For patients with rheumatoid arthritis (RA) for whom a first Janus kinase inhibitor (JAKi) has failed, there appears to be no difference in treatment effectiveness whether the patient is cycled to a second JAKi or receives a biologic disease-modifying antirheumatic drug (bDMARD), a study of international patient registry data suggests.

However, patients who are prescribed a different JAKi after the first has failed them tend to have conditions that are more difficult to treat than do patients who are switched to a bDMARD after JAKi failure. In addition, adverse events that occur with the first JAKi are likely to occur again if a different agent in the same class is used, reported Manuel Pombo-Suarez, MD, PhD, adjunct professor of medicine at the University Hospital of Santiago de Compostela, Spain.

“When the first JAK inhibitor was stopped due to an adverse event, it was also more likely that the second JAK inhibitor would be stopped for the same reason,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

The 2019 update of the European Alliance of Associations for Rheumatology (EULAR) guidelines for RA recommend that for patients for whom a first JAKi has failed, clinicians can consider a different JAKi or switch to a bDMARD. But at the time the guidelines were published, no data were available from studies in which a second JAKi was used after the failure of a first JAKi, Dr. Pombo-Suarez noted.

“We are trying to shed a light on this growing population of patients, as prescription of these drugs is increasing and new JAK inhibitors come into play, meaning that this scenario, we propose, is becoming more and more frequent in real life. We must provide a solution for these patients,” he said.
 

Pooled registry data

The investigators compared the effectiveness of the two approaches with respect to rates of drug retention and Disease Activity Score in 28 joints (DAS28).

They conducted a nested cohort study using data from 14 national registries that are part of the JAK-pot collaboration.

They pooled data from each registry on patients with RA for whom a first JAKi had failed and who were then treated with either a second JAKi or a bDMARD.

They identified a total of 708 patients for whom a JAKi had failed initially. Of these patients, 154 were given a different JAKi, and 554 were switched to a bDMARD. In each group, women accounted for a large majority of patients.

The mean age was slightly older among those who received a second JAKi (58.41 years vs. 54.74 years for patients who were given a bDMARD). The mean disease duration was 13.95 years and 11.37 years, respectively.

In each group, approximately 77% of patients received tofacitinib (Xeljanz).

At baseline, the mean DAS28 scores were similar between the groups: 4.10 in the group that received a second JAKi, and 4.17 in the group given a bDMARD.

Reasons for initially stopping use of a JAKi were as follows: adverse events (27.3% of those who took a second JAKi after they had stopped taking one initially, and 17.9% of patients who received a bDMARD); lack of efficacy (61% and 65%, respectively), and other reasons (11.7% and 17.1%, respectively).

At 2 years’ follow-up, drug survival rates were similar between the two treatment arms, although there was a nonsignificant trend toward a higher rate of discontinuation among patients who were given a second JAKi after they stopped taking the first JAKi because of adverse events. In contrast, there was also a nonsignificant trend toward lower discontinuation rates among patients who were given a second JAKi after they had stopped taking the first JAKi because of lack of efficacy.

As noted before, patients who stopped taking the first JAKi because of an adverse event were more likely to stop taking the second JAKi because of they experienced either the same or a different adverse event, whereas patients who started taking a bDMARD were equally likely to stop taking the second therapy because of either adverse events or lack of efficacy.

The treatment strategies were virtually identical with respect to improvement of DAS28 at 7 months after the start of therapy.

Dr. Pombo-Suarez acknowledged that the study was limited by the fact that heterogeneity between countries could not be assessed, owing to the small sample sizes in each nation’s registry. Other limitations include short follow-up and the fact that tofacitinib was used as the first JAKi by the large majority of patients.

What’s your practice?

In a media briefing during which Dr. Pombo-Suarez discussed the study findings, this news organization polled other speakers who were not involved in the study about their go-to strategies when JAKi therapy fails.

Silje Watterdal Syversen, MD, PhD, a consultant rheumatologist and researcher at Diakonhjemmet Hospital, Oslo, said that she would choose to switch to a tumor necrosis factor [TNF] inhibitor.

“I think it would depend on what prior treatment the patient had received,” said April Jorge, MD, a rheumatologist at Massachusetts General Hospital, Boston. “In my practice, patients receiving a JAK inhibitor typically failed on their biologics. I haven’t had many fail a JAK inhibitor – a small sample size.”

“That’s what we see in our study,” Dr. Pombo-Suarez said. “Most of the patients that cycled JAK inhibitors had higher numbers of biologics compared with switchers.”

“I can share my experience, which is a greater comfort level with cycling a TNF antagonist. I agree with Dr Jorge: I don’t use JAK inhibitors in the first line for rheumatoid arthritis, but based on the work that’s been described here and future data, I might have a greater comfort level cycling JAK inhibitors once the data support such an approach,” commented H. Michael Belmont, MD, professor of medicine at New York University, co-director of the NYU Lupus Center, and medical director of Bellevue Hospital Lupus Center, New York.

The JAK-pot study is supported by unrestricted research grants from AbbVie and Galapagos. Dr. Pombo-Suarez has received adviser and speaker honoraria from several companies other than the funders. Dr. Syversen has received honoraria from Thermo Fisher. Dr. Jorge has disclosed no relevant financial relationships. Dr. Belmont has received honoraria from Alexion.

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

For patients with rheumatoid arthritis (RA) for whom a first Janus kinase inhibitor (JAKi) has failed, there appears to be no difference in treatment effectiveness whether the patient is cycled to a second JAKi or receives a biologic disease-modifying antirheumatic drug (bDMARD), a study of international patient registry data suggests.

However, patients who are prescribed a different JAKi after the first has failed them tend to have conditions that are more difficult to treat than do patients who are switched to a bDMARD after JAKi failure. In addition, adverse events that occur with the first JAKi are likely to occur again if a different agent in the same class is used, reported Manuel Pombo-Suarez, MD, PhD, adjunct professor of medicine at the University Hospital of Santiago de Compostela, Spain.

“When the first JAK inhibitor was stopped due to an adverse event, it was also more likely that the second JAK inhibitor would be stopped for the same reason,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

The 2019 update of the European Alliance of Associations for Rheumatology (EULAR) guidelines for RA recommend that for patients for whom a first JAKi has failed, clinicians can consider a different JAKi or switch to a bDMARD. But at the time the guidelines were published, no data were available from studies in which a second JAKi was used after the failure of a first JAKi, Dr. Pombo-Suarez noted.

“We are trying to shed a light on this growing population of patients, as prescription of these drugs is increasing and new JAK inhibitors come into play, meaning that this scenario, we propose, is becoming more and more frequent in real life. We must provide a solution for these patients,” he said.
 

Pooled registry data

The investigators compared the effectiveness of the two approaches with respect to rates of drug retention and Disease Activity Score in 28 joints (DAS28).

They conducted a nested cohort study using data from 14 national registries that are part of the JAK-pot collaboration.

They pooled data from each registry on patients with RA for whom a first JAKi had failed and who were then treated with either a second JAKi or a bDMARD.

They identified a total of 708 patients for whom a JAKi had failed initially. Of these patients, 154 were given a different JAKi, and 554 were switched to a bDMARD. In each group, women accounted for a large majority of patients.

The mean age was slightly older among those who received a second JAKi (58.41 years vs. 54.74 years for patients who were given a bDMARD). The mean disease duration was 13.95 years and 11.37 years, respectively.

In each group, approximately 77% of patients received tofacitinib (Xeljanz).

At baseline, the mean DAS28 scores were similar between the groups: 4.10 in the group that received a second JAKi, and 4.17 in the group given a bDMARD.

Reasons for initially stopping use of a JAKi were as follows: adverse events (27.3% of those who took a second JAKi after they had stopped taking one initially, and 17.9% of patients who received a bDMARD); lack of efficacy (61% and 65%, respectively), and other reasons (11.7% and 17.1%, respectively).

At 2 years’ follow-up, drug survival rates were similar between the two treatment arms, although there was a nonsignificant trend toward a higher rate of discontinuation among patients who were given a second JAKi after they stopped taking the first JAKi because of adverse events. In contrast, there was also a nonsignificant trend toward lower discontinuation rates among patients who were given a second JAKi after they had stopped taking the first JAKi because of lack of efficacy.

As noted before, patients who stopped taking the first JAKi because of an adverse event were more likely to stop taking the second JAKi because of they experienced either the same or a different adverse event, whereas patients who started taking a bDMARD were equally likely to stop taking the second therapy because of either adverse events or lack of efficacy.

The treatment strategies were virtually identical with respect to improvement of DAS28 at 7 months after the start of therapy.

Dr. Pombo-Suarez acknowledged that the study was limited by the fact that heterogeneity between countries could not be assessed, owing to the small sample sizes in each nation’s registry. Other limitations include short follow-up and the fact that tofacitinib was used as the first JAKi by the large majority of patients.

What’s your practice?

In a media briefing during which Dr. Pombo-Suarez discussed the study findings, this news organization polled other speakers who were not involved in the study about their go-to strategies when JAKi therapy fails.

Silje Watterdal Syversen, MD, PhD, a consultant rheumatologist and researcher at Diakonhjemmet Hospital, Oslo, said that she would choose to switch to a tumor necrosis factor [TNF] inhibitor.

“I think it would depend on what prior treatment the patient had received,” said April Jorge, MD, a rheumatologist at Massachusetts General Hospital, Boston. “In my practice, patients receiving a JAK inhibitor typically failed on their biologics. I haven’t had many fail a JAK inhibitor – a small sample size.”

“That’s what we see in our study,” Dr. Pombo-Suarez said. “Most of the patients that cycled JAK inhibitors had higher numbers of biologics compared with switchers.”

“I can share my experience, which is a greater comfort level with cycling a TNF antagonist. I agree with Dr Jorge: I don’t use JAK inhibitors in the first line for rheumatoid arthritis, but based on the work that’s been described here and future data, I might have a greater comfort level cycling JAK inhibitors once the data support such an approach,” commented H. Michael Belmont, MD, professor of medicine at New York University, co-director of the NYU Lupus Center, and medical director of Bellevue Hospital Lupus Center, New York.

The JAK-pot study is supported by unrestricted research grants from AbbVie and Galapagos. Dr. Pombo-Suarez has received adviser and speaker honoraria from several companies other than the funders. Dr. Syversen has received honoraria from Thermo Fisher. Dr. Jorge has disclosed no relevant financial relationships. Dr. Belmont has received honoraria from Alexion.

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

For patients with rheumatoid arthritis (RA) for whom a first Janus kinase inhibitor (JAKi) has failed, there appears to be no difference in treatment effectiveness whether the patient is cycled to a second JAKi or receives a biologic disease-modifying antirheumatic drug (bDMARD), a study of international patient registry data suggests.

However, patients who are prescribed a different JAKi after the first has failed them tend to have conditions that are more difficult to treat than do patients who are switched to a bDMARD after JAKi failure. In addition, adverse events that occur with the first JAKi are likely to occur again if a different agent in the same class is used, reported Manuel Pombo-Suarez, MD, PhD, adjunct professor of medicine at the University Hospital of Santiago de Compostela, Spain.

“When the first JAK inhibitor was stopped due to an adverse event, it was also more likely that the second JAK inhibitor would be stopped for the same reason,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

The 2019 update of the European Alliance of Associations for Rheumatology (EULAR) guidelines for RA recommend that for patients for whom a first JAKi has failed, clinicians can consider a different JAKi or switch to a bDMARD. But at the time the guidelines were published, no data were available from studies in which a second JAKi was used after the failure of a first JAKi, Dr. Pombo-Suarez noted.

“We are trying to shed a light on this growing population of patients, as prescription of these drugs is increasing and new JAK inhibitors come into play, meaning that this scenario, we propose, is becoming more and more frequent in real life. We must provide a solution for these patients,” he said.
 

Pooled registry data

The investigators compared the effectiveness of the two approaches with respect to rates of drug retention and Disease Activity Score in 28 joints (DAS28).

They conducted a nested cohort study using data from 14 national registries that are part of the JAK-pot collaboration.

They pooled data from each registry on patients with RA for whom a first JAKi had failed and who were then treated with either a second JAKi or a bDMARD.

They identified a total of 708 patients for whom a JAKi had failed initially. Of these patients, 154 were given a different JAKi, and 554 were switched to a bDMARD. In each group, women accounted for a large majority of patients.

The mean age was slightly older among those who received a second JAKi (58.41 years vs. 54.74 years for patients who were given a bDMARD). The mean disease duration was 13.95 years and 11.37 years, respectively.

In each group, approximately 77% of patients received tofacitinib (Xeljanz).

At baseline, the mean DAS28 scores were similar between the groups: 4.10 in the group that received a second JAKi, and 4.17 in the group given a bDMARD.

Reasons for initially stopping use of a JAKi were as follows: adverse events (27.3% of those who took a second JAKi after they had stopped taking one initially, and 17.9% of patients who received a bDMARD); lack of efficacy (61% and 65%, respectively), and other reasons (11.7% and 17.1%, respectively).

At 2 years’ follow-up, drug survival rates were similar between the two treatment arms, although there was a nonsignificant trend toward a higher rate of discontinuation among patients who were given a second JAKi after they stopped taking the first JAKi because of adverse events. In contrast, there was also a nonsignificant trend toward lower discontinuation rates among patients who were given a second JAKi after they had stopped taking the first JAKi because of lack of efficacy.

As noted before, patients who stopped taking the first JAKi because of an adverse event were more likely to stop taking the second JAKi because of they experienced either the same or a different adverse event, whereas patients who started taking a bDMARD were equally likely to stop taking the second therapy because of either adverse events or lack of efficacy.

The treatment strategies were virtually identical with respect to improvement of DAS28 at 7 months after the start of therapy.

Dr. Pombo-Suarez acknowledged that the study was limited by the fact that heterogeneity between countries could not be assessed, owing to the small sample sizes in each nation’s registry. Other limitations include short follow-up and the fact that tofacitinib was used as the first JAKi by the large majority of patients.

What’s your practice?

In a media briefing during which Dr. Pombo-Suarez discussed the study findings, this news organization polled other speakers who were not involved in the study about their go-to strategies when JAKi therapy fails.

Silje Watterdal Syversen, MD, PhD, a consultant rheumatologist and researcher at Diakonhjemmet Hospital, Oslo, said that she would choose to switch to a tumor necrosis factor [TNF] inhibitor.

“I think it would depend on what prior treatment the patient had received,” said April Jorge, MD, a rheumatologist at Massachusetts General Hospital, Boston. “In my practice, patients receiving a JAK inhibitor typically failed on their biologics. I haven’t had many fail a JAK inhibitor – a small sample size.”

“That’s what we see in our study,” Dr. Pombo-Suarez said. “Most of the patients that cycled JAK inhibitors had higher numbers of biologics compared with switchers.”

“I can share my experience, which is a greater comfort level with cycling a TNF antagonist. I agree with Dr Jorge: I don’t use JAK inhibitors in the first line for rheumatoid arthritis, but based on the work that’s been described here and future data, I might have a greater comfort level cycling JAK inhibitors once the data support such an approach,” commented H. Michael Belmont, MD, professor of medicine at New York University, co-director of the NYU Lupus Center, and medical director of Bellevue Hospital Lupus Center, New York.

The JAK-pot study is supported by unrestricted research grants from AbbVie and Galapagos. Dr. Pombo-Suarez has received adviser and speaker honoraria from several companies other than the funders. Dr. Syversen has received honoraria from Thermo Fisher. Dr. Jorge has disclosed no relevant financial relationships. Dr. Belmont has received honoraria from Alexion.

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

As the United States rounds out its second year of the pandemic, many people are trying to figure out just how vulnerable they may be to COVID-19 infection, and whether it’s finally safe to fully return to all the activities they miss.

On an individual basis, the degree and durability of the immunity a person gets after vaccination versus an infection is not an easy question to answer. But it’s one that science is hotly pursing.

“This virus is teaching us a lot about immunology,” says Gregory Poland, MD, who studies how the body responds to vaccines at the Mayo Clinic in Rochester, Minn. Dr. Poland says this moment in science reminds him of a quote attributed to Ralph Waldo Emerson: “We learn about geology the morning after the earthquake.”

“And that’s the case here. It is and will continue to teach us a lot of immunology,” he says.

It’s vital to understand how a COVID-19 infection reshapes the body’s immune defenses so that researchers can tailor vaccines and therapies to do the same or better.

“Because, of course, it’s much more risky to get infected with the actual virus, than with the vaccine,” says Daniela Weiskopf, PhD, a researcher at the La Jolla Institute for Immunology in California.

What is known so far is that how much protection you get and how long you may have it depends on several factors. Those include your age, whether you’ve had COVID-19 before and how severe your symptoms were, your vaccination status, and how long it has been since you were infected or inoculated. Your underlying health matters, too. Immune protection also depends on the virus and how much it is changing as it evolves to evade all our hard-won defenses.

In a new scientific brief, the Centers for Disease Control and Prevention digs into the evidence behind the immune protection created by infection compared with immunity after vaccination. Here’s what we know so far:
 

Durability of immunity

The agency’s researchers say if you’ve recovered from a COVID-19 infection or are fully vaccinated, you’re probably in good shape for at least 6 months. That’s why this is the recommended interval for people to consider getting a booster dose.

Even though the protection you get after infection and vaccination is generally strong, it’s not perfect.

Getting COVID-19 after you’ve been vaccinated or recovered is still possible. But having some immunity -- whether from infection or vaccination -- really drops the odds of this happening to you. And if you do happen to catch COVID, if your immune system has already gotten a heads up about the virus, your infection is much less likely to be one that lands you in the hospital or morgue.

According to CDC data, at the height of the Delta surge in August, fully vaccinated people were six times less likely to get a COVID-19 infection compared with unvaccinated people, and 11 times less likely to die if they did get it.
 

How strong is immunity after a COVID-19 Infection?

About 90% of people develop some number of protective antibodies after a COVID-19 infection, according to the CDC. But how high those levels climb appears to be all over the map. Studies show peak antibody concentrations can vary as much as 200-fold, or 2,000%.

Where you fall within that very large range will depend on your age and how sick you became from your COVID-19 infection. It also depends on whether you have an underlying health condition or take a medication that blunts immune function.

Our immune system slows down with age. Immunosenescence starts to affect a person’s health around the age of 60. But there’s no bright line for failure. People who exercise and are generally healthy will have better immune function than someone who doesn’t, no matter their age. In general, though, the older you are, the less likely you are to get a robust immune response after an infection or a vaccination. That’s why this group has been prioritized both for first vaccine doses and boosters.

Beyond age, your protection from future infection seems to depend on how ill you were with the first. Several studies have shown that blood levels of antibodies rise faster and reach a higher peak in people with more severe infections.

In general, people with cold-like symptoms who tested positive but recovered at home are better protected than people who didn’t get any symptoms. And people who were hospitalized for their infections are better protected over the long term than people with milder infections. They may have paid a steep price for that protection: Many hospitalized patients continue to have debilitating symptoms that last for months after they go home.

On average, though, protection after infection seems to be comparable to vaccination, at least for a while. Six large studies from different countries have looked into this question, and five of them have used the very sensitive real-time polymerase chain reaction test (RT-PCR) to count people as truly being previously infected. These studies found that for 6 to 9 months after recovery, a person was 80% to 93% less likely to get COVID-19 again.

There are some caveats to mention, though. Early in the pandemic when supplies were scarce, it was hard to get tested unless you were so sick you landed in the hospital. Studies have shown that the concentration of antibodies a person makes after an infection seems to depend on how sick they got in the first place.

People who had milder infections, or who didn’t have any symptoms at all, may not develop as much protection as those who have more severe symptoms. So these studies may reflect the immunity developed by people who were pretty ill during their first infections.

One study of 25,000 health care workers, who were all tested every 2 weeks -- whether they had symptoms or not -- may offer a clearer picture. In this study, health care workers who’d previously tested positive for COVID-19 were 84% less likely to test positive for the virus again. They were 93% less likely to get an infection that made them sick, and 52% less likely to get an infection without symptoms, for at least 6 months after they recovered.
 

How does protection after infection compare to vaccination?

Two weeks after your final vaccine dose, protection against a COVID-19 infection is high -- around 90% for the Pfizer and Moderna mRNA vaccines and 66% for the one-dose Johnson & Johnson shot. Clinical trials conducted by the manufacturer have shown that a second dose of the Johnson & Johnson vaccine given at least 2 months after vaccination boosts protection against illness in the United States to about 94%, which is why another dose has been recommended for all Johnson & Johnson vaccine recipients 2 months after their first shot.

It’s not yet known how long the COVID-19 vaccines remain protective. There’s some evidence that protection against symptomatic infections wanes a bit over time as antibody levels drop. But protection against severe illness, including hospitalization and death, has remained high so far, even without a booster.
 

Are antibodies different after infection compared to vaccination?

Yes. And researchers don’t yet understand what these differences mean.

It seems to come down to a question of quality versus quantity. Vaccines seem to produce higher peak antibody levels than natural infections do. But these antibodies are highly specialized, able to recognize only the parts of the virus they were designed to target.

“The mRNA vaccine directs all the immune responses to the single spike protein,” says Alice Cho, PhD, who is studying the differences in vaccine and infection-created immunity at the Rockefeller University in New York. “There’s a lot more to respond to with a virus than there is in a vaccine.”

During an infection, the immune system learns to recognize and grab onto many parts of the virus, not just its spike.

The job of remembering the various pieces and parts of a foreign invader, so that it can be quickly recognized and disarmed should it ever return, falls to memory B cells.

Memory B cells, in turn, make plasma cells that then crank out antibodies that are custom tailored to attach to their targets.

Antibody levels gradually fall over a few months’ time as the plasma cells that make them die off. But memory B cells live for extended periods. One study that was attempting to measure the lifespan of individual memory B cells in mice found that these cells probably live as long as the mouse itself. Memory B cells induced by smallpox vaccination may live at least 60 years -- virtually an entire lifetime.

Dr. Cho’s research team has found that when memory B cells are trained by the vaccine, they become one-hit wonders, cranking out copious amounts of the same kinds of antibodies over and over again.

Memory B cells trained by viral infection, however, are more versatile. They continue to evolve over several months and produce higher quality antibodies that appear to become more potent over time and can even develop activity against future variants.

Still, the researchers stress that it’s not smart to wait to get a COVID-19 infection in hopes of getting these more versatile antibodies.

“While a natural infection may induce maturation of antibodies with broader activity than a vaccine does -- a natural infection can also kill you,” says Michel Nussenzweig, MD, PhD, head of Rockefeller’s Laboratory of Molecular Immunology.

Sure, memory B cells generated by infections may be immunological Swiss Army Knives, but maybe, argues Donna Farber, PhD, an immunologist at Columbia University in New York, we really only need a single blade.

“The thing with the vaccine is that it’s really focused,” she says. “It’s not giving you all these other viral proteins. It’s only giving you the spike.”

“It may be even better than the level of neutralizing spike antibodies you’re going to get from the infection,” she says. “With a viral infection, the immune response really has a lot to do. It’s really being distracted by all these other proteins.”

“Whereas with the vaccine, it’s just saying to the immune response, ‘This is the immunity we need,’” Dr. Farber says. “‘Just generate this immunity.’ So it’s focusing the immune response in a way that’s going to guarantee that you’re going to get that protective response.”
 

What if you had COVID and later got vaccinated?

This is called hybrid immunity, and it’s the best of both worlds.

“You have the benefit of very deep, but narrow, immunity produced by vaccine, and very broad, but not very deep, immunity produced by infection,” Dr. Poland says. He says you’ve effectively cross-trained your immune system.

In studies of people who recovered from COVID-19 and then went on to get an mRNA vaccine, after one dose, their antibodies were as high as someone who had been fully vaccinated. After two doses, their antibody levels were about double the average levels seen in someone who’d only been vaccinated.

Studies have shown this kind of immunity has real benefits, too. A recent study by researchers at the University of Kentucky and the CDC found that people who’d gotten COVID-19 in 2020, but had not been vaccinated, were about twice as likely to be reinfected in May and June compared with those who recovered and went on to get their vaccines.
 

What antibody level is protective?

Scientists aren’t exactly sure how high antibody levels need to be for protection, or even which kinds of antibodies or other immune components matter most yet.

But vaccines appear to generate higher antibody levels than infections do. In a recent study published in the journal Science , Dr. Weiskopf and her colleagues at the La Jolla Institute of Immunology detail the findings of a de-escalation study, where they gave people one-quarter of the normal dose of the Moderna mRNA vaccine and then collected blood samples over time to study their immune responses.

Their immune responses were scaled down with the dose.

“We saw that this has the exact same levels as natural infection,” Dr. Weiskopf says. “People who are vaccinated have much higher immune memory than people who are naturally infected,” she says.

Antibody levels are not easy to determine in the real world. Can you take a test to find out how protected you are? The answer is no, because we don’t yet know what antibody level, or even which kind of antibodies, correlate with protection.

Also, there are many different kinds of antibody tests and they all use a slightly different scale, so there’s no broadly agreed upon way to measure them yet. It’s difficult to compare levels test to test.
 

Weeks or months between doses? Which is best?

Both the Pfizer and Moderna vaccines were tested to be given 3 and 4 weeks apart, respectively. But when the vaccines were first rolling out, shortages prompted some countries to stretch the interval between doses to 4 or more months.

Researchers who have studied the immune responses of people who were inoculated on an extended dosing schedule noticed something interesting: When the interval was stretched, people had better antibody responses. In fact, their antibody responses looked like the sky-high levels people got with hybrid immunity.

Susanna Dunachie, PhD, a global research professor at the University of Oxford in the United Kingdom, wondered why. She’s leading a team of researchers who are doing detailed studies of the immune responses of health care workers after their vaccinations.

“We found that B cells, which are the cells that make antibodies to the viral spike protein after vaccination, carry on increasing in number between 4 and 10 weeks after vaccination,” she says.

Waiting to give the second vaccine 6 to 14 weeks seems to stimulate the immune system when all of its antibody-making factories are finally up and running.

For this reason, giving the second dose at 3 weeks, she says, might be premature.

But there’s a tradeoff involved in waiting. If there are high levels of the virus circulating in a community, you want to get people fully vaccinated as quickly as possible to maximize their protection in the shortest window of time, which is what we decided to do in the United States.

Researchers say it might be a good idea to revisit the dosing interval when it’s less risky to try it.
 

