MDedge Rheumatology

Changes in Medicare law will help some patients who need costly rheumatology treatments, including several medicines for which competition has been kept in check for many years.

In fact, this field of medicine includes prime examples of the kinds of products that drove Congress to give the giant federal health program leverage to try to restrain rising pharmaceutical costs through negotiations. The Inflation Reduction Act, signed into law by President Joe Biden on Aug. 16, also provides some fairly quick aid for people enrolled in Medicare who struggle with pharmacy bills.

Getty

As described in an official summary from the Congressional Research Service, the law establishes:

• A cap on annual Medicare Part D out-of-pocket spending that starts in 2025 at $2,000, with planned annual adjustments thereafter.
• A limit on cost-sharing under Medicare Part D for a month’s supply of covered insulin products at $35 for 2023 through 2025, with plans for continued limits on this cost in the years after pegged to negotiated prices.
• A program under which drug manufacturers provide discounts to beneficiaries who have incurred costs above the annual deductible beginning in 2025.
• A requirement that drugmakers issue rebates to Medicare for certain brand-name drugs covered without generic equivalents for which prices increase faster than inflation.
• An obligation for Medicare Part D plans to pay for adult vaccines that are recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices without requiring cost sharing.

The law’s marquee health provision sets the stage for Medicare, the nation’s largest purchaser of drugs, for the first time to leverage its clout directly in negotiating for lower costs for medicines. Democrats sought to build what amount to guardrails into this program, seeking to spare from competition new and innovative drugs and ones developed by smaller companies. Drugs likely to soon face competition from copycat versions also would fall outside of the pool for negotiations.

In effect, the design of the program would allow Medicare to negotiate in the future in cases such as those seen in recent years with blockbuster medicines often in rheumatology. That’s due in a large part to legal challenges that have helped thwart the introduction of copycat versions of these kinds of products known as biosimilars.

Etanercept (Enbrel) has been sold in the United States since 1998 and adalimumab (Humira) since 2003. Both products face competition from copycat versions called biosimilars in other nations, but the introductions of these products have been delayed in the United States until 2029 for etanercept and 2023 for adalimumab, the Office of Inspector General for the Department of Health & Human Services said in a March 2022 report. The OIG said in the report that the combined 2019 Medicare Part D tab for the two biologics was more than $5 billion.

Rheumatology drugs rival cancer medicines for dominance among the most expensive drugs for people enrolled in Medicare. The average 2020 spending for the most widely used forms of adalimumab by people in Medicare’s Part D pharmacy program topped $51,000, according to federal data. The price per dosage-unit for the drug rose about 7% from 2019 to 2020.

The pharmaceutical industry defends the high introductory costs of medicines and subsequent rising prices as necessary payback for research on products sold and the ones still in development. Since the initial Food and Drug Administration approval of adalimumab on Dec. 31, 2002, Abbott Laboratories and its AbbVie spin-off have made changes to the drug’s administration and paid for studies to expand its approved indications.

Still, the investment in adalimumab appears to have been paid well.

Abbott Labs acquired adalimumab as part of its purchase of BASF’s pharmaceutical operations in 2001, a purchase that also included the thyroid drug Synthroid. Abbott paid $7.2 billion, or roughly $12 billion in current dollars. In 2021 alone, Humira sales were $20.7 billion, with the United States accounting for $17.3 billion of the product’s revenue.
 

Losing access to treatment when moving to Medicare

Sue Lee of Crestwood, Ky., is among the patients waiting to see if the changes in Medicare law might allow her to again afford adalimumab. For now, Ms. Lee said she is hoping her plaque psoriasis stays manageable with the topical ointments and moisturizers she has been using since losing access to adalimumab. Ms. Lee, 80, took the medicine during her working years for her plaque psoriasis.

“I told people: ‘I’m on the wonder drug. Look at me. I can show my skin now. I don’t have all of these sores,’ ” she said in an interview.

But after she retired at 75, she was shocked at the tab she faced after switching from private insurance to Medicare. She said it could have cost her close to $10,000 a year to take Humira. Ms. Lee’s Social Security earnings make her ineligible for certain assistance with drug costs.

“I cried a lot,” she said about the loss of affordable access to the drug.
 

What’s the path ahead?

The American College of Rheumatology and the Coalition of State Rheumatology Organizations are among the physician groups that pressed Congress for years for action to lower drug costs. Their members have been on the frontline of the crisis in the United States among patients unable to afford medicines.

“The financial burden of skyrocketing drug prices has forced many of our patients to spread their treatment out longer than prescribed, delay care, abandon prescriptions, or forgo treatment entirely – all of which risks flare-ups, disease regression, permanent disability, and even premature death,” said Blair Solow, MD, chair of the ACR’s Government Affairs Committee, in a statement on the new Medicare provisions.

In an interview, Dr. Solow, an assistant professor of medicine in the division of rheumatic diseases at University of Texas Southwestern Medical Center, Dallas, noted that there are concerns about how changes in Medicare drug pricing might affect future development of medicines. This has been a chief criticism of the pharmaceutical industry of efforts to allow Medicare to negotiate for lower prices.

“Of note, drug companies research, create, and produce medications that will perform well in the market, not necessarily those that may be most needed,” Dr. Solow wrote. “We can hope the new medications put forth by manufacturers are those that improve the lives of patients.”

In July, the Congressional Budget Office released a report on an earlier version of the Democrats’ plans for Medicare drug negotiations that suggested the potential loss to drugmakers’ productivity may be relatively small. The CBO expects that about 1,300 drugs will be approved over the next 30 years. The legislation as proposed in July might reduce the tally by 15 drugs. The CBO said these estimates fell in the middle of the distribution of possible outcomes and are subject to uncertainty, and it is still working on an estimate of the expects effects of the final version of the law.

“CBO did not predict what kind of drugs would be affected or analyze the effects of forgone innovation on public health,” the agency said.

Dr. Solow also said there may be some challenges for physicians in explaining to patients the timeline for the new law’s Medicare provisions. People need to be aware of how long it will take to implement the plan and the potential for changes or delays.

“I think this is important, because the interpretation of the law can be done in a way that was not necessarily what Congress intended, and depending on the control of Congress and the Administration, this could impact downstream effects in how this law plays out,” she said in an interview.

CMS has substantial work ahead of it in choosing the drugs for which there will be subject to negotiations. The new law limits the number of drugs that can be negotiated to 10 annually in 2026, increasing to 20 drugs annually by 2029. Drugs would be eligible for negotiated prices from 9 years after drug approval or 13 years for biologics, until entry of a generic or biosimilar competitor.

The new law calls for taxes and other penalties for companies that refuse to negotiate or offer the agreed price, Thomas J. Hwang, MD; Aaron S. Kesselheim, MD, JD, MPH; and Benjamin N. Rome, MD, MPH, all of Harvard Medical School, Boston, wrote in an Aug. 19 viewpoint article in JAMA. U.S. lawmakers took a different approach to negotiations about drug prices than those used in other countries, they wrote.

“Notably, the Inflation Reduction Act shields new drugs from negotiated prices for the first 9-13 years on the market,” they wrote. “In contrast, most other peer countries typically negotiate drug prices at the time of market entry, and no peer country limits the number of drugs negotiated.”


 

Missed opportunities

Madelaine Feldman, MD, president of the CSRO and a rheumatologist in private practice with The Rheumatology Group in New Orleans, said in an interview that she welcomes many of the provisions of the new law, as they will help her rheumatology patients afford their medicine.

But she considers one of the provisions of the law to be a disappointment. The law further delays the start date for a federal rule intended to allow people on Medicare Part D to directly benefit from discounts negotiated on drugs. This is a point often overlooked in news reports on the law.

Insurers use what are called pharmacy benefit manager (PBM) services to obtain rebates on medicines, but they don’t fully or directly share these price reductions with people enrolled in Part D plans. Instead, people in the Part D plans have their cost sharing pegged closer to listed prices, the ones set before the rebates obtained by PBMs. The PBM industry argues that the rebates, often based on the list price of the drug, serve to keep monthly insurance premiums low. But there’s been concern about perverse incentives in this approach, where more expensive drugs are preferred by PBMs, leading to higher rebates.

Congress had already delayed its implementation of the PBM rule, which would apply savings more directly to patients, until 2027 and did so again in the Inflation Reduction Act.

Implementing this rule on Medicare Part D prescription drug rebates would be a help for patients struggling to pay for costly drugs, such as those used in rheumatology, Dr. Feldman said.

“It just doesn’t make any sense to hold off on these changes if you really want to cut Medicare’s beneficiaries’ cost sharing and attempt to stop the perverse incentive that puts higher priced drugs on Part D formularies,” she said.

Changes in Medicare law will help some patients who need costly rheumatology treatments, including several medicines for which competition has been kept in check for many years.

In fact, this field of medicine includes prime examples of the kinds of products that drove Congress to give the giant federal health program leverage to try to restrain rising pharmaceutical costs through negotiations. The Inflation Reduction Act, signed into law by President Joe Biden on Aug. 16, also provides some fairly quick aid for people enrolled in Medicare who struggle with pharmacy bills.

Getty

As described in an official summary from the Congressional Research Service, the law establishes:

• A cap on annual Medicare Part D out-of-pocket spending that starts in 2025 at $2,000, with planned annual adjustments thereafter.
• A limit on cost-sharing under Medicare Part D for a month’s supply of covered insulin products at $35 for 2023 through 2025, with plans for continued limits on this cost in the years after pegged to negotiated prices.
• A program under which drug manufacturers provide discounts to beneficiaries who have incurred costs above the annual deductible beginning in 2025.
• A requirement that drugmakers issue rebates to Medicare for certain brand-name drugs covered without generic equivalents for which prices increase faster than inflation.
• An obligation for Medicare Part D plans to pay for adult vaccines that are recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices without requiring cost sharing.

The law’s marquee health provision sets the stage for Medicare, the nation’s largest purchaser of drugs, for the first time to leverage its clout directly in negotiating for lower costs for medicines. Democrats sought to build what amount to guardrails into this program, seeking to spare from competition new and innovative drugs and ones developed by smaller companies. Drugs likely to soon face competition from copycat versions also would fall outside of the pool for negotiations.

In effect, the design of the program would allow Medicare to negotiate in the future in cases such as those seen in recent years with blockbuster medicines often in rheumatology. That’s due in a large part to legal challenges that have helped thwart the introduction of copycat versions of these kinds of products known as biosimilars.

Etanercept (Enbrel) has been sold in the United States since 1998 and adalimumab (Humira) since 2003. Both products face competition from copycat versions called biosimilars in other nations, but the introductions of these products have been delayed in the United States until 2029 for etanercept and 2023 for adalimumab, the Office of Inspector General for the Department of Health & Human Services said in a March 2022 report. The OIG said in the report that the combined 2019 Medicare Part D tab for the two biologics was more than $5 billion.

Rheumatology drugs rival cancer medicines for dominance among the most expensive drugs for people enrolled in Medicare. The average 2020 spending for the most widely used forms of adalimumab by people in Medicare’s Part D pharmacy program topped $51,000, according to federal data. The price per dosage-unit for the drug rose about 7% from 2019 to 2020.

The pharmaceutical industry defends the high introductory costs of medicines and subsequent rising prices as necessary payback for research on products sold and the ones still in development. Since the initial Food and Drug Administration approval of adalimumab on Dec. 31, 2002, Abbott Laboratories and its AbbVie spin-off have made changes to the drug’s administration and paid for studies to expand its approved indications.

Still, the investment in adalimumab appears to have been paid well.

Abbott Labs acquired adalimumab as part of its purchase of BASF’s pharmaceutical operations in 2001, a purchase that also included the thyroid drug Synthroid. Abbott paid $7.2 billion, or roughly $12 billion in current dollars. In 2021 alone, Humira sales were $20.7 billion, with the United States accounting for $17.3 billion of the product’s revenue.
 

Losing access to treatment when moving to Medicare

Sue Lee of Crestwood, Ky., is among the patients waiting to see if the changes in Medicare law might allow her to again afford adalimumab. For now, Ms. Lee said she is hoping her plaque psoriasis stays manageable with the topical ointments and moisturizers she has been using since losing access to adalimumab. Ms. Lee, 80, took the medicine during her working years for her plaque psoriasis.

“I told people: ‘I’m on the wonder drug. Look at me. I can show my skin now. I don’t have all of these sores,’ ” she said in an interview.

But after she retired at 75, she was shocked at the tab she faced after switching from private insurance to Medicare. She said it could have cost her close to $10,000 a year to take Humira. Ms. Lee’s Social Security earnings make her ineligible for certain assistance with drug costs.

“I cried a lot,” she said about the loss of affordable access to the drug.
 

What’s the path ahead?

The American College of Rheumatology and the Coalition of State Rheumatology Organizations are among the physician groups that pressed Congress for years for action to lower drug costs. Their members have been on the frontline of the crisis in the United States among patients unable to afford medicines.

“The financial burden of skyrocketing drug prices has forced many of our patients to spread their treatment out longer than prescribed, delay care, abandon prescriptions, or forgo treatment entirely – all of which risks flare-ups, disease regression, permanent disability, and even premature death,” said Blair Solow, MD, chair of the ACR’s Government Affairs Committee, in a statement on the new Medicare provisions.

In an interview, Dr. Solow, an assistant professor of medicine in the division of rheumatic diseases at University of Texas Southwestern Medical Center, Dallas, noted that there are concerns about how changes in Medicare drug pricing might affect future development of medicines. This has been a chief criticism of the pharmaceutical industry of efforts to allow Medicare to negotiate for lower prices.

“Of note, drug companies research, create, and produce medications that will perform well in the market, not necessarily those that may be most needed,” Dr. Solow wrote. “We can hope the new medications put forth by manufacturers are those that improve the lives of patients.”

In July, the Congressional Budget Office released a report on an earlier version of the Democrats’ plans for Medicare drug negotiations that suggested the potential loss to drugmakers’ productivity may be relatively small. The CBO expects that about 1,300 drugs will be approved over the next 30 years. The legislation as proposed in July might reduce the tally by 15 drugs. The CBO said these estimates fell in the middle of the distribution of possible outcomes and are subject to uncertainty, and it is still working on an estimate of the expects effects of the final version of the law.

“CBO did not predict what kind of drugs would be affected or analyze the effects of forgone innovation on public health,” the agency said.

Dr. Solow also said there may be some challenges for physicians in explaining to patients the timeline for the new law’s Medicare provisions. People need to be aware of how long it will take to implement the plan and the potential for changes or delays.

“I think this is important, because the interpretation of the law can be done in a way that was not necessarily what Congress intended, and depending on the control of Congress and the Administration, this could impact downstream effects in how this law plays out,” she said in an interview.

