Federal Practitioner

Medicare has received a key endorsement of its plan to restrict payment for the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) – but also drew pleas from other groups for more generous reimbursement of the drug, as well as expected similar medications currently in development.

The Centers for Medicare & Medicaid Services received more than 9,900 comments on its plan, according to the current tally posted on its website. However, it is unclear when the final count will be available.

CMS intends to limit federal payment for monoclonal antibodies that target amyloid to clinical trials. Among supporters of this approach is the influential Medicare Payment Advisory Commission, an expert panel that helps Congress and CMS manage the federal health program.

Opponents of the CMS plan include several pharmaceutical companies. Patient and consumer groups, individuals, and lawmakers had mixed views.

CMS officials will weigh the feedback provided in the comments when setting a final coverage policy for aducanumab. It is expected the agency’s final decision will be announced on April 11.
 

Ongoing debate

The comments submitted to CMS reflect ongoing debate about whether the evidence proves aducanumab provides significant clinical benefit.

The Food and Drug Administration’s unusual approach to clearing the drug for U.S. sales triggered a review of its management of the accelerated approval process by the Office of Inspector General for the Department of Health & Human Services.

The FDA granted an accelerated approval for aducanumab in June based on evidence that the drug clears amyloid in the brain. However, it is unclear whether clearing the protein from the brain results in clinical benefit.

Usually, accelerated approvals precede the completion of phase 3 drug trials, with the FDA allowing early access to a medicine while awaiting confirmatory trials.

In the case of aducanumab, results of the phase 3 confirmatory trials ENGAGE and EMERGE were available at the time of FDA approval. However, interpretation of the findings is controversial.

Biogen contends that the amyloid-clearing effect of the higher dose of aducanumab shown in EMERGE indicates the drug has clinical potential. However, others argue that amyloid clearance does not indicate clinical benefit.

Limiting Medicare coverage of aducanumab for treatment of AD means “the progression of disease, for nearly all beneficiaries, would continue unabated,” Biogen wrote in its comment to CMS.
 

Conflicting data

Supporters of the CMS plan have a different view of the trial data. They note the failure of aducanumab in the companion ENGAGE trial, while also questioning the magnitude of benefit suggested by even the most positive data cited for the drug in the EMERGE trial.

Both studies used the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, an 18-point scale measuring cognition and function.

In his comment to CMS, MedPAC chairman Michael E. Chernew, PhD, noted the change in CDR-SB score of 0.39 in EMERGE’s high-dose aducanumab group. CMS has described this as being “less than the 1-2 point change that has been suggested as a minimal clinically important difference,” Dr. Chernew wrote.

MedPAC does not normally comment on Medicare coverage decisions, but did so in this case because of its significance and because of the potential fiscal implications, he noted.

“Though there is only limited, conflicting data on Aduhelm’s clinical effectiveness, Medicare would pay a high price for the product,” Dr. Chernew wrote, pointing out the $28,200 annual U.S. price of the drug.

MedPAC thus endorsed the coverage-with-evidence-development (CED) pathway. Under this approach, Medicare would pay for these drugs when used in clinical trials that meet certain criteria.
 

Legal challenge?

In its comment to CMS, Biogen questioned the agency’s legal grounds for limiting coverage of aducanumab. A mandate on clinical trials as part of the CED proposal “runs afoul of the Administrative Procedure Act’s prohibition against arbitrary and capricious agency action,” Biogen said.

The drug company argued that its own planned follow-on studies would provide the kind of data Medicare officials want to see. It also argued for greater use of observational data, including real-world evidence, and of information from Medicare claims.

Roche’s Genentech, which is also developing antiamyloid drugs for AD, echoed some of Biogen’s concerns about the aducanumab plan.

CMS’ CED plan would be “unnecessarily restrictive and discouraging for patients living with this destructive disease,” David Burt, executive director for federal government affairs at Genentech, wrote in a comment to CMS.

CMS should clarify that the CED requirement would not apply to cases of FDA-approved antiamyloid therapies that have demonstrated “clinically meaningful improvement,” Mr. Burt added. He noted there are phase 3 trials of drugs in this class that could soon produce data.