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

As the United States rounds out its second year of the pandemic, many people are trying to figure out just how vulnerable they may be to COVID-19 infection, and whether it’s finally safe to fully return to all the activities they miss.

On an individual basis, the degree and durability of the immunity a person gets after vaccination versus an infection is not an easy question to answer. But it’s one that science is hotly pursing.

“This virus is teaching us a lot about immunology,” says Gregory Poland, MD, who studies how the body responds to vaccines at the Mayo Clinic in Rochester, Minn. Dr. Poland says this moment in science reminds him of a quote attributed to Ralph Waldo Emerson: “We learn about geology the morning after the earthquake.”

“And that’s the case here. It is and will continue to teach us a lot of immunology,” he says.

It’s vital to understand how a COVID-19 infection reshapes the body’s immune defenses so that researchers can tailor vaccines and therapies to do the same or better.

“Because, of course, it’s much more risky to get infected with the actual virus, than with the vaccine,” says Daniela Weiskopf, PhD, a researcher at the La Jolla Institute for Immunology in California.

What is known so far is that how much protection you get and how long you may have it depends on several factors. Those include your age, whether you’ve had COVID-19 before and how severe your symptoms were, your vaccination status, and how long it has been since you were infected or inoculated. Your underlying health matters, too. Immune protection also depends on the virus and how much it is changing as it evolves to evade all our hard-won defenses.

In a new scientific brief, the Centers for Disease Control and Prevention digs into the evidence behind the immune protection created by infection compared with immunity after vaccination. Here’s what we know so far:
 

Durability of immunity

The agency’s researchers say if you’ve recovered from a COVID-19 infection or are fully vaccinated, you’re probably in good shape for at least 6 months. That’s why this is the recommended interval for people to consider getting a booster dose.

Even though the protection you get after infection and vaccination is generally strong, it’s not perfect.

Getting COVID-19 after you’ve been vaccinated or recovered is still possible. But having some immunity -- whether from infection or vaccination -- really drops the odds of this happening to you. And if you do happen to catch COVID, if your immune system has already gotten a heads up about the virus, your infection is much less likely to be one that lands you in the hospital or morgue.

According to CDC data, at the height of the Delta surge in August, fully vaccinated people were six times less likely to get a COVID-19 infection compared with unvaccinated people, and 11 times less likely to die if they did get it.
 

How strong is immunity after a COVID-19 Infection?

About 90% of people develop some number of protective antibodies after a COVID-19 infection, according to the CDC. But how high those levels climb appears to be all over the map. Studies show peak antibody concentrations can vary as much as 200-fold, or 2,000%.

Where you fall within that very large range will depend on your age and how sick you became from your COVID-19 infection. It also depends on whether you have an underlying health condition or take a medication that blunts immune function.

Our immune system slows down with age. Immunosenescence starts to affect a person’s health around the age of 60. But there’s no bright line for failure. People who exercise and are generally healthy will have better immune function than someone who doesn’t, no matter their age. In general, though, the older you are, the less likely you are to get a robust immune response after an infection or a vaccination. That’s why this group has been prioritized both for first vaccine doses and boosters.

Beyond age, your protection from future infection seems to depend on how ill you were with the first. Several studies have shown that blood levels of antibodies rise faster and reach a higher peak in people with more severe infections.

In general, people with cold-like symptoms who tested positive but recovered at home are better protected than people who didn’t get any symptoms. And people who were hospitalized for their infections are better protected over the long term than people with milder infections. They may have paid a steep price for that protection: Many hospitalized patients continue to have debilitating symptoms that last for months after they go home.

On average, though, protection after infection seems to be comparable to vaccination, at least for a while. Six large studies from different countries have looked into this question, and five of them have used the very sensitive real-time polymerase chain reaction test (RT-PCR) to count people as truly being previously infected. These studies found that for 6 to 9 months after recovery, a person was 80% to 93% less likely to get COVID-19 again.

There are some caveats to mention, though. Early in the pandemic when supplies were scarce, it was hard to get tested unless you were so sick you landed in the hospital. Studies have shown that the concentration of antibodies a person makes after an infection seems to depend on how sick they got in the first place.

People who had milder infections, or who didn’t have any symptoms at all, may not develop as much protection as those who have more severe symptoms. So these studies may reflect the immunity developed by people who were pretty ill during their first infections.

One study of 25,000 health care workers, who were all tested every 2 weeks -- whether they had symptoms or not -- may offer a clearer picture. In this study, health care workers who’d previously tested positive for COVID-19 were 84% less likely to test positive for the virus again. They were 93% less likely to get an infection that made them sick, and 52% less likely to get an infection without symptoms, for at least 6 months after they recovered.
 

How does protection after infection compare to vaccination?

Two weeks after your final vaccine dose, protection against a COVID-19 infection is high -- around 90% for the Pfizer and Moderna mRNA vaccines and 66% for the one-dose Johnson & Johnson shot. Clinical trials conducted by the manufacturer have shown that a second dose of the Johnson & Johnson vaccine given at least 2 months after vaccination boosts protection against illness in the United States to about 94%, which is why another dose has been recommended for all Johnson & Johnson vaccine recipients 2 months after their first shot.

It’s not yet known how long the COVID-19 vaccines remain protective. There’s some evidence that protection against symptomatic infections wanes a bit over time as antibody levels drop. But protection against severe illness, including hospitalization and death, has remained high so far, even without a booster.
 

Are antibodies different after infection compared to vaccination?

Yes. And researchers don’t yet understand what these differences mean.

It seems to come down to a question of quality versus quantity. Vaccines seem to produce higher peak antibody levels than natural infections do. But these antibodies are highly specialized, able to recognize only the parts of the virus they were designed to target.

“The mRNA vaccine directs all the immune responses to the single spike protein,” says Alice Cho, PhD, who is studying the differences in vaccine and infection-created immunity at the Rockefeller University in New York. “There’s a lot more to respond to with a virus than there is in a vaccine.”

During an infection, the immune system learns to recognize and grab onto many parts of the virus, not just its spike.

The job of remembering the various pieces and parts of a foreign invader, so that it can be quickly recognized and disarmed should it ever return, falls to memory B cells.

Memory B cells, in turn, make plasma cells that then crank out antibodies that are custom tailored to attach to their targets.

Antibody levels gradually fall over a few months’ time as the plasma cells that make them die off. But memory B cells live for extended periods. One study that was attempting to measure the lifespan of individual memory B cells in mice found that these cells probably live as long as the mouse itself. Memory B cells induced by smallpox vaccination may live at least 60 years -- virtually an entire lifetime.

Dr. Cho’s research team has found that when memory B cells are trained by the vaccine, they become one-hit wonders, cranking out copious amounts of the same kinds of antibodies over and over again.

Memory B cells trained by viral infection, however, are more versatile. They continue to evolve over several months and produce higher quality antibodies that appear to become more potent over time and can even develop activity against future variants.

Still, the researchers stress that it’s not smart to wait to get a COVID-19 infection in hopes of getting these more versatile antibodies.

“While a natural infection may induce maturation of antibodies with broader activity than a vaccine does -- a natural infection can also kill you,” says Michel Nussenzweig, MD, PhD, head of Rockefeller’s Laboratory of Molecular Immunology.

Sure, memory B cells generated by infections may be immunological Swiss Army Knives, but maybe, argues Donna Farber, PhD, an immunologist at Columbia University in New York, we really only need a single blade.

“The thing with the vaccine is that it’s really focused,” she says. “It’s not giving you all these other viral proteins. It’s only giving you the spike.”

“It may be even better than the level of neutralizing spike antibodies you’re going to get from the infection,” she says. “With a viral infection, the immune response really has a lot to do. It’s really being distracted by all these other proteins.”

“Whereas with the vaccine, it’s just saying to the immune response, ‘This is the immunity we need,’” Dr. Farber says. “‘Just generate this immunity.’ So it’s focusing the immune response in a way that’s going to guarantee that you’re going to get that protective response.”
 

What if you had COVID and later got vaccinated?

This is called hybrid immunity, and it’s the best of both worlds.

“You have the benefit of very deep, but narrow, immunity produced by vaccine, and very broad, but not very deep, immunity produced by infection,” Dr. Poland says. He says you’ve effectively cross-trained your immune system.

In studies of people who recovered from COVID-19 and then went on to get an mRNA vaccine, after one dose, their antibodies were as high as someone who had been fully vaccinated. After two doses, their antibody levels were about double the average levels seen in someone who’d only been vaccinated.

Studies have shown this kind of immunity has real benefits, too. A recent study by researchers at the University of Kentucky and the CDC found that people who’d gotten COVID-19 in 2020, but had not been vaccinated, were about twice as likely to be reinfected in May and June compared with those who recovered and went on to get their vaccines.
 

What antibody level is protective?

Scientists aren’t exactly sure how high antibody levels need to be for protection, or even which kinds of antibodies or other immune components matter most yet.

But vaccines appear to generate higher antibody levels than infections do. In a recent study published in the journal Science , Dr. Weiskopf and her colleagues at the La Jolla Institute of Immunology detail the findings of a de-escalation study, where they gave people one-quarter of the normal dose of the Moderna mRNA vaccine and then collected blood samples over time to study their immune responses.

Their immune responses were scaled down with the dose.

“We saw that this has the exact same levels as natural infection,” Dr. Weiskopf says. “People who are vaccinated have much higher immune memory than people who are naturally infected,” she says.

Antibody levels are not easy to determine in the real world. Can you take a test to find out how protected you are? The answer is no, because we don’t yet know what antibody level, or even which kind of antibodies, correlate with protection.

Also, there are many different kinds of antibody tests and they all use a slightly different scale, so there’s no broadly agreed upon way to measure them yet. It’s difficult to compare levels test to test.
 

Weeks or months between doses? Which is best?

Both the Pfizer and Moderna vaccines were tested to be given 3 and 4 weeks apart, respectively. But when the vaccines were first rolling out, shortages prompted some countries to stretch the interval between doses to 4 or more months.

Researchers who have studied the immune responses of people who were inoculated on an extended dosing schedule noticed something interesting: When the interval was stretched, people had better antibody responses. In fact, their antibody responses looked like the sky-high levels people got with hybrid immunity.

Susanna Dunachie, PhD, a global research professor at the University of Oxford in the United Kingdom, wondered why. She’s leading a team of researchers who are doing detailed studies of the immune responses of health care workers after their vaccinations.

“We found that B cells, which are the cells that make antibodies to the viral spike protein after vaccination, carry on increasing in number between 4 and 10 weeks after vaccination,” she says.

Waiting to give the second vaccine 6 to 14 weeks seems to stimulate the immune system when all of its antibody-making factories are finally up and running.

For this reason, giving the second dose at 3 weeks, she says, might be premature.

But there’s a tradeoff involved in waiting. If there are high levels of the virus circulating in a community, you want to get people fully vaccinated as quickly as possible to maximize their protection in the shortest window of time, which is what we decided to do in the United States.

Researchers say it might be a good idea to revisit the dosing interval when it’s less risky to try it.
 

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

As the United States rounds out its second year of the pandemic, many people are trying to figure out just how vulnerable they may be to COVID-19 infection, and whether it’s finally safe to fully return to all the activities they miss.

On an individual basis, the degree and durability of the immunity a person gets after vaccination versus an infection is not an easy question to answer. But it’s one that science is hotly pursing.

“This virus is teaching us a lot about immunology,” says Gregory Poland, MD, who studies how the body responds to vaccines at the Mayo Clinic in Rochester, Minn. Dr. Poland says this moment in science reminds him of a quote attributed to Ralph Waldo Emerson: “We learn about geology the morning after the earthquake.”

“And that’s the case here. It is and will continue to teach us a lot of immunology,” he says.

It’s vital to understand how a COVID-19 infection reshapes the body’s immune defenses so that researchers can tailor vaccines and therapies to do the same or better.

“Because, of course, it’s much more risky to get infected with the actual virus, than with the vaccine,” says Daniela Weiskopf, PhD, a researcher at the La Jolla Institute for Immunology in California.

What is known so far is that how much protection you get and how long you may have it depends on several factors. Those include your age, whether you’ve had COVID-19 before and how severe your symptoms were, your vaccination status, and how long it has been since you were infected or inoculated. Your underlying health matters, too. Immune protection also depends on the virus and how much it is changing as it evolves to evade all our hard-won defenses.

In a new scientific brief, the Centers for Disease Control and Prevention digs into the evidence behind the immune protection created by infection compared with immunity after vaccination. Here’s what we know so far:
 

Durability of immunity

The agency’s researchers say if you’ve recovered from a COVID-19 infection or are fully vaccinated, you’re probably in good shape for at least 6 months. That’s why this is the recommended interval for people to consider getting a booster dose.

Even though the protection you get after infection and vaccination is generally strong, it’s not perfect.

Getting COVID-19 after you’ve been vaccinated or recovered is still possible. But having some immunity -- whether from infection or vaccination -- really drops the odds of this happening to you. And if you do happen to catch COVID, if your immune system has already gotten a heads up about the virus, your infection is much less likely to be one that lands you in the hospital or morgue.

According to CDC data, at the height of the Delta surge in August, fully vaccinated people were six times less likely to get a COVID-19 infection compared with unvaccinated people, and 11 times less likely to die if they did get it.
 

How strong is immunity after a COVID-19 Infection?

About 90% of people develop some number of protective antibodies after a COVID-19 infection, according to the CDC. But how high those levels climb appears to be all over the map. Studies show peak antibody concentrations can vary as much as 200-fold, or 2,000%.

Where you fall within that very large range will depend on your age and how sick you became from your COVID-19 infection. It also depends on whether you have an underlying health condition or take a medication that blunts immune function.

Our immune system slows down with age. Immunosenescence starts to affect a person’s health around the age of 60. But there’s no bright line for failure. People who exercise and are generally healthy will have better immune function than someone who doesn’t, no matter their age. In general, though, the older you are, the less likely you are to get a robust immune response after an infection or a vaccination. That’s why this group has been prioritized both for first vaccine doses and boosters.

Beyond age, your protection from future infection seems to depend on how ill you were with the first. Several studies have shown that blood levels of antibodies rise faster and reach a higher peak in people with more severe infections.

In general, people with cold-like symptoms who tested positive but recovered at home are better protected than people who didn’t get any symptoms. And people who were hospitalized for their infections are better protected over the long term than people with milder infections. They may have paid a steep price for that protection: Many hospitalized patients continue to have debilitating symptoms that last for months after they go home.

On average, though, protection after infection seems to be comparable to vaccination, at least for a while. Six large studies from different countries have looked into this question, and five of them have used the very sensitive real-time polymerase chain reaction test (RT-PCR) to count people as truly being previously infected. These studies found that for 6 to 9 months after recovery, a person was 80% to 93% less likely to get COVID-19 again.

There are some caveats to mention, though. Early in the pandemic when supplies were scarce, it was hard to get tested unless you were so sick you landed in the hospital. Studies have shown that the concentration of antibodies a person makes after an infection seems to depend on how sick they got in the first place.

People who had milder infections, or who didn’t have any symptoms at all, may not develop as much protection as those who have more severe symptoms. So these studies may reflect the immunity developed by people who were pretty ill during their first infections.

One study of 25,000 health care workers, who were all tested every 2 weeks -- whether they had symptoms or not -- may offer a clearer picture. In this study, health care workers who’d previously tested positive for COVID-19 were 84% less likely to test positive for the virus again. They were 93% less likely to get an infection that made them sick, and 52% less likely to get an infection without symptoms, for at least 6 months after they recovered.
 

How does protection after infection compare to vaccination?

Two weeks after your final vaccine dose, protection against a COVID-19 infection is high -- around 90% for the Pfizer and Moderna mRNA vaccines and 66% for the one-dose Johnson & Johnson shot. Clinical trials conducted by the manufacturer have shown that a second dose of the Johnson & Johnson vaccine given at least 2 months after vaccination boosts protection against illness in the United States to about 94%, which is why another dose has been recommended for all Johnson & Johnson vaccine recipients 2 months after their first shot.

It’s not yet known how long the COVID-19 vaccines remain protective. There’s some evidence that protection against symptomatic infections wanes a bit over time as antibody levels drop. But protection against severe illness, including hospitalization and death, has remained high so far, even without a booster.
 

Are antibodies different after infection compared to vaccination?

Yes. And researchers don’t yet understand what these differences mean.

It seems to come down to a question of quality versus quantity. Vaccines seem to produce higher peak antibody levels than natural infections do. But these antibodies are highly specialized, able to recognize only the parts of the virus they were designed to target.

“The mRNA vaccine directs all the immune responses to the single spike protein,” says Alice Cho, PhD, who is studying the differences in vaccine and infection-created immunity at the Rockefeller University in New York. “There’s a lot more to respond to with a virus than there is in a vaccine.”

During an infection, the immune system learns to recognize and grab onto many parts of the virus, not just its spike.

The job of remembering the various pieces and parts of a foreign invader, so that it can be quickly recognized and disarmed should it ever return, falls to memory B cells.

Memory B cells, in turn, make plasma cells that then crank out antibodies that are custom tailored to attach to their targets.

Antibody levels gradually fall over a few months’ time as the plasma cells that make them die off. But memory B cells live for extended periods. One study that was attempting to measure the lifespan of individual memory B cells in mice found that these cells probably live as long as the mouse itself. Memory B cells induced by smallpox vaccination may live at least 60 years -- virtually an entire lifetime.

Dr. Cho’s research team has found that when memory B cells are trained by the vaccine, they become one-hit wonders, cranking out copious amounts of the same kinds of antibodies over and over again.

Memory B cells trained by viral infection, however, are more versatile. They continue to evolve over several months and produce higher quality antibodies that appear to become more potent over time and can even develop activity against future variants.

Still, the researchers stress that it’s not smart to wait to get a COVID-19 infection in hopes of getting these more versatile antibodies.

“While a natural infection may induce maturation of antibodies with broader activity than a vaccine does -- a natural infection can also kill you,” says Michel Nussenzweig, MD, PhD, head of Rockefeller’s Laboratory of Molecular Immunology.

Sure, memory B cells generated by infections may be immunological Swiss Army Knives, but maybe, argues Donna Farber, PhD, an immunologist at Columbia University in New York, we really only need a single blade.

“The thing with the vaccine is that it’s really focused,” she says. “It’s not giving you all these other viral proteins. It’s only giving you the spike.”

“It may be even better than the level of neutralizing spike antibodies you’re going to get from the infection,” she says. “With a viral infection, the immune response really has a lot to do. It’s really being distracted by all these other proteins.”

“Whereas with the vaccine, it’s just saying to the immune response, ‘This is the immunity we need,’” Dr. Farber says. “‘Just generate this immunity.’ So it’s focusing the immune response in a way that’s going to guarantee that you’re going to get that protective response.”
 

What if you had COVID and later got vaccinated?

This is called hybrid immunity, and it’s the best of both worlds.

“You have the benefit of very deep, but narrow, immunity produced by vaccine, and very broad, but not very deep, immunity produced by infection,” Dr. Poland says. He says you’ve effectively cross-trained your immune system.

In studies of people who recovered from COVID-19 and then went on to get an mRNA vaccine, after one dose, their antibodies were as high as someone who had been fully vaccinated. After two doses, their antibody levels were about double the average levels seen in someone who’d only been vaccinated.

Studies have shown this kind of immunity has real benefits, too. A recent study by researchers at the University of Kentucky and the CDC found that people who’d gotten COVID-19 in 2020, but had not been vaccinated, were about twice as likely to be reinfected in May and June compared with those who recovered and went on to get their vaccines.
 

What antibody level is protective?

Scientists aren’t exactly sure how high antibody levels need to be for protection, or even which kinds of antibodies or other immune components matter most yet.

But vaccines appear to generate higher antibody levels than infections do. In a recent study published in the journal Science , Dr. Weiskopf and her colleagues at the La Jolla Institute of Immunology detail the findings of a de-escalation study, where they gave people one-quarter of the normal dose of the Moderna mRNA vaccine and then collected blood samples over time to study their immune responses.

Their immune responses were scaled down with the dose.

“We saw that this has the exact same levels as natural infection,” Dr. Weiskopf says. “People who are vaccinated have much higher immune memory than people who are naturally infected,” she says.

Antibody levels are not easy to determine in the real world. Can you take a test to find out how protected you are? The answer is no, because we don’t yet know what antibody level, or even which kind of antibodies, correlate with protection.

Also, there are many different kinds of antibody tests and they all use a slightly different scale, so there’s no broadly agreed upon way to measure them yet. It’s difficult to compare levels test to test.
 

Weeks or months between doses? Which is best?

Both the Pfizer and Moderna vaccines were tested to be given 3 and 4 weeks apart, respectively. But when the vaccines were first rolling out, shortages prompted some countries to stretch the interval between doses to 4 or more months.

Researchers who have studied the immune responses of people who were inoculated on an extended dosing schedule noticed something interesting: When the interval was stretched, people had better antibody responses. In fact, their antibody responses looked like the sky-high levels people got with hybrid immunity.

Susanna Dunachie, PhD, a global research professor at the University of Oxford in the United Kingdom, wondered why. She’s leading a team of researchers who are doing detailed studies of the immune responses of health care workers after their vaccinations.

“We found that B cells, which are the cells that make antibodies to the viral spike protein after vaccination, carry on increasing in number between 4 and 10 weeks after vaccination,” she says.

Waiting to give the second vaccine 6 to 14 weeks seems to stimulate the immune system when all of its antibody-making factories are finally up and running.

For this reason, giving the second dose at 3 weeks, she says, might be premature.

But there’s a tradeoff involved in waiting. If there are high levels of the virus circulating in a community, you want to get people fully vaccinated as quickly as possible to maximize their protection in the shortest window of time, which is what we decided to do in the United States.

Researchers say it might be a good idea to revisit the dosing interval when it’s less risky to try it.
 

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

The National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB), a 30-minute, automated, iPad-based battery of psychological tests, offers some key advantages over gold standard cognitive assessments in patients with relapsing-remitting multiple sclerosis (RRMS), new research shows.

An indicator of disease activity?

Cognitive deficits affecting a range of functions – including memory, attention and communication – are common in MS and affect 34% to 65% of patients with the disease, and the ability to detect and monitor such deficits has important implications.

Cognitive changes can provide a unique opportunity to identify acute disease activity in patients with MS that might be already occurring before physical manifestations become apparent, said Ms. Manglani. “If we can detect subtle changes in cognition that might foreshadow other symptoms of disease worsening, we can then allocate interventions that might stave off cognitive decline,” she explained.

While there is an array of well-established neuropsychological tests for the assessment of cognitive deficits, each has limitations, so a shorter, computerized, convenient, and reliable test could prove beneficial.

The NIHTB-CB has been validated in a large, nationally representative sample of individuals aged 8 to 85 and represents a potentially attractive option, yielding composite measures and scores corrected for age, gender, education, race, and ethnicity.
 

Comparative testing

To compare the test with other leading cognition tools used in MS, the investigators recruited 87 patients with RRMS (79% female, mean age 47.3 years). Participants were recruited to perform the full NIHTB-CB (about 30 minutes) and the full Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS), which takes about 90 minutes, as well as some subsets from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) covering processing speed and working memory. All patients had an EDSS of 5.0 or below and, on average, had been living with MS for about a decade.

The results showed the normative scores for NIHTB-CB had significant concordance with the other measures in terms of processing speed (concordance correlation coefficient [CCC] range = 0.28-0.48), working memory (CCC range = 0.27-0.37), and episodic memory (CCC range = 0.21-0.32). However, agreement was not shown for executive function (CCC range = 0.096-0.11).

Ms. Manglani noted executive function included various submeasures such as planning and inhibitory control. “Perhaps our gold standard measures tapped into a different facet of executive function than measured by the NIHTB,” she said.

The investigators found the proportion of participants classified as cognitively impaired was similar between the MACFIMS and the NIHTB tests.

Further assessment of fluid cognition on the NIHTB-CB – a composite of processing speed, working memory, episodic memory, and executive function that is automatically generated by the toolbox – showed the measure was negatively associated with disease severity, as measured by the EDSS (P = .006). However, the measure was not associated with a difference in depression (P = .39) or fatigue (P = .69).

Of note, a similar association with lower disease severity on the EDSS was not observed with MACFIMS.

“Interestingly, we found that only the NIHTB-CB fluid cognition was associated with disease severity, such that it was associated with nearly 11% of the variance in EDSS scores, and we were surprised that we didn’t see this with MACFIMS,” Ms. Manglani said.
 

Key advantages

The NIHTB-CB was developed as part of the NIH Blueprint for Neuroscience Research initiative and commissioned by 16 NIH Institutes to provide brief, efficient assessment measures of cognitive function.

The battery has been validated in healthy individuals and tested in other populations with neurologic disorders, including patients who have suffered stroke and traumatic brain injury.

Ms. Manglani noted that the NIHTB-CB had key advantages over other tests. “First, it is a 30-minute iPad-based battery, which is shorter than most cognitive batteries available, and one of the few that is completely computerized. In addition, it automatically scores performance and yields a report with both composite scores and scores for each subtest,” she said.

In addition, said Ms. Manglani, “the NIH toolbox has a large validation sample of individuals between 8-85 years of age and provides normative scores that account for age, gender, education, and race/ethnicity, which allows individuals’ performances to be compared with their peers.”

The findings underscore that with further validation, the battery could have an important role in MS, she added.

“The NIH Toolbox needs to be tested in all subtypes of MS, with a full range of disease severity, and in MS clinics to gauge the clinical feasibility. Larger samples and repeated assessments are also needed to assess the test-retest reliability,” she said.

The study had no specific funding. The authors have disclosed no relevant financial relationships.

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

The National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB), a 30-minute, automated, iPad-based battery of psychological tests, offers some key advantages over gold standard cognitive assessments in patients with relapsing-remitting multiple sclerosis (RRMS), new research shows.

An indicator of disease activity?

Cognitive deficits affecting a range of functions – including memory, attention and communication – are common in MS and affect 34% to 65% of patients with the disease, and the ability to detect and monitor such deficits has important implications.

Cognitive changes can provide a unique opportunity to identify acute disease activity in patients with MS that might be already occurring before physical manifestations become apparent, said Ms. Manglani. “If we can detect subtle changes in cognition that might foreshadow other symptoms of disease worsening, we can then allocate interventions that might stave off cognitive decline,” she explained.

While there is an array of well-established neuropsychological tests for the assessment of cognitive deficits, each has limitations, so a shorter, computerized, convenient, and reliable test could prove beneficial.