CMS has substantial work ahead of it in choosing the drugs for which there will be subject to negotiations. The new law limits the number of drugs that can be negotiated to 10 annually in 2026, increasing to 20 drugs annually by 2029. Drugs would be eligible for negotiated prices from 9 years after drug approval or 13 years for biologics, until entry of a generic or biosimilar competitor.

The new law calls for taxes and other penalties for companies that refuse to negotiate or offer the agreed price, Thomas J. Hwang, MD; Aaron S. Kesselheim, MD, JD, MPH; and Benjamin N. Rome, MD, MPH, all of Harvard Medical School, Boston, wrote in an Aug. 19 viewpoint article in JAMA. U.S. lawmakers took a different approach to negotiations about drug prices than those used in other countries, they wrote.

“Notably, the Inflation Reduction Act shields new drugs from negotiated prices for the first 9-13 years on the market,” they wrote. “In contrast, most other peer countries typically negotiate drug prices at the time of market entry, and no peer country limits the number of drugs negotiated.”


 

Missed opportunities

Madelaine Feldman, MD, president of the CSRO and a rheumatologist in private practice with The Rheumatology Group in New Orleans, said in an interview that she welcomes many of the provisions of the new law, as they will help her rheumatology patients afford their medicine.

But she considers one of the provisions of the law to be a disappointment. The law further delays the start date for a federal rule intended to allow people on Medicare Part D to directly benefit from discounts negotiated on drugs. This is a point often overlooked in news reports on the law.

Insurers use what are called pharmacy benefit manager (PBM) services to obtain rebates on medicines, but they don’t fully or directly share these price reductions with people enrolled in Part D plans. Instead, people in the Part D plans have their cost sharing pegged closer to listed prices, the ones set before the rebates obtained by PBMs. The PBM industry argues that the rebates, often based on the list price of the drug, serve to keep monthly insurance premiums low. But there’s been concern about perverse incentives in this approach, where more expensive drugs are preferred by PBMs, leading to higher rebates.

Congress had already delayed its implementation of the PBM rule, which would apply savings more directly to patients, until 2027 and did so again in the Inflation Reduction Act.

Implementing this rule on Medicare Part D prescription drug rebates would be a help for patients struggling to pay for costly drugs, such as those used in rheumatology, Dr. Feldman said.

“It just doesn’t make any sense to hold off on these changes if you really want to cut Medicare’s beneficiaries’ cost sharing and attempt to stop the perverse incentive that puts higher priced drugs on Part D formularies,” she said.

Changes in Medicare law will help some patients who need costly rheumatology treatments, including several medicines for which competition has been kept in check for many years.

In fact, this field of medicine includes prime examples of the kinds of products that drove Congress to give the giant federal health program leverage to try to restrain rising pharmaceutical costs through negotiations. The Inflation Reduction Act, signed into law by President Joe Biden on Aug. 16, also provides some fairly quick aid for people enrolled in Medicare who struggle with pharmacy bills.

Getty

As described in an official summary from the Congressional Research Service, the law establishes:

• A cap on annual Medicare Part D out-of-pocket spending that starts in 2025 at $2,000, with planned annual adjustments thereafter.
• A limit on cost-sharing under Medicare Part D for a month’s supply of covered insulin products at $35 for 2023 through 2025, with plans for continued limits on this cost in the years after pegged to negotiated prices.
• A program under which drug manufacturers provide discounts to beneficiaries who have incurred costs above the annual deductible beginning in 2025.
• A requirement that drugmakers issue rebates to Medicare for certain brand-name drugs covered without generic equivalents for which prices increase faster than inflation.
• An obligation for Medicare Part D plans to pay for adult vaccines that are recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices without requiring cost sharing.

The law’s marquee health provision sets the stage for Medicare, the nation’s largest purchaser of drugs, for the first time to leverage its clout directly in negotiating for lower costs for medicines. Democrats sought to build what amount to guardrails into this program, seeking to spare from competition new and innovative drugs and ones developed by smaller companies. Drugs likely to soon face competition from copycat versions also would fall outside of the pool for negotiations.

In effect, the design of the program would allow Medicare to negotiate in the future in cases such as those seen in recent years with blockbuster medicines often in rheumatology. That’s due in a large part to legal challenges that have helped thwart the introduction of copycat versions of these kinds of products known as biosimilars.

Etanercept (Enbrel) has been sold in the United States since 1998 and adalimumab (Humira) since 2003. Both products face competition from copycat versions called biosimilars in other nations, but the introductions of these products have been delayed in the United States until 2029 for etanercept and 2023 for adalimumab, the Office of Inspector General for the Department of Health & Human Services said in a March 2022 report. The OIG said in the report that the combined 2019 Medicare Part D tab for the two biologics was more than $5 billion.

Rheumatology drugs rival cancer medicines for dominance among the most expensive drugs for people enrolled in Medicare. The average 2020 spending for the most widely used forms of adalimumab by people in Medicare’s Part D pharmacy program topped $51,000, according to federal data. The price per dosage-unit for the drug rose about 7% from 2019 to 2020.

The pharmaceutical industry defends the high introductory costs of medicines and subsequent rising prices as necessary payback for research on products sold and the ones still in development. Since the initial Food and Drug Administration approval of adalimumab on Dec. 31, 2002, Abbott Laboratories and its AbbVie spin-off have made changes to the drug’s administration and paid for studies to expand its approved indications.

Still, the investment in adalimumab appears to have been paid well.

Abbott Labs acquired adalimumab as part of its purchase of BASF’s pharmaceutical operations in 2001, a purchase that also included the thyroid drug Synthroid. Abbott paid $7.2 billion, or roughly $12 billion in current dollars. In 2021 alone, Humira sales were $20.7 billion, with the United States accounting for $17.3 billion of the product’s revenue.
 

Losing access to treatment when moving to Medicare

Sue Lee of Crestwood, Ky., is among the patients waiting to see if the changes in Medicare law might allow her to again afford adalimumab. For now, Ms. Lee said she is hoping her plaque psoriasis stays manageable with the topical ointments and moisturizers she has been using since losing access to adalimumab. Ms. Lee, 80, took the medicine during her working years for her plaque psoriasis.

“I told people: ‘I’m on the wonder drug. Look at me. I can show my skin now. I don’t have all of these sores,’ ” she said in an interview.

But after she retired at 75, she was shocked at the tab she faced after switching from private insurance to Medicare. She said it could have cost her close to $10,000 a year to take Humira. Ms. Lee’s Social Security earnings make her ineligible for certain assistance with drug costs.

“I cried a lot,” she said about the loss of affordable access to the drug.
 

What’s the path ahead?

The American College of Rheumatology and the Coalition of State Rheumatology Organizations are among the physician groups that pressed Congress for years for action to lower drug costs. Their members have been on the frontline of the crisis in the United States among patients unable to afford medicines.

“The financial burden of skyrocketing drug prices has forced many of our patients to spread their treatment out longer than prescribed, delay care, abandon prescriptions, or forgo treatment entirely – all of which risks flare-ups, disease regression, permanent disability, and even premature death,” said Blair Solow, MD, chair of the ACR’s Government Affairs Committee, in a statement on the new Medicare provisions.

In an interview, Dr. Solow, an assistant professor of medicine in the division of rheumatic diseases at University of Texas Southwestern Medical Center, Dallas, noted that there are concerns about how changes in Medicare drug pricing might affect future development of medicines. This has been a chief criticism of the pharmaceutical industry of efforts to allow Medicare to negotiate for lower prices.

“Of note, drug companies research, create, and produce medications that will perform well in the market, not necessarily those that may be most needed,” Dr. Solow wrote. “We can hope the new medications put forth by manufacturers are those that improve the lives of patients.”

In July, the Congressional Budget Office released a report on an earlier version of the Democrats’ plans for Medicare drug negotiations that suggested the potential loss to drugmakers’ productivity may be relatively small. The CBO expects that about 1,300 drugs will be approved over the next 30 years. The legislation as proposed in July might reduce the tally by 15 drugs. The CBO said these estimates fell in the middle of the distribution of possible outcomes and are subject to uncertainty, and it is still working on an estimate of the expects effects of the final version of the law.

“CBO did not predict what kind of drugs would be affected or analyze the effects of forgone innovation on public health,” the agency said.

Dr. Solow also said there may be some challenges for physicians in explaining to patients the timeline for the new law’s Medicare provisions. People need to be aware of how long it will take to implement the plan and the potential for changes or delays.

“I think this is important, because the interpretation of the law can be done in a way that was not necessarily what Congress intended, and depending on the control of Congress and the Administration, this could impact downstream effects in how this law plays out,” she said in an interview.

CMS has substantial work ahead of it in choosing the drugs for which there will be subject to negotiations. The new law limits the number of drugs that can be negotiated to 10 annually in 2026, increasing to 20 drugs annually by 2029. Drugs would be eligible for negotiated prices from 9 years after drug approval or 13 years for biologics, until entry of a generic or biosimilar competitor.

The new law calls for taxes and other penalties for companies that refuse to negotiate or offer the agreed price, Thomas J. Hwang, MD; Aaron S. Kesselheim, MD, JD, MPH; and Benjamin N. Rome, MD, MPH, all of Harvard Medical School, Boston, wrote in an Aug. 19 viewpoint article in JAMA. U.S. lawmakers took a different approach to negotiations about drug prices than those used in other countries, they wrote.

“Notably, the Inflation Reduction Act shields new drugs from negotiated prices for the first 9-13 years on the market,” they wrote. “In contrast, most other peer countries typically negotiate drug prices at the time of market entry, and no peer country limits the number of drugs negotiated.”


 

Missed opportunities

Madelaine Feldman, MD, president of the CSRO and a rheumatologist in private practice with The Rheumatology Group in New Orleans, said in an interview that she welcomes many of the provisions of the new law, as they will help her rheumatology patients afford their medicine.

But she considers one of the provisions of the law to be a disappointment. The law further delays the start date for a federal rule intended to allow people on Medicare Part D to directly benefit from discounts negotiated on drugs. This is a point often overlooked in news reports on the law.

Insurers use what are called pharmacy benefit manager (PBM) services to obtain rebates on medicines, but they don’t fully or directly share these price reductions with people enrolled in Part D plans. Instead, people in the Part D plans have their cost sharing pegged closer to listed prices, the ones set before the rebates obtained by PBMs. The PBM industry argues that the rebates, often based on the list price of the drug, serve to keep monthly insurance premiums low. But there’s been concern about perverse incentives in this approach, where more expensive drugs are preferred by PBMs, leading to higher rebates.

Congress had already delayed its implementation of the PBM rule, which would apply savings more directly to patients, until 2027 and did so again in the Inflation Reduction Act.

Implementing this rule on Medicare Part D prescription drug rebates would be a help for patients struggling to pay for costly drugs, such as those used in rheumatology, Dr. Feldman said.

“It just doesn’t make any sense to hold off on these changes if you really want to cut Medicare’s beneficiaries’ cost sharing and attempt to stop the perverse incentive that puts higher priced drugs on Part D formularies,” she said.

Clinical research in rheumatology was suffering from an identity crisis of sorts 40 years ago. A lack of consensus across continents resulted in differing views about clinical outcome measures and judgments about treatments.

Patients were not allowed to be the generating source of a clinical outcome, according to Peter Tugwell, MSc, MD. “The only outcomes that were acceptable were clinician assessments, blood tests, and imaging,” said Dr. Tugwell, professor of medicine, epidemiology, and public health at the University of Ottawa (Ont.) and a practicing rheumatologist at Ottawa Hospital.

Clinicians were coming to different conclusions about patient responses to treatment when managing rheumatoid arthritis in clinical practice.

OMERACT sought to address this lack of uniformity. This international group, formed in 1992, leverages stakeholder groups to improve outcome measurement in rheumatology endpoints through a consensus-building, data-driven format.

It was originally known as “Outcome Measures in Rheumatoid Arthritis Clinical Trials,” but its leaders have since broadened its scope to “Outcome Measures in Rheumatology.” Over the years, it has evolved into an international network that assesses measurement across a wide variety of intervention studies. Now 30 years old, the network spans 40 active working groups and has influenced work in patient outcomes across 500 peer-reviewed publications.

The network meets every 2 years to address what is always a challenging agenda, said Dr. Tugwell, one of its founding members and chair. “There’s lots of strong opinions.” Participating in the discussions are individuals from all stages of seniority in rheumatology and clinical epidemiology, patient research partners, industry, approval agencies, and many countries who are committed to the spirit of OMERACT.

“The secret to our success has been getting world leaders to come together and have those discussions, work them through, and identify common ground in such a way that the approval agencies accept these outcome measures in clinical trials,” he added.

“My impression was the founders perceived a problem in the early 1990s and devised a consensus method in an attempt to quantify clinical parameters to define disease activity in rheumatoid arthritis – an important first step to do clinical trials and allow comparisons between them,” said Patricia Woo, CBE, FMedSci, FRCP, emeritus professor of pediatric rheumatology and previous head of the Centre for Paediatric and Adolescent Rheumatology at UCL, London. At that time, even disease definitions varied between the United States and Europe and other parts of the world, said Dr. Woo, who is not a part of OMERACT. “This was especially true for pediatric rheumatology.”
 

Fusing the continental divide

OMERACT arose from a need to streamline clinical outcome measures in rheumatology. Research papers during the 1980s demonstrated a lack of coherence in managing patients with rheumatoid arthritis in routine practice. In addition, the measures used to define clinical endpoints in clinical trials operated in silos – they were either too specific to a certain trial, overlapped with other concepts, or didn’t reflect changes in treatment.

Approval agencies in Europe and North America were approving only outcomes measures developed by their respective researchers. This was also true of patients they tested on. “This seemed crazy,” Dr. Tugwell said.

Dr. Tugwell was involved in the Cochrane collaboration, which conducts systematic reviews of best evidence across the world that assesses the magnitude of benefits versus harms.

To achieve this goal, “you need to pull studies from around the world,” he said. Maarten Boers, MD, PhD, a rheumatologist (and later professor of clinical epidemiology at Amsterdam University Medical Center) from the Netherlands, spent a year in Ontario, Canada, to train as a clinical epidemiologist. Together, Dr. Tugwell and Dr. Boers began discussing options to develop more streamlined outcome measures.

Courtesy OMERACT

They initiated the first OMERACT conference in Maastricht, the Netherlands, in 1992. The Food and Drug Administration and European Medicines Agency participated, along with leaders of outcomes measurement in Europe and in North America.

Discussions centered on methods to develop outcomes in a meaningful fashion. During the first meeting, North American and European approval agencies agreed to accept each other’s studies and endpoints and patient reported outcomes.

Agreement was achieved on a preliminary set of outcome domains and measures that later became known as the WHO-ILAR (World Health Organization–International League of Associations for Rheumatology) core set. The set included seven outcome domains: tender joints, swollen joints, pain, physician global assessment, patient global assessment, physical disability, and acute phase reactants, and one additional outcome domain for studies lasting 1 year or more: radiographs of the joints.

