during the 

But since the study, called DARE-19, enrolled only 1250 patients, it’s too soon to declare this experiment over. Today's presentation covered the first 30 days after patients began taking dapagliflozin, and the numbers favored the SGLT2 inhibitor over placebo. Lead investigator Mikhail N. Kosiborod, MD, of Saint Luke’s MidAmerica Heart Institute, said that his team is still waiting to see how things look for patients after 90 days.

A study that misses its mark would not typically generate this much interest, especially after trial sponsor 

 last month that results fell short of statistical significance. But with SGTL2 inhibitors gaining indications in heart failure and CKD, along with their original T2D approvals—conditions that put patients in danger when they get COVID-19—many suspect this weekend’s results will not be the last word.

Since Kosiborod is one of the world’s leading experts on SGLT2 inhibitors, it’s likely the curiosity will continue as the 90-day data mature. For one primary end point, 11.2% of patients treated with dapagliflozin experienced organ failure or death after 30 days (70 events) compared with 13.8% of those treated with placebo (86 events); the HR was 0.80 (95% CI, 0.58-1.10, 

 = .168). Among patients in the dapagliflozin group, 6.6% died compared with 8.6% in the placebo group. 

Of great importance, the study showed that dapagliflozin is safe for patients who have COVID-19 and should not be discontinued, something that was hotly debated when the pandemic began.

“Our findings show that dapagliflozin is well tolerated in patients hospitalized with COVID-19, with no new safety issues being observed,” Kosiborod said. “This should have implications for clinical practice given that our results do not support discontinuation of SGLT2 inhibitors in this setting, as long as patients are monitored.”

The DARE-19 trial is the first phase 3 study to examine whether this SGLT2 inhibitor, which has proven effective for multiple chronic conditions, might be similarly useful in an acute setting.

“We realized very early in the course of the pandemic, that patients that have cardiometabolic comorbidities like type 2 diabetes, for example, heart failure, respiratory cardiovascular disease, chronic kidney disease, are also the patients that are the highest risk of developing complications, or even dying from COVID-19 [if] they're infected,” Kosiborod said in an interview with 

®. “And we knew once the pandemic started about a year ago that if you are admitted to a hospital, if you are sick enough to be in the hospital with COVID-19 and you have one of these risk factors, your outcomes tend to be much worse than if you don't have to be hospitalize—or even if you're hospitalized, but don't have those risk factors.”

Drawing on knowledge gained from earlier trials involving SGLT2 inhibitors, Kosiborod explained, “There are mechanistic data that suggest that some of the key pathophysiologic processes that are dysregulated in the setting of COVID-19 are also the same processes that SGLT2 inhibitors might have a favorable impact on.”

“Our study opens the door to asking additional questions,” he said. “The idea for DARE-19 was quite unorthodox when we started—everyone was concentrating on antivirals and anti-inflammatory drugs—so it is fascinating to hypothesize that SGLT2 inhibitors may provide organ protection in acute illness. This should inform future clinical science and hopefully lead to further investigations.”

The study team randomized 1250 patients at 95 sites in the United States, Brazil, Mexico, Argentina, India, Canada, and the United Kingdom between April 2020 and January 2021. Patients, who also had risk factors that included high blood pressure, diabetes, atherosclerotic vascular disease, heart failure, or CKD were randomized 1:1 to 10 mg of dapagliflozin or placebo once a day. Patients began taking the drug as soon as possible and no later than 4 days following admission to the hospital for 30 days—including after discharge. Patients, doctors, and study personnel were all unaware who was taking dapagliflozin and who was taking placebo.

: this measured the time to the first major clinical event, including (1) respiratory, defined as invasive or noninvasive mechanical ventilation; (2) cardiovascular, defined as pressor, inotropes, new or worsened heart failure, sustained ventricular tachycardia/ventricular fibrillation, resuscitated cardiac arrest; (3) kidney, defined as doubling of creatinine or initiation of dialysis; and (4) death from any cause.

this hierarchical composite ranked each patient using the order of (1) death, (2) organ failure, (3) clinical status if still hospitalized after 30 days, and (4) time to discharge before day 30, which ended up being the leading driver of the end point.

Kosiborod said that although the results did not reach statistical significance, all were directionally favorable to dapagliflozin. This points to the need for further study, he said.

“Our study generates a hypothesis that dapagliflozin may offer organ protection in acutely ill patients who are hospitalized with COVID-19, but we were not able to prove this beyond a reasonable doubt because patient outcomes rapidly improved during the study period, making it much harder to accrue enough events and reach statistical certainty,” Kosiborod said.

Because the standard of care was rapidly evolving from the start of the pandemic through the summer of 2020, the share of hospitalized patients who died dropped from 25% in April to 5% by August of 2020, which likely affected the results. Thus, the second primary end point of recovery ended up being very similar between the 2 groups of patients.