CMS should “fully consider the broad ramifications and significant unintended consequences of prematurely placing unduly severe restrictions on the entire class of antiamyloid monoclonal antibodies,” Mr. Burt wrote.
 

Health care inequity

In its comment to CMS, Biogen also noted the Medicare proposal would “compound the already pervasive inequities in access to treatment and will ultimately prove highly detrimental to health equity.”

There are already concerns about the access of Black and Latinx patients to clinical trials. The planned CED approach would tightly restrict access to aducanumab, as well as expected follow-ons in the amyloid-directed monoclonal antibody (mAb) drug class, the company said.

“Many of the trial sites for Aduhelm, as well as for other amyloid-directed [monoclonal antibodies] are not hospital-based outpatient settings, but include infusion centers, private practices, and medical research centers,” Biogen wrote.

Patient groups such as UsAgainstAlzheimer’s told CMS the CED approach would worsen disparities, despite the aim of Medicare officials to increase participation of Black and Latinx patients in future testing.

“CMS will be hard-pressed to achieve diversity if such hospitals are the only locations where Medicare beneficiaries are able to access mAbs,” USAgainstAlzheimer’s wrote in a Feb. 10 comment.

In contrast, the nonprofit National Center for Health Research praised CMS for what it described as an effort to address a lack of representation of Black and Latinx patients in earlier aducanumab research.

However, the NCHR also suggested CMS revise its plan to mandate that clinical trials include patients who are representative of the national population diagnosed with AD.

“Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups,” the NCHR wrote.
 

Patient health, Medicare at risk

On Feb. 8, a group of House Republican lawmakers asked CMS to reverse its stance. In a publicly released letter, Rep. Cathy McMorris Rodgers of Washington state, the ranking Republican on the House Energy and Commerce Committee, and colleagues urged broader coverage of aducanumab.

In the letter, the group emphasized the idea of aducanumab as a potential treatment for patients with Down syndrome who are at risk for AD.

“The link between Down Syndrome and AD is still being researched by scientists,” Rep. Rodgers and colleagues wrote.

“However, there appears to be a correlation between the additional 21st chromosome present in people with Down Syndrome and the chromosome’s gene that makes amyloid precursor proteins and can cause a build-up of the beta-amyloid plaques common amongst those with AD,” they add.

On the other hand, CMS garnered earlier support from influential Democrats. On Jan. 13, House Energy and Commerce Chairman Frank Pallone Jr (D-N.J.) and House Oversight and Reform Chairwoman Carolyn B. Maloney (D-N.Y.) released a letter praising CMS for its plan for covering aducanumab.

In addition to the HHS-OIG review of the FDA’s approval of the drug, the two House committees are in the midst of their own investigation of the agency’s decision to clear the drug.

“Any broader coverage determination before there is clarity on Aduhelm’s approval process and findings from the myriad ongoing investigations may put the health of millions of Alzheimer’s patients on the line and the financial stability of the nation’s health insurance program for American seniors at risk,” Rep. Pallone and Rep. Maloney wrote.

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

Medicare has received a key endorsement of its plan to restrict payment for the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) – but also drew pleas from other groups for more generous reimbursement of the drug, as well as expected similar medications currently in development.

The Centers for Medicare & Medicaid Services received more than 9,900 comments on its plan, according to the current tally posted on its website. However, it is unclear when the final count will be available.

CMS intends to limit federal payment for monoclonal antibodies that target amyloid to clinical trials. Among supporters of this approach is the influential Medicare Payment Advisory Commission, an expert panel that helps Congress and CMS manage the federal health program.

Opponents of the CMS plan include several pharmaceutical companies. Patient and consumer groups, individuals, and lawmakers had mixed views.

CMS officials will weigh the feedback provided in the comments when setting a final coverage policy for aducanumab. It is expected the agency’s final decision will be announced on April 11.
 

Ongoing debate

The comments submitted to CMS reflect ongoing debate about whether the evidence proves aducanumab provides significant clinical benefit.

The Food and Drug Administration’s unusual approach to clearing the drug for U.S. sales triggered a review of its management of the accelerated approval process by the Office of Inspector General for the Department of Health & Human Services.