“A proactive program was planned to test not only the validity of these endpoints, but also the methods for their measurement. This was the start of a continuing process,” OMERACT members said in a joint statement for this article. Meetings have since taken place every 2 years.

Courtesy OMERACT

OMERACT accomplishments

OMERACT now requires buy-in from four continents: Asia, Australia, Europe, and North America.

Its leaders have developed an explicit process for gaining endorsement of core outcome domains and instrument measurement sets. To fully capture the possibilities of “what to measure,” i.e., “measurable aspects of health conditions,” OMERACT has developed a framework of concepts, core areas, and outcome domains. The key concepts are pathophysiology (with a core area termed “manifestations/abnormalities”) and impact (with core areas of “death/lifespan,” and “life impact,” and the optional area of “societal/resource use”). An outcome domain defines an element of a core area to measure the effects of a treatment, such as blood markers, pain intensity, physical function, or emotional well-being.

A core outcome domain set is developed by agreeing to at least one outcome domain within one of the three core areas. Subsequently, a core outcome measurement set is developed by agreeing to at least one applicable measurement instrument for each core outcome domain. This requires documentation of validity, summarized under three metrics: truth, discrimination, and feasibility.

OMERACT’s handbook provides tutelage on establishing and implementing core outcomes, and several workbooks offer guidance on developing core outcome domain sets, selecting instruments for core outcome measurement sets, and OMERACT methodology.

All this work has led to widespread adoption.

Approval agencies have accepted OMERACT’s filter and methods advances, which have been adopted by many research groups in rheumatology and among nonrheumatology research groups. Organizations such as the U.S. National Institutes of Health’s National Institute of Neurological Disorders and Stroke have sought its advice.

Its core outcomes have been adopted and used for approval in the great majority of studies on rheumatoid arthritis, Dr. Tugwell said.

Several BMJ articles underscore the influence and uptake of OMERACT’s core outcome set. One 2017 paper, which analyzed 273 randomized trials of rheumatoid arthritis drug treatments on ClinicalTrials.gov, found that the WHO-ILAR arthritis core outcome set was reported in 81% of the studies. “The adoption of a core outcome set has the potential to increase consistency in outcomes measured across trials and ensure that trials are more likely to measure appropriate outcomes,” the authors concluded.

Since the initial 1992 meeting, OMERACT has broadened its focus from rheumatoid arthritis to 25 other musculoskeletal conditions.

For example, other OMERACT conferences have led to consensus on core sets of measures for osteoarthritis and osteoporosis, psoriasis/psoriatic arthritis, psychosocial measures, and a core set of data for cost-effectiveness evaluations.
 

‘Speed is a limitation’

OMERACT is a bottom-up volunteer organization. It doesn’t represent any official organization of any clinical society. “We’ve not asked to be adopted by the American College of Rheumatology, EULAR [European Alliance of Associations for Rheumatology], or other international organizations,” Dr. Tugwell said. It offers a chance for patients, users, and doers of research to work together to agree on rigorous criteria accepted by the approval agencies and take the necessary time to work things through.

This is not a fast process, usually taking 4-6 years to initiate and establish an outcome domain set, he emphasized. “It would be beneficial to do it faster if we had the resources to meet every year. The fact is we’re a volunteer organization that meets every 2 years.”

Speed is a limitation, he acknowledged, but it’s an acceptable trade-off for doing things correctly.

The group has faced other challenges during the COVID-19 pandemic, pivoting to a virtual format that had benefits and limitations.

In one respect, moving to a virtual meeting increased uptake in participation and voting, Dr. Tugwell said. Patient participants with severe rheumatoid arthritis no longer faced the challenges of travel. “On the other hand, we didn’t have the same opportunity to achieve common ground virtually,” he said. “Where there are strong disagreements, I’m a great believer that people need to know one another. There needs to be relationship building.”

OMERACT’s emerging leader program has been a cornerstone of its in-person meetings, engaging young rheumatologists to interact with some of the leaders of outcome measurement. The virtual format dampened this process somewhat, eliminating those important “café chats” between the stakeholders.

The hope is to bring people face-to-face once more at the next meeting in May 2023. The agenda will focus on relationship building, identifying controversial areas, and bringing younger people to develop relationships, Dr. Tugwell said. OMERACT will retain a virtual option for the worldwide voting, “which will allow for more buy-in from so many more people,” he added.
 

A consensus on pain

The onus of developing outcome measures that move with the times is sometimes too great for one group to manage. In 2018, OMERACT became a part of the Red Hat Group (RHG), an organization conceived at the COMET (Core Outcome Measures in Effectiveness Trials) VII meeting in Amsterdam.

RHG aims to improve the choice of outcomes in health research. It includes eight groups: COMET; OMERACT; the Cochrane Skin Core Outcome Set Initiative; Grading of Recommendations, Assessment, Development and Evaluations; Center for Medical Technology Policy; COnsensus-based Standards for the selection of health Measurement Instruments; Clinical Data Interchange Standards Consortium; and Standardized Outcomes in Nephrology.

The collaboration between groups offers a “very interesting interface between consensus building as well as hard evidence,” Dr. Tugwell said. The focus goes beyond rheumatology to other clinical areas of common interest, exploring how one classifies outcome domains in terms of symptoms, life impact, or death.

Pain is an important common denominator that the RHG has evaluated.

“We believe it’s too general. We’re trying to define pain across all Red Hat Groups because it’s clear that the research community has all these different scales for defining pain severity,” Dr. Tugwell said. “We have to find a way to make ruthless decisions and rules for doing it. And of course, it has to be transparent.”
 

Looking ahead

As part of its ongoing work, OMERACT is evaluating the robustness of instruments that rheumatologists use as outcome measures in clinical trials, which can be a laborious process. The OMERACT Filter 2.0, part of the latest iteration of the handbook, offers strong guidance for researchers but needs a long-term strategy and key methodological support. “To that end, we set up a technical advisory group to help people in the instrument selection work and that remains an ongoing process,” OMERACT leaders said in their joint statement.

OMERACT is looking at opportunities to create benchmark processes for developing core sets outside of rheumatology and a methodology around outcome measures such as contextual factors, composites, and surrogates.

It will also be taking a step back to solicit opinions from the approval agencies represented by the OMERACT membership on the OMERACT handbook.

The goal is to make sure the handbook aligns with everyone else’s approval and labeling requirements.
 

OMERACT’s patient participants bring important perspectives

OMERACT over the years has sought to become a more patient-centered group. Patients have been involved in OMERACT activities since its sixth meeting, forming an independent, yet integrated, group within the network. They have their own steering committee and produced and helped to update a glossary for OMERACT patients and professionals. 

Catherine (McGowan) Hofstetter, who was diagnosed with rheumatoid arthritis 30 years ago, chairs OMERACT’s Patient Research Partners Support Team. In a Q&A, she discussed the importance of patient voices and OMERACT’s plans to further educate and include patients in the dialogue on outcomes.

Question: Have patients always been a part of OMERACT meetings? 

Answer: Patients have been involved with OMERACT since 2002. The patient voice adds relevance to all the work that OMERACT does. You can’t begin to talk about outcomes unless there is a patient at the table with lived experience.

Q: Can you cite a few examples of how the patient voice enriches the conversation on outcomes research? 

A: Outcomes and priorities that are important to patients are often completely different than those of the clinician. For instance, a work outcome is important to someone who doesn’t have any medical insurance or disability insurance, so that you can ensure that there is food on the table and a roof over your head. Or it may be important to someone because the employment provides medical and disability insurance to provide security for them and their family. These are two different perspectives on work and therefore work priorities and outcomes.

Q: What have been some of the challenges of getting patients to participate?

A: Training patients is one challenge. OMERACT’s work has a very steep learning curve, and while the basics are the same between the groups in terms of looking at what we measure and how we measure it, the nuances of different working groups require a lot of time and energy to be comfortable enough with the work, and then be confident enough to bring your perspective and lived experience to the table. It’s also a very accomplished group, which can be quite intimidating. Self-disclosure is a very personal and intimate undertaking that requires patience, compassion, and respect.

Q: Are there any plans to enhance patient engagement?

A: When we had OMERACT 2020 it was a virtual conference that took place over about 6 months. We had far more patient research partners [PRPs] participate than we have ever had at any OMERACT face-to-face meeting. There is a desire and passion on the part of patients to lend their voices to the work. The working groups meet virtually throughout the year to advance their agendas, and PRPs are a part of each of the working groups. 

Hopefully, we can start working toward including more voices at the conferences by enabling a hybrid model. The PRP Support Team will begin engaging patients this fall with education, mentoring, and team-building exercises so by the time we meet in person in May 2023, they will have enough background knowledge and information to give them the confidence that will enhance their experience at the face-to-face meeting.

We also need to ensure that those patients who want to stay engaged can. This means that the education and training should continue long after the face-to-face meeting is over. We need to build capacity in the PRP group and look to succession planning and be a resource to working groups struggling to find PRPs to work with them on a longer-term basis.

Clinical research in rheumatology was suffering from an identity crisis of sorts 40 years ago. A lack of consensus across continents resulted in differing views about clinical outcome measures and judgments about treatments.

Patients were not allowed to be the generating source of a clinical outcome, according to Peter Tugwell, MSc, MD. “The only outcomes that were acceptable were clinician assessments, blood tests, and imaging,” said Dr. Tugwell, professor of medicine, epidemiology, and public health at the University of Ottawa (Ont.) and a practicing rheumatologist at Ottawa Hospital.

Clinicians were coming to different conclusions about patient responses to treatment when managing rheumatoid arthritis in clinical practice.

OMERACT sought to address this lack of uniformity. This international group, formed in 1992, leverages stakeholder groups to improve outcome measurement in rheumatology endpoints through a consensus-building, data-driven format.

It was originally known as “Outcome Measures in Rheumatoid Arthritis Clinical Trials,” but its leaders have since broadened its scope to “Outcome Measures in Rheumatology.” Over the years, it has evolved into an international network that assesses measurement across a wide variety of intervention studies. Now 30 years old, the network spans 40 active working groups and has influenced work in patient outcomes across 500 peer-reviewed publications.

The network meets every 2 years to address what is always a challenging agenda, said Dr. Tugwell, one of its founding members and chair. “There’s lots of strong opinions.” Participating in the discussions are individuals from all stages of seniority in rheumatology and clinical epidemiology, patient research partners, industry, approval agencies, and many countries who are committed to the spirit of OMERACT.

“The secret to our success has been getting world leaders to come together and have those discussions, work them through, and identify common ground in such a way that the approval agencies accept these outcome measures in clinical trials,” he added.

“My impression was the founders perceived a problem in the early 1990s and devised a consensus method in an attempt to quantify clinical parameters to define disease activity in rheumatoid arthritis – an important first step to do clinical trials and allow comparisons between them,” said Patricia Woo, CBE, FMedSci, FRCP, emeritus professor of pediatric rheumatology and previous head of the Centre for Paediatric and Adolescent Rheumatology at UCL, London. At that time, even disease definitions varied between the United States and Europe and other parts of the world, said Dr. Woo, who is not a part of OMERACT. “This was especially true for pediatric rheumatology.”
 

Fusing the continental divide

OMERACT arose from a need to streamline clinical outcome measures in rheumatology. Research papers during the 1980s demonstrated a lack of coherence in managing patients with rheumatoid arthritis in routine practice. In addition, the measures used to define clinical endpoints in clinical trials operated in silos – they were either too specific to a certain trial, overlapped with other concepts, or didn’t reflect changes in treatment.

Approval agencies in Europe and North America were approving only outcomes measures developed by their respective researchers. This was also true of patients they tested on. “This seemed crazy,” Dr. Tugwell said.

Dr. Tugwell was involved in the Cochrane collaboration, which conducts systematic reviews of best evidence across the world that assesses the magnitude of benefits versus harms.

To achieve this goal, “you need to pull studies from around the world,” he said. Maarten Boers, MD, PhD, a rheumatologist (and later professor of clinical epidemiology at Amsterdam University Medical Center) from the Netherlands, spent a year in Ontario, Canada, to train as a clinical epidemiologist. Together, Dr. Tugwell and Dr. Boers began discussing options to develop more streamlined outcome measures.

Courtesy OMERACT

They initiated the first OMERACT conference in Maastricht, the Netherlands, in 1992. The Food and Drug Administration and European Medicines Agency participated, along with leaders of outcomes measurement in Europe and in North America.

Discussions centered on methods to develop outcomes in a meaningful fashion. During the first meeting, North American and European approval agencies agreed to accept each other’s studies and endpoints and patient reported outcomes.

Agreement was achieved on a preliminary set of outcome domains and measures that later became known as the WHO-ILAR (World Health Organization–International League of Associations for Rheumatology) core set. The set included seven outcome domains: tender joints, swollen joints, pain, physician global assessment, patient global assessment, physical disability, and acute phase reactants, and one additional outcome domain for studies lasting 1 year or more: radiographs of the joints.

“A proactive program was planned to test not only the validity of these endpoints, but also the methods for their measurement. This was the start of a continuing process,” OMERACT members said in a joint statement for this article. Meetings have since taken place every 2 years.

Courtesy OMERACT

OMERACT accomplishments

OMERACT now requires buy-in from four continents: Asia, Australia, Europe, and North America.

Its leaders have developed an explicit process for gaining endorsement of core outcome domains and instrument measurement sets. To fully capture the possibilities of “what to measure,” i.e., “measurable aspects of health conditions,” OMERACT has developed a framework of concepts, core areas, and outcome domains. The key concepts are pathophysiology (with a core area termed “manifestations/abnormalities”) and impact (with core areas of “death/lifespan,” and “life impact,” and the optional area of “societal/resource use”). An outcome domain defines an element of a core area to measure the effects of a treatment, such as blood markers, pain intensity, physical function, or emotional well-being.

A core outcome domain set is developed by agreeing to at least one outcome domain within one of the three core areas. Subsequently, a core outcome measurement set is developed by agreeing to at least one applicable measurement instrument for each core outcome domain. This requires documentation of validity, summarized under three metrics: truth, discrimination, and feasibility.

OMERACT’s handbook provides tutelage on establishing and implementing core outcomes, and several workbooks offer guidance on developing core outcome domain sets, selecting instruments for core outcome measurement sets, and OMERACT methodology.

All this work has led to widespread adoption.

Approval agencies have accepted OMERACT’s filter and methods advances, which have been adopted by many research groups in rheumatology and among nonrheumatology research groups. Organizations such as the U.S. National Institutes of Health’s National Institute of Neurological Disorders and Stroke have sought its advice.

Its core outcomes have been adopted and used for approval in the great majority of studies on rheumatoid arthritis, Dr. Tugwell said.