The NIHTB-CB has been validated in a large, nationally representative sample of individuals aged 8 to 85 and represents a potentially attractive option, yielding composite measures and scores corrected for age, gender, education, race, and ethnicity.
 

Comparative testing

To compare the test with other leading cognition tools used in MS, the investigators recruited 87 patients with RRMS (79% female, mean age 47.3 years). Participants were recruited to perform the full NIHTB-CB (about 30 minutes) and the full Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS), which takes about 90 minutes, as well as some subsets from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) covering processing speed and working memory. All patients had an EDSS of 5.0 or below and, on average, had been living with MS for about a decade.

The results showed the normative scores for NIHTB-CB had significant concordance with the other measures in terms of processing speed (concordance correlation coefficient [CCC] range = 0.28-0.48), working memory (CCC range = 0.27-0.37), and episodic memory (CCC range = 0.21-0.32). However, agreement was not shown for executive function (CCC range = 0.096-0.11).

Ms. Manglani noted executive function included various submeasures such as planning and inhibitory control. “Perhaps our gold standard measures tapped into a different facet of executive function than measured by the NIHTB,” she said.

The investigators found the proportion of participants classified as cognitively impaired was similar between the MACFIMS and the NIHTB tests.

Further assessment of fluid cognition on the NIHTB-CB – a composite of processing speed, working memory, episodic memory, and executive function that is automatically generated by the toolbox – showed the measure was negatively associated with disease severity, as measured by the EDSS (P = .006). However, the measure was not associated with a difference in depression (P = .39) or fatigue (P = .69).

Of note, a similar association with lower disease severity on the EDSS was not observed with MACFIMS.

“Interestingly, we found that only the NIHTB-CB fluid cognition was associated with disease severity, such that it was associated with nearly 11% of the variance in EDSS scores, and we were surprised that we didn’t see this with MACFIMS,” Ms. Manglani said.
 

Key advantages

The NIHTB-CB was developed as part of the NIH Blueprint for Neuroscience Research initiative and commissioned by 16 NIH Institutes to provide brief, efficient assessment measures of cognitive function.

The battery has been validated in healthy individuals and tested in other populations with neurologic disorders, including patients who have suffered stroke and traumatic brain injury.

Ms. Manglani noted that the NIHTB-CB had key advantages over other tests. “First, it is a 30-minute iPad-based battery, which is shorter than most cognitive batteries available, and one of the few that is completely computerized. In addition, it automatically scores performance and yields a report with both composite scores and scores for each subtest,” she said.

In addition, said Ms. Manglani, “the NIH toolbox has a large validation sample of individuals between 8-85 years of age and provides normative scores that account for age, gender, education, and race/ethnicity, which allows individuals’ performances to be compared with their peers.”

The findings underscore that with further validation, the battery could have an important role in MS, she added.

“The NIH Toolbox needs to be tested in all subtypes of MS, with a full range of disease severity, and in MS clinics to gauge the clinical feasibility. Larger samples and repeated assessments are also needed to assess the test-retest reliability,” she said.

The study had no specific funding. The authors have disclosed no relevant financial relationships.

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

The National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB), a 30-minute, automated, iPad-based battery of psychological tests, offers some key advantages over gold standard cognitive assessments in patients with relapsing-remitting multiple sclerosis (RRMS), new research shows.

An indicator of disease activity?

Cognitive deficits affecting a range of functions – including memory, attention and communication – are common in MS and affect 34% to 65% of patients with the disease, and the ability to detect and monitor such deficits has important implications.

Cognitive changes can provide a unique opportunity to identify acute disease activity in patients with MS that might be already occurring before physical manifestations become apparent, said Ms. Manglani. “If we can detect subtle changes in cognition that might foreshadow other symptoms of disease worsening, we can then allocate interventions that might stave off cognitive decline,” she explained.

While there is an array of well-established neuropsychological tests for the assessment of cognitive deficits, each has limitations, so a shorter, computerized, convenient, and reliable test could prove beneficial.

The NIHTB-CB has been validated in a large, nationally representative sample of individuals aged 8 to 85 and represents a potentially attractive option, yielding composite measures and scores corrected for age, gender, education, race, and ethnicity.
 

Comparative testing

To compare the test with other leading cognition tools used in MS, the investigators recruited 87 patients with RRMS (79% female, mean age 47.3 years). Participants were recruited to perform the full NIHTB-CB (about 30 minutes) and the full Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS), which takes about 90 minutes, as well as some subsets from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) covering processing speed and working memory. All patients had an EDSS of 5.0 or below and, on average, had been living with MS for about a decade.

The results showed the normative scores for NIHTB-CB had significant concordance with the other measures in terms of processing speed (concordance correlation coefficient [CCC] range = 0.28-0.48), working memory (CCC range = 0.27-0.37), and episodic memory (CCC range = 0.21-0.32). However, agreement was not shown for executive function (CCC range = 0.096-0.11).

Ms. Manglani noted executive function included various submeasures such as planning and inhibitory control. “Perhaps our gold standard measures tapped into a different facet of executive function than measured by the NIHTB,” she said.

The investigators found the proportion of participants classified as cognitively impaired was similar between the MACFIMS and the NIHTB tests.

Further assessment of fluid cognition on the NIHTB-CB – a composite of processing speed, working memory, episodic memory, and executive function that is automatically generated by the toolbox – showed the measure was negatively associated with disease severity, as measured by the EDSS (P = .006). However, the measure was not associated with a difference in depression (P = .39) or fatigue (P = .69).

Of note, a similar association with lower disease severity on the EDSS was not observed with MACFIMS.

“Interestingly, we found that only the NIHTB-CB fluid cognition was associated with disease severity, such that it was associated with nearly 11% of the variance in EDSS scores, and we were surprised that we didn’t see this with MACFIMS,” Ms. Manglani said.
 

Key advantages

The NIHTB-CB was developed as part of the NIH Blueprint for Neuroscience Research initiative and commissioned by 16 NIH Institutes to provide brief, efficient assessment measures of cognitive function.

The battery has been validated in healthy individuals and tested in other populations with neurologic disorders, including patients who have suffered stroke and traumatic brain injury.

Ms. Manglani noted that the NIHTB-CB had key advantages over other tests. “First, it is a 30-minute iPad-based battery, which is shorter than most cognitive batteries available, and one of the few that is completely computerized. In addition, it automatically scores performance and yields a report with both composite scores and scores for each subtest,” she said.

In addition, said Ms. Manglani, “the NIH toolbox has a large validation sample of individuals between 8-85 years of age and provides normative scores that account for age, gender, education, and race/ethnicity, which allows individuals’ performances to be compared with their peers.”

The findings underscore that with further validation, the battery could have an important role in MS, she added.

“The NIH Toolbox needs to be tested in all subtypes of MS, with a full range of disease severity, and in MS clinics to gauge the clinical feasibility. Larger samples and repeated assessments are also needed to assess the test-retest reliability,” she said.

The study had no specific funding. The authors have disclosed no relevant financial relationships.

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

Specialty pharmacists play a key and growing role in navigating the complexities of initiating disease-modifying therapies (DMTs) for multiple sclerosis (MS), resulting in earlier treatment, new data suggest.

Aids early intervention

A report on the Kaiser Permanente Washington (KPWA) MS Pharmacy Program detailed significant reductions in the time to address patients’ needs through the use of specialty pharmacists. In an assessment of 391 referrals to the program from 2019 to 2020, the average total time spent per patient per year dropped from 145 minutes in 2019 to 109 minutes in 2020.

Services included assessment of medication adherence, adverse drug reaction consultation, lab monitoring, patient counseling on initiation of a DMT, shared decision making, and follow-up visits.

“The KPWA MS Pharmacy Program plays an integral role in the care of patients with MS. The MS clinical pharmacists ensure patients are well informed about their DMT options and are fully educated about selected treatment,” the investigators noted.

A report on an outpatient MS clinic at Emory Healthcare, Atlanta, described how use of specialty pharmacist services resulted in a 49% reduction in time to treatment initiation with fingolimod. The time decreased from 83.9 days to 42.9 days following the introduction of specialty pharmacist services.

“Integration of a clinical pharmacy specialist in the therapeutic management of MS patients is crucial to early intervention with disease-modifying therapy,” the investigators noted.

A report on the specialty pharmacy services provided at Johns Hopkins MS Precision Medicine Center of Excellence, Baltimore, described an evaluation of 708 assessments between July 2019 and June 2020. Results showed that the vast majority (98%) of patients reported no missed days from work or school due to MS-related symptoms and that 99.3% reported no hospitalizations due to MS relapses, which are both key measures of MS treatment adherence.
 

High patient satisfaction

Patients reported high satisfaction with the in-house pharmacy on the National Association of Specialty Pharmacy’s patient satisfaction survey. In the survey, the average score was 82, compared with 79 for external specialty pharmacies.

“Moreover, patients were highly satisfied with the services provided at the pharmacy and were likely to continue receiving their comprehensive pharmacy care at our institution,” the researchers reported.

The study “highlights the value of pharmacists’ involvement in patient care and supports the need for continuation of integrated clinical services in health system specialty pharmacy,” the investigators noted.

CMSC President Scott D. Newsome, DO, director of the Neurosciences Consultation and Infusion Center at Green Spring Station, Lutherville, Maryland, and associate professor of neurology at Johns Hopkins University School of Medicine, said that as a clinician, he is highly satisfied with the specialty pharmacy services for MS at Johns Hopkins.

“Our pharmacists are fantastic in communicating with the prescriber if something comes up related to medication safety or they are concerned that the patient isn’t adhering to the medication,” Dr. Newsome said.

He noted that in addition to helping to alleviate the burden of a myriad of tasks associated with prescribing for patients with MS, specialty pharmacists may have an important impact on outcomes, although more data are needed.

“Having a specialty pharmacy involved in the care of our patients can help navigate the challenges associated with the process of obtaining approval for DMTs,” he said. “We know how important it is to expedite and shorten the time frame from writing the prescription to getting the person on their DMT.”
 

Telemedicine, other models

Although integrated specialty pharmacist services may seem out of reach for smaller MS clinics, the use of telemedicine and other models may help achieve similar results.

“A model I have seen is having pharmacists split their time between a specialty pharmacy and the MS clinic,” said Dr. Montgomery.

“A telemedicine model can also be utilized, in which a pharmacist can reach out to patients by telephone or through video visits. This would allow a pharmacist to be utilized for multiple clinics or as an MS specialist within a specialty pharmacy,” she added.

Whether provided in house or through telemedicine, a key benefit for clinicians is in freeing up valuable time, which has a domino effect in improving quality all around.

“In addition to improving safety outcomes, specialty pharmacists help with the allocation of clinic staff to other clinic responsibilities, and the utilization of services by patients results in more resources allocated for their care,” Dr. Montgomery said.

Dr. Montgomery is a nonpromotional speaker for Novartis and is on its advisory board.

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

Specialty pharmacists play a key and growing role in navigating the complexities of initiating disease-modifying therapies (DMTs) for multiple sclerosis (MS), resulting in earlier treatment, new data suggest.

Aids early intervention

A report on the Kaiser Permanente Washington (KPWA) MS Pharmacy Program detailed significant reductions in the time to address patients’ needs through the use of specialty pharmacists. In an assessment of 391 referrals to the program from 2019 to 2020, the average total time spent per patient per year dropped from 145 minutes in 2019 to 109 minutes in 2020.

Services included assessment of medication adherence, adverse drug reaction consultation, lab monitoring, patient counseling on initiation of a DMT, shared decision making, and follow-up visits.

“The KPWA MS Pharmacy Program plays an integral role in the care of patients with MS. The MS clinical pharmacists ensure patients are well informed about their DMT options and are fully educated about selected treatment,” the investigators noted.

A report on an outpatient MS clinic at Emory Healthcare, Atlanta, described how use of specialty pharmacist services resulted in a 49% reduction in time to treatment initiation with fingolimod. The time decreased from 83.9 days to 42.9 days following the introduction of specialty pharmacist services.

“Integration of a clinical pharmacy specialist in the therapeutic management of MS patients is crucial to early intervention with disease-modifying therapy,” the investigators noted.

A report on the specialty pharmacy services provided at Johns Hopkins MS Precision Medicine Center of Excellence, Baltimore, described an evaluation of 708 assessments between July 2019 and June 2020. Results showed that the vast majority (98%) of patients reported no missed days from work or school due to MS-related symptoms and that 99.3% reported no hospitalizations due to MS relapses, which are both key measures of MS treatment adherence.
 

High patient satisfaction

Patients reported high satisfaction with the in-house pharmacy on the National Association of Specialty Pharmacy’s patient satisfaction survey. In the survey, the average score was 82, compared with 79 for external specialty pharmacies.

“Moreover, patients were highly satisfied with the services provided at the pharmacy and were likely to continue receiving their comprehensive pharmacy care at our institution,” the researchers reported.

The study “highlights the value of pharmacists’ involvement in patient care and supports the need for continuation of integrated clinical services in health system specialty pharmacy,” the investigators noted.

CMSC President Scott D. Newsome, DO, director of the Neurosciences Consultation and Infusion Center at Green Spring Station, Lutherville, Maryland, and associate professor of neurology at Johns Hopkins University School of Medicine, said that as a clinician, he is highly satisfied with the specialty pharmacy services for MS at Johns Hopkins.

“Our pharmacists are fantastic in communicating with the prescriber if something comes up related to medication safety or they are concerned that the patient isn’t adhering to the medication,” Dr. Newsome said.

He noted that in addition to helping to alleviate the burden of a myriad of tasks associated with prescribing for patients with MS, specialty pharmacists may have an important impact on outcomes, although more data are needed.

“Having a specialty pharmacy involved in the care of our patients can help navigate the challenges associated with the process of obtaining approval for DMTs,” he said. “We know how important it is to expedite and shorten the time frame from writing the prescription to getting the person on their DMT.”
 

Telemedicine, other models

Although integrated specialty pharmacist services may seem out of reach for smaller MS clinics, the use of telemedicine and other models may help achieve similar results.

“A model I have seen is having pharmacists split their time between a specialty pharmacy and the MS clinic,” said Dr. Montgomery.

“A telemedicine model can also be utilized, in which a pharmacist can reach out to patients by telephone or through video visits. This would allow a pharmacist to be utilized for multiple clinics or as an MS specialist within a specialty pharmacy,” she added.

Whether provided in house or through telemedicine, a key benefit for clinicians is in freeing up valuable time, which has a domino effect in improving quality all around.

“In addition to improving safety outcomes, specialty pharmacists help with the allocation of clinic staff to other clinic responsibilities, and the utilization of services by patients results in more resources allocated for their care,” Dr. Montgomery said.

Dr. Montgomery is a nonpromotional speaker for Novartis and is on its advisory board.

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

Specialty pharmacists play a key and growing role in navigating the complexities of initiating disease-modifying therapies (DMTs) for multiple sclerosis (MS), resulting in earlier treatment, new data suggest.

Aids early intervention

A report on the Kaiser Permanente Washington (KPWA) MS Pharmacy Program detailed significant reductions in the time to address patients’ needs through the use of specialty pharmacists. In an assessment of 391 referrals to the program from 2019 to 2020, the average total time spent per patient per year dropped from 145 minutes in 2019 to 109 minutes in 2020.

Services included assessment of medication adherence, adverse drug reaction consultation, lab monitoring, patient counseling on initiation of a DMT, shared decision making, and follow-up visits.

“The KPWA MS Pharmacy Program plays an integral role in the care of patients with MS. The MS clinical pharmacists ensure patients are well informed about their DMT options and are fully educated about selected treatment,” the investigators noted.

A report on an outpatient MS clinic at Emory Healthcare, Atlanta, described how use of specialty pharmacist services resulted in a 49% reduction in time to treatment initiation with fingolimod. The time decreased from 83.9 days to 42.9 days following the introduction of specialty pharmacist services.

“Integration of a clinical pharmacy specialist in the therapeutic management of MS patients is crucial to early intervention with disease-modifying therapy,” the investigators noted.

A report on the specialty pharmacy services provided at Johns Hopkins MS Precision Medicine Center of Excellence, Baltimore, described an evaluation of 708 assessments between July 2019 and June 2020. Results showed that the vast majority (98%) of patients reported no missed days from work or school due to MS-related symptoms and that 99.3% reported no hospitalizations due to MS relapses, which are both key measures of MS treatment adherence.
 

High patient satisfaction

Patients reported high satisfaction with the in-house pharmacy on the National Association of Specialty Pharmacy’s patient satisfaction survey. In the survey, the average score was 82, compared with 79 for external specialty pharmacies.

“Moreover, patients were highly satisfied with the services provided at the pharmacy and were likely to continue receiving their comprehensive pharmacy care at our institution,” the researchers reported.

The study “highlights the value of pharmacists’ involvement in patient care and supports the need for continuation of integrated clinical services in health system specialty pharmacy,” the investigators noted.

CMSC President Scott D. Newsome, DO, director of the Neurosciences Consultation and Infusion Center at Green Spring Station, Lutherville, Maryland, and associate professor of neurology at Johns Hopkins University School of Medicine, said that as a clinician, he is highly satisfied with the specialty pharmacy services for MS at Johns Hopkins.

“Our pharmacists are fantastic in communicating with the prescriber if something comes up related to medication safety or they are concerned that the patient isn’t adhering to the medication,” Dr. Newsome said.

He noted that in addition to helping to alleviate the burden of a myriad of tasks associated with prescribing for patients with MS, specialty pharmacists may have an important impact on outcomes, although more data are needed.

“Having a specialty pharmacy involved in the care of our patients can help navigate the challenges associated with the process of obtaining approval for DMTs,” he said. “We know how important it is to expedite and shorten the time frame from writing the prescription to getting the person on their DMT.”
 

Telemedicine, other models

Although integrated specialty pharmacist services may seem out of reach for smaller MS clinics, the use of telemedicine and other models may help achieve similar results.

“A model I have seen is having pharmacists split their time between a specialty pharmacy and the MS clinic,” said Dr. Montgomery.

“A telemedicine model can also be utilized, in which a pharmacist can reach out to patients by telephone or through video visits. This would allow a pharmacist to be utilized for multiple clinics or as an MS specialist within a specialty pharmacy,” she added.

Whether provided in house or through telemedicine, a key benefit for clinicians is in freeing up valuable time, which has a domino effect in improving quality all around.

“In addition to improving safety outcomes, specialty pharmacists help with the allocation of clinic staff to other clinic responsibilities, and the utilization of services by patients results in more resources allocated for their care,” Dr. Montgomery said.

Dr. Montgomery is a nonpromotional speaker for Novartis and is on its advisory board.

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

In 2016, 17.6 million deaths occurred globally due to cardiovascular disease (CVD) with coronary artery disease (CAD) and ischemic stroke as top contributors.¹ Elevated low-density lipoprotein cholesterol (LDL-C) has been linked to greater risk of atherosclerotic cardiovascular disease (ASCVD); therefore, LDL-C reduction is imperative to decrease risk of cardiovascular (CV) morbidity and mortality.² Since 1987, statin therapy has been the mainstay of treatment for hypercholesterolemia, and current practice guidelines recommend statins as first-line therapy given demonstrated reductions in LDL-C and CV mortality reduction in robust clinical trials.^2-4 Although generally safe and well tolerated, muscle-related adverse events (AEs) limit optimal use of statins in up to 20% of individuals who have an indication for statin therapy.⁵ As a consequence, these patients receive suboptimal statin doses or no statin therapy and are at a higher risk for ASCVD.⁵

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly lower LDL-C when used as monotherapy or in combination with statins and/or other lipid-lowering therapies.⁵ These agents are currently approved by the US Food and Drug Administration as an adjunct to diet with or without other lipid-lowering therapies for the management of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia), homozygous familial hypercholesterolemia (evolocumab only), and for use in patients with established CVD unable to achieve their lipid-lowering goals with maximally tolerated statin doses and ezetimibe.⁴ With the ability to reduce LDL-C by up to 65%, PCSK9 inhibitors offer an alternative option for LDL-C and potentially CV risk reduction in statin-intolerant patients.⁵

Alirocumab, the formulary preferred PCSK9 inhibitor at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas, has been increasingly used in high-risk statin-intolerant veterans. The primary objective of this case series was to assess LDL-C reduction associated with alirocumab use in statin-intolerant veterans at the MEDVAMC. The secondary objective was to assess the incidence of CV events. This study was approved by the MEDVAMC Quality Assurance and Regulatory Affairs committee.

Methods

In this single-center case series, a retrospective chart review was conducted to identify statin-intolerant veterans who were initiated on treatment with alirocumab for LDL-C and/or CV risk reduction between June 2017 and May 2019. Adult veterans with a diagnosis of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) and/or CAD with documented statin intolerance were included in the study. Statin intolerance was defined in accordance with the National Lipid Association (NLA) definition as aninability to tolerate ≥ 2 statins with a trial of at least 1 statin at its lowest daily dose.⁵ Veterans who previously received treatment with evolocumab, those prescribed concurrent statin therapies, and those missing follow-up lipid panels at 24 weeks were excluded from the study. To assess LDL-C reduction, LDL-C at baseline was compared with LDL-C at 4 and 24 weeks. Incident CV events before and after alirocumab initiation were documented. The US Department of Veteran Affairs (VA) Computerized Patient Record System was used to collect patient data.

Data Collection, Measures, and Analysis

Electronic health records of all eligible patients who received alirocumab were reviewed, and basic demographics (patient age, sex, and race/ethnicity) as well as medical characteristics at baseline were collected. To confirm statin intolerance, each veteran’s history of statin use and use of additional lipid-lowering agents was documented. CV history was measured with an index of categorical measures for hypertension, confirmed CAD, hyperlipidemia, heart failure, arrhythmias, peripheral artery disease, stroke, diabetes mellitus, and hypothyroidism. Additionally, concomitant medications, such as aspirin, P2Y₁₂ inhibitors, β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers that patients were taking also were collected. Each veteran’s lipid panel at baseline, and at 4 and 24 weeks posttreatment initiation, also was extracted. Continuous variables were summarized with means (SD), and categorical variables were summarized with frequencies and proportions. The paired Wilcoxon signed rank test was used to compare LDL-C at 4 and 24 weeks after alirocumab initiation with patients’ baseline LDL-C.

Results

Between June 2017 and May 2019, 122 veterans were initiated on alirocumab. Of these veterans, 98 were excluded: 35 concurrently received statin therapy, 33 missed follow-up lipid panels, 21 had previously received evolocumab, 6 failed to meet the NLA definition for statin intolerance, 2 did not fill active alirocumab prescriptions, and 1 had an incalculable LDL-C with a baseline triglyceride level of 3079 mg/dL. This resulted in 24 veterans included in the analysis.

Most participants were male (87.5%) and White veterans (79.2%) with a mean (SD) age of 66.0 (8.4) years and mean (SD) baseline LDL-C of 161.9 (74.3) mg/dL. At baseline, 21 veterans had a history of primary hyperlipidemia, 19 had a history of CAD, and 2 had a history of heterozygous familial hypercholesterolemia. Of the 24 patients included, the most trialed statins before alirocumab initiation were atorvastatin (95.8%), simvastatin (79.2%), rosuvastatin (79.2%), and pravastatin (62.5%) (Table).

LDL-C Reduction

Veterans were initially treated with alirocumab 75 mg administered subcutaneously every 2 weeks; however, 11 veterans required a dose increase to 150 mg every 2 weeks. At treatment week 4, the median LDL-C reduction was 78.5 mg/dL (IQR, 28.0-107.3; P < .01), and at treatment week 24, the median LDL-C reduction was 55.6 mg/dL (IQR, 18.6-85.3; P < .01). This equated to median LDL-C reductions from baseline of 48.5% at week 4 and 34.3% at week 24. A total of 3 veterans experienced LDL-C increases following initiation of alirocumab. At week 4, 9 veterans were noted to have an LDL-C reduction > 50%, 7 veterans had an LDL-C reduction between 30% and 50%, and 5 veterans had an LDL-C reduction of < 30%. At week 24, 6 had an LDL-C reduction > 50%, 9 veterans had an LDL-C reduction between 30% and 50%, and 6 had a LDL-C reduction < 30%.

Cardiovascular Events

Before alirocumab initiation, 22 CV events and interventions were reported in 16 veterans: 12 percutaneous coronary interventions, 5 coronary artery bypass surgeries (CABG), 4 myocardial infarctions, and 1 transient ischemic attack. One month following alirocumab initiation, 1 veteran underwent a CABG after a non-ST-elevation myocardial infarction (NSTEMI).

Safety and Tolerability

Alirocumab was discontinued in 5 veterans due to 4 cases of intolerance (reported memory loss, lethargy, myalgias, and body aches with dyspnea) and 1 case of persistent LDL-C of < 40 mg/dL. Alirocumab was discontinued after 1 year in 2 patients (persistent LDL-C < 40 mg/dL and reported memory loss) and after 6 months in the veteran who reported lethargy. Alirocumab was discontinued after 4 months in the veteran with myalgias and within 2 months in the veteran with body aches and dyspnea. No other AEs were reported.

Discussion

The Efficacy and Safety of Alirocumab vs Ezetimibe in Statin-Intolerant Veterans With a Statin Rechallenge Arm trial is the first clinical trial to examine the efficacy and safety of alirocumab use in statin-intolerant patients. In the trial, 314 patients were randomized to receive alirocumab, ezetimibe, or an atorvastatin rechallenge.⁶ At 24 weeks, alirocumab reduced mean (SE) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .01).⁶ Fewer skeletal-muscle-related events also were noted with alirocumab vs atorvastatin (hazard ratio, 0.61; 95% CI, 0.38-0.99; P = .04).⁶

In this case series, an LDL-C reduction of > 50% was observed in 9 veterans (42.9%) following 4 weeks of treatment; however, LDL-C reduction of > 50% compared with baseline was sustained in only 6 veterans (28.6%) at week 24. Additionally, LDL-C increases from baseline were observed in 3 veterans; the reasoning for the observed increase was unclear, but this may have been due to nonadherence and dietary factors.⁴ Although a majority of patients saw a significant and clinically meaningful reduction in LDL-C, the group of patients with an increase in the same may have benefitted from targeted intervention to improve medication and dietary adherence. PCSK9 inhibitor resistance also may have contributed to an increase in LDL-C during treatment.⁷

Of the 24 patients included, 4 reported AEs resulted in therapy discontinuation. Memory impairment, a rare AE of alirocumab, was reported 1 year following alirocumab initiation. Additionally, lethargy was reported after 6 months of treatment. Myalgia also was reported in a veteran 4 months following treatment, and 1 veteran experienced body aches and dyspnea < 2 months following treatment. The most common AEs associated with alirocumab, as noted in previous safety and efficacy clinical trials, included: nasopharyngitis, injection site reaction, influenza, urinary tract infection, and myalgias.⁸ Many of these more common AEs may be subclinical and underreported. This small case series, however, detected 4 events severe enough to lead to therapy discontinuation. Although this sample is not representative of all statin-intolerant patients who receive treatment with alirocumab, our findings suggest the need for patient education on potential AEs before therapy initiation and clinician monitoring at follow-up visits.