The FDA granted an accelerated approval for aducanumab in June based on evidence that the drug clears amyloid in the brain. However, it is unclear whether clearing the protein from the brain results in clinical benefit.

Usually, accelerated approvals precede the completion of phase 3 drug trials, with the FDA allowing early access to a medicine while awaiting confirmatory trials.

In the case of aducanumab, results of the phase 3 confirmatory trials ENGAGE and EMERGE were available at the time of FDA approval. However, interpretation of the findings is controversial.

Biogen contends that the amyloid-clearing effect of the higher dose of aducanumab shown in EMERGE indicates the drug has clinical potential. However, others argue that amyloid clearance does not indicate clinical benefit.

Limiting Medicare coverage of aducanumab for treatment of AD means “the progression of disease, for nearly all beneficiaries, would continue unabated,” Biogen wrote in its comment to CMS.
 

Conflicting data

Supporters of the CMS plan have a different view of the trial data. They note the failure of aducanumab in the companion ENGAGE trial, while also questioning the magnitude of benefit suggested by even the most positive data cited for the drug in the EMERGE trial.

Both studies used the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, an 18-point scale measuring cognition and function.

In his comment to CMS, MedPAC chairman Michael E. Chernew, PhD, noted the change in CDR-SB score of 0.39 in EMERGE’s high-dose aducanumab group. CMS has described this as being “less than the 1-2 point change that has been suggested as a minimal clinically important difference,” Dr. Chernew wrote.

MedPAC does not normally comment on Medicare coverage decisions, but did so in this case because of its significance and because of the potential fiscal implications, he noted.

“Though there is only limited, conflicting data on Aduhelm’s clinical effectiveness, Medicare would pay a high price for the product,” Dr. Chernew wrote, pointing out the $28,200 annual U.S. price of the drug.

MedPAC thus endorsed the coverage-with-evidence-development (CED) pathway. Under this approach, Medicare would pay for these drugs when used in clinical trials that meet certain criteria.
 

Legal challenge?

In its comment to CMS, Biogen questioned the agency’s legal grounds for limiting coverage of aducanumab. A mandate on clinical trials as part of the CED proposal “runs afoul of the Administrative Procedure Act’s prohibition against arbitrary and capricious agency action,” Biogen said.

The drug company argued that its own planned follow-on studies would provide the kind of data Medicare officials want to see. It also argued for greater use of observational data, including real-world evidence, and of information from Medicare claims.

Roche’s Genentech, which is also developing antiamyloid drugs for AD, echoed some of Biogen’s concerns about the aducanumab plan.

CMS’ CED plan would be “unnecessarily restrictive and discouraging for patients living with this destructive disease,” David Burt, executive director for federal government affairs at Genentech, wrote in a comment to CMS.

CMS should clarify that the CED requirement would not apply to cases of FDA-approved antiamyloid therapies that have demonstrated “clinically meaningful improvement,” Mr. Burt added. He noted there are phase 3 trials of drugs in this class that could soon produce data.

CMS should “fully consider the broad ramifications and significant unintended consequences of prematurely placing unduly severe restrictions on the entire class of antiamyloid monoclonal antibodies,” Mr. Burt wrote.
 

Health care inequity

In its comment to CMS, Biogen also noted the Medicare proposal would “compound the already pervasive inequities in access to treatment and will ultimately prove highly detrimental to health equity.”

There are already concerns about the access of Black and Latinx patients to clinical trials. The planned CED approach would tightly restrict access to aducanumab, as well as expected follow-ons in the amyloid-directed monoclonal antibody (mAb) drug class, the company said.

“Many of the trial sites for Aduhelm, as well as for other amyloid-directed [monoclonal antibodies] are not hospital-based outpatient settings, but include infusion centers, private practices, and medical research centers,” Biogen wrote.

Patient groups such as UsAgainstAlzheimer’s told CMS the CED approach would worsen disparities, despite the aim of Medicare officials to increase participation of Black and Latinx patients in future testing.

“CMS will be hard-pressed to achieve diversity if such hospitals are the only locations where Medicare beneficiaries are able to access mAbs,” USAgainstAlzheimer’s wrote in a Feb. 10 comment.