The composite kidney end point had a numerical difference on par with the overall primary end point (events in 10.4% of the placebo group vs 7.7% of the dapagliflozin group). This comes as acute kidney injury (AKI) has emerged as a particularly serious problem during COVID-19, not only among at-risk patients but even among previously healthy patients, according to the 

. AKI is a distinctly different condition from CKD and can leave patients at risk for chronic kidney failure.

There were numerically fewer serious adverse events in patients receiving dapagliflozin vs placebo, Two nonsevere cases of diabetic ketoacidosis were seen in the dapagliflozin group, both in patients with a prior history of T2D.

During today's late-breaking session, discussant Jim Januzzi, MD, of Massachusetts General Hospital praised Kosiborod's team for getting an international trial up at running in the pandemic's early chaotic weeks. He asked how many patients would need to be enrolled for the DARE-19 study team to have a clearer picture of whether dapagliflozin offers the organ protection they hypothesized; Kosiborod said at least 3000, and preferably 5000.

"A study size of 5000 sounds large," Januzzi responded, "but yesterday, globally, there were 836,000 cases of COVID-19, which comes down to approximately 580 per minute. So, it is certainly reasonable to expect that a study of that size would be feasible."

Maggie L. Shaw contributed to this report.

The Dapagliflozin in Respiratory Failure in Patients With COVID-19 trial is the first phase 3 study to examine whether this SGLT2 inhibitor, which has proven effective for multiple chronic conditions, might be similarly useful in an acute setting.

Dapagliflozin Misses Early Mark in COVID-19, but Kosiborod Sees Reasons for More Study

Although both the oral or enteral formulation and the intravenous (IV) formulation of branched-chain amino acids (BCAA) were effective in treating hospitalized patients with maple syrup urine disease (

), the IV formula yielded a shorter time to episode resolution, according to a recent study.

, highlighted some of the cases where the IV formulation may be necessary and used real-world data to show heterogeneity in treatment approaches for patients facing a MSUD-related decompensation episode.

“The particular strength of this study is that it is the largest cohort study in MSUD yet conducted, building on a previous analysis, to provide greater insight into the optimal management of decompensation episodes and offers further confirmation of the clinical efficacy, safety, and utility of the IV BCAA-free treatment for use in emergency settings,” wrote the investigators.

MSUD is a rare autosomal metabolic disease characterized by an inability to break down BCAAs, such as valine, isoleucine, and leucine. MSUD is usually diagnosed during infancy and is estimated to affect 1 in 185,000 to 491,000 births.

The clinical phenotype of MSUD can vary in severity, often causing feeding difficulties shortly after birth. If left untreated, the condition could result in seizures, coma, impairments in energy homeostasis, development delays, irreversible neurological damage, and death.

MSUD is typically managed by a protein-restricted diet with BCAA-free formula supplements. Early diagnoses and treatment can generally lead to a good prognosis. However, patients who adhere to dietary restrictions can still have metabolic decompensations, which can occur at any age.

Patients who experience metabolic decompensations require urgent treatments to normalize leucine levels and avoid permanent brain damage and death. Decompensation episodes are treated by providing a higher concentration of BCAA-free formula than administered at home. There is currently no drug specifically targeted to treat metabolic decompensation.

Although there are some published management recommendations, real-world evidence on MSUD decompensation episodes is limited. Oral or enteral BCAA-free formulations may be difficult or impossible to administer, suggesting that IV formulations may provide an additional avenue to provide care.

The investigators extrapolated data from medical records on patients with MSUD hospitalized for decompensation episodes from 4 rare disease reference centers in France and 1 in Germany. Hospitalizations occurred between January 1, 2010 and December 31, 2016.

Patients were included based on their diagnosis, whether they were under surveillance during hospitalization, had a fully documented medical history, and experienced at least 1 decompensation episode requiring more than 24 hours of hospitalization with a plasma leucine level of over 381 μmol/L at admission.

Data was available for 55 patients (51% male) and 129 episodes, of which 126 episodes for 54 patients were included in the analysis.

Administration of BCAA-free formula intravenously was required for patients with gastric intolerance (33%), refusal to undergo nasogastric tubing (31%), “emergency” (14%), coma (8%), and as prophylaxis prior to a scheduled surgery (6%).

The mean time that it took to achieve episode resolution was shorter in the IV group, amounting to 7.4 days, compared with 9.2 days for the oral and enteral formula group.

Additionally, normalization of leucine levels at discharge was achieved in approximately 80% in both administration groups, taking roughly 2.9 days in the oral or enteral group and 4 days in the IV group.

The investigators said that “this apparent but albeit not significant difference may have resulted from the ‘time to episode resolution’ variable encompassing both leucine normalization and/or the resolution of clinical signs and symptoms as determined by the attending physician, which may have biased these findings.”

In the pediatric subgroup, there were no significant differences between administration groups for any outcome.

Analysis of the adult subgroup revealed a shorter mean time to episode resolution (7.7 days) for the IV group compared with the oral or enteral formula group (15.8 days; 

 = .008). Also, duration of hospitalization in this subgroup lasted for a mean of 4.6 days in the IV group and 6 days in the oral/enteral group.