The ODYSSEY OUTCOMES trial established a CV benefit associated with alirocumab; however, patients included had a recent acute coronary syndrome event and were receiving a high-intensity statin.⁹ This case series is unique in that before alirocumab initiation, 22 CV events/interventions were reported in the sample of 24 patients. After therapy initiation, 1 patient underwent a CABG after an NSTEMI in the month following initiation. This suggests that cardiac complications are possible after PCSK-9 initiation; however, little information can be gained from 1 patient. Nevertheless, early therapy failure should be investigated in the context of real-world use in statin-intolerant patients. This is a complex task, however, given the difficulties of achieving a balanced study design. Statin intolerance is a clear source of selection bias into treatment with alirocumab as patients in this population have already initiated and failed statin therapy. The prevalence of prior CV events and the time-dependent association between prior and future CV events stand as another complex confounder. Although there is a clear and pressing need to understand the risks and benefits of PCSK9 therapy in statin-intolerant patients, future research in this area will need to cautiously address these important sources of bias.

Overall, the results of this case series support LDL-C reduction associated with alirocumab in the absence of statin therapy. Despite favorable results, use of alirocumab may be limited by cost and its subcutaneous route of administration. Bempedoic acid, an oral, once-daily lipid-lowering agent poses an alternative to PCSK9 inhibitors, but further data regarding CV outcomes with this agent is needed.^10,11 Robust randomized controlled trials also are needed to evaluate CV outcomes for alirocumab use in statin-intolerant veterans.

Limitations

Only 24 veterans were included in the study, reflecting 20% of the charts reviewed (80% exclusion rate), and in this small sample, only 1 CV event was observed. Both of these serve as threats to external validity. As the study information was extracted from chart review, the results may be limited by coding or historical bias. Medical information from outside institutions may be missing from medical records. Additionally, results may be skewed by possible documentation errors. Furthermore, the period between previous CV events and alirocumab initiation is unclear as event dates were often not recorded if treatment was received at an outside institution.

Due to the short follow-up period, the case series is limited in its assessment of CV outcomes and safety outcomes. Larger studies over an extended period are needed to assess CV outcomes and safety of alirocumab use in statin-intolerant patients. Also, medication adherence was not assessed. Given the impact of medication adherence on LDL-C reduction, it is unclear what role medication adherence played in the LDL-C reduction observed in this study.⁴

Conclusions

Alirocumab use in 24 statin-intolerant veterans resulted in a significant reduction in LDL-C at 4 and 24 weeks after initiation. In addition, 1 CV event/intervention was observed following alirocumab initiation, although this should be interpreted with caution due to the retrospective nature of this case series, small sample size, and short follow-up period. Large, long-term studies would better evaluate the CV benefit associated with alirocumab therapy in a veteran population.

In 2016, 17.6 million deaths occurred globally due to cardiovascular disease (CVD) with coronary artery disease (CAD) and ischemic stroke as top contributors.¹ Elevated low-density lipoprotein cholesterol (LDL-C) has been linked to greater risk of atherosclerotic cardiovascular disease (ASCVD); therefore, LDL-C reduction is imperative to decrease risk of cardiovascular (CV) morbidity and mortality.² Since 1987, statin therapy has been the mainstay of treatment for hypercholesterolemia, and current practice guidelines recommend statins as first-line therapy given demonstrated reductions in LDL-C and CV mortality reduction in robust clinical trials.^2-4 Although generally safe and well tolerated, muscle-related adverse events (AEs) limit optimal use of statins in up to 20% of individuals who have an indication for statin therapy.⁵ As a consequence, these patients receive suboptimal statin doses or no statin therapy and are at a higher risk for ASCVD.⁵

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly lower LDL-C when used as monotherapy or in combination with statins and/or other lipid-lowering therapies.⁵ These agents are currently approved by the US Food and Drug Administration as an adjunct to diet with or without other lipid-lowering therapies for the management of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia), homozygous familial hypercholesterolemia (evolocumab only), and for use in patients with established CVD unable to achieve their lipid-lowering goals with maximally tolerated statin doses and ezetimibe.⁴ With the ability to reduce LDL-C by up to 65%, PCSK9 inhibitors offer an alternative option for LDL-C and potentially CV risk reduction in statin-intolerant patients.⁵

Alirocumab, the formulary preferred PCSK9 inhibitor at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas, has been increasingly used in high-risk statin-intolerant veterans. The primary objective of this case series was to assess LDL-C reduction associated with alirocumab use in statin-intolerant veterans at the MEDVAMC. The secondary objective was to assess the incidence of CV events. This study was approved by the MEDVAMC Quality Assurance and Regulatory Affairs committee.

Methods

In this single-center case series, a retrospective chart review was conducted to identify statin-intolerant veterans who were initiated on treatment with alirocumab for LDL-C and/or CV risk reduction between June 2017 and May 2019. Adult veterans with a diagnosis of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) and/or CAD with documented statin intolerance were included in the study. Statin intolerance was defined in accordance with the National Lipid Association (NLA) definition as aninability to tolerate ≥ 2 statins with a trial of at least 1 statin at its lowest daily dose.⁵ Veterans who previously received treatment with evolocumab, those prescribed concurrent statin therapies, and those missing follow-up lipid panels at 24 weeks were excluded from the study. To assess LDL-C reduction, LDL-C at baseline was compared with LDL-C at 4 and 24 weeks. Incident CV events before and after alirocumab initiation were documented. The US Department of Veteran Affairs (VA) Computerized Patient Record System was used to collect patient data.

Data Collection, Measures, and Analysis

Electronic health records of all eligible patients who received alirocumab were reviewed, and basic demographics (patient age, sex, and race/ethnicity) as well as medical characteristics at baseline were collected. To confirm statin intolerance, each veteran’s history of statin use and use of additional lipid-lowering agents was documented. CV history was measured with an index of categorical measures for hypertension, confirmed CAD, hyperlipidemia, heart failure, arrhythmias, peripheral artery disease, stroke, diabetes mellitus, and hypothyroidism. Additionally, concomitant medications, such as aspirin, P2Y₁₂ inhibitors, β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers that patients were taking also were collected. Each veteran’s lipid panel at baseline, and at 4 and 24 weeks posttreatment initiation, also was extracted. Continuous variables were summarized with means (SD), and categorical variables were summarized with frequencies and proportions. The paired Wilcoxon signed rank test was used to compare LDL-C at 4 and 24 weeks after alirocumab initiation with patients’ baseline LDL-C.

Results

Between June 2017 and May 2019, 122 veterans were initiated on alirocumab. Of these veterans, 98 were excluded: 35 concurrently received statin therapy, 33 missed follow-up lipid panels, 21 had previously received evolocumab, 6 failed to meet the NLA definition for statin intolerance, 2 did not fill active alirocumab prescriptions, and 1 had an incalculable LDL-C with a baseline triglyceride level of 3079 mg/dL. This resulted in 24 veterans included in the analysis.

Most participants were male (87.5%) and White veterans (79.2%) with a mean (SD) age of 66.0 (8.4) years and mean (SD) baseline LDL-C of 161.9 (74.3) mg/dL. At baseline, 21 veterans had a history of primary hyperlipidemia, 19 had a history of CAD, and 2 had a history of heterozygous familial hypercholesterolemia. Of the 24 patients included, the most trialed statins before alirocumab initiation were atorvastatin (95.8%), simvastatin (79.2%), rosuvastatin (79.2%), and pravastatin (62.5%) (Table).

LDL-C Reduction

Veterans were initially treated with alirocumab 75 mg administered subcutaneously every 2 weeks; however, 11 veterans required a dose increase to 150 mg every 2 weeks. At treatment week 4, the median LDL-C reduction was 78.5 mg/dL (IQR, 28.0-107.3; P < .01), and at treatment week 24, the median LDL-C reduction was 55.6 mg/dL (IQR, 18.6-85.3; P < .01). This equated to median LDL-C reductions from baseline of 48.5% at week 4 and 34.3% at week 24. A total of 3 veterans experienced LDL-C increases following initiation of alirocumab. At week 4, 9 veterans were noted to have an LDL-C reduction > 50%, 7 veterans had an LDL-C reduction between 30% and 50%, and 5 veterans had an LDL-C reduction of < 30%. At week 24, 6 had an LDL-C reduction > 50%, 9 veterans had an LDL-C reduction between 30% and 50%, and 6 had a LDL-C reduction < 30%.

Cardiovascular Events

Before alirocumab initiation, 22 CV events and interventions were reported in 16 veterans: 12 percutaneous coronary interventions, 5 coronary artery bypass surgeries (CABG), 4 myocardial infarctions, and 1 transient ischemic attack. One month following alirocumab initiation, 1 veteran underwent a CABG after a non-ST-elevation myocardial infarction (NSTEMI).

Safety and Tolerability

Alirocumab was discontinued in 5 veterans due to 4 cases of intolerance (reported memory loss, lethargy, myalgias, and body aches with dyspnea) and 1 case of persistent LDL-C of < 40 mg/dL. Alirocumab was discontinued after 1 year in 2 patients (persistent LDL-C < 40 mg/dL and reported memory loss) and after 6 months in the veteran who reported lethargy. Alirocumab was discontinued after 4 months in the veteran with myalgias and within 2 months in the veteran with body aches and dyspnea. No other AEs were reported.

Discussion

The Efficacy and Safety of Alirocumab vs Ezetimibe in Statin-Intolerant Veterans With a Statin Rechallenge Arm trial is the first clinical trial to examine the efficacy and safety of alirocumab use in statin-intolerant patients. In the trial, 314 patients were randomized to receive alirocumab, ezetimibe, or an atorvastatin rechallenge.⁶ At 24 weeks, alirocumab reduced mean (SE) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .01).⁶ Fewer skeletal-muscle-related events also were noted with alirocumab vs atorvastatin (hazard ratio, 0.61; 95% CI, 0.38-0.99; P = .04).⁶

In this case series, an LDL-C reduction of > 50% was observed in 9 veterans (42.9%) following 4 weeks of treatment; however, LDL-C reduction of > 50% compared with baseline was sustained in only 6 veterans (28.6%) at week 24. Additionally, LDL-C increases from baseline were observed in 3 veterans; the reasoning for the observed increase was unclear, but this may have been due to nonadherence and dietary factors.⁴ Although a majority of patients saw a significant and clinically meaningful reduction in LDL-C, the group of patients with an increase in the same may have benefitted from targeted intervention to improve medication and dietary adherence. PCSK9 inhibitor resistance also may have contributed to an increase in LDL-C during treatment.⁷

Of the 24 patients included, 4 reported AEs resulted in therapy discontinuation. Memory impairment, a rare AE of alirocumab, was reported 1 year following alirocumab initiation. Additionally, lethargy was reported after 6 months of treatment. Myalgia also was reported in a veteran 4 months following treatment, and 1 veteran experienced body aches and dyspnea < 2 months following treatment. The most common AEs associated with alirocumab, as noted in previous safety and efficacy clinical trials, included: nasopharyngitis, injection site reaction, influenza, urinary tract infection, and myalgias.⁸ Many of these more common AEs may be subclinical and underreported. This small case series, however, detected 4 events severe enough to lead to therapy discontinuation. Although this sample is not representative of all statin-intolerant patients who receive treatment with alirocumab, our findings suggest the need for patient education on potential AEs before therapy initiation and clinician monitoring at follow-up visits.

The ODYSSEY OUTCOMES trial established a CV benefit associated with alirocumab; however, patients included had a recent acute coronary syndrome event and were receiving a high-intensity statin.⁹ This case series is unique in that before alirocumab initiation, 22 CV events/interventions were reported in the sample of 24 patients. After therapy initiation, 1 patient underwent a CABG after an NSTEMI in the month following initiation. This suggests that cardiac complications are possible after PCSK-9 initiation; however, little information can be gained from 1 patient. Nevertheless, early therapy failure should be investigated in the context of real-world use in statin-intolerant patients. This is a complex task, however, given the difficulties of achieving a balanced study design. Statin intolerance is a clear source of selection bias into treatment with alirocumab as patients in this population have already initiated and failed statin therapy. The prevalence of prior CV events and the time-dependent association between prior and future CV events stand as another complex confounder. Although there is a clear and pressing need to understand the risks and benefits of PCSK9 therapy in statin-intolerant patients, future research in this area will need to cautiously address these important sources of bias.

Overall, the results of this case series support LDL-C reduction associated with alirocumab in the absence of statin therapy. Despite favorable results, use of alirocumab may be limited by cost and its subcutaneous route of administration. Bempedoic acid, an oral, once-daily lipid-lowering agent poses an alternative to PCSK9 inhibitors, but further data regarding CV outcomes with this agent is needed.^10,11 Robust randomized controlled trials also are needed to evaluate CV outcomes for alirocumab use in statin-intolerant veterans.

Limitations

Only 24 veterans were included in the study, reflecting 20% of the charts reviewed (80% exclusion rate), and in this small sample, only 1 CV event was observed. Both of these serve as threats to external validity. As the study information was extracted from chart review, the results may be limited by coding or historical bias. Medical information from outside institutions may be missing from medical records. Additionally, results may be skewed by possible documentation errors. Furthermore, the period between previous CV events and alirocumab initiation is unclear as event dates were often not recorded if treatment was received at an outside institution.

Due to the short follow-up period, the case series is limited in its assessment of CV outcomes and safety outcomes. Larger studies over an extended period are needed to assess CV outcomes and safety of alirocumab use in statin-intolerant patients. Also, medication adherence was not assessed. Given the impact of medication adherence on LDL-C reduction, it is unclear what role medication adherence played in the LDL-C reduction observed in this study.⁴

Conclusions

Alirocumab use in 24 statin-intolerant veterans resulted in a significant reduction in LDL-C at 4 and 24 weeks after initiation. In addition, 1 CV event/intervention was observed following alirocumab initiation, although this should be interpreted with caution due to the retrospective nature of this case series, small sample size, and short follow-up period. Large, long-term studies would better evaluate the CV benefit associated with alirocumab therapy in a veteran population.

In 2016, 17.6 million deaths occurred globally due to cardiovascular disease (CVD) with coronary artery disease (CAD) and ischemic stroke as top contributors.¹ Elevated low-density lipoprotein cholesterol (LDL-C) has been linked to greater risk of atherosclerotic cardiovascular disease (ASCVD); therefore, LDL-C reduction is imperative to decrease risk of cardiovascular (CV) morbidity and mortality.² Since 1987, statin therapy has been the mainstay of treatment for hypercholesterolemia, and current practice guidelines recommend statins as first-line therapy given demonstrated reductions in LDL-C and CV mortality reduction in robust clinical trials.^2-4 Although generally safe and well tolerated, muscle-related adverse events (AEs) limit optimal use of statins in up to 20% of individuals who have an indication for statin therapy.⁵ As a consequence, these patients receive suboptimal statin doses or no statin therapy and are at a higher risk for ASCVD.⁵

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly lower LDL-C when used as monotherapy or in combination with statins and/or other lipid-lowering therapies.⁵ These agents are currently approved by the US Food and Drug Administration as an adjunct to diet with or without other lipid-lowering therapies for the management of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia), homozygous familial hypercholesterolemia (evolocumab only), and for use in patients with established CVD unable to achieve their lipid-lowering goals with maximally tolerated statin doses and ezetimibe.⁴ With the ability to reduce LDL-C by up to 65%, PCSK9 inhibitors offer an alternative option for LDL-C and potentially CV risk reduction in statin-intolerant patients.⁵

Alirocumab, the formulary preferred PCSK9 inhibitor at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas, has been increasingly used in high-risk statin-intolerant veterans. The primary objective of this case series was to assess LDL-C reduction associated with alirocumab use in statin-intolerant veterans at the MEDVAMC. The secondary objective was to assess the incidence of CV events. This study was approved by the MEDVAMC Quality Assurance and Regulatory Affairs committee.

Methods

In this single-center case series, a retrospective chart review was conducted to identify statin-intolerant veterans who were initiated on treatment with alirocumab for LDL-C and/or CV risk reduction between June 2017 and May 2019. Adult veterans with a diagnosis of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) and/or CAD with documented statin intolerance were included in the study. Statin intolerance was defined in accordance with the National Lipid Association (NLA) definition as aninability to tolerate ≥ 2 statins with a trial of at least 1 statin at its lowest daily dose.⁵ Veterans who previously received treatment with evolocumab, those prescribed concurrent statin therapies, and those missing follow-up lipid panels at 24 weeks were excluded from the study. To assess LDL-C reduction, LDL-C at baseline was compared with LDL-C at 4 and 24 weeks. Incident CV events before and after alirocumab initiation were documented. The US Department of Veteran Affairs (VA) Computerized Patient Record System was used to collect patient data.

Data Collection, Measures, and Analysis

Electronic health records of all eligible patients who received alirocumab were reviewed, and basic demographics (patient age, sex, and race/ethnicity) as well as medical characteristics at baseline were collected. To confirm statin intolerance, each veteran’s history of statin use and use of additional lipid-lowering agents was documented. CV history was measured with an index of categorical measures for hypertension, confirmed CAD, hyperlipidemia, heart failure, arrhythmias, peripheral artery disease, stroke, diabetes mellitus, and hypothyroidism. Additionally, concomitant medications, such as aspirin, P2Y₁₂ inhibitors, β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers that patients were taking also were collected. Each veteran’s lipid panel at baseline, and at 4 and 24 weeks posttreatment initiation, also was extracted. Continuous variables were summarized with means (SD), and categorical variables were summarized with frequencies and proportions. The paired Wilcoxon signed rank test was used to compare LDL-C at 4 and 24 weeks after alirocumab initiation with patients’ baseline LDL-C.

Results

Between June 2017 and May 2019, 122 veterans were initiated on alirocumab. Of these veterans, 98 were excluded: 35 concurrently received statin therapy, 33 missed follow-up lipid panels, 21 had previously received evolocumab, 6 failed to meet the NLA definition for statin intolerance, 2 did not fill active alirocumab prescriptions, and 1 had an incalculable LDL-C with a baseline triglyceride level of 3079 mg/dL. This resulted in 24 veterans included in the analysis.

Most participants were male (87.5%) and White veterans (79.2%) with a mean (SD) age of 66.0 (8.4) years and mean (SD) baseline LDL-C of 161.9 (74.3) mg/dL. At baseline, 21 veterans had a history of primary hyperlipidemia, 19 had a history of CAD, and 2 had a history of heterozygous familial hypercholesterolemia. Of the 24 patients included, the most trialed statins before alirocumab initiation were atorvastatin (95.8%), simvastatin (79.2%), rosuvastatin (79.2%), and pravastatin (62.5%) (Table).

LDL-C Reduction

Veterans were initially treated with alirocumab 75 mg administered subcutaneously every 2 weeks; however, 11 veterans required a dose increase to 150 mg every 2 weeks. At treatment week 4, the median LDL-C reduction was 78.5 mg/dL (IQR, 28.0-107.3; P < .01), and at treatment week 24, the median LDL-C reduction was 55.6 mg/dL (IQR, 18.6-85.3; P < .01). This equated to median LDL-C reductions from baseline of 48.5% at week 4 and 34.3% at week 24. A total of 3 veterans experienced LDL-C increases following initiation of alirocumab. At week 4, 9 veterans were noted to have an LDL-C reduction > 50%, 7 veterans had an LDL-C reduction between 30% and 50%, and 5 veterans had an LDL-C reduction of < 30%. At week 24, 6 had an LDL-C reduction > 50%, 9 veterans had an LDL-C reduction between 30% and 50%, and 6 had a LDL-C reduction < 30%.

Cardiovascular Events

Before alirocumab initiation, 22 CV events and interventions were reported in 16 veterans: 12 percutaneous coronary interventions, 5 coronary artery bypass surgeries (CABG), 4 myocardial infarctions, and 1 transient ischemic attack. One month following alirocumab initiation, 1 veteran underwent a CABG after a non-ST-elevation myocardial infarction (NSTEMI).

Safety and Tolerability

Alirocumab was discontinued in 5 veterans due to 4 cases of intolerance (reported memory loss, lethargy, myalgias, and body aches with dyspnea) and 1 case of persistent LDL-C of < 40 mg/dL. Alirocumab was discontinued after 1 year in 2 patients (persistent LDL-C < 40 mg/dL and reported memory loss) and after 6 months in the veteran who reported lethargy. Alirocumab was discontinued after 4 months in the veteran with myalgias and within 2 months in the veteran with body aches and dyspnea. No other AEs were reported.

Discussion

The Efficacy and Safety of Alirocumab vs Ezetimibe in Statin-Intolerant Veterans With a Statin Rechallenge Arm trial is the first clinical trial to examine the efficacy and safety of alirocumab use in statin-intolerant patients. In the trial, 314 patients were randomized to receive alirocumab, ezetimibe, or an atorvastatin rechallenge.⁶ At 24 weeks, alirocumab reduced mean (SE) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .01).⁶ Fewer skeletal-muscle-related events also were noted with alirocumab vs atorvastatin (hazard ratio, 0.61; 95% CI, 0.38-0.99; P = .04).⁶

In this case series, an LDL-C reduction of > 50% was observed in 9 veterans (42.9%) following 4 weeks of treatment; however, LDL-C reduction of > 50% compared with baseline was sustained in only 6 veterans (28.6%) at week 24. Additionally, LDL-C increases from baseline were observed in 3 veterans; the reasoning for the observed increase was unclear, but this may have been due to nonadherence and dietary factors.⁴ Although a majority of patients saw a significant and clinically meaningful reduction in LDL-C, the group of patients with an increase in the same may have benefitted from targeted intervention to improve medication and dietary adherence. PCSK9 inhibitor resistance also may have contributed to an increase in LDL-C during treatment.⁷

Of the 24 patients included, 4 reported AEs resulted in therapy discontinuation. Memory impairment, a rare AE of alirocumab, was reported 1 year following alirocumab initiation. Additionally, lethargy was reported after 6 months of treatment. Myalgia also was reported in a veteran 4 months following treatment, and 1 veteran experienced body aches and dyspnea < 2 months following treatment. The most common AEs associated with alirocumab, as noted in previous safety and efficacy clinical trials, included: nasopharyngitis, injection site reaction, influenza, urinary tract infection, and myalgias.⁸ Many of these more common AEs may be subclinical and underreported. This small case series, however, detected 4 events severe enough to lead to therapy discontinuation. Although this sample is not representative of all statin-intolerant patients who receive treatment with alirocumab, our findings suggest the need for patient education on potential AEs before therapy initiation and clinician monitoring at follow-up visits.

The ODYSSEY OUTCOMES trial established a CV benefit associated with alirocumab; however, patients included had a recent acute coronary syndrome event and were receiving a high-intensity statin.⁹ This case series is unique in that before alirocumab initiation, 22 CV events/interventions were reported in the sample of 24 patients. After therapy initiation, 1 patient underwent a CABG after an NSTEMI in the month following initiation. This suggests that cardiac complications are possible after PCSK-9 initiation; however, little information can be gained from 1 patient. Nevertheless, early therapy failure should be investigated in the context of real-world use in statin-intolerant patients. This is a complex task, however, given the difficulties of achieving a balanced study design. Statin intolerance is a clear source of selection bias into treatment with alirocumab as patients in this population have already initiated and failed statin therapy. The prevalence of prior CV events and the time-dependent association between prior and future CV events stand as another complex confounder. Although there is a clear and pressing need to understand the risks and benefits of PCSK9 therapy in statin-intolerant patients, future research in this area will need to cautiously address these important sources of bias.

Overall, the results of this case series support LDL-C reduction associated with alirocumab in the absence of statin therapy. Despite favorable results, use of alirocumab may be limited by cost and its subcutaneous route of administration. Bempedoic acid, an oral, once-daily lipid-lowering agent poses an alternative to PCSK9 inhibitors, but further data regarding CV outcomes with this agent is needed.^10,11 Robust randomized controlled trials also are needed to evaluate CV outcomes for alirocumab use in statin-intolerant veterans.

Limitations

Only 24 veterans were included in the study, reflecting 20% of the charts reviewed (80% exclusion rate), and in this small sample, only 1 CV event was observed. Both of these serve as threats to external validity. As the study information was extracted from chart review, the results may be limited by coding or historical bias. Medical information from outside institutions may be missing from medical records. Additionally, results may be skewed by possible documentation errors. Furthermore, the period between previous CV events and alirocumab initiation is unclear as event dates were often not recorded if treatment was received at an outside institution.

Due to the short follow-up period, the case series is limited in its assessment of CV outcomes and safety outcomes. Larger studies over an extended period are needed to assess CV outcomes and safety of alirocumab use in statin-intolerant patients. Also, medication adherence was not assessed. Given the impact of medication adherence on LDL-C reduction, it is unclear what role medication adherence played in the LDL-C reduction observed in this study.⁴

Conclusions

Alirocumab use in 24 statin-intolerant veterans resulted in a significant reduction in LDL-C at 4 and 24 weeks after initiation. In addition, 1 CV event/intervention was observed following alirocumab initiation, although this should be interpreted with caution due to the retrospective nature of this case series, small sample size, and short follow-up period. Large, long-term studies would better evaluate the CV benefit associated with alirocumab therapy in a veteran population.