In contrast, the nonprofit National Center for Health Research praised CMS for what it described as an effort to address a lack of representation of Black and Latinx patients in earlier aducanumab research.

However, the NCHR also suggested CMS revise its plan to mandate that clinical trials include patients who are representative of the national population diagnosed with AD.

“Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups,” the NCHR wrote.
 

Patient health, Medicare at risk

On Feb. 8, a group of House Republican lawmakers asked CMS to reverse its stance. In a publicly released letter, Rep. Cathy McMorris Rodgers of Washington state, the ranking Republican on the House Energy and Commerce Committee, and colleagues urged broader coverage of aducanumab.

In the letter, the group emphasized the idea of aducanumab as a potential treatment for patients with Down syndrome who are at risk for AD.

“The link between Down Syndrome and AD is still being researched by scientists,” Rep. Rodgers and colleagues wrote.

“However, there appears to be a correlation between the additional 21st chromosome present in people with Down Syndrome and the chromosome’s gene that makes amyloid precursor proteins and can cause a build-up of the beta-amyloid plaques common amongst those with AD,” they add.

On the other hand, CMS garnered earlier support from influential Democrats. On Jan. 13, House Energy and Commerce Chairman Frank Pallone Jr (D-N.J.) and House Oversight and Reform Chairwoman Carolyn B. Maloney (D-N.Y.) released a letter praising CMS for its plan for covering aducanumab.

In addition to the HHS-OIG review of the FDA’s approval of the drug, the two House committees are in the midst of their own investigation of the agency’s decision to clear the drug.

“Any broader coverage determination before there is clarity on Aduhelm’s approval process and findings from the myriad ongoing investigations may put the health of millions of Alzheimer’s patients on the line and the financial stability of the nation’s health insurance program for American seniors at risk,” Rep. Pallone and Rep. Maloney wrote.

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

Medicare has received a key endorsement of its plan to restrict payment for the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) – but also drew pleas from other groups for more generous reimbursement of the drug, as well as expected similar medications currently in development.

The Centers for Medicare & Medicaid Services received more than 9,900 comments on its plan, according to the current tally posted on its website. However, it is unclear when the final count will be available.

CMS intends to limit federal payment for monoclonal antibodies that target amyloid to clinical trials. Among supporters of this approach is the influential Medicare Payment Advisory Commission, an expert panel that helps Congress and CMS manage the federal health program.

Opponents of the CMS plan include several pharmaceutical companies. Patient and consumer groups, individuals, and lawmakers had mixed views.

CMS officials will weigh the feedback provided in the comments when setting a final coverage policy for aducanumab. It is expected the agency’s final decision will be announced on April 11.
 

Ongoing debate

The comments submitted to CMS reflect ongoing debate about whether the evidence proves aducanumab provides significant clinical benefit.

The Food and Drug Administration’s unusual approach to clearing the drug for U.S. sales triggered a review of its management of the accelerated approval process by the Office of Inspector General for the Department of Health & Human Services.

The FDA granted an accelerated approval for aducanumab in June based on evidence that the drug clears amyloid in the brain. However, it is unclear whether clearing the protein from the brain results in clinical benefit.

Usually, accelerated approvals precede the completion of phase 3 drug trials, with the FDA allowing early access to a medicine while awaiting confirmatory trials.

In the case of aducanumab, results of the phase 3 confirmatory trials ENGAGE and EMERGE were available at the time of FDA approval. However, interpretation of the findings is controversial.

Biogen contends that the amyloid-clearing effect of the higher dose of aducanumab shown in EMERGE indicates the drug has clinical potential. However, others argue that amyloid clearance does not indicate clinical benefit.

Limiting Medicare coverage of aducanumab for treatment of AD means “the progression of disease, for nearly all beneficiaries, would continue unabated,” Biogen wrote in its comment to CMS.
 

Conflicting data

Supporters of the CMS plan have a different view of the trial data. They note the failure of aducanumab in the companion ENGAGE trial, while also questioning the magnitude of benefit suggested by even the most positive data cited for the drug in the EMERGE trial.