Several BMJ articles underscore the influence and uptake of OMERACT’s core outcome set. One 2017 paper, which analyzed 273 randomized trials of rheumatoid arthritis drug treatments on ClinicalTrials.gov, found that the WHO-ILAR arthritis core outcome set was reported in 81% of the studies. “The adoption of a core outcome set has the potential to increase consistency in outcomes measured across trials and ensure that trials are more likely to measure appropriate outcomes,” the authors concluded.

Since the initial 1992 meeting, OMERACT has broadened its focus from rheumatoid arthritis to 25 other musculoskeletal conditions.

For example, other OMERACT conferences have led to consensus on core sets of measures for osteoarthritis and osteoporosis, psoriasis/psoriatic arthritis, psychosocial measures, and a core set of data for cost-effectiveness evaluations.
 

‘Speed is a limitation’

OMERACT is a bottom-up volunteer organization. It doesn’t represent any official organization of any clinical society. “We’ve not asked to be adopted by the American College of Rheumatology, EULAR [European Alliance of Associations for Rheumatology], or other international organizations,” Dr. Tugwell said. It offers a chance for patients, users, and doers of research to work together to agree on rigorous criteria accepted by the approval agencies and take the necessary time to work things through.

This is not a fast process, usually taking 4-6 years to initiate and establish an outcome domain set, he emphasized. “It would be beneficial to do it faster if we had the resources to meet every year. The fact is we’re a volunteer organization that meets every 2 years.”

Speed is a limitation, he acknowledged, but it’s an acceptable trade-off for doing things correctly.

The group has faced other challenges during the COVID-19 pandemic, pivoting to a virtual format that had benefits and limitations.

In one respect, moving to a virtual meeting increased uptake in participation and voting, Dr. Tugwell said. Patient participants with severe rheumatoid arthritis no longer faced the challenges of travel. “On the other hand, we didn’t have the same opportunity to achieve common ground virtually,” he said. “Where there are strong disagreements, I’m a great believer that people need to know one another. There needs to be relationship building.”

OMERACT’s emerging leader program has been a cornerstone of its in-person meetings, engaging young rheumatologists to interact with some of the leaders of outcome measurement. The virtual format dampened this process somewhat, eliminating those important “café chats” between the stakeholders.

The hope is to bring people face-to-face once more at the next meeting in May 2023. The agenda will focus on relationship building, identifying controversial areas, and bringing younger people to develop relationships, Dr. Tugwell said. OMERACT will retain a virtual option for the worldwide voting, “which will allow for more buy-in from so many more people,” he added.
 

A consensus on pain

The onus of developing outcome measures that move with the times is sometimes too great for one group to manage. In 2018, OMERACT became a part of the Red Hat Group (RHG), an organization conceived at the COMET (Core Outcome Measures in Effectiveness Trials) VII meeting in Amsterdam.

RHG aims to improve the choice of outcomes in health research. It includes eight groups: COMET; OMERACT; the Cochrane Skin Core Outcome Set Initiative; Grading of Recommendations, Assessment, Development and Evaluations; Center for Medical Technology Policy; COnsensus-based Standards for the selection of health Measurement Instruments; Clinical Data Interchange Standards Consortium; and Standardized Outcomes in Nephrology.

The collaboration between groups offers a “very interesting interface between consensus building as well as hard evidence,” Dr. Tugwell said. The focus goes beyond rheumatology to other clinical areas of common interest, exploring how one classifies outcome domains in terms of symptoms, life impact, or death.

Pain is an important common denominator that the RHG has evaluated.

“We believe it’s too general. We’re trying to define pain across all Red Hat Groups because it’s clear that the research community has all these different scales for defining pain severity,” Dr. Tugwell said. “We have to find a way to make ruthless decisions and rules for doing it. And of course, it has to be transparent.”
 

Looking ahead

As part of its ongoing work, OMERACT is evaluating the robustness of instruments that rheumatologists use as outcome measures in clinical trials, which can be a laborious process. The OMERACT Filter 2.0, part of the latest iteration of the handbook, offers strong guidance for researchers but needs a long-term strategy and key methodological support. “To that end, we set up a technical advisory group to help people in the instrument selection work and that remains an ongoing process,” OMERACT leaders said in their joint statement.

OMERACT is looking at opportunities to create benchmark processes for developing core sets outside of rheumatology and a methodology around outcome measures such as contextual factors, composites, and surrogates.

It will also be taking a step back to solicit opinions from the approval agencies represented by the OMERACT membership on the OMERACT handbook.

The goal is to make sure the handbook aligns with everyone else’s approval and labeling requirements.
 

OMERACT’s patient participants bring important perspectives

OMERACT over the years has sought to become a more patient-centered group. Patients have been involved in OMERACT activities since its sixth meeting, forming an independent, yet integrated, group within the network. They have their own steering committee and produced and helped to update a glossary for OMERACT patients and professionals. 

Catherine (McGowan) Hofstetter, who was diagnosed with rheumatoid arthritis 30 years ago, chairs OMERACT’s Patient Research Partners Support Team. In a Q&A, she discussed the importance of patient voices and OMERACT’s plans to further educate and include patients in the dialogue on outcomes.

Question: Have patients always been a part of OMERACT meetings? 

Answer: Patients have been involved with OMERACT since 2002. The patient voice adds relevance to all the work that OMERACT does. You can’t begin to talk about outcomes unless there is a patient at the table with lived experience.

Q: Can you cite a few examples of how the patient voice enriches the conversation on outcomes research? 

A: Outcomes and priorities that are important to patients are often completely different than those of the clinician. For instance, a work outcome is important to someone who doesn’t have any medical insurance or disability insurance, so that you can ensure that there is food on the table and a roof over your head. Or it may be important to someone because the employment provides medical and disability insurance to provide security for them and their family. These are two different perspectives on work and therefore work priorities and outcomes.

Q: What have been some of the challenges of getting patients to participate?

A: Training patients is one challenge. OMERACT’s work has a very steep learning curve, and while the basics are the same between the groups in terms of looking at what we measure and how we measure it, the nuances of different working groups require a lot of time and energy to be comfortable enough with the work, and then be confident enough to bring your perspective and lived experience to the table. It’s also a very accomplished group, which can be quite intimidating. Self-disclosure is a very personal and intimate undertaking that requires patience, compassion, and respect.

Q: Are there any plans to enhance patient engagement?

A: When we had OMERACT 2020 it was a virtual conference that took place over about 6 months. We had far more patient research partners [PRPs] participate than we have ever had at any OMERACT face-to-face meeting. There is a desire and passion on the part of patients to lend their voices to the work. The working groups meet virtually throughout the year to advance their agendas, and PRPs are a part of each of the working groups. 

Hopefully, we can start working toward including more voices at the conferences by enabling a hybrid model. The PRP Support Team will begin engaging patients this fall with education, mentoring, and team-building exercises so by the time we meet in person in May 2023, they will have enough background knowledge and information to give them the confidence that will enhance their experience at the face-to-face meeting.

We also need to ensure that those patients who want to stay engaged can. This means that the education and training should continue long after the face-to-face meeting is over. We need to build capacity in the PRP group and look to succession planning and be a resource to working groups struggling to find PRPs to work with them on a longer-term basis.

Clinical research in rheumatology was suffering from an identity crisis of sorts 40 years ago. A lack of consensus across continents resulted in differing views about clinical outcome measures and judgments about treatments.

Patients were not allowed to be the generating source of a clinical outcome, according to Peter Tugwell, MSc, MD. “The only outcomes that were acceptable were clinician assessments, blood tests, and imaging,” said Dr. Tugwell, professor of medicine, epidemiology, and public health at the University of Ottawa (Ont.) and a practicing rheumatologist at Ottawa Hospital.

Clinicians were coming to different conclusions about patient responses to treatment when managing rheumatoid arthritis in clinical practice.

OMERACT sought to address this lack of uniformity. This international group, formed in 1992, leverages stakeholder groups to improve outcome measurement in rheumatology endpoints through a consensus-building, data-driven format.

It was originally known as “Outcome Measures in Rheumatoid Arthritis Clinical Trials,” but its leaders have since broadened its scope to “Outcome Measures in Rheumatology.” Over the years, it has evolved into an international network that assesses measurement across a wide variety of intervention studies. Now 30 years old, the network spans 40 active working groups and has influenced work in patient outcomes across 500 peer-reviewed publications.

The network meets every 2 years to address what is always a challenging agenda, said Dr. Tugwell, one of its founding members and chair. “There’s lots of strong opinions.” Participating in the discussions are individuals from all stages of seniority in rheumatology and clinical epidemiology, patient research partners, industry, approval agencies, and many countries who are committed to the spirit of OMERACT.

“The secret to our success has been getting world leaders to come together and have those discussions, work them through, and identify common ground in such a way that the approval agencies accept these outcome measures in clinical trials,” he added.

“My impression was the founders perceived a problem in the early 1990s and devised a consensus method in an attempt to quantify clinical parameters to define disease activity in rheumatoid arthritis – an important first step to do clinical trials and allow comparisons between them,” said Patricia Woo, CBE, FMedSci, FRCP, emeritus professor of pediatric rheumatology and previous head of the Centre for Paediatric and Adolescent Rheumatology at UCL, London. At that time, even disease definitions varied between the United States and Europe and other parts of the world, said Dr. Woo, who is not a part of OMERACT. “This was especially true for pediatric rheumatology.”
 

Fusing the continental divide

OMERACT arose from a need to streamline clinical outcome measures in rheumatology. Research papers during the 1980s demonstrated a lack of coherence in managing patients with rheumatoid arthritis in routine practice. In addition, the measures used to define clinical endpoints in clinical trials operated in silos – they were either too specific to a certain trial, overlapped with other concepts, or didn’t reflect changes in treatment.

Approval agencies in Europe and North America were approving only outcomes measures developed by their respective researchers. This was also true of patients they tested on. “This seemed crazy,” Dr. Tugwell said.

Dr. Tugwell was involved in the Cochrane collaboration, which conducts systematic reviews of best evidence across the world that assesses the magnitude of benefits versus harms.

To achieve this goal, “you need to pull studies from around the world,” he said. Maarten Boers, MD, PhD, a rheumatologist (and later professor of clinical epidemiology at Amsterdam University Medical Center) from the Netherlands, spent a year in Ontario, Canada, to train as a clinical epidemiologist. Together, Dr. Tugwell and Dr. Boers began discussing options to develop more streamlined outcome measures.

Courtesy OMERACT

They initiated the first OMERACT conference in Maastricht, the Netherlands, in 1992. The Food and Drug Administration and European Medicines Agency participated, along with leaders of outcomes measurement in Europe and in North America.

Discussions centered on methods to develop outcomes in a meaningful fashion. During the first meeting, North American and European approval agencies agreed to accept each other’s studies and endpoints and patient reported outcomes.

Agreement was achieved on a preliminary set of outcome domains and measures that later became known as the WHO-ILAR (World Health Organization–International League of Associations for Rheumatology) core set. The set included seven outcome domains: tender joints, swollen joints, pain, physician global assessment, patient global assessment, physical disability, and acute phase reactants, and one additional outcome domain for studies lasting 1 year or more: radiographs of the joints.

“A proactive program was planned to test not only the validity of these endpoints, but also the methods for their measurement. This was the start of a continuing process,” OMERACT members said in a joint statement for this article. Meetings have since taken place every 2 years.

Courtesy OMERACT

OMERACT accomplishments

OMERACT now requires buy-in from four continents: Asia, Australia, Europe, and North America.

Its leaders have developed an explicit process for gaining endorsement of core outcome domains and instrument measurement sets. To fully capture the possibilities of “what to measure,” i.e., “measurable aspects of health conditions,” OMERACT has developed a framework of concepts, core areas, and outcome domains. The key concepts are pathophysiology (with a core area termed “manifestations/abnormalities”) and impact (with core areas of “death/lifespan,” and “life impact,” and the optional area of “societal/resource use”). An outcome domain defines an element of a core area to measure the effects of a treatment, such as blood markers, pain intensity, physical function, or emotional well-being.

A core outcome domain set is developed by agreeing to at least one outcome domain within one of the three core areas. Subsequently, a core outcome measurement set is developed by agreeing to at least one applicable measurement instrument for each core outcome domain. This requires documentation of validity, summarized under three metrics: truth, discrimination, and feasibility.

OMERACT’s handbook provides tutelage on establishing and implementing core outcomes, and several workbooks offer guidance on developing core outcome domain sets, selecting instruments for core outcome measurement sets, and OMERACT methodology.

All this work has led to widespread adoption.

Approval agencies have accepted OMERACT’s filter and methods advances, which have been adopted by many research groups in rheumatology and among nonrheumatology research groups. Organizations such as the U.S. National Institutes of Health’s National Institute of Neurological Disorders and Stroke have sought its advice.

Its core outcomes have been adopted and used for approval in the great majority of studies on rheumatoid arthritis, Dr. Tugwell said.

Several BMJ articles underscore the influence and uptake of OMERACT’s core outcome set. One 2017 paper, which analyzed 273 randomized trials of rheumatoid arthritis drug treatments on ClinicalTrials.gov, found that the WHO-ILAR arthritis core outcome set was reported in 81% of the studies. “The adoption of a core outcome set has the potential to increase consistency in outcomes measured across trials and ensure that trials are more likely to measure appropriate outcomes,” the authors concluded.

Since the initial 1992 meeting, OMERACT has broadened its focus from rheumatoid arthritis to 25 other musculoskeletal conditions.

For example, other OMERACT conferences have led to consensus on core sets of measures for osteoarthritis and osteoporosis, psoriasis/psoriatic arthritis, psychosocial measures, and a core set of data for cost-effectiveness evaluations.
 

‘Speed is a limitation’

OMERACT is a bottom-up volunteer organization. It doesn’t represent any official organization of any clinical society. “We’ve not asked to be adopted by the American College of Rheumatology, EULAR [European Alliance of Associations for Rheumatology], or other international organizations,” Dr. Tugwell said. It offers a chance for patients, users, and doers of research to work together to agree on rigorous criteria accepted by the approval agencies and take the necessary time to work things through.

This is not a fast process, usually taking 4-6 years to initiate and establish an outcome domain set, he emphasized. “It would be beneficial to do it faster if we had the resources to meet every year. The fact is we’re a volunteer organization that meets every 2 years.”

Speed is a limitation, he acknowledged, but it’s an acceptable trade-off for doing things correctly.

The group has faced other challenges during the COVID-19 pandemic, pivoting to a virtual format that had benefits and limitations.

In one respect, moving to a virtual meeting increased uptake in participation and voting, Dr. Tugwell said. Patient participants with severe rheumatoid arthritis no longer faced the challenges of travel. “On the other hand, we didn’t have the same opportunity to achieve common ground virtually,” he said. “Where there are strong disagreements, I’m a great believer that people need to know one another. There needs to be relationship building.”

OMERACT’s emerging leader program has been a cornerstone of its in-person meetings, engaging young rheumatologists to interact with some of the leaders of outcome measurement. The virtual format dampened this process somewhat, eliminating those important “café chats” between the stakeholders.