Nearly 25% of patients served in the US Department of Veterans Affairs (VA) have been diagnosed with type 2 diabetes mellitus (T2DM), although the prevalence among adults in the United States is 9%.¹ Patients with DM typically monitor their blood glucose using intermittent fingerstick self-testing. Continuous glucose monitoring (CGM) might offer a more comprehensive picture of glucose control to improve disease management. Within the VA, criteria for CGM use varies among facilities, but generally veterans prescribed at least 3 daily insulin injections and 4 daily blood glucose checks qualify.²

CGM therapy has been extensively researched for type 1 DM (T1DM); however, outcomes of CGM use among older adults with T2DM have not been fully evaluated. In a 2018 review of randomized clinical trials evaluating CGM use, 17 trials examined only patients with T1DM (2009 participants), 4 included only patients with T2DM patients (547 patients), 3 evaluated patients with T1DM or T2DM (655 patients), and 3 included women with gestational diabetes (585 patients).³ Of 27 studies that included change in hemoglobin A_1c (HbA_1c) as an endpoint, 15 found a statistically significant reduction in HbA_1c for the CGM group. Four trials evaluated CGM use in adults with T2DM and 3 found no difference in HbA_1c overall. However, 1 study found a difference in HbA_1c only in individuals aged < 65 years, and another study found a greater improvement in the CGM group (approximately 0.5%).^4,5 These mixed results indicate a need for further subgroup analysis in specific populations to determine the optimal use of CGM in adults with T2DM. Although this study was not designed to measure changes in hypoglycemic episodes or the relative efficacy of different CGM products, it establishes a baseline from which to conduct additional research.

Our primary objective was to determine change in HbA_1c in each patient from the year before CGM initiation to the year after. Secondary objectives included changes in blood pressure (BP), weight, and diabetes-related hospital and clinic visits during the same time frame. We also completed subanalysis comparing primary outcomes in engaged or adherent patients compared with the entire study group. This study was completed as a quality improvement project with approval from the Lexington Veterans Affairs Health Care System in Kentucky information security office and was exempted from institutional review board review.

Methods

This project was a retrospective evaluation using the VA database of patient records. Rather than using a control group, our study used a pre–post model to determine the impact of CGM for each patient. For the primary outcome, average HbA_1c values were calculated for the year before and year after CGM initiation. Hemoglobin and hematocrit values were included if reported within 3 months of the HbA_1c values to ensure validity of HbA_1c results. Average HbA_1c was 13.37 g/dL (range, 10.5-17.3), and average hematocrit was 43.3% (range, 36-52). Change in average HbA_1c was recorded for each patient. Based on research by Taylor and colleagues, a change in HbA_1c of 0.8% was considered clinically significant for this project.⁶

Mean BP and weight were calculated for the years before and after CGM initiation. Only values for routine clinic visits were included; values taken during an acute health incident, inpatient stay, infusion clinic appointments, or home readings were excluded. Changes were recorded for each patient. Patient encounter notes were used to determine the number of DM-related hospital, emergency department, and clinic visits, such as nephrology, podiatry, vascular medicine, or infectious disease clinic or inpatient encounters during the study period. Routine endocrinology or primary care visits were not included, and patient care notes were consulted to ensure that the encounters were related to a DM complication. The change in number of visits was calculated for each patient.

Adherence was defined as patients receiving active medication management, documented treatment regimen adherence, and > 4 annual endocrinology clinic visits. Active medication management was defined as having > 1 dosage or medication change for oral or noninsulin antihyperglycemics, initiation, or adjustment of insulin dosages according to the patient records. Treatment adherence was determined based on medication reconciliation notes and refill request history. Only endocrinology clinic visits at VA outpatient clinics were included.

Study Population

A sample of 166 patients was needed to detect an HbA_1c change of 0.8 per power analysis. The normal approximation method using the z statistic was used, with 2-tailed α = 0.05, β = 0.05, E = 0.8, and S = 1.2. We randomly selected 175 patients among all individuals with an active prescription for CGM in 2018 and 2019, who had a diagnosis of T2DM, and were managed by VA endocrinology clinics (including endocrine clinics, diabetes clinics, and patient aligned care team clinics) at 87 VA medical centers. Patients with types of DM other than T2DM were excluded, as well as those with a diagnosed hemoglobinopathy or HbA_1c < 10 g/dL. The adherent subgroup included 40 patients of the 175 sample population (Table 1).

Results

Both the total population and the adherent subgroup showed reduction in HbA_1c, the primary endpoint. The complete population showed a HbA_1c change of –0.3 (95% CI, –0.4 to –0.2), and the adherent subgroup had a change of –1.3 (95% CI, –1.5 to –1.2). The total survey population had a mean change in weight of –1.9 lb (–0.9 kg) (95% CI, –3.7 to –0.1) and the adherent subgroup had an average change of –8.0 lb (–3.6 kg) (95% CI, –12.3 to –3.8). Average systolic BP changes were –0.1 mm Hg (95% CI, –1.6 to 1.5) in the total population and +3.3 mm Hg (95% CI, –0.01 to 6.22) in the adherent subgroup. A decrease in total encounters for DM complications was observed in the population (–0.3 total encounters per patient, 95% CI, –0.5 to –0.2) and the adherent subgroup (–0.6 total encounters per patient, 95% CI, –1.0 to –0.1) (Table 2).

Before the study, 107 (61.1%) patients were taking oral or noninsulin DM medication only, 4 (2.3%) were on insulin only, and 64 (36.6%) were prescribed both insulin and oral/noninsulin antihyperglycemics. Noninsulin and oral antihyperglycemic regimens included combinations of biguanide, dipeptidyl peptidase- 4 inhibitor, sodium-glucose cotransporter-2 inhibitor, sulfonylurea, meglitinide, β-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) analog, and thiazolidinedione drug classes. Nearly 70% (122) had no reported changes in DM treatment beyond dosage titrations. Among these patients, 18 (10.3%) were on an insulin pump for the duration of the study. Among the 53 (30.3%) patients who had changes in treatment, 31 (17.7%) transitioned from insulin injections to an insulin pump, 13 (7.4%) changed from 1 insulin injection to another (ie, addition of long-acting insulin, transition to u500 insulin, changing from 1 insulin category or brand to another), 8 (4.6%) began an oral/noninsulin antihyperglycemic, 4 (2.3%) began insulin injections, 13 (7.4%) discontinued noninsulin or oral antihyperglycemics, and 2 (1.1%) discontinued insulin during the study period.

Data showed that 113 (64.5%) patients had no changes in antihypertensives. The remaining 62 (35.4%) had the following adjustments: 14 (8%) increased dose of current medication(s), 9 (5.1%) decreased dose of current medication(s), 8 (4.6%) discontinued all antihypertensive medications, 10 (5.7%) switched to a different antihypertensive class, and 16 (9.1%) added additional antihypertensive medication(s) to their existing regimen during the study period.

Patients in the study group used 7 different types of CGM sensors. Chart review revealed that 84 (47.7%) patients used Medtronic devices, with 26 (14.8%) using first-generation Guardian sensors, 50 (28.4%) using Enlite sensors, and 8 (4.5) using Guardian 3 sensors. We found that 81 (46.0%) veterans were prescribed Dexcom devices, with 5 (2.8%) using SEVEN PLUS sensors, 68 (38.6%) using G4-5 sensors, and 8 (4.5%) using G6 sensors. The remaining 10 (5.7%) patients were using Freestyle Libre sensors during the study period.

Discussion

CGM did not correspond with clinically significant reductions in HbA_1c. However, veterans with increased health care engagement were likely to achieve clinically significant HbA_1c improvements. The veterans in the adherent subgroup had a higher baseline HbA_1c, which could be because of a variety of factors mentioned in patient care notes, including insulin resistance, poor dietary habits, and exercise regimen nonadherence. These patients might have had more room to improve their glycemic control without concern of hypoglycemia, and their higher baseline HbA_1c could have provided increased motivation for improving their health during the study period.

Adherent patients also had a greater reduction in weight and hospital or clinic visits with CGM compared with the total population. These veterans’ increased involvement in their health care might have led to better dietary and exercise adherence, which would have decreased insulin dosing and contributed to weight loss. Only 1 patient in the adherent subgroup initiated a GLP-1 agonist during the study period, making it unlikely that medication changes had a significant impact on weight loss in the subgroup analysis. This improvement in overall health status might have contributed to the reduction in hospital or clinic visits observed in this population.

Average systolic BP data decreased minimally in the total survey population and increased in the adherent subgroup over the course of the study. These results were determined to be statistically significant. Changes in systolic BP readings were minimal, indicating that it is unlikely that these changes contributed meaningfully to the patients’ overall health status.

Although not related to the study objectives, the adherent population required less antihypertensive adjustments with similar BP control. This could be explained by improved overall health or better adherence and engagement in therapy. The results of this project show that despite limited medication changes, T2DM management improved among adherent patients using CGM. The general study population, which was more likely to have documented nonadherence with treatment or clinic appointments, had minimal benefit. CGM technology in the T2DM veteran population is more likely to have significant clinical benefit in patients who are adherent with their medication regimens and follow-up appointments compared with the larger study population.

The results of this study are in line with previous studies on CGM use in the T2DM patient population. We agree with the previously published research that CGM alone does not have a meaningful impact on HbA_1c reduction. Our study population also was older than those in previous studies, adding to the Haak and colleagues conclusion that patients aged < 65 years might have better outcomes with CGM.⁴

Limitations

Limitations of this study include retrospective design, a small sample size, and solely focusing on T2DM. As a retrospective study, we cannot rule out the influence of outside factors, such as participation in a non-VA weight loss program. This study lacked the power to assess the impact of the different CGM brands. The study did not include data on severe hypoglycemic or hyperglycemic episodes as veterans might have needed emergent care at non-VA facilities. Future research will evaluate the impact of CGM on symptomatic and severe hypoglycemic episodes and use of insulin vs oral or noninsulin antihyperglycemics and the comparative efficacy of different CGM brands among veterans.

Conclusions

CGM did not correspond with clinically significant reductions in HbA_1c. However, veterans with increased health care engagement were likely to achieve clinically significant HbA_1c improvements. Adherent patients also had more reduction in weight and hospital or clinic visits with CGM compared with the total population. These veterans’ increased involvement in their health care might have led to better dietary and exercise adherence, which would have decreased insulin dosing and contributed to weight loss.

Nearly 25% of patients served in the US Department of Veterans Affairs (VA) have been diagnosed with type 2 diabetes mellitus (T2DM), although the prevalence among adults in the United States is 9%.¹ Patients with DM typically monitor their blood glucose using intermittent fingerstick self-testing. Continuous glucose monitoring (CGM) might offer a more comprehensive picture of glucose control to improve disease management. Within the VA, criteria for CGM use varies among facilities, but generally veterans prescribed at least 3 daily insulin injections and 4 daily blood glucose checks qualify.²

CGM therapy has been extensively researched for type 1 DM (T1DM); however, outcomes of CGM use among older adults with T2DM have not been fully evaluated. In a 2018 review of randomized clinical trials evaluating CGM use, 17 trials examined only patients with T1DM (2009 participants), 4 included only patients with T2DM patients (547 patients), 3 evaluated patients with T1DM or T2DM (655 patients), and 3 included women with gestational diabetes (585 patients).³ Of 27 studies that included change in hemoglobin A_1c (HbA_1c) as an endpoint, 15 found a statistically significant reduction in HbA_1c for the CGM group. Four trials evaluated CGM use in adults with T2DM and 3 found no difference in HbA_1c overall. However, 1 study found a difference in HbA_1c only in individuals aged < 65 years, and another study found a greater improvement in the CGM group (approximately 0.5%).^4,5 These mixed results indicate a need for further subgroup analysis in specific populations to determine the optimal use of CGM in adults with T2DM. Although this study was not designed to measure changes in hypoglycemic episodes or the relative efficacy of different CGM products, it establishes a baseline from which to conduct additional research.

Our primary objective was to determine change in HbA_1c in each patient from the year before CGM initiation to the year after. Secondary objectives included changes in blood pressure (BP), weight, and diabetes-related hospital and clinic visits during the same time frame. We also completed subanalysis comparing primary outcomes in engaged or adherent patients compared with the entire study group. This study was completed as a quality improvement project with approval from the Lexington Veterans Affairs Health Care System in Kentucky information security office and was exempted from institutional review board review.

Methods

This project was a retrospective evaluation using the VA database of patient records. Rather than using a control group, our study used a pre–post model to determine the impact of CGM for each patient. For the primary outcome, average HbA_1c values were calculated for the year before and year after CGM initiation. Hemoglobin and hematocrit values were included if reported within 3 months of the HbA_1c values to ensure validity of HbA_1c results. Average HbA_1c was 13.37 g/dL (range, 10.5-17.3), and average hematocrit was 43.3% (range, 36-52). Change in average HbA_1c was recorded for each patient. Based on research by Taylor and colleagues, a change in HbA_1c of 0.8% was considered clinically significant for this project.⁶

Mean BP and weight were calculated for the years before and after CGM initiation. Only values for routine clinic visits were included; values taken during an acute health incident, inpatient stay, infusion clinic appointments, or home readings were excluded. Changes were recorded for each patient. Patient encounter notes were used to determine the number of DM-related hospital, emergency department, and clinic visits, such as nephrology, podiatry, vascular medicine, or infectious disease clinic or inpatient encounters during the study period. Routine endocrinology or primary care visits were not included, and patient care notes were consulted to ensure that the encounters were related to a DM complication. The change in number of visits was calculated for each patient.

Adherence was defined as patients receiving active medication management, documented treatment regimen adherence, and > 4 annual endocrinology clinic visits. Active medication management was defined as having > 1 dosage or medication change for oral or noninsulin antihyperglycemics, initiation, or adjustment of insulin dosages according to the patient records. Treatment adherence was determined based on medication reconciliation notes and refill request history. Only endocrinology clinic visits at VA outpatient clinics were included.

Study Population

A sample of 166 patients was needed to detect an HbA_1c change of 0.8 per power analysis. The normal approximation method using the z statistic was used, with 2-tailed α = 0.05, β = 0.05, E = 0.8, and S = 1.2. We randomly selected 175 patients among all individuals with an active prescription for CGM in 2018 and 2019, who had a diagnosis of T2DM, and were managed by VA endocrinology clinics (including endocrine clinics, diabetes clinics, and patient aligned care team clinics) at 87 VA medical centers. Patients with types of DM other than T2DM were excluded, as well as those with a diagnosed hemoglobinopathy or HbA_1c < 10 g/dL. The adherent subgroup included 40 patients of the 175 sample population (Table 1).

Results

Both the total population and the adherent subgroup showed reduction in HbA_1c, the primary endpoint. The complete population showed a HbA_1c change of –0.3 (95% CI, –0.4 to –0.2), and the adherent subgroup had a change of –1.3 (95% CI, –1.5 to –1.2). The total survey population had a mean change in weight of –1.9 lb (–0.9 kg) (95% CI, –3.7 to –0.1) and the adherent subgroup had an average change of –8.0 lb (–3.6 kg) (95% CI, –12.3 to –3.8). Average systolic BP changes were –0.1 mm Hg (95% CI, –1.6 to 1.5) in the total population and +3.3 mm Hg (95% CI, –0.01 to 6.22) in the adherent subgroup. A decrease in total encounters for DM complications was observed in the population (–0.3 total encounters per patient, 95% CI, –0.5 to –0.2) and the adherent subgroup (–0.6 total encounters per patient, 95% CI, –1.0 to –0.1) (Table 2).

Before the study, 107 (61.1%) patients were taking oral or noninsulin DM medication only, 4 (2.3%) were on insulin only, and 64 (36.6%) were prescribed both insulin and oral/noninsulin antihyperglycemics. Noninsulin and oral antihyperglycemic regimens included combinations of biguanide, dipeptidyl peptidase- 4 inhibitor, sodium-glucose cotransporter-2 inhibitor, sulfonylurea, meglitinide, β-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) analog, and thiazolidinedione drug classes. Nearly 70% (122) had no reported changes in DM treatment beyond dosage titrations. Among these patients, 18 (10.3%) were on an insulin pump for the duration of the study. Among the 53 (30.3%) patients who had changes in treatment, 31 (17.7%) transitioned from insulin injections to an insulin pump, 13 (7.4%) changed from 1 insulin injection to another (ie, addition of long-acting insulin, transition to u500 insulin, changing from 1 insulin category or brand to another), 8 (4.6%) began an oral/noninsulin antihyperglycemic, 4 (2.3%) began insulin injections, 13 (7.4%) discontinued noninsulin or oral antihyperglycemics, and 2 (1.1%) discontinued insulin during the study period.

Data showed that 113 (64.5%) patients had no changes in antihypertensives. The remaining 62 (35.4%) had the following adjustments: 14 (8%) increased dose of current medication(s), 9 (5.1%) decreased dose of current medication(s), 8 (4.6%) discontinued all antihypertensive medications, 10 (5.7%) switched to a different antihypertensive class, and 16 (9.1%) added additional antihypertensive medication(s) to their existing regimen during the study period.

Patients in the study group used 7 different types of CGM sensors. Chart review revealed that 84 (47.7%) patients used Medtronic devices, with 26 (14.8%) using first-generation Guardian sensors, 50 (28.4%) using Enlite sensors, and 8 (4.5) using Guardian 3 sensors. We found that 81 (46.0%) veterans were prescribed Dexcom devices, with 5 (2.8%) using SEVEN PLUS sensors, 68 (38.6%) using G4-5 sensors, and 8 (4.5%) using G6 sensors. The remaining 10 (5.7%) patients were using Freestyle Libre sensors during the study period.

Discussion

CGM did not correspond with clinically significant reductions in HbA_1c. However, veterans with increased health care engagement were likely to achieve clinically significant HbA_1c improvements. The veterans in the adherent subgroup had a higher baseline HbA_1c, which could be because of a variety of factors mentioned in patient care notes, including insulin resistance, poor dietary habits, and exercise regimen nonadherence. These patients might have had more room to improve their glycemic control without concern of hypoglycemia, and their higher baseline HbA_1c could have provided increased motivation for improving their health during the study period.

Adherent patients also had a greater reduction in weight and hospital or clinic visits with CGM compared with the total population. These veterans’ increased involvement in their health care might have led to better dietary and exercise adherence, which would have decreased insulin dosing and contributed to weight loss. Only 1 patient in the adherent subgroup initiated a GLP-1 agonist during the study period, making it unlikely that medication changes had a significant impact on weight loss in the subgroup analysis. This improvement in overall health status might have contributed to the reduction in hospital or clinic visits observed in this population.

Average systolic BP data decreased minimally in the total survey population and increased in the adherent subgroup over the course of the study. These results were determined to be statistically significant. Changes in systolic BP readings were minimal, indicating that it is unlikely that these changes contributed meaningfully to the patients’ overall health status.

Although not related to the study objectives, the adherent population required less antihypertensive adjustments with similar BP control. This could be explained by improved overall health or better adherence and engagement in therapy. The results of this project show that despite limited medication changes, T2DM management improved among adherent patients using CGM. The general study population, which was more likely to have documented nonadherence with treatment or clinic appointments, had minimal benefit. CGM technology in the T2DM veteran population is more likely to have significant clinical benefit in patients who are adherent with their medication regimens and follow-up appointments compared with the larger study population.

The results of this study are in line with previous studies on CGM use in the T2DM patient population. We agree with the previously published research that CGM alone does not have a meaningful impact on HbA_1c reduction. Our study population also was older than those in previous studies, adding to the Haak and colleagues conclusion that patients aged < 65 years might have better outcomes with CGM.⁴

Limitations

Limitations of this study include retrospective design, a small sample size, and solely focusing on T2DM. As a retrospective study, we cannot rule out the influence of outside factors, such as participation in a non-VA weight loss program. This study lacked the power to assess the impact of the different CGM brands. The study did not include data on severe hypoglycemic or hyperglycemic episodes as veterans might have needed emergent care at non-VA facilities. Future research will evaluate the impact of CGM on symptomatic and severe hypoglycemic episodes and use of insulin vs oral or noninsulin antihyperglycemics and the comparative efficacy of different CGM brands among veterans.

Conclusions

CGM did not correspond with clinically significant reductions in HbA_1c. However, veterans with increased health care engagement were likely to achieve clinically significant HbA_1c improvements. Adherent patients also had more reduction in weight and hospital or clinic visits with CGM compared with the total population. These veterans’ increased involvement in their health care might have led to better dietary and exercise adherence, which would have decreased insulin dosing and contributed to weight loss.

Nearly 25% of patients served in the US Department of Veterans Affairs (VA) have been diagnosed with type 2 diabetes mellitus (T2DM), although the prevalence among adults in the United States is 9%.¹ Patients with DM typically monitor their blood glucose using intermittent fingerstick self-testing. Continuous glucose monitoring (CGM) might offer a more comprehensive picture of glucose control to improve disease management. Within the VA, criteria for CGM use varies among facilities, but generally veterans prescribed at least 3 daily insulin injections and 4 daily blood glucose checks qualify.²

CGM therapy has been extensively researched for type 1 DM (T1DM); however, outcomes of CGM use among older adults with T2DM have not been fully evaluated. In a 2018 review of randomized clinical trials evaluating CGM use, 17 trials examined only patients with T1DM (2009 participants), 4 included only patients with T2DM patients (547 patients), 3 evaluated patients with T1DM or T2DM (655 patients), and 3 included women with gestational diabetes (585 patients).³ Of 27 studies that included change in hemoglobin A_1c (HbA_1c) as an endpoint, 15 found a statistically significant reduction in HbA_1c for the CGM group. Four trials evaluated CGM use in adults with T2DM and 3 found no difference in HbA_1c overall. However, 1 study found a difference in HbA_1c only in individuals aged < 65 years, and another study found a greater improvement in the CGM group (approximately 0.5%).^4,5 These mixed results indicate a need for further subgroup analysis in specific populations to determine the optimal use of CGM in adults with T2DM. Although this study was not designed to measure changes in hypoglycemic episodes or the relative efficacy of different CGM products, it establishes a baseline from which to conduct additional research.

Our primary objective was to determine change in HbA_1c in each patient from the year before CGM initiation to the year after. Secondary objectives included changes in blood pressure (BP), weight, and diabetes-related hospital and clinic visits during the same time frame. We also completed subanalysis comparing primary outcomes in engaged or adherent patients compared with the entire study group. This study was completed as a quality improvement project with approval from the Lexington Veterans Affairs Health Care System in Kentucky information security office and was exempted from institutional review board review.

Methods

This project was a retrospective evaluation using the VA database of patient records. Rather than using a control group, our study used a pre–post model to determine the impact of CGM for each patient. For the primary outcome, average HbA_1c values were calculated for the year before and year after CGM initiation. Hemoglobin and hematocrit values were included if reported within 3 months of the HbA_1c values to ensure validity of HbA_1c results. Average HbA_1c was 13.37 g/dL (range, 10.5-17.3), and average hematocrit was 43.3% (range, 36-52). Change in average HbA_1c was recorded for each patient. Based on research by Taylor and colleagues, a change in HbA_1c of 0.8% was considered clinically significant for this project.⁶

Mean BP and weight were calculated for the years before and after CGM initiation. Only values for routine clinic visits were included; values taken during an acute health incident, inpatient stay, infusion clinic appointments, or home readings were excluded. Changes were recorded for each patient. Patient encounter notes were used to determine the number of DM-related hospital, emergency department, and clinic visits, such as nephrology, podiatry, vascular medicine, or infectious disease clinic or inpatient encounters during the study period. Routine endocrinology or primary care visits were not included, and patient care notes were consulted to ensure that the encounters were related to a DM complication. The change in number of visits was calculated for each patient.

Adherence was defined as patients receiving active medication management, documented treatment regimen adherence, and > 4 annual endocrinology clinic visits. Active medication management was defined as having > 1 dosage or medication change for oral or noninsulin antihyperglycemics, initiation, or adjustment of insulin dosages according to the patient records. Treatment adherence was determined based on medication reconciliation notes and refill request history. Only endocrinology clinic visits at VA outpatient clinics were included.

Study Population

A sample of 166 patients was needed to detect an HbA_1c change of 0.8 per power analysis. The normal approximation method using the z statistic was used, with 2-tailed α = 0.05, β = 0.05, E = 0.8, and S = 1.2. We randomly selected 175 patients among all individuals with an active prescription for CGM in 2018 and 2019, who had a diagnosis of T2DM, and were managed by VA endocrinology clinics (including endocrine clinics, diabetes clinics, and patient aligned care team clinics) at 87 VA medical centers. Patients with types of DM other than T2DM were excluded, as well as those with a diagnosed hemoglobinopathy or HbA_1c < 10 g/dL. The adherent subgroup included 40 patients of the 175 sample population (Table 1).

Results

Both the total population and the adherent subgroup showed reduction in HbA_1c, the primary endpoint. The complete population showed a HbA_1c change of –0.3 (95% CI, –0.4 to –0.2), and the adherent subgroup had a change of –1.3 (95% CI, –1.5 to –1.2). The total survey population had a mean change in weight of –1.9 lb (–0.9 kg) (95% CI, –3.7 to –0.1) and the adherent subgroup had an average change of –8.0 lb (–3.6 kg) (95% CI, –12.3 to –3.8). Average systolic BP changes were –0.1 mm Hg (95% CI, –1.6 to 1.5) in the total population and +3.3 mm Hg (95% CI, –0.01 to 6.22) in the adherent subgroup. A decrease in total encounters for DM complications was observed in the population (–0.3 total encounters per patient, 95% CI, –0.5 to –0.2) and the adherent subgroup (–0.6 total encounters per patient, 95% CI, –1.0 to –0.1) (Table 2).

Before the study, 107 (61.1%) patients were taking oral or noninsulin DM medication only, 4 (2.3%) were on insulin only, and 64 (36.6%) were prescribed both insulin and oral/noninsulin antihyperglycemics. Noninsulin and oral antihyperglycemic regimens included combinations of biguanide, dipeptidyl peptidase- 4 inhibitor, sodium-glucose cotransporter-2 inhibitor, sulfonylurea, meglitinide, β-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) analog, and thiazolidinedione drug classes. Nearly 70% (122) had no reported changes in DM treatment beyond dosage titrations. Among these patients, 18 (10.3%) were on an insulin pump for the duration of the study. Among the 53 (30.3%) patients who had changes in treatment, 31 (17.7%) transitioned from insulin injections to an insulin pump, 13 (7.4%) changed from 1 insulin injection to another (ie, addition of long-acting insulin, transition to u500 insulin, changing from 1 insulin category or brand to another), 8 (4.6%) began an oral/noninsulin antihyperglycemic, 4 (2.3%) began insulin injections, 13 (7.4%) discontinued noninsulin or oral antihyperglycemics, and 2 (1.1%) discontinued insulin during the study period.

Data showed that 113 (64.5%) patients had no changes in antihypertensives. The remaining 62 (35.4%) had the following adjustments: 14 (8%) increased dose of current medication(s), 9 (5.1%) decreased dose of current medication(s), 8 (4.6%) discontinued all antihypertensive medications, 10 (5.7%) switched to a different antihypertensive class, and 16 (9.1%) added additional antihypertensive medication(s) to their existing regimen during the study period.