Seven adverse events were recorded in 2 patients, of which only 2, nausea and vomiting, were considered treatment related and all eventually resolved.

The investigators identified several study limitations, including that the retrospective design, inclusion of episodes involving hemodialysis and hemofiltration, subjective and heterogeneous definition of “episode resolution”, the different methodologies for measuring leucine levels may all have contributed to some form of bias.

“Considering that excessive leucine levels are a clinical emergency condition, IV administration of BCAA-free formula may be a particularly useful alternative in emergency settings, if the patient is not able to receive or cannot tolerate oral treatment or enteral tubing,” wrote the investigators.

de Lonlay P, Posset R, Mütze U, et al. Real-world management of maple syrup urine disease (MSUD) metabolic decompensations with branched chain amino acid-free formulas in France and Germany: A retrospective observational study. 

. March 6, 2021;59(1):110-119. doi: 10.1002/jmd2.12207

Hospitalized infants with the rare metabolic disorder maple syrup urine disease (MSUD), who are intolerant to oral or enteral administration of branched-chain amino acid-free formula, may benefit from an intravenous formulation.

Real-World Evidence Supports Conditional Use of IV Formula in Hospitalized Infants With MSUD

Pregnant women with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) would benefit from a multidisciplinary clinical pathway, according to a recent report in 

In a retrospective analysis, researchers compared pregnant patients with SLE/APS who were managed in a multidisciplinary clinical pathway, which included pre-pregnancy counseling, with patients who were not managed in a clinical pathway. The primary outcome was disease flares for patients with SLE and thromboembolic events (TEE) for patients with APS.

A total of 78 patients with 112 pregnancies were analyzed. The pathway cohort was made up of 30 patients and 41 pregnancies (12 patients with SLE and 18 patients with APS). Of those patients awaiting pregnancy, 6 patients had disease flares during the follow-up period, 2 had active disease and were told to postpone conception, and 1 patient conceived against medical advice.

In the group not managed on a pathway, 47 patients and 71 pregnancies were included (33 patients with SLE and 15 patients with APS).

Results showed that the pathway cohort had significantly fewer composite end point disease-related SLE and TEE flares (7% vs 28%) during pregnancy.

Another report from Rheumatology Network described a recent analysis examining attitudes and beliefs about exercise in patients with rheumatoid arthritis. The disease itself can be either a motivating or demotivating factor behind levels of exercise, according to the study. 

Studies show that although activity can reduce symptoms and comorbidity risk, regular exercise levels remain low in these patients for many reasons; some patients cite pain and fatigue, time and cost, low motivation and poor self-regulation skills, physical limitations, and a lack of knowledge on the part of both providers and patients alike.

Researchers reviewed 15 studies, which included 233 patients with RA (177 women, 56 men, aged 21-87 years). The studies all captured patient perspectives on exercise as an agile, lifelong behavior. Seven themes emerged: considering aggravated symptoms, acknowledging the impact on health, becoming empowered and taking action, keeping informed to increase awareness, creating body awareness, dealing with social support, and feeling satisfied with circumstances and achievements

 (PsA) and minimal disease activity who continued ixekizumab had better results than those who stopped using the drug, according to a 

. In addition, continuing ixekizumab after a relapse rapidly restored disease control.

The multicenter, randomized, double-blind study involved adult patients with a confirmed diagnosis of PsA for 6 or more months and inadequate response or intolerance to at least 1 conventional synthetic disease-modifying antirheumatic drug and psoriatic skin lesions or a history of plaque psoriasis.

Patients with PsA received 160 mg of ixekizumab at week 0, and then 80 mg every 2 weeks (IXE Q2W) for 36 weeks. Patients with sustained minimal disease activity for more than 3 months were then randomized 1:1 to either a blinded IXE Q2W withdrawal group and received a placebo between weeks 36-64, or continued treatment through week 104.

Investigators analyzed time to relapse, or loss of minimal disease activity, for this patient group. If a relapse occurred, they were subsequently treated with IXE Q2W for the remainder of the study. The remainder of the patients (133) did not achieve MDA and continued on IXE Q2W.

Those in the withdrawal group relapsed in a significantly shorter time (median 22.3 weeks [95% CI, 16.1-28.3]); there was also a higher proportion of patients who relapsed in that group, compared with those who continued receiving ixekizumab. In the withdrawal group, 73% patients relapsed, compared with only 34% patients who continued IXE Q2W. When patients in the withdrawal group continued treatment, they were able to return to having minimal disease activity.

Some of the latest rheumatology news includes updates on pregnancy, exercise, and treatment for psoriatic arthritis.

Rheumatology Rundown: Pregnancy and Lupus, Attitudes Toward Exercise, and More

Current vaccine development builds upon hundreds of years of scientific history, noted a featured speaker who highlighted vaccines in the pipeline for targeted diseases and specific populations during a session of the 

A pediatric infectious disease expert reviewed some developments in the vaccine development pipeline, especially new efforts targeting infant health through maternal immunizations.