The hope is to bring people face-to-face once more at the next meeting in May 2023. The agenda will focus on relationship building, identifying controversial areas, and bringing younger people to develop relationships, Dr. Tugwell said. OMERACT will retain a virtual option for the worldwide voting, “which will allow for more buy-in from so many more people,” he added.
 

A consensus on pain

The onus of developing outcome measures that move with the times is sometimes too great for one group to manage. In 2018, OMERACT became a part of the Red Hat Group (RHG), an organization conceived at the COMET (Core Outcome Measures in Effectiveness Trials) VII meeting in Amsterdam.

RHG aims to improve the choice of outcomes in health research. It includes eight groups: COMET; OMERACT; the Cochrane Skin Core Outcome Set Initiative; Grading of Recommendations, Assessment, Development and Evaluations; Center for Medical Technology Policy; COnsensus-based Standards for the selection of health Measurement Instruments; Clinical Data Interchange Standards Consortium; and Standardized Outcomes in Nephrology.

The collaboration between groups offers a “very interesting interface between consensus building as well as hard evidence,” Dr. Tugwell said. The focus goes beyond rheumatology to other clinical areas of common interest, exploring how one classifies outcome domains in terms of symptoms, life impact, or death.

Pain is an important common denominator that the RHG has evaluated.

“We believe it’s too general. We’re trying to define pain across all Red Hat Groups because it’s clear that the research community has all these different scales for defining pain severity,” Dr. Tugwell said. “We have to find a way to make ruthless decisions and rules for doing it. And of course, it has to be transparent.”
 

Looking ahead

As part of its ongoing work, OMERACT is evaluating the robustness of instruments that rheumatologists use as outcome measures in clinical trials, which can be a laborious process. The OMERACT Filter 2.0, part of the latest iteration of the handbook, offers strong guidance for researchers but needs a long-term strategy and key methodological support. “To that end, we set up a technical advisory group to help people in the instrument selection work and that remains an ongoing process,” OMERACT leaders said in their joint statement.

OMERACT is looking at opportunities to create benchmark processes for developing core sets outside of rheumatology and a methodology around outcome measures such as contextual factors, composites, and surrogates.

It will also be taking a step back to solicit opinions from the approval agencies represented by the OMERACT membership on the OMERACT handbook.

The goal is to make sure the handbook aligns with everyone else’s approval and labeling requirements.
 

OMERACT’s patient participants bring important perspectives

OMERACT over the years has sought to become a more patient-centered group. Patients have been involved in OMERACT activities since its sixth meeting, forming an independent, yet integrated, group within the network. They have their own steering committee and produced and helped to update a glossary for OMERACT patients and professionals. 

Catherine (McGowan) Hofstetter, who was diagnosed with rheumatoid arthritis 30 years ago, chairs OMERACT’s Patient Research Partners Support Team. In a Q&A, she discussed the importance of patient voices and OMERACT’s plans to further educate and include patients in the dialogue on outcomes.

Question: Have patients always been a part of OMERACT meetings? 

Answer: Patients have been involved with OMERACT since 2002. The patient voice adds relevance to all the work that OMERACT does. You can’t begin to talk about outcomes unless there is a patient at the table with lived experience.

Q: Can you cite a few examples of how the patient voice enriches the conversation on outcomes research? 

A: Outcomes and priorities that are important to patients are often completely different than those of the clinician. For instance, a work outcome is important to someone who doesn’t have any medical insurance or disability insurance, so that you can ensure that there is food on the table and a roof over your head. Or it may be important to someone because the employment provides medical and disability insurance to provide security for them and their family. These are two different perspectives on work and therefore work priorities and outcomes.

Q: What have been some of the challenges of getting patients to participate?

A: Training patients is one challenge. OMERACT’s work has a very steep learning curve, and while the basics are the same between the groups in terms of looking at what we measure and how we measure it, the nuances of different working groups require a lot of time and energy to be comfortable enough with the work, and then be confident enough to bring your perspective and lived experience to the table. It’s also a very accomplished group, which can be quite intimidating. Self-disclosure is a very personal and intimate undertaking that requires patience, compassion, and respect.

Q: Are there any plans to enhance patient engagement?

A: When we had OMERACT 2020 it was a virtual conference that took place over about 6 months. We had far more patient research partners [PRPs] participate than we have ever had at any OMERACT face-to-face meeting. There is a desire and passion on the part of patients to lend their voices to the work. The working groups meet virtually throughout the year to advance their agendas, and PRPs are a part of each of the working groups. 

Hopefully, we can start working toward including more voices at the conferences by enabling a hybrid model. The PRP Support Team will begin engaging patients this fall with education, mentoring, and team-building exercises so by the time we meet in person in May 2023, they will have enough background knowledge and information to give them the confidence that will enhance their experience at the face-to-face meeting.

We also need to ensure that those patients who want to stay engaged can. This means that the education and training should continue long after the face-to-face meeting is over. We need to build capacity in the PRP group and look to succession planning and be a resource to working groups struggling to find PRPs to work with them on a longer-term basis.

Early in 2020, Anne Peters, MD, caught COVID-19. The author of Medscape’s “Peters on Diabetes” column was sick in March 2020 before state-mandated lockdowns, and well before there were any vaccines.

She remembers sitting in a small exam room with two patients who had flown to her Los Angeles office from New York. The elderly couple had hearing difficulties, so Dr. Peters sat close to them, putting on a continuous glucose monitor. “At that time, we didn’t think of COVID-19 as being in L.A.,” Dr. Peters recalled, “so I think we were not terribly consistent at mask-wearing due to the need to educate.”

“Several days later, I got COVID, but I didn’t know I had COVID per se. I felt crappy, had a terrible sore throat, lost my sense of taste and smell [which was not yet described as a COVID symptom], was completely exhausted, but had no fever or cough, which were the only criteria for getting COVID tested at the time. I didn’t know I had been exposed until 2 weeks later, when the patient’s assistant returned the sensor warning us to ‘be careful’ with it because the patient and his wife were recovering from COVID.”

That early battle with COVID-19 was just the beginning of what would become a 2-year struggle, including familial loss amid her own health problems and concerns about the under-resourced patients she cares for. Here, she shares her journey through the pandemic with this news organization.
 

Question: Thanks for talking to us. Let’s discuss your journey over these past 2.5 years.

Answer: Everybody has their own COVID story because we all went through this together. Some of us have worse COVID stories, and some of us have better ones, but all have been impacted.

I’m not a sick person. I’m a very healthy person but COVID made me so unwell for 2 years. The brain fog and fatigue were nothing compared to the autonomic neuropathy that affected my heart. It was really limiting for me. And I still don’t know the long-term implications, looking 20-30 years from now.
 

Q: When you initially had COVID, what were your symptoms? What was the impact?

A: I had all the symptoms of COVID, except for a cough and fever. I lost my sense of taste and smell. I had a horrible headache, a sore throat, and I was exhausted. I couldn’t get tested because I didn’t have the right symptoms.

Despite being sick, I never stopped working but just switched to telemedicine. I also took my regular monthly trip to our cabin in Montana. I unknowingly flew on a plane with COVID. I wore a well-fitted N95 mask, so I don’t think I gave anybody COVID. I didn’t give COVID to my partner, Eric, which is hard to believe as – at 77 – he’s older than me. He has diabetes, heart disease, and every other high-risk characteristic. If he’d gotten COVID back then, it would have been terrible, as there were no treatments, but luckily he didn’t get it.
 

Q: When were you officially diagnosed?

A: Two or 3 months after I thought I might have had COVID, I checked my antibodies, which tested strongly positive for a prior COVID infection. That was when I knew all the symptoms I’d had were due to the disease.

Q: Not only were you dealing with your own illness, but also that of those close to you. Can you talk about that?

A: In April 2020, my mother who was in her 90s and otherwise healthy except for dementia, got COVID. She could have gotten it from me. I visited often but wore a mask. She had all the horrible pulmonary symptoms. In her advance directive, she didn’t want to be hospitalized so I kept her in her home. She died from COVID in her own bed. It was fairly brutal, but at least I kept her where she felt comforted.

My 91-year-old dad was living in a different residential facility. Throughout COVID he had become very depressed because his social patterns had changed. Prior to COVID, they all ate together, but during the pandemic they were unable to. He missed his social connections, disliked being isolated in his room, hated everyone in masks.

He was a bit demented, but not so much that he couldn’t communicate with me or remember where his grandson was going to law school. I wasn’t allowed inside the facility, which was hard on him. I hadn’t told him his wife died because the hospice social workers advised me that I shouldn’t give him news that he couldn’t process readily until I could spend time with him. Unfortunately, that time never came. In December 2020, he got COVID. One of the people in that facility had gone to the hospital, came back, and tested negative, but actually had COVID and gave it to my dad. The guy who gave it to my dad didn’t die but my dad was terribly ill. He died 2 weeks short of getting his vaccine. He was coherent enough to have a conversation. I asked him: ‘Do you want to go to the hospital?’ And he said: ‘No, because it would be too scary,’ since he couldn’t be with me. I put him on hospice and held his hand as he died from pulmonary COVID, which was awful. I couldn’t give him enough morphine or valium to ease his breathing. But his last words to me were “I love you,” and at the very end he seemed peaceful, which was a blessing.

I got an autopsy, because he wanted one. Nothing else was wrong with him other than COVID. It destroyed his lungs. The rest of him was fine – no heart disease, cancer, or anything else. He died of COVID-19, the same as my mother.

That same week, my aunt, my only surviving older relative, who was in Des Moines, Iowa, died of COVID-19. All three family members died before the vaccine came out.

It was hard to lose my parents. I’m the only surviving child because my sister died in her 20s. It’s not been an easy pandemic. But what pandemic is easy? I just happened to have lost more people than most. Ironically, my grandfather was one of the legionnaires at the Bellevue-Stratford Hotel in Philadelphia in 1976 and died of Legionnaire’s disease before we knew what was causing the outbreak.
 

Q: Were you still struggling with COVID?

A: COVID impacted my whole body. I lost a lot of weight. I didn’t want to eat, and my gastrointestinal system was not happy. It took a while for my sense of taste and smell to come back. Nothing tasted good. I’m not a foodie; I don’t really care about food. We could get takeout or whatever, but none of it appealed to me. I’m not so sure it was a taste thing, I just didn’t feel like eating.

I didn’t realize I had “brain fog” per se, because I felt stressed and overwhelmed by the pandemic and my patients’ concerns. But one day, about 3 months after I had developed COVID, I woke up without the fog. Which made me aware that I hadn’t been feeling right up until that point.

The worst symptoms, however, were cardiac. I noticed also immediately that my heart rate went up very quickly with minimal exertion. My pulse has always been in the 55-60 bpm range, and suddenly just walking across a room made it go up to over 140 bpm. If I did any aerobic activity, it went up over 160 and would be associated with dyspnea and chest pain. I believed these were all post-COVID symptoms and felt validated when reports of others having similar issues were published in the literature.

Q: Did you continue seeing patients?

A: Yes, of course. Patients never needed their doctors more. In East L.A., where patients don’t have easy access to telemedicine, I kept going into clinic throughout the pandemic. In the more affluent Westside of Los Angeles, we switched to telemedicine, which was quite effective for most. However, because diabetes was associated with an increased risk of hospitalization and death from COVID, my patients were understandably afraid. I’ve never been busier, but (like all health care providers), I became more of a COVID provider than a diabetologist.

Q: Do you feel your battle with COVID impacted your work?

A: It didn’t affect me at work. If I was sitting still, I was fine. Sitting at home at a desk, I didn’t notice any symptoms. But as a habitual stair-user, I would be gasping for breath in the stairwell because I couldn’t go up the stairs to my office as I once could.

I think you empathize more with people who had COVID (when you’ve had it yourself). There was such a huge patient burden. And I think that’s been the thing that’s affected health care providers the most – no matter what specialty we’re in – that nobody has answers.
 

Q: What happened after you had your vaccine?

A: The vaccine itself was fine. I didn’t have any reaction to the first two doses. But the first booster made my cardiac issues worse.

By this point, my cardiac problems stopped me from exercising. I even went to the ER with chest pain once because I was having palpitations and chest pressure caused by simply taking my morning shower. Fortunately, I wasn’t having an MI, but I certainly wasn’t “normal.”

My measure of my fitness is the cross-country skiing trail I use in Montana. I know exactly how far I can ski. Usually I can do the loop in 35 minutes. After COVID, I lasted 10 minutes. I would be tachycardic, short of breath with chest pain radiating down my left arm. I would rest and try to keep going. But with each rest period, I only got worse. I would be laying in the snow and strangers would ask if I needed help.
 

Q: What helped you?

A: I’ve read a lot about long COVID and have tried to learn from the experts. Of course, I never went to a doctor directly, although I did ask colleagues for advice. What I learned was to never push myself. I forced myself to create an exercise schedule where I only exercised three times a week with rest days in between. When exercising, the second my heart rate went above 140 bpm, I stopped until I could get it back down. I would push against this new limit, even though my limit was low.

Additionally, I worked on my breathing patterns and did meditative breathing for 10 minutes twice daily using a commercially available app.

Although progress was slow, I did improve, and by June 2022, I seemed back to normal. I was not as fit as I was prior to COVID and needed to improve, but the tachycardic response to exercise and cardiac symptoms were gone. I felt like my normal self. Normal enough to go on a spot packing trip in the Sierras in August. (Horses carried us and a mule carried the gear over the 12,000-foot pass into the mountains, and then left my friend and me high in the Sierras for a week.) We were camped above 10,000 feet and every day hiked up to another high mountain lake where we fly-fished for trout that we ate for dinner. The hikes were a challenge, but not abnormally so. Not as they would have been while I had long COVID.
 

Q: What is the current atmosphere in your clinic?

A: COVID is much milder now in my vaccinated patients, but I feel most health care providers are exhausted. Many of my staff left when COVID hit because they didn’t want to keep working. It made practicing medicine exhausting. There’s been a shortage of nurses, a shortage of everything. We’ve been required to do a whole lot more than we ever did before. It’s much harder to be a doctor. This pandemic is the first time I’ve ever thought of quitting. Granted, I lost my whole family, or at least the older generation, but it’s just been almost overwhelming.

On the plus side, almost every one of my patients has been vaccinated, because early on, people would ask: “Do you trust this vaccine?” I would reply: “I saw my parents die from COVID when they weren’t vaccinated, so you’re getting vaccinated. This is real and the vaccines help.” It made me very good at convincing people to get vaccines because I knew what it was like to see someone dying from COVID up close.
 

Q: What advice do you have for those struggling with the COVID pandemic?