Patients in the study group used 7 different types of CGM sensors. Chart review revealed that 84 (47.7%) patients used Medtronic devices, with 26 (14.8%) using first-generation Guardian sensors, 50 (28.4%) using Enlite sensors, and 8 (4.5) using Guardian 3 sensors. We found that 81 (46.0%) veterans were prescribed Dexcom devices, with 5 (2.8%) using SEVEN PLUS sensors, 68 (38.6%) using G4-5 sensors, and 8 (4.5%) using G6 sensors. The remaining 10 (5.7%) patients were using Freestyle Libre sensors during the study period.

Discussion

CGM did not correspond with clinically significant reductions in HbA_1c. However, veterans with increased health care engagement were likely to achieve clinically significant HbA_1c improvements. The veterans in the adherent subgroup had a higher baseline HbA_1c, which could be because of a variety of factors mentioned in patient care notes, including insulin resistance, poor dietary habits, and exercise regimen nonadherence. These patients might have had more room to improve their glycemic control without concern of hypoglycemia, and their higher baseline HbA_1c could have provided increased motivation for improving their health during the study period.

Adherent patients also had a greater reduction in weight and hospital or clinic visits with CGM compared with the total population. These veterans’ increased involvement in their health care might have led to better dietary and exercise adherence, which would have decreased insulin dosing and contributed to weight loss. Only 1 patient in the adherent subgroup initiated a GLP-1 agonist during the study period, making it unlikely that medication changes had a significant impact on weight loss in the subgroup analysis. This improvement in overall health status might have contributed to the reduction in hospital or clinic visits observed in this population.

Average systolic BP data decreased minimally in the total survey population and increased in the adherent subgroup over the course of the study. These results were determined to be statistically significant. Changes in systolic BP readings were minimal, indicating that it is unlikely that these changes contributed meaningfully to the patients’ overall health status.

Although not related to the study objectives, the adherent population required less antihypertensive adjustments with similar BP control. This could be explained by improved overall health or better adherence and engagement in therapy. The results of this project show that despite limited medication changes, T2DM management improved among adherent patients using CGM. The general study population, which was more likely to have documented nonadherence with treatment or clinic appointments, had minimal benefit. CGM technology in the T2DM veteran population is more likely to have significant clinical benefit in patients who are adherent with their medication regimens and follow-up appointments compared with the larger study population.

The results of this study are in line with previous studies on CGM use in the T2DM patient population. We agree with the previously published research that CGM alone does not have a meaningful impact on HbA_1c reduction. Our study population also was older than those in previous studies, adding to the Haak and colleagues conclusion that patients aged < 65 years might have better outcomes with CGM.⁴

Limitations

Limitations of this study include retrospective design, a small sample size, and solely focusing on T2DM. As a retrospective study, we cannot rule out the influence of outside factors, such as participation in a non-VA weight loss program. This study lacked the power to assess the impact of the different CGM brands. The study did not include data on severe hypoglycemic or hyperglycemic episodes as veterans might have needed emergent care at non-VA facilities. Future research will evaluate the impact of CGM on symptomatic and severe hypoglycemic episodes and use of insulin vs oral or noninsulin antihyperglycemics and the comparative efficacy of different CGM brands among veterans.

Conclusions

CGM did not correspond with clinically significant reductions in HbA_1c. However, veterans with increased health care engagement were likely to achieve clinically significant HbA_1c improvements. Adherent patients also had more reduction in weight and hospital or clinic visits with CGM compared with the total population. These veterans’ increased involvement in their health care might have led to better dietary and exercise adherence, which would have decreased insulin dosing and contributed to weight loss.

Abnormalities in the T-wave morphology of an electrocardiogram (ECG) are classically attributed to ischemic cardiac disease. However, these changes can be seen in a variety of other etiologies, including noncardiac pathology, which should be considered whenever reviewing an ECG: central nervous system disease, including stroke and subarachnoid hemorrhage; hypothermia; pulmonary disease, such as pulmonary embolism or chronic obstructive pulmonary disease; myopericarditis; drug effects; and electrolyte abnormalities.

Prolongation of the QT interval, on the other hand, can be precipitated by medications, metabolic derangements, or genetic phenotypes. The QT interval is measured from the beginning of the QRS complex to the termination of the T wave and represents the total time for ventricular depolarization and repolarization. The QT interval must be corrected based on the patient’s heart rate, known as the QTc. As the QTc interval lengthens, there is increased risk of R-on-T phenomena, which may result in Torsades de Pointes (TdP). Typical features of TdP include an antecedent prolonged QTc, cyclic polymorphic ventricular tachycardia on the surface ECG, and either a short-lived spontaneously terminating course or degeneration into ventricular fibrillation (VF) and sudden cardiac death.¹ These dysrhythmias become more likely as the QTc interval exceeds 500 msec.²

The combination of new-onset global T-wave inversions with prolongation of the QT interval has been reported in only a few limited conditions. Some known causes of these QT T changes include cardiac ischemia, status epilepticus, pheochromocytoma, and acute cocaine intoxication.³ One uncommon and rarely reported cause of extreme QT prolongation and T-wave inversion is acute pulmonary edema. The ECG findings are not present on initial patient presentation; rather the dynamic changes occur after resolution of the pulmonary symptoms. Despite significant ECG changes, all prior reported cases describe ECG normalization without significant morbidity.^4,5 We report a case of extreme QT prolongation following acute pulmonary edema that resulted in cardiac arrest secondary to VF.

Case Presentation

A 72-year-old male with medical history of combined systolic and diastolic heart failure, ischemic cardiomyopathy, coronary artery disease, cerebral vascular accident, hypertension, hyperlipidemia, type 2 diabetes mellitus, and tobacco dependence presented to the emergency department (ED) by emergency medical services after awaking with acute onset of dyspnea and diaphoresis. On arrival at the ED, the patient was noted to be in respiratory distress (ie, unable to speak single words) and was extremely diaphoretic. His initial vital signs included blood pressure, 186/113 mm Hg, heart rate, 104 beats per minute, respiratory rate, 40 breaths per minute, and temperature, 36.4 °C. The patient was quickly placed on bilevel positive airway pressure and given sublingual nitroglycerin followed by transdermal nitroglycerin with a single dose of 40 mg IV furosemide, which improved his respiratory status. A chest X-ray was consistent with pulmonary edema, and his brain natriuretic peptide was 1654 pg/mL. An ECG demonstrated new T-wave inversions, and his troponin increased from 0.04 to 0.24 ng/mL during his ED stay (Figure 1). He was started on a heparin infusion and admitted to the hospital for hypertensive emergency with presumed acute decompensated heart failure and non-ST-elevated myocardial infarction.

Throughout the patient’s first night, the troponin level started to down-trend after peaking at 0.24 ng/mL, and his oxygen requirements decreased allowing transition to nasal cannula. However, his repeat ECGs demonstrated significant T-wave abnormalities, new premature ventricular contractions, bradycardia, and a prolonging QTc interval to 703 msec (Figure 2). At this time, the patient’s electrolytes were normal, specifically a potassium level of 4.4 mEq/L, calcium 8.8 mg/dL, magnesium 2.0 mg/dL, and phosphorus 2.6 mg/dL. Given the worsening ECG changes, a computed tomography scan of his head was ordered to rule out intracranial pathology. While in the scanner, the patient went into pulseless VF, prompting defibrillation with 200 J. In addition, he was given 75 mg IV lidocaine, 2 g IV magnesium, and 1 ampule of both calcium chloride and sodium bicarbonate. With treatment, he had return of spontaneous circulation and was taken promptly to cardiac catheterization. The catheterization showed no significant obstructive coronary artery disease, and no interventions were performed. The patient was transferred to the cardiac intensive care unit for continued care.

During his course in the intensive care unit, the patient’s potassium and magnesium levels were maintained at high-normal levels. The patient was started on a dobutamine infusion to increase his heart rate and attempt to decrease his QTc. The patient also underwent cardiac magnetic resonance imaging (MRI) to evaluate for possible myocarditis, which showed no evidence of acute inflammation. Echocardiogram demonstrated an ejection fraction of 40% and global hypokinesis but no specific regional abnormalities and no change from prior echocardiogram performed 1 year earlier. Over the course of 3 days, his ECG normalized and his QTc shortened to 477 msec. Genetic testing was performed and did not reveal any mutations associated with long QT syndrome. Ultimately, an automated internal cardiac defibrillator (AICD) was placed, and the patient was discharged home.

Over the 2 years since his initial event, the patient has not experienced recurrent VF and his AICD has not fired. The patient continues to have ED presentations for heart-failure symptoms, though he has been stable from an electrophysiologic standpoint and his QTc remains less than 500 msec.

Discussion

Prolongation of the QT interval as a result of deep, global T-wave inversions after resolution of acute pulmonary edema has been minimally reported.^4,5 This phenomenon has been described in the cardiology literature but has not been discussed in the emergency medicine literature and bears consideration in this case.^4,5 As noted, an extensive evaluation did not reveal another cause of QTc prolongation. The patient had normal electrolytes and temperature, his neurologic examination and computed tomography were not remarkable. The patient had no obstructive coronary artery disease on catheterization, no evidence of acute myocarditis on cardiac MRI, no prescribed medications associated with QT prolongation, and no evidence of genetic mutations associated with QT prolongation on testing. The minimal troponin elevation was felt to represent a type II myocardial infarction related to ischemia due to supply-demand mismatch rather than acute plaque rupture.

Littmann published a case series of 9 cases of delayed onset T-wave inversion and extreme QTc prolongation in the 24 to 48 hours following treatment and symptomatic improvement in acute pulmonary edema.⁴ In each of his patients, an ischemic cardiac insult was ruled out as the etiology of the pulmonary edema by laboratory assessment, echocardiography, and left heart catheterization.All of the patients in this case series recovered without incident and with normalization of the QTc interval.⁴ Similarly, in our patient, significant QT T changes occurred approximately 22 hours after presentation and with resolution of symptoms of pulmonary edema. Pascale and colleagues also published a series of 3 patients developing similar ECG patterns following a hypertensive crisis with resolution of ECG findings and without any morbidity.⁵ In contrast, our patient experienced significant morbidity secondary to the extreme QTc prolongation.

Conclusions

We believe this is the first reported case of excessive prolongation of the QTc with VF arrest secondary to resolution of acute pulmonary edema. The pattern observed in our patient follows the patterns outlined in the previous case series—patients present with acute pulmonary edema and hypertensive crisis but develop significant ECG abnormalities about 24 hours after the resolution of the high catecholamine state. Our patient did have a history of prior cardiac insult, given the QTc changes developed acutely, with frequent premature ventricular contractions, and the cardiac arrest occurred at maximal QTc prolongation, yet after resolution of the high catecholamine state, the treatment team felt there was likely an uncaptured and short-lived episode of TdP that degenerated into VF. This theory is further supported by the lack of recurrent VF episodes, confirmed by AICD interrogation, after normalization of the QTc in our patient.

Abnormalities in the T-wave morphology of an electrocardiogram (ECG) are classically attributed to ischemic cardiac disease. However, these changes can be seen in a variety of other etiologies, including noncardiac pathology, which should be considered whenever reviewing an ECG: central nervous system disease, including stroke and subarachnoid hemorrhage; hypothermia; pulmonary disease, such as pulmonary embolism or chronic obstructive pulmonary disease; myopericarditis; drug effects; and electrolyte abnormalities.

Prolongation of the QT interval, on the other hand, can be precipitated by medications, metabolic derangements, or genetic phenotypes. The QT interval is measured from the beginning of the QRS complex to the termination of the T wave and represents the total time for ventricular depolarization and repolarization. The QT interval must be corrected based on the patient’s heart rate, known as the QTc. As the QTc interval lengthens, there is increased risk of R-on-T phenomena, which may result in Torsades de Pointes (TdP). Typical features of TdP include an antecedent prolonged QTc, cyclic polymorphic ventricular tachycardia on the surface ECG, and either a short-lived spontaneously terminating course or degeneration into ventricular fibrillation (VF) and sudden cardiac death.¹ These dysrhythmias become more likely as the QTc interval exceeds 500 msec.²

The combination of new-onset global T-wave inversions with prolongation of the QT interval has been reported in only a few limited conditions. Some known causes of these QT T changes include cardiac ischemia, status epilepticus, pheochromocytoma, and acute cocaine intoxication.³ One uncommon and rarely reported cause of extreme QT prolongation and T-wave inversion is acute pulmonary edema. The ECG findings are not present on initial patient presentation; rather the dynamic changes occur after resolution of the pulmonary symptoms. Despite significant ECG changes, all prior reported cases describe ECG normalization without significant morbidity.^4,5 We report a case of extreme QT prolongation following acute pulmonary edema that resulted in cardiac arrest secondary to VF.

Case Presentation

A 72-year-old male with medical history of combined systolic and diastolic heart failure, ischemic cardiomyopathy, coronary artery disease, cerebral vascular accident, hypertension, hyperlipidemia, type 2 diabetes mellitus, and tobacco dependence presented to the emergency department (ED) by emergency medical services after awaking with acute onset of dyspnea and diaphoresis. On arrival at the ED, the patient was noted to be in respiratory distress (ie, unable to speak single words) and was extremely diaphoretic. His initial vital signs included blood pressure, 186/113 mm Hg, heart rate, 104 beats per minute, respiratory rate, 40 breaths per minute, and temperature, 36.4 °C. The patient was quickly placed on bilevel positive airway pressure and given sublingual nitroglycerin followed by transdermal nitroglycerin with a single dose of 40 mg IV furosemide, which improved his respiratory status. A chest X-ray was consistent with pulmonary edema, and his brain natriuretic peptide was 1654 pg/mL. An ECG demonstrated new T-wave inversions, and his troponin increased from 0.04 to 0.24 ng/mL during his ED stay (Figure 1). He was started on a heparin infusion and admitted to the hospital for hypertensive emergency with presumed acute decompensated heart failure and non-ST-elevated myocardial infarction.

Throughout the patient’s first night, the troponin level started to down-trend after peaking at 0.24 ng/mL, and his oxygen requirements decreased allowing transition to nasal cannula. However, his repeat ECGs demonstrated significant T-wave abnormalities, new premature ventricular contractions, bradycardia, and a prolonging QTc interval to 703 msec (Figure 2). At this time, the patient’s electrolytes were normal, specifically a potassium level of 4.4 mEq/L, calcium 8.8 mg/dL, magnesium 2.0 mg/dL, and phosphorus 2.6 mg/dL. Given the worsening ECG changes, a computed tomography scan of his head was ordered to rule out intracranial pathology. While in the scanner, the patient went into pulseless VF, prompting defibrillation with 200 J. In addition, he was given 75 mg IV lidocaine, 2 g IV magnesium, and 1 ampule of both calcium chloride and sodium bicarbonate. With treatment, he had return of spontaneous circulation and was taken promptly to cardiac catheterization. The catheterization showed no significant obstructive coronary artery disease, and no interventions were performed. The patient was transferred to the cardiac intensive care unit for continued care.

During his course in the intensive care unit, the patient’s potassium and magnesium levels were maintained at high-normal levels. The patient was started on a dobutamine infusion to increase his heart rate and attempt to decrease his QTc. The patient also underwent cardiac magnetic resonance imaging (MRI) to evaluate for possible myocarditis, which showed no evidence of acute inflammation. Echocardiogram demonstrated an ejection fraction of 40% and global hypokinesis but no specific regional abnormalities and no change from prior echocardiogram performed 1 year earlier. Over the course of 3 days, his ECG normalized and his QTc shortened to 477 msec. Genetic testing was performed and did not reveal any mutations associated with long QT syndrome. Ultimately, an automated internal cardiac defibrillator (AICD) was placed, and the patient was discharged home.

Over the 2 years since his initial event, the patient has not experienced recurrent VF and his AICD has not fired. The patient continues to have ED presentations for heart-failure symptoms, though he has been stable from an electrophysiologic standpoint and his QTc remains less than 500 msec.

Discussion

Prolongation of the QT interval as a result of deep, global T-wave inversions after resolution of acute pulmonary edema has been minimally reported.^4,5 This phenomenon has been described in the cardiology literature but has not been discussed in the emergency medicine literature and bears consideration in this case.^4,5 As noted, an extensive evaluation did not reveal another cause of QTc prolongation. The patient had normal electrolytes and temperature, his neurologic examination and computed tomography were not remarkable. The patient had no obstructive coronary artery disease on catheterization, no evidence of acute myocarditis on cardiac MRI, no prescribed medications associated with QT prolongation, and no evidence of genetic mutations associated with QT prolongation on testing. The minimal troponin elevation was felt to represent a type II myocardial infarction related to ischemia due to supply-demand mismatch rather than acute plaque rupture.

Littmann published a case series of 9 cases of delayed onset T-wave inversion and extreme QTc prolongation in the 24 to 48 hours following treatment and symptomatic improvement in acute pulmonary edema.⁴ In each of his patients, an ischemic cardiac insult was ruled out as the etiology of the pulmonary edema by laboratory assessment, echocardiography, and left heart catheterization.All of the patients in this case series recovered without incident and with normalization of the QTc interval.⁴ Similarly, in our patient, significant QT T changes occurred approximately 22 hours after presentation and with resolution of symptoms of pulmonary edema. Pascale and colleagues also published a series of 3 patients developing similar ECG patterns following a hypertensive crisis with resolution of ECG findings and without any morbidity.⁵ In contrast, our patient experienced significant morbidity secondary to the extreme QTc prolongation.

Conclusions

We believe this is the first reported case of excessive prolongation of the QTc with VF arrest secondary to resolution of acute pulmonary edema. The pattern observed in our patient follows the patterns outlined in the previous case series—patients present with acute pulmonary edema and hypertensive crisis but develop significant ECG abnormalities about 24 hours after the resolution of the high catecholamine state. Our patient did have a history of prior cardiac insult, given the QTc changes developed acutely, with frequent premature ventricular contractions, and the cardiac arrest occurred at maximal QTc prolongation, yet after resolution of the high catecholamine state, the treatment team felt there was likely an uncaptured and short-lived episode of TdP that degenerated into VF. This theory is further supported by the lack of recurrent VF episodes, confirmed by AICD interrogation, after normalization of the QTc in our patient.

Abnormalities in the T-wave morphology of an electrocardiogram (ECG) are classically attributed to ischemic cardiac disease. However, these changes can be seen in a variety of other etiologies, including noncardiac pathology, which should be considered whenever reviewing an ECG: central nervous system disease, including stroke and subarachnoid hemorrhage; hypothermia; pulmonary disease, such as pulmonary embolism or chronic obstructive pulmonary disease; myopericarditis; drug effects; and electrolyte abnormalities.

Prolongation of the QT interval, on the other hand, can be precipitated by medications, metabolic derangements, or genetic phenotypes. The QT interval is measured from the beginning of the QRS complex to the termination of the T wave and represents the total time for ventricular depolarization and repolarization. The QT interval must be corrected based on the patient’s heart rate, known as the QTc. As the QTc interval lengthens, there is increased risk of R-on-T phenomena, which may result in Torsades de Pointes (TdP). Typical features of TdP include an antecedent prolonged QTc, cyclic polymorphic ventricular tachycardia on the surface ECG, and either a short-lived spontaneously terminating course or degeneration into ventricular fibrillation (VF) and sudden cardiac death.¹ These dysrhythmias become more likely as the QTc interval exceeds 500 msec.²

The combination of new-onset global T-wave inversions with prolongation of the QT interval has been reported in only a few limited conditions. Some known causes of these QT T changes include cardiac ischemia, status epilepticus, pheochromocytoma, and acute cocaine intoxication.³ One uncommon and rarely reported cause of extreme QT prolongation and T-wave inversion is acute pulmonary edema. The ECG findings are not present on initial patient presentation; rather the dynamic changes occur after resolution of the pulmonary symptoms. Despite significant ECG changes, all prior reported cases describe ECG normalization without significant morbidity.^4,5 We report a case of extreme QT prolongation following acute pulmonary edema that resulted in cardiac arrest secondary to VF.

Case Presentation

A 72-year-old male with medical history of combined systolic and diastolic heart failure, ischemic cardiomyopathy, coronary artery disease, cerebral vascular accident, hypertension, hyperlipidemia, type 2 diabetes mellitus, and tobacco dependence presented to the emergency department (ED) by emergency medical services after awaking with acute onset of dyspnea and diaphoresis. On arrival at the ED, the patient was noted to be in respiratory distress (ie, unable to speak single words) and was extremely diaphoretic. His initial vital signs included blood pressure, 186/113 mm Hg, heart rate, 104 beats per minute, respiratory rate, 40 breaths per minute, and temperature, 36.4 °C. The patient was quickly placed on bilevel positive airway pressure and given sublingual nitroglycerin followed by transdermal nitroglycerin with a single dose of 40 mg IV furosemide, which improved his respiratory status. A chest X-ray was consistent with pulmonary edema, and his brain natriuretic peptide was 1654 pg/mL. An ECG demonstrated new T-wave inversions, and his troponin increased from 0.04 to 0.24 ng/mL during his ED stay (Figure 1). He was started on a heparin infusion and admitted to the hospital for hypertensive emergency with presumed acute decompensated heart failure and non-ST-elevated myocardial infarction.

Throughout the patient’s first night, the troponin level started to down-trend after peaking at 0.24 ng/mL, and his oxygen requirements decreased allowing transition to nasal cannula. However, his repeat ECGs demonstrated significant T-wave abnormalities, new premature ventricular contractions, bradycardia, and a prolonging QTc interval to 703 msec (Figure 2). At this time, the patient’s electrolytes were normal, specifically a potassium level of 4.4 mEq/L, calcium 8.8 mg/dL, magnesium 2.0 mg/dL, and phosphorus 2.6 mg/dL. Given the worsening ECG changes, a computed tomography scan of his head was ordered to rule out intracranial pathology. While in the scanner, the patient went into pulseless VF, prompting defibrillation with 200 J. In addition, he was given 75 mg IV lidocaine, 2 g IV magnesium, and 1 ampule of both calcium chloride and sodium bicarbonate. With treatment, he had return of spontaneous circulation and was taken promptly to cardiac catheterization. The catheterization showed no significant obstructive coronary artery disease, and no interventions were performed. The patient was transferred to the cardiac intensive care unit for continued care.

During his course in the intensive care unit, the patient’s potassium and magnesium levels were maintained at high-normal levels. The patient was started on a dobutamine infusion to increase his heart rate and attempt to decrease his QTc. The patient also underwent cardiac magnetic resonance imaging (MRI) to evaluate for possible myocarditis, which showed no evidence of acute inflammation. Echocardiogram demonstrated an ejection fraction of 40% and global hypokinesis but no specific regional abnormalities and no change from prior echocardiogram performed 1 year earlier. Over the course of 3 days, his ECG normalized and his QTc shortened to 477 msec. Genetic testing was performed and did not reveal any mutations associated with long QT syndrome. Ultimately, an automated internal cardiac defibrillator (AICD) was placed, and the patient was discharged home.

Over the 2 years since his initial event, the patient has not experienced recurrent VF and his AICD has not fired. The patient continues to have ED presentations for heart-failure symptoms, though he has been stable from an electrophysiologic standpoint and his QTc remains less than 500 msec.

Discussion

Prolongation of the QT interval as a result of deep, global T-wave inversions after resolution of acute pulmonary edema has been minimally reported.^4,5 This phenomenon has been described in the cardiology literature but has not been discussed in the emergency medicine literature and bears consideration in this case.^4,5 As noted, an extensive evaluation did not reveal another cause of QTc prolongation. The patient had normal electrolytes and temperature, his neurologic examination and computed tomography were not remarkable. The patient had no obstructive coronary artery disease on catheterization, no evidence of acute myocarditis on cardiac MRI, no prescribed medications associated with QT prolongation, and no evidence of genetic mutations associated with QT prolongation on testing. The minimal troponin elevation was felt to represent a type II myocardial infarction related to ischemia due to supply-demand mismatch rather than acute plaque rupture.

Littmann published a case series of 9 cases of delayed onset T-wave inversion and extreme QTc prolongation in the 24 to 48 hours following treatment and symptomatic improvement in acute pulmonary edema.⁴ In each of his patients, an ischemic cardiac insult was ruled out as the etiology of the pulmonary edema by laboratory assessment, echocardiography, and left heart catheterization.All of the patients in this case series recovered without incident and with normalization of the QTc interval.⁴ Similarly, in our patient, significant QT T changes occurred approximately 22 hours after presentation and with resolution of symptoms of pulmonary edema. Pascale and colleagues also published a series of 3 patients developing similar ECG patterns following a hypertensive crisis with resolution of ECG findings and without any morbidity.⁵ In contrast, our patient experienced significant morbidity secondary to the extreme QTc prolongation.

Conclusions

We believe this is the first reported case of excessive prolongation of the QTc with VF arrest secondary to resolution of acute pulmonary edema. The pattern observed in our patient follows the patterns outlined in the previous case series—patients present with acute pulmonary edema and hypertensive crisis but develop significant ECG abnormalities about 24 hours after the resolution of the high catecholamine state. Our patient did have a history of prior cardiac insult, given the QTc changes developed acutely, with frequent premature ventricular contractions, and the cardiac arrest occurred at maximal QTc prolongation, yet after resolution of the high catecholamine state, the treatment team felt there was likely an uncaptured and short-lived episode of TdP that degenerated into VF. This theory is further supported by the lack of recurrent VF episodes, confirmed by AICD interrogation, after normalization of the QTc in our patient.

Aortitis is the all-encompassing term ascribed to the inflammatory process in the aortic wall that can be either infective or noninfective in origin, commonly autoimmune or inflammatory large-vessel vasculitis.¹ Infectious aortitis, also known as bacterial, microbial, or cryptogenic aortitis, as well as mycotic or infected aneurysm, is a rare entity in the current antibiotic era but potentially a life-threatening disorder.² The potential complications of infectious aortitis include emphysematous aortitis (EA), pseudoaneurysm, aortic rupture, septic emboli, and fistula formation (eg, aorto-enteric fistula).^2,3

EA is a rare but serious inflammatory condition of the aorta with a nonspecific clinical presentation associated with high morbidity and mortality.^2-6 The condition is characterized by a localized collection of gas and purulent exudate at the aortic wall.^1,3 A few cases of EA have previously been reported; however, no known cases have been reported in the literature due to Klebsiella pneumoniae (K pneumoniae).

The pathophysiology of EA is the presence of underlying damage to the arterial wall caused by a hematogenously inoculated gas-producing organism.^2,3 Most reported cases of EA are due to endovascular graft complications. Under normal circumstances, the aortic intima is highly resistant to infectious pathogens; however, certain risk factors, such as diabetes mellitus (DM), atherosclerotic disease, preexisting aneurysm, cystic medial necrosis, vascular malformation, presence of medical devices, surgery, or impaired immunity can alter the integrity of the aortic intimal layer and predispose the aortic intima to infection.^1,4-7 Bacteria are the most common causative organisms that can infect the aorta, especially Staphylococcus, Enterococcus, Streptococcus, Salmonella, and spirochete Treponema pallidum (syphilis).^1,2,4,8 The site of the primary infection remains unclear in some patients.^2,3,5,6 Infection of the aorta can arise by several mechanisms: direct extension of a local infection to an existing intimal injury or atherosclerotic plaque (the most common mechanism), septic embolism from endocarditis, direct bacterial inoculation from traumatic contamination, contiguous infection extending to the aorta wall, or a distant source of bacteremia.^2,3

Clinical manifestations of EA depend on the site and the extent of infection. The diagnosis should be considered in patients with atherosclerosis, fever, abdominal pain, and leukocytosis.^2,4-8 The differential diagnosis for EA includes (1) noninfective causes of aortitis, including rheumatoid arthritis and systemic lupus erythematosus; (2) tuberculous aortitis; (3) syphilitic aortitis; and (4) idiopathic isolated aortitis. Establishing an early diagnosis of infectious aortitis is extremely important because this condition is associated with a high rate of morbidity and mortality secondary to aortic rupture.^2-7

Imaging is critical for a reliable and quick diagnosis of acute aortic pathology. Noninvasive cross-sectional imaging modalities, such as contrast-enhanced computed tomography (CT), magnetic resonance imaging, nuclear medicine, or positron emission tomography, are used for both the initial diagnosis and follow-up of aortitis.¹ CT is the primary imaging method in most medical centers because it is widely available with short acquisition time in critically ill patients.³ CT allows rapid detection of abnormalities in wall thickness, diameter, and density, and enhancement of periaortic structures, enabling reliable exclusion of other aortic pathologies that may resemble acute aortitis. Also, CT aids in planning the optimal therapeutic approach.^1,3,5-8

This case illustrates EA associated with infection by K pneumoniae in a patient with poorly controlled type 2 DM (T2DM). In this single case, our patient presented to the Bay Pines Veterans Affairs Healthcare System (BPVAHS) in Florida with recent superficial soft tissue injury, severe hyperglycemia, worsening abdominal pain, and leukocytosis without fever or chills. The correct diagnosis of EA was confirmed by characteristic CT findings.

Case Presentation

A 72-year-old male with a history of T2DM, hypertension, atherosclerotic vascular disease, obstructive lung disease, and smoking 1.5 packs per day for 40 years presented with diabetic ketoacidosis, a urinary tract infection, and abdominal pain of 1-week duration that started to worsen the morning he arrived at the BPVAHS emergency department. He reported no nausea, vomiting, diarrhea, constipation, chest pain, shortness of breath, fever, chills, fatigue, or dysuria. He had a nonhealing laceration on his left medial foot that occurred 18 days before admission and was treated at an outside hospital.

The patient’s surgical history included a left common femoral endarterectomy and a left femoral popliteal above-knee reverse saphenous vein bypass 4 years ago for severe critical limb ischemia due to occlusion of his left superficial femoral artery with distal embolization to the first and fifth toes. About 6 months later, he developed disabling claudication in his left lower extremity due to distal popliteal artery occlusion and had another bypass surgery to the below-knee popliteal artery with a reverse saphenous vein graft harvested from the right thigh.

Discussion

This case contributes to the evidence that poorly controlled T2DM can be a predisposing factor for multiple vascular complications, including the infection of the aortic wall with progression to EA. Klebsiella species are considered opportunistic, Gram-negative pathogens that may disseminate to other tissues, causing life-threatening infections, including pneumonia, UTIs, bacteremia, and sepsis.⁹K pneumoniae infections are particularly challenging in neonates, the elderly, and immunocompromised individuals.⁹ CT is sensitive and specific in the detection of this pathologic entity.^1,3 In patients with a suspected infectious etiology, the presence of foci of gas on CT in solid organ tissues is usually associated with an anaerobic infection. Gas can also be produced by Gram-negative facultative anaerobes that can ferment glucose in necrotic tissues.⁹

Although any microorganism can infect the aorta, K pneumoniae cultured from the blood specimen, urine culture, and intraoperative specimens in our patient was responsible for the formed gas in the aortic wall. Occurrence of spontaneous gas by this microorganism is usually associated with conditions leading to either increased vulnerability to infections and/or enhanced bacterial virulence.⁹ Although a relationship between EA and T2DM has not been proved, it is well known that patients with T2DM have a defect in their host-defense mechanisms, making them more susceptible to infections such as EA. Furthermore, because patients with T2DM are prone to the development of Gram-negative sepsis, organisms such as K pneumoniae would tend to emerge. Patients with poorly controlled T2DM and the presence of an infectious source can be predisposed to infectious aortitis, eventually leading to a gas-forming infection of the aorta.^5,7

Conclusions

This case report can help bring awareness of this rare and potentially life-threatening condition in patients with T2DM. Clinicians should be aware of the risk of AE, particularly in patients with several additional risk factors: recent skin/soft tissue trauma, prior vascular graft surgery, and an underlying pancreatic mass. CT is the imaging method of choice that helps to rapidly choose a necessary emergent treatment approach.

Aortitis is the all-encompassing term ascribed to the inflammatory process in the aortic wall that can be either infective or noninfective in origin, commonly autoimmune or inflammatory large-vessel vasculitis.¹ Infectious aortitis, also known as bacterial, microbial, or cryptogenic aortitis, as well as mycotic or infected aneurysm, is a rare entity in the current antibiotic era but potentially a life-threatening disorder.² The potential complications of infectious aortitis include emphysematous aortitis (EA), pseudoaneurysm, aortic rupture, septic emboli, and fistula formation (eg, aorto-enteric fistula).^2,3

EA is a rare but serious inflammatory condition of the aorta with a nonspecific clinical presentation associated with high morbidity and mortality.^2-6 The condition is characterized by a localized collection of gas and purulent exudate at the aortic wall.^1,3 A few cases of EA have previously been reported; however, no known cases have been reported in the literature due to Klebsiella pneumoniae (K pneumoniae).

The pathophysiology of EA is the presence of underlying damage to the arterial wall caused by a hematogenously inoculated gas-producing organism.^2,3 Most reported cases of EA are due to endovascular graft complications. Under normal circumstances, the aortic intima is highly resistant to infectious pathogens; however, certain risk factors, such as diabetes mellitus (DM), atherosclerotic disease, preexisting aneurysm, cystic medial necrosis, vascular malformation, presence of medical devices, surgery, or impaired immunity can alter the integrity of the aortic intimal layer and predispose the aortic intima to infection.^1,4-7 Bacteria are the most common causative organisms that can infect the aorta, especially Staphylococcus, Enterococcus, Streptococcus, Salmonella, and spirochete Treponema pallidum (syphilis).^1,2,4,8 The site of the primary infection remains unclear in some patients.^2,3,5,6 Infection of the aorta can arise by several mechanisms: direct extension of a local infection to an existing intimal injury or atherosclerotic plaque (the most common mechanism), septic embolism from endocarditis, direct bacterial inoculation from traumatic contamination, contiguous infection extending to the aorta wall, or a distant source of bacteremia.^2,3

Clinical manifestations of EA depend on the site and the extent of infection. The diagnosis should be considered in patients with atherosclerosis, fever, abdominal pain, and leukocytosis.^2,4-8 The differential diagnosis for EA includes (1) noninfective causes of aortitis, including rheumatoid arthritis and systemic lupus erythematosus; (2) tuberculous aortitis; (3) syphilitic aortitis; and (4) idiopathic isolated aortitis. Establishing an early diagnosis of infectious aortitis is extremely important because this condition is associated with a high rate of morbidity and mortality secondary to aortic rupture.^2-7

Imaging is critical for a reliable and quick diagnosis of acute aortic pathology. Noninvasive cross-sectional imaging modalities, such as contrast-enhanced computed tomography (CT), magnetic resonance imaging, nuclear medicine, or positron emission tomography, are used for both the initial diagnosis and follow-up of aortitis.¹ CT is the primary imaging method in most medical centers because it is widely available with short acquisition time in critically ill patients.³ CT allows rapid detection of abnormalities in wall thickness, diameter, and density, and enhancement of periaortic structures, enabling reliable exclusion of other aortic pathologies that may resemble acute aortitis. Also, CT aids in planning the optimal therapeutic approach.^1,3,5-8

This case illustrates EA associated with infection by K pneumoniae in a patient with poorly controlled type 2 DM (T2DM). In this single case, our patient presented to the Bay Pines Veterans Affairs Healthcare System (BPVAHS) in Florida with recent superficial soft tissue injury, severe hyperglycemia, worsening abdominal pain, and leukocytosis without fever or chills. The correct diagnosis of EA was confirmed by characteristic CT findings.

Case Presentation

A 72-year-old male with a history of T2DM, hypertension, atherosclerotic vascular disease, obstructive lung disease, and smoking 1.5 packs per day for 40 years presented with diabetic ketoacidosis, a urinary tract infection, and abdominal pain of 1-week duration that started to worsen the morning he arrived at the BPVAHS emergency department. He reported no nausea, vomiting, diarrhea, constipation, chest pain, shortness of breath, fever, chills, fatigue, or dysuria. He had a nonhealing laceration on his left medial foot that occurred 18 days before admission and was treated at an outside hospital.

The patient’s surgical history included a left common femoral endarterectomy and a left femoral popliteal above-knee reverse saphenous vein bypass 4 years ago for severe critical limb ischemia due to occlusion of his left superficial femoral artery with distal embolization to the first and fifth toes. About 6 months later, he developed disabling claudication in his left lower extremity due to distal popliteal artery occlusion and had another bypass surgery to the below-knee popliteal artery with a reverse saphenous vein graft harvested from the right thigh.

Discussion

This case contributes to the evidence that poorly controlled T2DM can be a predisposing factor for multiple vascular complications, including the infection of the aortic wall with progression to EA. Klebsiella species are considered opportunistic, Gram-negative pathogens that may disseminate to other tissues, causing life-threatening infections, including pneumonia, UTIs, bacteremia, and sepsis.⁹K pneumoniae infections are particularly challenging in neonates, the elderly, and immunocompromised individuals.⁹ CT is sensitive and specific in the detection of this pathologic entity.^1,3 In patients with a suspected infectious etiology, the presence of foci of gas on CT in solid organ tissues is usually associated with an anaerobic infection. Gas can also be produced by Gram-negative facultative anaerobes that can ferment glucose in necrotic tissues.⁹

Although any microorganism can infect the aorta, K pneumoniae cultured from the blood specimen, urine culture, and intraoperative specimens in our patient was responsible for the formed gas in the aortic wall. Occurrence of spontaneous gas by this microorganism is usually associated with conditions leading to either increased vulnerability to infections and/or enhanced bacterial virulence.⁹ Although a relationship between EA and T2DM has not been proved, it is well known that patients with T2DM have a defect in their host-defense mechanisms, making them more susceptible to infections such as EA. Furthermore, because patients with T2DM are prone to the development of Gram-negative sepsis, organisms such as K pneumoniae would tend to emerge. Patients with poorly controlled T2DM and the presence of an infectious source can be predisposed to infectious aortitis, eventually leading to a gas-forming infection of the aorta.^5,7

Conclusions

This case report can help bring awareness of this rare and potentially life-threatening condition in patients with T2DM. Clinicians should be aware of the risk of AE, particularly in patients with several additional risk factors: recent skin/soft tissue trauma, prior vascular graft surgery, and an underlying pancreatic mass. CT is the imaging method of choice that helps to rapidly choose a necessary emergent treatment approach.

Aortitis is the all-encompassing term ascribed to the inflammatory process in the aortic wall that can be either infective or noninfective in origin, commonly autoimmune or inflammatory large-vessel vasculitis.¹ Infectious aortitis, also known as bacterial, microbial, or cryptogenic aortitis, as well as mycotic or infected aneurysm, is a rare entity in the current antibiotic era but potentially a life-threatening disorder.² The potential complications of infectious aortitis include emphysematous aortitis (EA), pseudoaneurysm, aortic rupture, septic emboli, and fistula formation (eg, aorto-enteric fistula).^2,3

EA is a rare but serious inflammatory condition of the aorta with a nonspecific clinical presentation associated with high morbidity and mortality.^2-6 The condition is characterized by a localized collection of gas and purulent exudate at the aortic wall.^1,3 A few cases of EA have previously been reported; however, no known cases have been reported in the literature due to Klebsiella pneumoniae (K pneumoniae).

The pathophysiology of EA is the presence of underlying damage to the arterial wall caused by a hematogenously inoculated gas-producing organism.^2,3 Most reported cases of EA are due to endovascular graft complications. Under normal circumstances, the aortic intima is highly resistant to infectious pathogens; however, certain risk factors, such as diabetes mellitus (DM), atherosclerotic disease, preexisting aneurysm, cystic medial necrosis, vascular malformation, presence of medical devices, surgery, or impaired immunity can alter the integrity of the aortic intimal layer and predispose the aortic intima to infection.^1,4-7 Bacteria are the most common causative organisms that can infect the aorta, especially Staphylococcus, Enterococcus, Streptococcus, Salmonella, and spirochete Treponema pallidum (syphilis).^1,2,4,8 The site of the primary infection remains unclear in some patients.^2,3,5,6 Infection of the aorta can arise by several mechanisms: direct extension of a local infection to an existing intimal injury or atherosclerotic plaque (the most common mechanism), septic embolism from endocarditis, direct bacterial inoculation from traumatic contamination, contiguous infection extending to the aorta wall, or a distant source of bacteremia.^2,3

Clinical manifestations of EA depend on the site and the extent of infection. The diagnosis should be considered in patients with atherosclerosis, fever, abdominal pain, and leukocytosis.^2,4-8 The differential diagnosis for EA includes (1) noninfective causes of aortitis, including rheumatoid arthritis and systemic lupus erythematosus; (2) tuberculous aortitis; (3) syphilitic aortitis; and (4) idiopathic isolated aortitis. Establishing an early diagnosis of infectious aortitis is extremely important because this condition is associated with a high rate of morbidity and mortality secondary to aortic rupture.^2-7

Imaging is critical for a reliable and quick diagnosis of acute aortic pathology. Noninvasive cross-sectional imaging modalities, such as contrast-enhanced computed tomography (CT), magnetic resonance imaging, nuclear medicine, or positron emission tomography, are used for both the initial diagnosis and follow-up of aortitis.¹ CT is the primary imaging method in most medical centers because it is widely available with short acquisition time in critically ill patients.³ CT allows rapid detection of abnormalities in wall thickness, diameter, and density, and enhancement of periaortic structures, enabling reliable exclusion of other aortic pathologies that may resemble acute aortitis. Also, CT aids in planning the optimal therapeutic approach.^1,3,5-8

This case illustrates EA associated with infection by K pneumoniae in a patient with poorly controlled type 2 DM (T2DM). In this single case, our patient presented to the Bay Pines Veterans Affairs Healthcare System (BPVAHS) in Florida with recent superficial soft tissue injury, severe hyperglycemia, worsening abdominal pain, and leukocytosis without fever or chills. The correct diagnosis of EA was confirmed by characteristic CT findings.

Case Presentation

A 72-year-old male with a history of T2DM, hypertension, atherosclerotic vascular disease, obstructive lung disease, and smoking 1.5 packs per day for 40 years presented with diabetic ketoacidosis, a urinary tract infection, and abdominal pain of 1-week duration that started to worsen the morning he arrived at the BPVAHS emergency department. He reported no nausea, vomiting, diarrhea, constipation, chest pain, shortness of breath, fever, chills, fatigue, or dysuria. He had a nonhealing laceration on his left medial foot that occurred 18 days before admission and was treated at an outside hospital.

The patient’s surgical history included a left common femoral endarterectomy and a left femoral popliteal above-knee reverse saphenous vein bypass 4 years ago for severe critical limb ischemia due to occlusion of his left superficial femoral artery with distal embolization to the first and fifth toes. About 6 months later, he developed disabling claudication in his left lower extremity due to distal popliteal artery occlusion and had another bypass surgery to the below-knee popliteal artery with a reverse saphenous vein graft harvested from the right thigh.

Discussion

This case contributes to the evidence that poorly controlled T2DM can be a predisposing factor for multiple vascular complications, including the infection of the aortic wall with progression to EA. Klebsiella species are considered opportunistic, Gram-negative pathogens that may disseminate to other tissues, causing life-threatening infections, including pneumonia, UTIs, bacteremia, and sepsis.⁹K pneumoniae infections are particularly challenging in neonates, the elderly, and immunocompromised individuals.⁹ CT is sensitive and specific in the detection of this pathologic entity.^1,3 In patients with a suspected infectious etiology, the presence of foci of gas on CT in solid organ tissues is usually associated with an anaerobic infection. Gas can also be produced by Gram-negative facultative anaerobes that can ferment glucose in necrotic tissues.⁹

Although any microorganism can infect the aorta, K pneumoniae cultured from the blood specimen, urine culture, and intraoperative specimens in our patient was responsible for the formed gas in the aortic wall. Occurrence of spontaneous gas by this microorganism is usually associated with conditions leading to either increased vulnerability to infections and/or enhanced bacterial virulence.⁹ Although a relationship between EA and T2DM has not been proved, it is well known that patients with T2DM have a defect in their host-defense mechanisms, making them more susceptible to infections such as EA. Furthermore, because patients with T2DM are prone to the development of Gram-negative sepsis, organisms such as K pneumoniae would tend to emerge. Patients with poorly controlled T2DM and the presence of an infectious source can be predisposed to infectious aortitis, eventually leading to a gas-forming infection of the aorta.^5,7

Conclusions

This case report can help bring awareness of this rare and potentially life-threatening condition in patients with T2DM. Clinicians should be aware of the risk of AE, particularly in patients with several additional risk factors: recent skin/soft tissue trauma, prior vascular graft surgery, and an underlying pancreatic mass. CT is the imaging method of choice that helps to rapidly choose a necessary emergent treatment approach.

Attention should be paid to changing a tolerated medication to another within its class. Many drugs approved by the US Food and Drug Administration (FDA), have equivalent therapeutic properties as existing drugs. Rarely do such medications share the same potency and adverse effect (AE) profile.

Case Presentation

A 77-year-old man presented to the emergency department (ED) at the Raymond G. Murphy Medical Center in Albuquerque, New Mexico, with a 1-month history of progressive muscle weakness, which was so severe that he required assistance rising from chairs. The symptoms began when he switched from atorvastatin 40 mg daily to rosuvastatin 40 mg daily. A nephrology consultation was requested for an elevated plasma creatinine.

The patient reported strict adherence to his prescribed medications. In the days following the switch to rosuvastatin, he noticed that his urine turned black. He described the color as “like burnt coffee.” The color gradually cleared before his ED presentation. The patient stopped taking rosuvastatin the day prior to presentation and noted improvement of his symptoms. Review of symptoms was significant for lower extremity paresthesia and numbness the day he started rosuvastatin. He had no symptoms of decompensated heart failure and no recent exacerbations requiring alteration of his diuretic regimen.

The patient’s medical history was significant for traumatic brain injury with complex partial seizures, carpal tunnel syndrome, dyslipidemia, coronary artery disease with percutaneous intervention to the right coronary artery in the late 1990s, atrial fibrillation and ventricular tachycardia, status post implantable cardioverter defibrillator, heart failure with reduced ejection fraction (25%) attributed to ischemic cardiomyopathy, hypertension, lower urinary tract symptoms/prostatism, and previous bladder cancer. In the mid-1960s, the patient served in the US Army and had been deployed to South Korea. After the service, he worked for the local city government. He was retired for about 15 years. He reported no tobacco, alcohol, or recreational drug use and no tattoos. He did not require prior blood or blood product transfusions. None of his family members—parents, siblings, or children—had any history of kidney disease.

The patient’s outpatient medications included levetiracetam 750 mg twice daily, melatonin 9 mg at night, menthol 16%/methyl-salicylate 30% topically up to 4 times per day as needed, aspirin 81 mg once daily, fish oil 1000 mg twice daily, amiodarone 400 mg twice daily, hydralazine 20 mg 3 times daily, isosorbide mononitrate 60 mg daily, metoprolol succinate 100 mg daily, and tamsulosin 0.4 mg at night. His vital signs were stable: afebrile (97.5 ºF), normocardic (74 beats per minute), normotensive (118/78 mm Hg), and normoxic (98% on room air). On examination, he appeared elderly, somewhat frail, and chronically ill but in no acute distress. Affect was pleasant and appropriate, attention was high, and his thought process was logical. He had sparse, grey scalp hair. Extraocular movements were intact. Oral mucosa was pink and moist. His back was nontender, and there was no costovertebral tenderness bilaterally. The patient was in no respiratory distress, with a slightly hyperresonant chest to percussion bilaterally, very faint inspiratory basilar crepitant rales (that cleared with repeat inspiration), and was otherwise clear to auscultation throughout. An outline of an implanted pacemaker was evident on the chest under his left clavicle, with a laterally displaced apical impulse. The rate was normal and the rhythm was regular. Upper extremities demonstrated papyraceous skin but without cyanosis, clubbing, or edema. Radial pulses were slightly diminished. He had no lower extremity edema.

His laboratory values are provided in Table 1. Kidney function was stable months prior to admission. Of note, the blood urea nitrogen and plasma creatinine were increased from his baseline up to 47 and 5.89 mg/dL, respectively. The serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase were 1051 U/L and 408 U/L, respectively. Plasma amylase and lipase levels also were elevated, 230 U/L and 892 U/L, respectively. Creatine kinase was 41,099 U/L. Urinalysis demonstrated a specific gravity of 1.017, pH of 5, and a large amount of blood (92 red blood cells/high power field).

Discussion

Statin-class drugs inhibit the HMG-CoA reductase (Table 2). Upregulation of low-density lipoprotein cholesterol (LDL-C) receptors in the liver result in increased LDL-C uptake and cholesterol catabolism.¹ Prescribed inhibitors of the HMG-CoA reductase—statins—are known to reduce mortality due to cardiovascular disease (CVD). Much like any other pharmaceutical agent with any measurable potency, HMG-CoA inhibitors can have AEs. Statin therapy has been associated with pancreatitis.² Muscle toxicity is a complication of HMG-CoA reductase inhibitors, and statin-associated symptoms are a leading cause of nonadherence.³ Rosuvastatin had higher AE and drug reactions compared with that of atorvastatin and pitavastatin (35.6%, 8.7%, and 22.2%, respectively) in clinical trials for approval.⁴ We have reported concomitant adermatopathic dermatomyositis with statin-induced myopathy in a 48-year-old man from simvastatin (40 to 80 mg daily).¹

Toxin-induced myopathy should be considered early in the differential diagnosis of weakness.⁵ All HMG-CoA inhibitors have been associated with acute kidney injury, particularly at high doses and also are known to induce myopathies, sometimes with inclusion bodies.¹ Muscle-related AEs correlate with the potency of an HMG-CoA reductase inhibitor according to an analysis using the FDA AE Reporting System (AERS).⁶ Myalgia and rhabdomyolysis are well-known AEs of this class of medications. Furthermore, type II muscle atrophy—particularly in the proximal limb muscles—has been reported.⁵ Patients may have difficulty rising from chairs.¹ Rosuvastatin had the strongest signal for muscular AEs (eg, myalgia, rhabdomyolysis, increased creatine phosphokinase level) from an FDA analysis of AERS.⁷

Rosuvastatin is the only HMG-CoA reductase inhibitor that causes dose-dependent increases in proteinuria and hematuria (Figure 4).⁸ Rosuvastatin at a 5-mg dose may induce 4 times the proteinuria as a placebo. Typically, other statins potentially reduce proteinuria (without hematuria). Proteinuria may be induced by rosuvastatin even at low doses.⁸ Proteinuria is attributed to how rosuvastatin impacts proximal tubular function.⁹ The drug is transported into the proximal tubule by the organic anion transporter-3. Acute kidney injury has been associated with several statins, including rosuvastatin.^7,10 This may be associated with denuded tubular epithelia, active urinary sediment, acute tubular toxicity, vacuolated epithelial cells, and tubular cell casts. Unlike atorvastatin, the increase in proteinuria and hematuria also is dose dependent.

In patients with renal insufficiency (short of end-stage renal disease [ESRD]), most statins other than rosuvastatin are well tolerated and recommended for reduction of overall and CVD mortality risk. However, these benefits seem to diminish once ESRD is reached. Atorvastatin did not impact CVD mortality in patients with type 2 diabetes mellitus (T2DM) and ESRD (despite decreasing LDL-C).¹¹ The AURORA study randomized 10 mg of statin vs placebo in 2776 maintenance dialysis patients aged 50 to 80 years. Rosuvastatin lowered the LDL-C but did not affect all-cause mortality (13.5 vs 14.0 events per 100 patient-years). Patients randomized to rosuvastatin had more than twice as many unclassified strokes (9 vs 4). Rosuvastatin, although efficacious in reducing LDL-C, had no impact on CVD mortality, nonfatal myocardial infarction, or nonfatal stroke.¹² Post hoc analysis demonstrated that in patients with T2DM with ESRD the hazard ratio for hemorrhagic stroke was 5.2.¹³

Rosuvastatin ranked lower than lovastatin, pravastatin, simvastatin, atorvastatin, and fluvastatin with respect to reduction of all-cause mortality in trials of participants with or without prior coronary artery disease.¹⁴ AEs, such as rhabdomyolysis, proteinuria, nephropathy, renal failure, liver, and muscle toxicity are higher with rosuvastatin than other medications in its class.¹⁵

Conclusions

For patients with existing CVD, standard clinical practice is to encourage increased and regular physical activity, cholesterol-lowering diets, weight loss, and smoking cessation. Hypertension should be treated. Glycemia should be well controlled in the setting of T2DM. β-blockers may be beneficial in those with histories of myocardial infarction or heart failure with reduced systolic function. Statins are a valuable tool in the treatment of dyslipidemia.