A: People need to decide what their own risk is for getting sick and how many times they want to get COVID. At this point, I want people to go out, but safely. In the beginning, when my patients said, “can I go visit my granddaughter?” I said, “no,” but that was before we had the vaccine. Now I feel it is safe to go out using common sense. I still have my patients wear masks on planes. I still have patients try to eat outside as much as possible. And I tell people to take the precautions that make sense, but I tell them to go out and do things because life is short.

I had a patient in his 70s who has many risk factors like heart disease and diabetes. His granddaughter’s Bat Mitzvah in Florida was coming up. He asked: “Can I go?” I told him “Yes,” but to be safe – to wear an N95 mask on the plane and at the event, and stay in his own hotel room, rather than with the whole family. I said, “You need to do this.” Earlier in the pandemic, I saw people who literally died from loneliness and isolation.

He and his wife flew there. He sent me a picture of himself with his granddaughter. When he returned, he showed me a handwritten note from her that said, “I love you so much. Everyone else canceled, which made me cry. You’re the only one who came. You have no idea how much this meant to me.”

He’s back in L.A., and he didn’t get COVID. He said, “It was the best thing I’ve done in years.” That’s what I need to help people with, navigating this world with COVID and assessing risks and benefits. As with all of medicine, my advice is individualized. My advice changes based on the major circulating variant and the rates of the virus in the population, as well as the risk factors of the individual.
 

Q: What are you doing now?

A: I’m trying to avoid getting COVID again, or another booster. I could get pre-exposure monoclonal antibodies but am waiting to do anything further until I see what happens over the fall and winter. I still wear a mask inside but now do a mix of in-person and telemedicine visits. I still try to go to outdoor restaurants, which is easy in California. But I’m flying to see my son in New York and plan to go to Europe this fall for a meeting. I also go to my cabin in Montana every month to get my “dose” of the wilderness. Overall, I travel for conferences and speaking engagements much less because I have learned the joy of staying home.

Thinking back on my life as a doctor, my career began as an intern at Stanford rotating through Ward 5B, the AIDS unit at San Francisco General Hospital, and will likely end with COVID. In spite of all our medical advances, my generation of physicians, much as many generations before us, has a front-row seat to the vulnerability of humans to infectious diseases and how far we still need to go to protect our patients from communicable illness.

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

Anne L. Peters, MD, is a professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts; three books on diabetes; and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.

Early in 2020, Anne Peters, MD, caught COVID-19. The author of Medscape’s “Peters on Diabetes” column was sick in March 2020 before state-mandated lockdowns, and well before there were any vaccines.

She remembers sitting in a small exam room with two patients who had flown to her Los Angeles office from New York. The elderly couple had hearing difficulties, so Dr. Peters sat close to them, putting on a continuous glucose monitor. “At that time, we didn’t think of COVID-19 as being in L.A.,” Dr. Peters recalled, “so I think we were not terribly consistent at mask-wearing due to the need to educate.”

“Several days later, I got COVID, but I didn’t know I had COVID per se. I felt crappy, had a terrible sore throat, lost my sense of taste and smell [which was not yet described as a COVID symptom], was completely exhausted, but had no fever or cough, which were the only criteria for getting COVID tested at the time. I didn’t know I had been exposed until 2 weeks later, when the patient’s assistant returned the sensor warning us to ‘be careful’ with it because the patient and his wife were recovering from COVID.”

That early battle with COVID-19 was just the beginning of what would become a 2-year struggle, including familial loss amid her own health problems and concerns about the under-resourced patients she cares for. Here, she shares her journey through the pandemic with this news organization.
 

Question: Thanks for talking to us. Let’s discuss your journey over these past 2.5 years.

Answer: Everybody has their own COVID story because we all went through this together. Some of us have worse COVID stories, and some of us have better ones, but all have been impacted.

I’m not a sick person. I’m a very healthy person but COVID made me so unwell for 2 years. The brain fog and fatigue were nothing compared to the autonomic neuropathy that affected my heart. It was really limiting for me. And I still don’t know the long-term implications, looking 20-30 years from now.
 

Q: When you initially had COVID, what were your symptoms? What was the impact?

A: I had all the symptoms of COVID, except for a cough and fever. I lost my sense of taste and smell. I had a horrible headache, a sore throat, and I was exhausted. I couldn’t get tested because I didn’t have the right symptoms.

Despite being sick, I never stopped working but just switched to telemedicine. I also took my regular monthly trip to our cabin in Montana. I unknowingly flew on a plane with COVID. I wore a well-fitted N95 mask, so I don’t think I gave anybody COVID. I didn’t give COVID to my partner, Eric, which is hard to believe as – at 77 – he’s older than me. He has diabetes, heart disease, and every other high-risk characteristic. If he’d gotten COVID back then, it would have been terrible, as there were no treatments, but luckily he didn’t get it.
 

Q: When were you officially diagnosed?

A: Two or 3 months after I thought I might have had COVID, I checked my antibodies, which tested strongly positive for a prior COVID infection. That was when I knew all the symptoms I’d had were due to the disease.

Q: Not only were you dealing with your own illness, but also that of those close to you. Can you talk about that?

A: In April 2020, my mother who was in her 90s and otherwise healthy except for dementia, got COVID. She could have gotten it from me. I visited often but wore a mask. She had all the horrible pulmonary symptoms. In her advance directive, she didn’t want to be hospitalized so I kept her in her home. She died from COVID in her own bed. It was fairly brutal, but at least I kept her where she felt comforted.

My 91-year-old dad was living in a different residential facility. Throughout COVID he had become very depressed because his social patterns had changed. Prior to COVID, they all ate together, but during the pandemic they were unable to. He missed his social connections, disliked being isolated in his room, hated everyone in masks.

He was a bit demented, but not so much that he couldn’t communicate with me or remember where his grandson was going to law school. I wasn’t allowed inside the facility, which was hard on him. I hadn’t told him his wife died because the hospice social workers advised me that I shouldn’t give him news that he couldn’t process readily until I could spend time with him. Unfortunately, that time never came. In December 2020, he got COVID. One of the people in that facility had gone to the hospital, came back, and tested negative, but actually had COVID and gave it to my dad. The guy who gave it to my dad didn’t die but my dad was terribly ill. He died 2 weeks short of getting his vaccine. He was coherent enough to have a conversation. I asked him: ‘Do you want to go to the hospital?’ And he said: ‘No, because it would be too scary,’ since he couldn’t be with me. I put him on hospice and held his hand as he died from pulmonary COVID, which was awful. I couldn’t give him enough morphine or valium to ease his breathing. But his last words to me were “I love you,” and at the very end he seemed peaceful, which was a blessing.

I got an autopsy, because he wanted one. Nothing else was wrong with him other than COVID. It destroyed his lungs. The rest of him was fine – no heart disease, cancer, or anything else. He died of COVID-19, the same as my mother.

That same week, my aunt, my only surviving older relative, who was in Des Moines, Iowa, died of COVID-19. All three family members died before the vaccine came out.

It was hard to lose my parents. I’m the only surviving child because my sister died in her 20s. It’s not been an easy pandemic. But what pandemic is easy? I just happened to have lost more people than most. Ironically, my grandfather was one of the legionnaires at the Bellevue-Stratford Hotel in Philadelphia in 1976 and died of Legionnaire’s disease before we knew what was causing the outbreak.
 

Q: Were you still struggling with COVID?

A: COVID impacted my whole body. I lost a lot of weight. I didn’t want to eat, and my gastrointestinal system was not happy. It took a while for my sense of taste and smell to come back. Nothing tasted good. I’m not a foodie; I don’t really care about food. We could get takeout or whatever, but none of it appealed to me. I’m not so sure it was a taste thing, I just didn’t feel like eating.

I didn’t realize I had “brain fog” per se, because I felt stressed and overwhelmed by the pandemic and my patients’ concerns. But one day, about 3 months after I had developed COVID, I woke up without the fog. Which made me aware that I hadn’t been feeling right up until that point.

The worst symptoms, however, were cardiac. I noticed also immediately that my heart rate went up very quickly with minimal exertion. My pulse has always been in the 55-60 bpm range, and suddenly just walking across a room made it go up to over 140 bpm. If I did any aerobic activity, it went up over 160 and would be associated with dyspnea and chest pain. I believed these were all post-COVID symptoms and felt validated when reports of others having similar issues were published in the literature.

Q: Did you continue seeing patients?

A: Yes, of course. Patients never needed their doctors more. In East L.A., where patients don’t have easy access to telemedicine, I kept going into clinic throughout the pandemic. In the more affluent Westside of Los Angeles, we switched to telemedicine, which was quite effective for most. However, because diabetes was associated with an increased risk of hospitalization and death from COVID, my patients were understandably afraid. I’ve never been busier, but (like all health care providers), I became more of a COVID provider than a diabetologist.

Q: Do you feel your battle with COVID impacted your work?

A: It didn’t affect me at work. If I was sitting still, I was fine. Sitting at home at a desk, I didn’t notice any symptoms. But as a habitual stair-user, I would be gasping for breath in the stairwell because I couldn’t go up the stairs to my office as I once could.

I think you empathize more with people who had COVID (when you’ve had it yourself). There was such a huge patient burden. And I think that’s been the thing that’s affected health care providers the most – no matter what specialty we’re in – that nobody has answers.
 

Q: What happened after you had your vaccine?

A: The vaccine itself was fine. I didn’t have any reaction to the first two doses. But the first booster made my cardiac issues worse.

By this point, my cardiac problems stopped me from exercising. I even went to the ER with chest pain once because I was having palpitations and chest pressure caused by simply taking my morning shower. Fortunately, I wasn’t having an MI, but I certainly wasn’t “normal.”

My measure of my fitness is the cross-country skiing trail I use in Montana. I know exactly how far I can ski. Usually I can do the loop in 35 minutes. After COVID, I lasted 10 minutes. I would be tachycardic, short of breath with chest pain radiating down my left arm. I would rest and try to keep going. But with each rest period, I only got worse. I would be laying in the snow and strangers would ask if I needed help.
 

Q: What helped you?

A: I’ve read a lot about long COVID and have tried to learn from the experts. Of course, I never went to a doctor directly, although I did ask colleagues for advice. What I learned was to never push myself. I forced myself to create an exercise schedule where I only exercised three times a week with rest days in between. When exercising, the second my heart rate went above 140 bpm, I stopped until I could get it back down. I would push against this new limit, even though my limit was low.

Additionally, I worked on my breathing patterns and did meditative breathing for 10 minutes twice daily using a commercially available app.

Although progress was slow, I did improve, and by June 2022, I seemed back to normal. I was not as fit as I was prior to COVID and needed to improve, but the tachycardic response to exercise and cardiac symptoms were gone. I felt like my normal self. Normal enough to go on a spot packing trip in the Sierras in August. (Horses carried us and a mule carried the gear over the 12,000-foot pass into the mountains, and then left my friend and me high in the Sierras for a week.) We were camped above 10,000 feet and every day hiked up to another high mountain lake where we fly-fished for trout that we ate for dinner. The hikes were a challenge, but not abnormally so. Not as they would have been while I had long COVID.
 

Q: What is the current atmosphere in your clinic?

A: COVID is much milder now in my vaccinated patients, but I feel most health care providers are exhausted. Many of my staff left when COVID hit because they didn’t want to keep working. It made practicing medicine exhausting. There’s been a shortage of nurses, a shortage of everything. We’ve been required to do a whole lot more than we ever did before. It’s much harder to be a doctor. This pandemic is the first time I’ve ever thought of quitting. Granted, I lost my whole family, or at least the older generation, but it’s just been almost overwhelming.

On the plus side, almost every one of my patients has been vaccinated, because early on, people would ask: “Do you trust this vaccine?” I would reply: “I saw my parents die from COVID when they weren’t vaccinated, so you’re getting vaccinated. This is real and the vaccines help.” It made me very good at convincing people to get vaccines because I knew what it was like to see someone dying from COVID up close.
 

Q: What advice do you have for those struggling with the COVID pandemic?

A: People need to decide what their own risk is for getting sick and how many times they want to get COVID. At this point, I want people to go out, but safely. In the beginning, when my patients said, “can I go visit my granddaughter?” I said, “no,” but that was before we had the vaccine. Now I feel it is safe to go out using common sense. I still have my patients wear masks on planes. I still have patients try to eat outside as much as possible. And I tell people to take the precautions that make sense, but I tell them to go out and do things because life is short.

I had a patient in his 70s who has many risk factors like heart disease and diabetes. His granddaughter’s Bat Mitzvah in Florida was coming up. He asked: “Can I go?” I told him “Yes,” but to be safe – to wear an N95 mask on the plane and at the event, and stay in his own hotel room, rather than with the whole family. I said, “You need to do this.” Earlier in the pandemic, I saw people who literally died from loneliness and isolation.

He and his wife flew there. He sent me a picture of himself with his granddaughter. When he returned, he showed me a handwritten note from her that said, “I love you so much. Everyone else canceled, which made me cry. You’re the only one who came. You have no idea how much this meant to me.”

He’s back in L.A., and he didn’t get COVID. He said, “It was the best thing I’ve done in years.” That’s what I need to help people with, navigating this world with COVID and assessing risks and benefits. As with all of medicine, my advice is individualized. My advice changes based on the major circulating variant and the rates of the virus in the population, as well as the risk factors of the individual.
 

Q: What are you doing now?

A: I’m trying to avoid getting COVID again, or another booster. I could get pre-exposure monoclonal antibodies but am waiting to do anything further until I see what happens over the fall and winter. I still wear a mask inside but now do a mix of in-person and telemedicine visits. I still try to go to outdoor restaurants, which is easy in California. But I’m flying to see my son in New York and plan to go to Europe this fall for a meeting. I also go to my cabin in Montana every month to get my “dose” of the wilderness. Overall, I travel for conferences and speaking engagements much less because I have learned the joy of staying home.

Thinking back on my life as a doctor, my career began as an intern at Stanford rotating through Ward 5B, the AIDS unit at San Francisco General Hospital, and will likely end with COVID. In spite of all our medical advances, my generation of physicians, much as many generations before us, has a front-row seat to the vulnerability of humans to infectious diseases and how far we still need to go to protect our patients from communicable illness.

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

Anne L. Peters, MD, is a professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts; three books on diabetes; and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.

Early in 2020, Anne Peters, MD, caught COVID-19. The author of Medscape’s “Peters on Diabetes” column was sick in March 2020 before state-mandated lockdowns, and well before there were any vaccines.

She remembers sitting in a small exam room with two patients who had flown to her Los Angeles office from New York. The elderly couple had hearing difficulties, so Dr. Peters sat close to them, putting on a continuous glucose monitor. “At that time, we didn’t think of COVID-19 as being in L.A.,” Dr. Peters recalled, “so I think we were not terribly consistent at mask-wearing due to the need to educate.”