Statin-induced muscle symptoms are a major reason for discontinuation and nonadherence.¹⁶ Statin-induced myalgia, myositis, and myopathy have been used interchangeably.¹⁷ Rhabdomyolysis, myalgia, increased creatine kinase, statin myopathy, and immune-mediated necrotizing myopathy are among the clinical phenotypes caused by statins.¹⁷ There are 33,695 serious cases—1808 deaths—reported with rosuvastatin in the FDA AERS as of June 30, 2021. Myalgia, pain in extremity, muscle spasms, pain, and arthralgia top the list of AEs. When statin-induced symptoms occur, adherence is rarely improved by dismissive clinicians.¹⁸

Drugs in the same class often have common therapeutic properties. Potencies and AE profiles are seldom uniform. The decision to add or change the brand of medication within a class should be balanced with considerations for the indication, duplications, simplification, AEs, appropriate dosage, and drug-drug interactions.

Acknowledgments

Brent Wagner is funded by a US Department of Veterans Affairs Merit Award (I01 BX001958), a National Institutes of Health R01 grant (DK-102085), Dialysis Clinic, Inc., and partially supported by the University of New Mexico Brain and Behavioral Health Institute (BBHI 2018-1008, 2020-21-002) and in part by the University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD); and the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust). Brent Wagner is an Associate Member to the University of New Mexico Health Sciences Center Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence (AIM CoBRE) supported by NIH grant P20GM121176.

Funding

National Institutes of Health Grant R01 DK-102085, Dialysis Clinic Inc., VA Merit Award I01 BX001958, Center for Integrated Nanotechnologies User Agreement 2019AU0120, Brain & Behavioral Health Institute (grants 2018-1008, 2020-21-002), University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD), the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust) and a metabolomics voucher from the AIM Center (NIH P20GM121176).

Attention should be paid to changing a tolerated medication to another within its class. Many drugs approved by the US Food and Drug Administration (FDA), have equivalent therapeutic properties as existing drugs. Rarely do such medications share the same potency and adverse effect (AE) profile.

Case Presentation

A 77-year-old man presented to the emergency department (ED) at the Raymond G. Murphy Medical Center in Albuquerque, New Mexico, with a 1-month history of progressive muscle weakness, which was so severe that he required assistance rising from chairs. The symptoms began when he switched from atorvastatin 40 mg daily to rosuvastatin 40 mg daily. A nephrology consultation was requested for an elevated plasma creatinine.

The patient reported strict adherence to his prescribed medications. In the days following the switch to rosuvastatin, he noticed that his urine turned black. He described the color as “like burnt coffee.” The color gradually cleared before his ED presentation. The patient stopped taking rosuvastatin the day prior to presentation and noted improvement of his symptoms. Review of symptoms was significant for lower extremity paresthesia and numbness the day he started rosuvastatin. He had no symptoms of decompensated heart failure and no recent exacerbations requiring alteration of his diuretic regimen.

The patient’s medical history was significant for traumatic brain injury with complex partial seizures, carpal tunnel syndrome, dyslipidemia, coronary artery disease with percutaneous intervention to the right coronary artery in the late 1990s, atrial fibrillation and ventricular tachycardia, status post implantable cardioverter defibrillator, heart failure with reduced ejection fraction (25%) attributed to ischemic cardiomyopathy, hypertension, lower urinary tract symptoms/prostatism, and previous bladder cancer. In the mid-1960s, the patient served in the US Army and had been deployed to South Korea. After the service, he worked for the local city government. He was retired for about 15 years. He reported no tobacco, alcohol, or recreational drug use and no tattoos. He did not require prior blood or blood product transfusions. None of his family members—parents, siblings, or children—had any history of kidney disease.

The patient’s outpatient medications included levetiracetam 750 mg twice daily, melatonin 9 mg at night, menthol 16%/methyl-salicylate 30% topically up to 4 times per day as needed, aspirin 81 mg once daily, fish oil 1000 mg twice daily, amiodarone 400 mg twice daily, hydralazine 20 mg 3 times daily, isosorbide mononitrate 60 mg daily, metoprolol succinate 100 mg daily, and tamsulosin 0.4 mg at night. His vital signs were stable: afebrile (97.5 ºF), normocardic (74 beats per minute), normotensive (118/78 mm Hg), and normoxic (98% on room air). On examination, he appeared elderly, somewhat frail, and chronically ill but in no acute distress. Affect was pleasant and appropriate, attention was high, and his thought process was logical. He had sparse, grey scalp hair. Extraocular movements were intact. Oral mucosa was pink and moist. His back was nontender, and there was no costovertebral tenderness bilaterally. The patient was in no respiratory distress, with a slightly hyperresonant chest to percussion bilaterally, very faint inspiratory basilar crepitant rales (that cleared with repeat inspiration), and was otherwise clear to auscultation throughout. An outline of an implanted pacemaker was evident on the chest under his left clavicle, with a laterally displaced apical impulse. The rate was normal and the rhythm was regular. Upper extremities demonstrated papyraceous skin but without cyanosis, clubbing, or edema. Radial pulses were slightly diminished. He had no lower extremity edema.

His laboratory values are provided in Table 1. Kidney function was stable months prior to admission. Of note, the blood urea nitrogen and plasma creatinine were increased from his baseline up to 47 and 5.89 mg/dL, respectively. The serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase were 1051 U/L and 408 U/L, respectively. Plasma amylase and lipase levels also were elevated, 230 U/L and 892 U/L, respectively. Creatine kinase was 41,099 U/L. Urinalysis demonstrated a specific gravity of 1.017, pH of 5, and a large amount of blood (92 red blood cells/high power field).

Discussion

Statin-class drugs inhibit the HMG-CoA reductase (Table 2). Upregulation of low-density lipoprotein cholesterol (LDL-C) receptors in the liver result in increased LDL-C uptake and cholesterol catabolism.¹ Prescribed inhibitors of the HMG-CoA reductase—statins—are known to reduce mortality due to cardiovascular disease (CVD). Much like any other pharmaceutical agent with any measurable potency, HMG-CoA inhibitors can have AEs. Statin therapy has been associated with pancreatitis.² Muscle toxicity is a complication of HMG-CoA reductase inhibitors, and statin-associated symptoms are a leading cause of nonadherence.³ Rosuvastatin had higher AE and drug reactions compared with that of atorvastatin and pitavastatin (35.6%, 8.7%, and 22.2%, respectively) in clinical trials for approval.⁴ We have reported concomitant adermatopathic dermatomyositis with statin-induced myopathy in a 48-year-old man from simvastatin (40 to 80 mg daily).¹

Toxin-induced myopathy should be considered early in the differential diagnosis of weakness.⁵ All HMG-CoA inhibitors have been associated with acute kidney injury, particularly at high doses and also are known to induce myopathies, sometimes with inclusion bodies.¹ Muscle-related AEs correlate with the potency of an HMG-CoA reductase inhibitor according to an analysis using the FDA AE Reporting System (AERS).⁶ Myalgia and rhabdomyolysis are well-known AEs of this class of medications. Furthermore, type II muscle atrophy—particularly in the proximal limb muscles—has been reported.⁵ Patients may have difficulty rising from chairs.¹ Rosuvastatin had the strongest signal for muscular AEs (eg, myalgia, rhabdomyolysis, increased creatine phosphokinase level) from an FDA analysis of AERS.⁷

Rosuvastatin is the only HMG-CoA reductase inhibitor that causes dose-dependent increases in proteinuria and hematuria (Figure 4).⁸ Rosuvastatin at a 5-mg dose may induce 4 times the proteinuria as a placebo. Typically, other statins potentially reduce proteinuria (without hematuria). Proteinuria may be induced by rosuvastatin even at low doses.⁸ Proteinuria is attributed to how rosuvastatin impacts proximal tubular function.⁹ The drug is transported into the proximal tubule by the organic anion transporter-3. Acute kidney injury has been associated with several statins, including rosuvastatin.^7,10 This may be associated with denuded tubular epithelia, active urinary sediment, acute tubular toxicity, vacuolated epithelial cells, and tubular cell casts. Unlike atorvastatin, the increase in proteinuria and hematuria also is dose dependent.

In patients with renal insufficiency (short of end-stage renal disease [ESRD]), most statins other than rosuvastatin are well tolerated and recommended for reduction of overall and CVD mortality risk. However, these benefits seem to diminish once ESRD is reached. Atorvastatin did not impact CVD mortality in patients with type 2 diabetes mellitus (T2DM) and ESRD (despite decreasing LDL-C).¹¹ The AURORA study randomized 10 mg of statin vs placebo in 2776 maintenance dialysis patients aged 50 to 80 years. Rosuvastatin lowered the LDL-C but did not affect all-cause mortality (13.5 vs 14.0 events per 100 patient-years). Patients randomized to rosuvastatin had more than twice as many unclassified strokes (9 vs 4). Rosuvastatin, although efficacious in reducing LDL-C, had no impact on CVD mortality, nonfatal myocardial infarction, or nonfatal stroke.¹² Post hoc analysis demonstrated that in patients with T2DM with ESRD the hazard ratio for hemorrhagic stroke was 5.2.¹³

Rosuvastatin ranked lower than lovastatin, pravastatin, simvastatin, atorvastatin, and fluvastatin with respect to reduction of all-cause mortality in trials of participants with or without prior coronary artery disease.¹⁴ AEs, such as rhabdomyolysis, proteinuria, nephropathy, renal failure, liver, and muscle toxicity are higher with rosuvastatin than other medications in its class.¹⁵

Conclusions

For patients with existing CVD, standard clinical practice is to encourage increased and regular physical activity, cholesterol-lowering diets, weight loss, and smoking cessation. Hypertension should be treated. Glycemia should be well controlled in the setting of T2DM. β-blockers may be beneficial in those with histories of myocardial infarction or heart failure with reduced systolic function. Statins are a valuable tool in the treatment of dyslipidemia.

Statin-induced muscle symptoms are a major reason for discontinuation and nonadherence.¹⁶ Statin-induced myalgia, myositis, and myopathy have been used interchangeably.¹⁷ Rhabdomyolysis, myalgia, increased creatine kinase, statin myopathy, and immune-mediated necrotizing myopathy are among the clinical phenotypes caused by statins.¹⁷ There are 33,695 serious cases—1808 deaths—reported with rosuvastatin in the FDA AERS as of June 30, 2021. Myalgia, pain in extremity, muscle spasms, pain, and arthralgia top the list of AEs. When statin-induced symptoms occur, adherence is rarely improved by dismissive clinicians.¹⁸

Drugs in the same class often have common therapeutic properties. Potencies and AE profiles are seldom uniform. The decision to add or change the brand of medication within a class should be balanced with considerations for the indication, duplications, simplification, AEs, appropriate dosage, and drug-drug interactions.

Acknowledgments

Brent Wagner is funded by a US Department of Veterans Affairs Merit Award (I01 BX001958), a National Institutes of Health R01 grant (DK-102085), Dialysis Clinic, Inc., and partially supported by the University of New Mexico Brain and Behavioral Health Institute (BBHI 2018-1008, 2020-21-002) and in part by the University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD); and the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust). Brent Wagner is an Associate Member to the University of New Mexico Health Sciences Center Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence (AIM CoBRE) supported by NIH grant P20GM121176.

Funding

National Institutes of Health Grant R01 DK-102085, Dialysis Clinic Inc., VA Merit Award I01 BX001958, Center for Integrated Nanotechnologies User Agreement 2019AU0120, Brain & Behavioral Health Institute (grants 2018-1008, 2020-21-002), University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD), the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust) and a metabolomics voucher from the AIM Center (NIH P20GM121176).

Attention should be paid to changing a tolerated medication to another within its class. Many drugs approved by the US Food and Drug Administration (FDA), have equivalent therapeutic properties as existing drugs. Rarely do such medications share the same potency and adverse effect (AE) profile.

Case Presentation

A 77-year-old man presented to the emergency department (ED) at the Raymond G. Murphy Medical Center in Albuquerque, New Mexico, with a 1-month history of progressive muscle weakness, which was so severe that he required assistance rising from chairs. The symptoms began when he switched from atorvastatin 40 mg daily to rosuvastatin 40 mg daily. A nephrology consultation was requested for an elevated plasma creatinine.

The patient reported strict adherence to his prescribed medications. In the days following the switch to rosuvastatin, he noticed that his urine turned black. He described the color as “like burnt coffee.” The color gradually cleared before his ED presentation. The patient stopped taking rosuvastatin the day prior to presentation and noted improvement of his symptoms. Review of symptoms was significant for lower extremity paresthesia and numbness the day he started rosuvastatin. He had no symptoms of decompensated heart failure and no recent exacerbations requiring alteration of his diuretic regimen.

The patient’s medical history was significant for traumatic brain injury with complex partial seizures, carpal tunnel syndrome, dyslipidemia, coronary artery disease with percutaneous intervention to the right coronary artery in the late 1990s, atrial fibrillation and ventricular tachycardia, status post implantable cardioverter defibrillator, heart failure with reduced ejection fraction (25%) attributed to ischemic cardiomyopathy, hypertension, lower urinary tract symptoms/prostatism, and previous bladder cancer. In the mid-1960s, the patient served in the US Army and had been deployed to South Korea. After the service, he worked for the local city government. He was retired for about 15 years. He reported no tobacco, alcohol, or recreational drug use and no tattoos. He did not require prior blood or blood product transfusions. None of his family members—parents, siblings, or children—had any history of kidney disease.

The patient’s outpatient medications included levetiracetam 750 mg twice daily, melatonin 9 mg at night, menthol 16%/methyl-salicylate 30% topically up to 4 times per day as needed, aspirin 81 mg once daily, fish oil 1000 mg twice daily, amiodarone 400 mg twice daily, hydralazine 20 mg 3 times daily, isosorbide mononitrate 60 mg daily, metoprolol succinate 100 mg daily, and tamsulosin 0.4 mg at night. His vital signs were stable: afebrile (97.5 ºF), normocardic (74 beats per minute), normotensive (118/78 mm Hg), and normoxic (98% on room air). On examination, he appeared elderly, somewhat frail, and chronically ill but in no acute distress. Affect was pleasant and appropriate, attention was high, and his thought process was logical. He had sparse, grey scalp hair. Extraocular movements were intact. Oral mucosa was pink and moist. His back was nontender, and there was no costovertebral tenderness bilaterally. The patient was in no respiratory distress, with a slightly hyperresonant chest to percussion bilaterally, very faint inspiratory basilar crepitant rales (that cleared with repeat inspiration), and was otherwise clear to auscultation throughout. An outline of an implanted pacemaker was evident on the chest under his left clavicle, with a laterally displaced apical impulse. The rate was normal and the rhythm was regular. Upper extremities demonstrated papyraceous skin but without cyanosis, clubbing, or edema. Radial pulses were slightly diminished. He had no lower extremity edema.

His laboratory values are provided in Table 1. Kidney function was stable months prior to admission. Of note, the blood urea nitrogen and plasma creatinine were increased from his baseline up to 47 and 5.89 mg/dL, respectively. The serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase were 1051 U/L and 408 U/L, respectively. Plasma amylase and lipase levels also were elevated, 230 U/L and 892 U/L, respectively. Creatine kinase was 41,099 U/L. Urinalysis demonstrated a specific gravity of 1.017, pH of 5, and a large amount of blood (92 red blood cells/high power field).

Discussion

Statin-class drugs inhibit the HMG-CoA reductase (Table 2). Upregulation of low-density lipoprotein cholesterol (LDL-C) receptors in the liver result in increased LDL-C uptake and cholesterol catabolism.¹ Prescribed inhibitors of the HMG-CoA reductase—statins—are known to reduce mortality due to cardiovascular disease (CVD). Much like any other pharmaceutical agent with any measurable potency, HMG-CoA inhibitors can have AEs. Statin therapy has been associated with pancreatitis.² Muscle toxicity is a complication of HMG-CoA reductase inhibitors, and statin-associated symptoms are a leading cause of nonadherence.³ Rosuvastatin had higher AE and drug reactions compared with that of atorvastatin and pitavastatin (35.6%, 8.7%, and 22.2%, respectively) in clinical trials for approval.⁴ We have reported concomitant adermatopathic dermatomyositis with statin-induced myopathy in a 48-year-old man from simvastatin (40 to 80 mg daily).¹

Toxin-induced myopathy should be considered early in the differential diagnosis of weakness.⁵ All HMG-CoA inhibitors have been associated with acute kidney injury, particularly at high doses and also are known to induce myopathies, sometimes with inclusion bodies.¹ Muscle-related AEs correlate with the potency of an HMG-CoA reductase inhibitor according to an analysis using the FDA AE Reporting System (AERS).⁶ Myalgia and rhabdomyolysis are well-known AEs of this class of medications. Furthermore, type II muscle atrophy—particularly in the proximal limb muscles—has been reported.⁵ Patients may have difficulty rising from chairs.¹ Rosuvastatin had the strongest signal for muscular AEs (eg, myalgia, rhabdomyolysis, increased creatine phosphokinase level) from an FDA analysis of AERS.⁷

Rosuvastatin is the only HMG-CoA reductase inhibitor that causes dose-dependent increases in proteinuria and hematuria (Figure 4).⁸ Rosuvastatin at a 5-mg dose may induce 4 times the proteinuria as a placebo. Typically, other statins potentially reduce proteinuria (without hematuria). Proteinuria may be induced by rosuvastatin even at low doses.⁸ Proteinuria is attributed to how rosuvastatin impacts proximal tubular function.⁹ The drug is transported into the proximal tubule by the organic anion transporter-3. Acute kidney injury has been associated with several statins, including rosuvastatin.^7,10 This may be associated with denuded tubular epithelia, active urinary sediment, acute tubular toxicity, vacuolated epithelial cells, and tubular cell casts. Unlike atorvastatin, the increase in proteinuria and hematuria also is dose dependent.

In patients with renal insufficiency (short of end-stage renal disease [ESRD]), most statins other than rosuvastatin are well tolerated and recommended for reduction of overall and CVD mortality risk. However, these benefits seem to diminish once ESRD is reached. Atorvastatin did not impact CVD mortality in patients with type 2 diabetes mellitus (T2DM) and ESRD (despite decreasing LDL-C).¹¹ The AURORA study randomized 10 mg of statin vs placebo in 2776 maintenance dialysis patients aged 50 to 80 years. Rosuvastatin lowered the LDL-C but did not affect all-cause mortality (13.5 vs 14.0 events per 100 patient-years). Patients randomized to rosuvastatin had more than twice as many unclassified strokes (9 vs 4). Rosuvastatin, although efficacious in reducing LDL-C, had no impact on CVD mortality, nonfatal myocardial infarction, or nonfatal stroke.¹² Post hoc analysis demonstrated that in patients with T2DM with ESRD the hazard ratio for hemorrhagic stroke was 5.2.¹³

Rosuvastatin ranked lower than lovastatin, pravastatin, simvastatin, atorvastatin, and fluvastatin with respect to reduction of all-cause mortality in trials of participants with or without prior coronary artery disease.¹⁴ AEs, such as rhabdomyolysis, proteinuria, nephropathy, renal failure, liver, and muscle toxicity are higher with rosuvastatin than other medications in its class.¹⁵

Conclusions

For patients with existing CVD, standard clinical practice is to encourage increased and regular physical activity, cholesterol-lowering diets, weight loss, and smoking cessation. Hypertension should be treated. Glycemia should be well controlled in the setting of T2DM. β-blockers may be beneficial in those with histories of myocardial infarction or heart failure with reduced systolic function. Statins are a valuable tool in the treatment of dyslipidemia.

Statin-induced muscle symptoms are a major reason for discontinuation and nonadherence.¹⁶ Statin-induced myalgia, myositis, and myopathy have been used interchangeably.¹⁷ Rhabdomyolysis, myalgia, increased creatine kinase, statin myopathy, and immune-mediated necrotizing myopathy are among the clinical phenotypes caused by statins.¹⁷ There are 33,695 serious cases—1808 deaths—reported with rosuvastatin in the FDA AERS as of June 30, 2021. Myalgia, pain in extremity, muscle spasms, pain, and arthralgia top the list of AEs. When statin-induced symptoms occur, adherence is rarely improved by dismissive clinicians.¹⁸

Drugs in the same class often have common therapeutic properties. Potencies and AE profiles are seldom uniform. The decision to add or change the brand of medication within a class should be balanced with considerations for the indication, duplications, simplification, AEs, appropriate dosage, and drug-drug interactions.

Acknowledgments

Brent Wagner is funded by a US Department of Veterans Affairs Merit Award (I01 BX001958), a National Institutes of Health R01 grant (DK-102085), Dialysis Clinic, Inc., and partially supported by the University of New Mexico Brain and Behavioral Health Institute (BBHI 2018-1008, 2020-21-002) and in part by the University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD); and the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust). Brent Wagner is an Associate Member to the University of New Mexico Health Sciences Center Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence (AIM CoBRE) supported by NIH grant P20GM121176.

Funding

National Institutes of Health Grant R01 DK-102085, Dialysis Clinic Inc., VA Merit Award I01 BX001958, Center for Integrated Nanotechnologies User Agreement 2019AU0120, Brain & Behavioral Health Institute (grants 2018-1008, 2020-21-002), University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD), the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust) and a metabolomics voucher from the AIM Center (NIH P20GM121176).

Pfizer and its European partner BioNTech on Nov. 9 asked the U.S. government to expand emergency use authorization (EUA) to allow everybody over 18 to receive their COVID-19 booster shots.

If the request is approved, the broader use of Pfizer boosters would be a step toward President Biden’s goal of boosters for all adults. He announced the goal last August but backed off after some scientists said younger people may not need boosters, especially with large parts of the world unvaccinated.

Pfizer is submitting a study of booster effects on 10,000 people to make its case, according to The Associated Press.

This would be Pfizer’s second attempt. In September, a Food and Drug Administration advisory panel turned down Pfizer’s idea of booster shots for everybody over 18.

However, the committee recommended Pfizer booster shots for people 65 and over, essential workers, and people with underlying health conditions.

The FDA and the Centers for Disease Control and Prevention authorized the Pfizer booster for those other groups and later authorization was granted for the same groups with Moderna and Johnson & Johnson boosters. People who got the two-shot Pfizer or Moderna vaccines should get a booster 6 months after the second dose and people who got the one-dose J&J vaccine should get a booster 2 months later.

The pro-booster argument has strengthened because new data have come in from Israel that confirm boosters provide protection as vaccine effectiveness wanes over time, The Washington Post reported. Also, health officials are worried about a post-holiday surge and because COVID-19 case counts and deaths are not dropping in every part of the country, though they are declining overall, according to the The Post report.

The regulatory path for a booster-for-all application is unclear. The Post, citing two unnamed officials, said the FDA probably won’t send the Pfizer application to the FDA advisory committee this time because the committee has already had extensive discussions about boosters. If the FDA gives the green light, CDC Director Rochelle Walensky, MD, would have to make updated recommendations on boosters, The Post article noted.
 

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

Pfizer and its European partner BioNTech on Nov. 9 asked the U.S. government to expand emergency use authorization (EUA) to allow everybody over 18 to receive their COVID-19 booster shots.

If the request is approved, the broader use of Pfizer boosters would be a step toward President Biden’s goal of boosters for all adults. He announced the goal last August but backed off after some scientists said younger people may not need boosters, especially with large parts of the world unvaccinated.

Pfizer is submitting a study of booster effects on 10,000 people to make its case, according to The Associated Press.

This would be Pfizer’s second attempt. In September, a Food and Drug Administration advisory panel turned down Pfizer’s idea of booster shots for everybody over 18.

However, the committee recommended Pfizer booster shots for people 65 and over, essential workers, and people with underlying health conditions.

The FDA and the Centers for Disease Control and Prevention authorized the Pfizer booster for those other groups and later authorization was granted for the same groups with Moderna and Johnson & Johnson boosters. People who got the two-shot Pfizer or Moderna vaccines should get a booster 6 months after the second dose and people who got the one-dose J&J vaccine should get a booster 2 months later.

The pro-booster argument has strengthened because new data have come in from Israel that confirm boosters provide protection as vaccine effectiveness wanes over time, The Washington Post reported. Also, health officials are worried about a post-holiday surge and because COVID-19 case counts and deaths are not dropping in every part of the country, though they are declining overall, according to the The Post report.

The regulatory path for a booster-for-all application is unclear. The Post, citing two unnamed officials, said the FDA probably won’t send the Pfizer application to the FDA advisory committee this time because the committee has already had extensive discussions about boosters. If the FDA gives the green light, CDC Director Rochelle Walensky, MD, would have to make updated recommendations on boosters, The Post article noted.
 

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

Pfizer and its European partner BioNTech on Nov. 9 asked the U.S. government to expand emergency use authorization (EUA) to allow everybody over 18 to receive their COVID-19 booster shots.

If the request is approved, the broader use of Pfizer boosters would be a step toward President Biden’s goal of boosters for all adults. He announced the goal last August but backed off after some scientists said younger people may not need boosters, especially with large parts of the world unvaccinated.

Pfizer is submitting a study of booster effects on 10,000 people to make its case, according to The Associated Press.

This would be Pfizer’s second attempt. In September, a Food and Drug Administration advisory panel turned down Pfizer’s idea of booster shots for everybody over 18.

However, the committee recommended Pfizer booster shots for people 65 and over, essential workers, and people with underlying health conditions.

The FDA and the Centers for Disease Control and Prevention authorized the Pfizer booster for those other groups and later authorization was granted for the same groups with Moderna and Johnson & Johnson boosters. People who got the two-shot Pfizer or Moderna vaccines should get a booster 6 months after the second dose and people who got the one-dose J&J vaccine should get a booster 2 months later.

The pro-booster argument has strengthened because new data have come in from Israel that confirm boosters provide protection as vaccine effectiveness wanes over time, The Washington Post reported. Also, health officials are worried about a post-holiday surge and because COVID-19 case counts and deaths are not dropping in every part of the country, though they are declining overall, according to the The Post report.

The regulatory path for a booster-for-all application is unclear. The Post, citing two unnamed officials, said the FDA probably won’t send the Pfizer application to the FDA advisory committee this time because the committee has already had extensive discussions about boosters. If the FDA gives the green light, CDC Director Rochelle Walensky, MD, would have to make updated recommendations on boosters, The Post article noted.
 

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