“Several days later, I got COVID, but I didn’t know I had COVID per se. I felt crappy, had a terrible sore throat, lost my sense of taste and smell [which was not yet described as a COVID symptom], was completely exhausted, but had no fever or cough, which were the only criteria for getting COVID tested at the time. I didn’t know I had been exposed until 2 weeks later, when the patient’s assistant returned the sensor warning us to ‘be careful’ with it because the patient and his wife were recovering from COVID.”

That early battle with COVID-19 was just the beginning of what would become a 2-year struggle, including familial loss amid her own health problems and concerns about the under-resourced patients she cares for. Here, she shares her journey through the pandemic with this news organization.
 

Question: Thanks for talking to us. Let’s discuss your journey over these past 2.5 years.

Answer: Everybody has their own COVID story because we all went through this together. Some of us have worse COVID stories, and some of us have better ones, but all have been impacted.

I’m not a sick person. I’m a very healthy person but COVID made me so unwell for 2 years. The brain fog and fatigue were nothing compared to the autonomic neuropathy that affected my heart. It was really limiting for me. And I still don’t know the long-term implications, looking 20-30 years from now.
 

Q: When you initially had COVID, what were your symptoms? What was the impact?

A: I had all the symptoms of COVID, except for a cough and fever. I lost my sense of taste and smell. I had a horrible headache, a sore throat, and I was exhausted. I couldn’t get tested because I didn’t have the right symptoms.

Despite being sick, I never stopped working but just switched to telemedicine. I also took my regular monthly trip to our cabin in Montana. I unknowingly flew on a plane with COVID. I wore a well-fitted N95 mask, so I don’t think I gave anybody COVID. I didn’t give COVID to my partner, Eric, which is hard to believe as – at 77 – he’s older than me. He has diabetes, heart disease, and every other high-risk characteristic. If he’d gotten COVID back then, it would have been terrible, as there were no treatments, but luckily he didn’t get it.
 

Q: When were you officially diagnosed?

A: Two or 3 months after I thought I might have had COVID, I checked my antibodies, which tested strongly positive for a prior COVID infection. That was when I knew all the symptoms I’d had were due to the disease.

Q: Not only were you dealing with your own illness, but also that of those close to you. Can you talk about that?

A: In April 2020, my mother who was in her 90s and otherwise healthy except for dementia, got COVID. She could have gotten it from me. I visited often but wore a mask. She had all the horrible pulmonary symptoms. In her advance directive, she didn’t want to be hospitalized so I kept her in her home. She died from COVID in her own bed. It was fairly brutal, but at least I kept her where she felt comforted.

My 91-year-old dad was living in a different residential facility. Throughout COVID he had become very depressed because his social patterns had changed. Prior to COVID, they all ate together, but during the pandemic they were unable to. He missed his social connections, disliked being isolated in his room, hated everyone in masks.

He was a bit demented, but not so much that he couldn’t communicate with me or remember where his grandson was going to law school. I wasn’t allowed inside the facility, which was hard on him. I hadn’t told him his wife died because the hospice social workers advised me that I shouldn’t give him news that he couldn’t process readily until I could spend time with him. Unfortunately, that time never came. In December 2020, he got COVID. One of the people in that facility had gone to the hospital, came back, and tested negative, but actually had COVID and gave it to my dad. The guy who gave it to my dad didn’t die but my dad was terribly ill. He died 2 weeks short of getting his vaccine. He was coherent enough to have a conversation. I asked him: ‘Do you want to go to the hospital?’ And he said: ‘No, because it would be too scary,’ since he couldn’t be with me. I put him on hospice and held his hand as he died from pulmonary COVID, which was awful. I couldn’t give him enough morphine or valium to ease his breathing. But his last words to me were “I love you,” and at the very end he seemed peaceful, which was a blessing.

I got an autopsy, because he wanted one. Nothing else was wrong with him other than COVID. It destroyed his lungs. The rest of him was fine – no heart disease, cancer, or anything else. He died of COVID-19, the same as my mother.

That same week, my aunt, my only surviving older relative, who was in Des Moines, Iowa, died of COVID-19. All three family members died before the vaccine came out.

It was hard to lose my parents. I’m the only surviving child because my sister died in her 20s. It’s not been an easy pandemic. But what pandemic is easy? I just happened to have lost more people than most. Ironically, my grandfather was one of the legionnaires at the Bellevue-Stratford Hotel in Philadelphia in 1976 and died of Legionnaire’s disease before we knew what was causing the outbreak.
 

Q: Were you still struggling with COVID?

A: COVID impacted my whole body. I lost a lot of weight. I didn’t want to eat, and my gastrointestinal system was not happy. It took a while for my sense of taste and smell to come back. Nothing tasted good. I’m not a foodie; I don’t really care about food. We could get takeout or whatever, but none of it appealed to me. I’m not so sure it was a taste thing, I just didn’t feel like eating.

I didn’t realize I had “brain fog” per se, because I felt stressed and overwhelmed by the pandemic and my patients’ concerns. But one day, about 3 months after I had developed COVID, I woke up without the fog. Which made me aware that I hadn’t been feeling right up until that point.

The worst symptoms, however, were cardiac. I noticed also immediately that my heart rate went up very quickly with minimal exertion. My pulse has always been in the 55-60 bpm range, and suddenly just walking across a room made it go up to over 140 bpm. If I did any aerobic activity, it went up over 160 and would be associated with dyspnea and chest pain. I believed these were all post-COVID symptoms and felt validated when reports of others having similar issues were published in the literature.

Q: Did you continue seeing patients?

A: Yes, of course. Patients never needed their doctors more. In East L.A., where patients don’t have easy access to telemedicine, I kept going into clinic throughout the pandemic. In the more affluent Westside of Los Angeles, we switched to telemedicine, which was quite effective for most. However, because diabetes was associated with an increased risk of hospitalization and death from COVID, my patients were understandably afraid. I’ve never been busier, but (like all health care providers), I became more of a COVID provider than a diabetologist.

Q: Do you feel your battle with COVID impacted your work?

A: It didn’t affect me at work. If I was sitting still, I was fine. Sitting at home at a desk, I didn’t notice any symptoms. But as a habitual stair-user, I would be gasping for breath in the stairwell because I couldn’t go up the stairs to my office as I once could.

I think you empathize more with people who had COVID (when you’ve had it yourself). There was such a huge patient burden. And I think that’s been the thing that’s affected health care providers the most – no matter what specialty we’re in – that nobody has answers.
 

Q: What happened after you had your vaccine?

A: The vaccine itself was fine. I didn’t have any reaction to the first two doses. But the first booster made my cardiac issues worse.

By this point, my cardiac problems stopped me from exercising. I even went to the ER with chest pain once because I was having palpitations and chest pressure caused by simply taking my morning shower. Fortunately, I wasn’t having an MI, but I certainly wasn’t “normal.”

My measure of my fitness is the cross-country skiing trail I use in Montana. I know exactly how far I can ski. Usually I can do the loop in 35 minutes. After COVID, I lasted 10 minutes. I would be tachycardic, short of breath with chest pain radiating down my left arm. I would rest and try to keep going. But with each rest period, I only got worse. I would be laying in the snow and strangers would ask if I needed help.
 

Q: What helped you?

A: I’ve read a lot about long COVID and have tried to learn from the experts. Of course, I never went to a doctor directly, although I did ask colleagues for advice. What I learned was to never push myself. I forced myself to create an exercise schedule where I only exercised three times a week with rest days in between. When exercising, the second my heart rate went above 140 bpm, I stopped until I could get it back down. I would push against this new limit, even though my limit was low.

Additionally, I worked on my breathing patterns and did meditative breathing for 10 minutes twice daily using a commercially available app.

Although progress was slow, I did improve, and by June 2022, I seemed back to normal. I was not as fit as I was prior to COVID and needed to improve, but the tachycardic response to exercise and cardiac symptoms were gone. I felt like my normal self. Normal enough to go on a spot packing trip in the Sierras in August. (Horses carried us and a mule carried the gear over the 12,000-foot pass into the mountains, and then left my friend and me high in the Sierras for a week.) We were camped above 10,000 feet and every day hiked up to another high mountain lake where we fly-fished for trout that we ate for dinner. The hikes were a challenge, but not abnormally so. Not as they would have been while I had long COVID.
 

Q: What is the current atmosphere in your clinic?

A: COVID is much milder now in my vaccinated patients, but I feel most health care providers are exhausted. Many of my staff left when COVID hit because they didn’t want to keep working. It made practicing medicine exhausting. There’s been a shortage of nurses, a shortage of everything. We’ve been required to do a whole lot more than we ever did before. It’s much harder to be a doctor. This pandemic is the first time I’ve ever thought of quitting. Granted, I lost my whole family, or at least the older generation, but it’s just been almost overwhelming.

On the plus side, almost every one of my patients has been vaccinated, because early on, people would ask: “Do you trust this vaccine?” I would reply: “I saw my parents die from COVID when they weren’t vaccinated, so you’re getting vaccinated. This is real and the vaccines help.” It made me very good at convincing people to get vaccines because I knew what it was like to see someone dying from COVID up close.
 

Q: What advice do you have for those struggling with the COVID pandemic?

A: People need to decide what their own risk is for getting sick and how many times they want to get COVID. At this point, I want people to go out, but safely. In the beginning, when my patients said, “can I go visit my granddaughter?” I said, “no,” but that was before we had the vaccine. Now I feel it is safe to go out using common sense. I still have my patients wear masks on planes. I still have patients try to eat outside as much as possible. And I tell people to take the precautions that make sense, but I tell them to go out and do things because life is short.

I had a patient in his 70s who has many risk factors like heart disease and diabetes. His granddaughter’s Bat Mitzvah in Florida was coming up. He asked: “Can I go?” I told him “Yes,” but to be safe – to wear an N95 mask on the plane and at the event, and stay in his own hotel room, rather than with the whole family. I said, “You need to do this.” Earlier in the pandemic, I saw people who literally died from loneliness and isolation.

He and his wife flew there. He sent me a picture of himself with his granddaughter. When he returned, he showed me a handwritten note from her that said, “I love you so much. Everyone else canceled, which made me cry. You’re the only one who came. You have no idea how much this meant to me.”

He’s back in L.A., and he didn’t get COVID. He said, “It was the best thing I’ve done in years.” That’s what I need to help people with, navigating this world with COVID and assessing risks and benefits. As with all of medicine, my advice is individualized. My advice changes based on the major circulating variant and the rates of the virus in the population, as well as the risk factors of the individual.
 

Q: What are you doing now?

A: I’m trying to avoid getting COVID again, or another booster. I could get pre-exposure monoclonal antibodies but am waiting to do anything further until I see what happens over the fall and winter. I still wear a mask inside but now do a mix of in-person and telemedicine visits. I still try to go to outdoor restaurants, which is easy in California. But I’m flying to see my son in New York and plan to go to Europe this fall for a meeting. I also go to my cabin in Montana every month to get my “dose” of the wilderness. Overall, I travel for conferences and speaking engagements much less because I have learned the joy of staying home.

Thinking back on my life as a doctor, my career began as an intern at Stanford rotating through Ward 5B, the AIDS unit at San Francisco General Hospital, and will likely end with COVID. In spite of all our medical advances, my generation of physicians, much as many generations before us, has a front-row seat to the vulnerability of humans to infectious diseases and how far we still need to go to protect our patients from communicable illness.

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

Anne L. Peters, MD, is a professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts; three books on diabetes; and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

A new study in The Lancet Rheumatology examines the strength and duration of SARS-CoV-2 vaccine–induced immunoglobulin-G antibody responses over time for patients with a variety of autoimmune diseases, compared with healthy controls.

The presence of humoral antibodies to SARS-CoV-2 has been shown to correlate with protection against COVID infection. But for patients with immune-mediated inflammatory diseases (IMIDs), host response to COVID infection or to vaccination is affected by the immune dysfunction imposed by the IMID and by the use of immune-modulating drugs to treat it.

This new study finds a weaker – as shown previously – and less sustained immune response to SARS-CoV-2 vaccines in patients with a variety of IMIDs, including rheumatoid arthritis, spondyloarthritis, psoriasis, inflammatory bowel diseases, and other systemic autoimmune diseases such as lupus. It also points toward the possibility of adjusting treatment and vaccination schedules and strategies for these patients based on their antibody levels, among other factors, to preserve best protection against severe COVID.

Kmatta/Moment/Getty Images

“It is important to assess immune response in these patients to see if they still have protection against severe COVID infection,” said lead author David Simon, MD, senior clinical scientist in clinical immunology and rheumatology at University Hospital Erlangen (Germany). “We know that antibody response is an immune correlate. Therefore, it is important to see how large and durable the immune response is to the coronavirus vaccine in these IMID patients, and whether specific drugs or therapies have negative effects on their immune response.”
 

What was studied?

For this large prospective cohort study, researchers registered 5076 coronavirus-vaccinated individuals. They analyzed serum samples obtained between December 15, 2020, and December 1, 2021, from 2,535 patients diagnosed with IMIDs and participating in a prospective coronavirus study program at the Deutsches Zentrum Immuntherapie in Erlangen. The IMID patients had a mean age of 55.0 years, and 58.9% were women.

A healthy control group of 1,198 individuals without IMID who had a mean age of 40.7 years, including 53.8% men, was also recruited for the analysis. All approved coronavirus vaccines were included, following standard vaccination schedules. Antibody response was measured over time by an enzyme-linked immunosorbent assay from 8 weeks after first vaccination to week 40.

Among the findings, the healthy controls had higher postvaccine antibody levels than did those with IMIDs. But the majority of vaccinated patients with IMID were able to build up a humoral immune response to SARS-CoV-2. Patients who were taking B-cell inhibitors like rituximab (Rituxan, Genentech; and biosimilars) and T-cell inhibitors like abatacept (Orencia, Bristol Myers Squibb) for IMIDs had significantly poorer antibody response.

Greater age and the use of combination therapies for IMIDs, compared with monotherapy, further reduced immune response to the vaccine. In terms of vaccination modality, messenger RNA–based vaccines induced higher antibody levels than did vector-based vaccines. The researchers noted that patients with IMID who were given a third vaccine dose could actually catch up well with the antibody responses observed in healthy controls.

“We looked at whether different IMIDs had a different humoral response, and we also assessed if there are effects from different therapeutic strategies,” Dr. Simon explained. “It doesn’t matter so much what kind of IMID patients have; much more important is the specific drug treatment and its impact on their antibody response.” Some participants were advised to briefly stop taking some immunosuppressive treatments before or after vaccination.

One of Dr. Simon’s coauthors, statistician and rheumatologist Koray Tascilar, MD, added, “This research is important because we looked not only at who responded less, which has been previously established, but who are at greater risk of losing their immune response, and how quickly.”
 

Need to take care

“Most treatments we as rheumatologists give to our patients don’t affect their SARS-CoV-2 humoral response,” Dr. Simon said. “However, there are specific drugs that are associated with lower antibody response. With respect to those drugs, we have to be more careful.”

It is important to be able to tell patients which drugs are safe and won’t have a negative impact on their immune response to vaccinations, Dr. Tascilar said. “But it would be too strong to say we’re ready to choose therapies based on their potential impact on protection against COVID. Yes, there is a risk from catching COVID, but we need to balance that risk with the risk of not giving patients the medications that are necessary to treat their rheumatologic condition.”

These diseases are serious, sometimes life-threatening. “We might think of strategies for how to mitigate the risk of underprotection from COVID that is brought about by these treatments,” he said. For example, offering boosters sooner or more frequently, or prophylactically treating with monoclonal antibodies.

“This study, along other recent studies, has found that antibody levels in patients with immune-mediated diseases wane more rapidly than in healthy controls, and this is especially true of those on medications that interfere with the B and T cells and anticytokine therapies,” Rebecca Haberman, MD, assistant professor, division of rheumatology, New York University Langone Health, noted in an email to this news organization.

“While there is no known antibody level that specifically correlates with clinical protection, and each patient needs to be thought of individually, these findings support the use of supplemental booster dosing in patients with immune-mediated inflammatory diseases,” Dr. Haberman said, adding that her own research in this area has shown similar results.

“As a rheumatologist, I would be more likely to encourage my patients – especially those on immunomodulatory medications – to get boosted.”

Dr. Tascilar said his study does not directly answer the question of whether an earlier booster shot would be an effective strategy for patients with IMID. “In our department, we have an early boosting strategy, based on level of immune response.” But the decision of revaccination or not, and when, is based on a number of factors, not only on the level of antibodies. “It’s just part of the instruments we are using.”

The study was supported by the Deutsche Forschungsgemeinschaft. Dr. Simon and Dr. Tascilar declared no relevant financial relationships.

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

A new study in The Lancet Rheumatology examines the strength and duration of SARS-CoV-2 vaccine–induced immunoglobulin-G antibody responses over time for patients with a variety of autoimmune diseases, compared with healthy controls.

The presence of humoral antibodies to SARS-CoV-2 has been shown to correlate with protection against COVID infection. But for patients with immune-mediated inflammatory diseases (IMIDs), host response to COVID infection or to vaccination is affected by the immune dysfunction imposed by the IMID and by the use of immune-modulating drugs to treat it.

This new study finds a weaker – as shown previously – and less sustained immune response to SARS-CoV-2 vaccines in patients with a variety of IMIDs, including rheumatoid arthritis, spondyloarthritis, psoriasis, inflammatory bowel diseases, and other systemic autoimmune diseases such as lupus. It also points toward the possibility of adjusting treatment and vaccination schedules and strategies for these patients based on their antibody levels, among other factors, to preserve best protection against severe COVID.

Kmatta/Moment/Getty Images

“It is important to assess immune response in these patients to see if they still have protection against severe COVID infection,” said lead author David Simon, MD, senior clinical scientist in clinical immunology and rheumatology at University Hospital Erlangen (Germany). “We know that antibody response is an immune correlate. Therefore, it is important to see how large and durable the immune response is to the coronavirus vaccine in these IMID patients, and whether specific drugs or therapies have negative effects on their immune response.”
 

What was studied?

For this large prospective cohort study, researchers registered 5076 coronavirus-vaccinated individuals. They analyzed serum samples obtained between December 15, 2020, and December 1, 2021, from 2,535 patients diagnosed with IMIDs and participating in a prospective coronavirus study program at the Deutsches Zentrum Immuntherapie in Erlangen. The IMID patients had a mean age of 55.0 years, and 58.9% were women.

A healthy control group of 1,198 individuals without IMID who had a mean age of 40.7 years, including 53.8% men, was also recruited for the analysis. All approved coronavirus vaccines were included, following standard vaccination schedules. Antibody response was measured over time by an enzyme-linked immunosorbent assay from 8 weeks after first vaccination to week 40.

Among the findings, the healthy controls had higher postvaccine antibody levels than did those with IMIDs. But the majority of vaccinated patients with IMID were able to build up a humoral immune response to SARS-CoV-2. Patients who were taking B-cell inhibitors like rituximab (Rituxan, Genentech; and biosimilars) and T-cell inhibitors like abatacept (Orencia, Bristol Myers Squibb) for IMIDs had significantly poorer antibody response.

Greater age and the use of combination therapies for IMIDs, compared with monotherapy, further reduced immune response to the vaccine. In terms of vaccination modality, messenger RNA–based vaccines induced higher antibody levels than did vector-based vaccines. The researchers noted that patients with IMID who were given a third vaccine dose could actually catch up well with the antibody responses observed in healthy controls.

“We looked at whether different IMIDs had a different humoral response, and we also assessed if there are effects from different therapeutic strategies,” Dr. Simon explained. “It doesn’t matter so much what kind of IMID patients have; much more important is the specific drug treatment and its impact on their antibody response.” Some participants were advised to briefly stop taking some immunosuppressive treatments before or after vaccination.

One of Dr. Simon’s coauthors, statistician and rheumatologist Koray Tascilar, MD, added, “This research is important because we looked not only at who responded less, which has been previously established, but who are at greater risk of losing their immune response, and how quickly.”
 

Need to take care

“Most treatments we as rheumatologists give to our patients don’t affect their SARS-CoV-2 humoral response,” Dr. Simon said. “However, there are specific drugs that are associated with lower antibody response. With respect to those drugs, we have to be more careful.”

It is important to be able to tell patients which drugs are safe and won’t have a negative impact on their immune response to vaccinations, Dr. Tascilar said. “But it would be too strong to say we’re ready to choose therapies based on their potential impact on protection against COVID. Yes, there is a risk from catching COVID, but we need to balance that risk with the risk of not giving patients the medications that are necessary to treat their rheumatologic condition.”

These diseases are serious, sometimes life-threatening. “We might think of strategies for how to mitigate the risk of underprotection from COVID that is brought about by these treatments,” he said. For example, offering boosters sooner or more frequently, or prophylactically treating with monoclonal antibodies.

“This study, along other recent studies, has found that antibody levels in patients with immune-mediated diseases wane more rapidly than in healthy controls, and this is especially true of those on medications that interfere with the B and T cells and anticytokine therapies,” Rebecca Haberman, MD, assistant professor, division of rheumatology, New York University Langone Health, noted in an email to this news organization.

“While there is no known antibody level that specifically correlates with clinical protection, and each patient needs to be thought of individually, these findings support the use of supplemental booster dosing in patients with immune-mediated inflammatory diseases,” Dr. Haberman said, adding that her own research in this area has shown similar results.

“As a rheumatologist, I would be more likely to encourage my patients – especially those on immunomodulatory medications – to get boosted.”

Dr. Tascilar said his study does not directly answer the question of whether an earlier booster shot would be an effective strategy for patients with IMID. “In our department, we have an early boosting strategy, based on level of immune response.” But the decision of revaccination or not, and when, is based on a number of factors, not only on the level of antibodies. “It’s just part of the instruments we are using.”

The study was supported by the Deutsche Forschungsgemeinschaft. Dr. Simon and Dr. Tascilar declared no relevant financial relationships.

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

A new study in The Lancet Rheumatology examines the strength and duration of SARS-CoV-2 vaccine–induced immunoglobulin-G antibody responses over time for patients with a variety of autoimmune diseases, compared with healthy controls.

The presence of humoral antibodies to SARS-CoV-2 has been shown to correlate with protection against COVID infection. But for patients with immune-mediated inflammatory diseases (IMIDs), host response to COVID infection or to vaccination is affected by the immune dysfunction imposed by the IMID and by the use of immune-modulating drugs to treat it.

This new study finds a weaker – as shown previously – and less sustained immune response to SARS-CoV-2 vaccines in patients with a variety of IMIDs, including rheumatoid arthritis, spondyloarthritis, psoriasis, inflammatory bowel diseases, and other systemic autoimmune diseases such as lupus. It also points toward the possibility of adjusting treatment and vaccination schedules and strategies for these patients based on their antibody levels, among other factors, to preserve best protection against severe COVID.

Kmatta/Moment/Getty Images

“It is important to assess immune response in these patients to see if they still have protection against severe COVID infection,” said lead author David Simon, MD, senior clinical scientist in clinical immunology and rheumatology at University Hospital Erlangen (Germany). “We know that antibody response is an immune correlate. Therefore, it is important to see how large and durable the immune response is to the coronavirus vaccine in these IMID patients, and whether specific drugs or therapies have negative effects on their immune response.”
 

What was studied?

For this large prospective cohort study, researchers registered 5076 coronavirus-vaccinated individuals. They analyzed serum samples obtained between December 15, 2020, and December 1, 2021, from 2,535 patients diagnosed with IMIDs and participating in a prospective coronavirus study program at the Deutsches Zentrum Immuntherapie in Erlangen. The IMID patients had a mean age of 55.0 years, and 58.9% were women.

A healthy control group of 1,198 individuals without IMID who had a mean age of 40.7 years, including 53.8% men, was also recruited for the analysis. All approved coronavirus vaccines were included, following standard vaccination schedules. Antibody response was measured over time by an enzyme-linked immunosorbent assay from 8 weeks after first vaccination to week 40.

Among the findings, the healthy controls had higher postvaccine antibody levels than did those with IMIDs. But the majority of vaccinated patients with IMID were able to build up a humoral immune response to SARS-CoV-2. Patients who were taking B-cell inhibitors like rituximab (Rituxan, Genentech; and biosimilars) and T-cell inhibitors like abatacept (Orencia, Bristol Myers Squibb) for IMIDs had significantly poorer antibody response.

Greater age and the use of combination therapies for IMIDs, compared with monotherapy, further reduced immune response to the vaccine. In terms of vaccination modality, messenger RNA–based vaccines induced higher antibody levels than did vector-based vaccines. The researchers noted that patients with IMID who were given a third vaccine dose could actually catch up well with the antibody responses observed in healthy controls.

“We looked at whether different IMIDs had a different humoral response, and we also assessed if there are effects from different therapeutic strategies,” Dr. Simon explained. “It doesn’t matter so much what kind of IMID patients have; much more important is the specific drug treatment and its impact on their antibody response.” Some participants were advised to briefly stop taking some immunosuppressive treatments before or after vaccination.

One of Dr. Simon’s coauthors, statistician and rheumatologist Koray Tascilar, MD, added, “This research is important because we looked not only at who responded less, which has been previously established, but who are at greater risk of losing their immune response, and how quickly.”
 

Need to take care

“Most treatments we as rheumatologists give to our patients don’t affect their SARS-CoV-2 humoral response,” Dr. Simon said. “However, there are specific drugs that are associated with lower antibody response. With respect to those drugs, we have to be more careful.”

It is important to be able to tell patients which drugs are safe and won’t have a negative impact on their immune response to vaccinations, Dr. Tascilar said. “But it would be too strong to say we’re ready to choose therapies based on their potential impact on protection against COVID. Yes, there is a risk from catching COVID, but we need to balance that risk with the risk of not giving patients the medications that are necessary to treat their rheumatologic condition.”

These diseases are serious, sometimes life-threatening. “We might think of strategies for how to mitigate the risk of underprotection from COVID that is brought about by these treatments,” he said. For example, offering boosters sooner or more frequently, or prophylactically treating with monoclonal antibodies.

“This study, along other recent studies, has found that antibody levels in patients with immune-mediated diseases wane more rapidly than in healthy controls, and this is especially true of those on medications that interfere with the B and T cells and anticytokine therapies,” Rebecca Haberman, MD, assistant professor, division of rheumatology, New York University Langone Health, noted in an email to this news organization.

“While there is no known antibody level that specifically correlates with clinical protection, and each patient needs to be thought of individually, these findings support the use of supplemental booster dosing in patients with immune-mediated inflammatory diseases,” Dr. Haberman said, adding that her own research in this area has shown similar results.

“As a rheumatologist, I would be more likely to encourage my patients – especially those on immunomodulatory medications – to get boosted.”

Dr. Tascilar said his study does not directly answer the question of whether an earlier booster shot would be an effective strategy for patients with IMID. “In our department, we have an early boosting strategy, based on level of immune response.” But the decision of revaccination or not, and when, is based on a number of factors, not only on the level of antibodies. “It’s just part of the instruments we are using.”

The study was supported by the Deutsche Forschungsgemeinschaft. Dr. Simon and Dr. Tascilar declared no relevant financial relationships.

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

The medical profession is held to a high standard of personal conduct, so physicians keep a sharp eye out for how fellow doctors behave. That goes for social media as well as in-person conduct.

This infographic explores what doctors think about how other physicians act on social media (and it’s not as egregious as you might think). If you’re interested in delving deeper into the data, check out the Medscape Physicians Behaving Badly Report 2022.

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

The medical profession is held to a high standard of personal conduct, so physicians keep a sharp eye out for how fellow doctors behave. That goes for social media as well as in-person conduct.

This infographic explores what doctors think about how other physicians act on social media (and it’s not as egregious as you might think). If you’re interested in delving deeper into the data, check out the Medscape Physicians Behaving Badly Report 2022.

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

The medical profession is held to a high standard of personal conduct, so physicians keep a sharp eye out for how fellow doctors behave. That goes for social media as well as in-person conduct.

This infographic explores what doctors think about how other physicians act on social media (and it’s not as egregious as you might think). If you’re interested in delving deeper into the data, check out the Medscape Physicians Behaving Badly Report 2022.

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

The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.

The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.

“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.

“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”

The research is considered one of the most thorough studies published to date about how well Paxlovid works, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.

Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.

The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.

Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.

Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.

Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.

Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.

For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.

The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.

The study didn’t receive any financial or in-kind support, the authors said.

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

The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.

The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.

“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.

“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”

The research is considered one of the most thorough studies published to date about how well Paxlovid works, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.

Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.

The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.

Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.

Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.

Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.

Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.

For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.

The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.

The study didn’t receive any financial or in-kind support, the authors said.

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

The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.

The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.

“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.

“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”

The research is considered one of the most thorough studies published to date about how well Paxlovid works, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.

Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.

The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.

Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.

Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.

Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.

Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.

For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.

The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.

The study didn’t receive any financial or in-kind support, the authors said.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.

Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).

This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.

“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.

The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.

“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”

Evidence gap

Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.

INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm²), left atrial spontaneous echo contrast, or left atrial thrombus.

Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.

Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.

During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).

The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
 

No easy explanation

Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).

“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”

Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).

By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.

Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.

Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
 

More physician contact

Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”

In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.

“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.

Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.

“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.

Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.

“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.

Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”

Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.

“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”

Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”

“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.

Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.

“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”

In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”

The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.

Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.

Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
 

Major risk is not receiving vaccine

These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.

Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.

The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.

However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”

The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.

The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.

“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).

“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.

Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.

“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.

“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.

“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”

95% of patients with HF in Denmark double vaccinated

The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.

Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.

The rates of vaccination in this study were much higher than those for patients with HF in the United States.

In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,

In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”

“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”

The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.

Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.

The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.

During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).

The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.

The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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