Both studies used the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, an 18-point scale measuring cognition and function.

In his comment to CMS, MedPAC chairman Michael E. Chernew, PhD, noted the change in CDR-SB score of 0.39 in EMERGE’s high-dose aducanumab group. CMS has described this as being “less than the 1-2 point change that has been suggested as a minimal clinically important difference,” Dr. Chernew wrote.

MedPAC does not normally comment on Medicare coverage decisions, but did so in this case because of its significance and because of the potential fiscal implications, he noted.

“Though there is only limited, conflicting data on Aduhelm’s clinical effectiveness, Medicare would pay a high price for the product,” Dr. Chernew wrote, pointing out the $28,200 annual U.S. price of the drug.

MedPAC thus endorsed the coverage-with-evidence-development (CED) pathway. Under this approach, Medicare would pay for these drugs when used in clinical trials that meet certain criteria.
 

Legal challenge?

In its comment to CMS, Biogen questioned the agency’s legal grounds for limiting coverage of aducanumab. A mandate on clinical trials as part of the CED proposal “runs afoul of the Administrative Procedure Act’s prohibition against arbitrary and capricious agency action,” Biogen said.

The drug company argued that its own planned follow-on studies would provide the kind of data Medicare officials want to see. It also argued for greater use of observational data, including real-world evidence, and of information from Medicare claims.

Roche’s Genentech, which is also developing antiamyloid drugs for AD, echoed some of Biogen’s concerns about the aducanumab plan.

CMS’ CED plan would be “unnecessarily restrictive and discouraging for patients living with this destructive disease,” David Burt, executive director for federal government affairs at Genentech, wrote in a comment to CMS.

CMS should clarify that the CED requirement would not apply to cases of FDA-approved antiamyloid therapies that have demonstrated “clinically meaningful improvement,” Mr. Burt added. He noted there are phase 3 trials of drugs in this class that could soon produce data.

CMS should “fully consider the broad ramifications and significant unintended consequences of prematurely placing unduly severe restrictions on the entire class of antiamyloid monoclonal antibodies,” Mr. Burt wrote.
 

Health care inequity

In its comment to CMS, Biogen also noted the Medicare proposal would “compound the already pervasive inequities in access to treatment and will ultimately prove highly detrimental to health equity.”

There are already concerns about the access of Black and Latinx patients to clinical trials. The planned CED approach would tightly restrict access to aducanumab, as well as expected follow-ons in the amyloid-directed monoclonal antibody (mAb) drug class, the company said.

“Many of the trial sites for Aduhelm, as well as for other amyloid-directed [monoclonal antibodies] are not hospital-based outpatient settings, but include infusion centers, private practices, and medical research centers,” Biogen wrote.

Patient groups such as UsAgainstAlzheimer’s told CMS the CED approach would worsen disparities, despite the aim of Medicare officials to increase participation of Black and Latinx patients in future testing.

“CMS will be hard-pressed to achieve diversity if such hospitals are the only locations where Medicare beneficiaries are able to access mAbs,” USAgainstAlzheimer’s wrote in a Feb. 10 comment.

In contrast, the nonprofit National Center for Health Research praised CMS for what it described as an effort to address a lack of representation of Black and Latinx patients in earlier aducanumab research.

However, the NCHR also suggested CMS revise its plan to mandate that clinical trials include patients who are representative of the national population diagnosed with AD.

“Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups,” the NCHR wrote.
 

Patient health, Medicare at risk

On Feb. 8, a group of House Republican lawmakers asked CMS to reverse its stance. In a publicly released letter, Rep. Cathy McMorris Rodgers of Washington state, the ranking Republican on the House Energy and Commerce Committee, and colleagues urged broader coverage of aducanumab.

In the letter, the group emphasized the idea of aducanumab as a potential treatment for patients with Down syndrome who are at risk for AD.

“The link between Down Syndrome and AD is still being researched by scientists,” Rep. Rodgers and colleagues wrote.

“However, there appears to be a correlation between the additional 21st chromosome present in people with Down Syndrome and the chromosome’s gene that makes amyloid precursor proteins and can cause a build-up of the beta-amyloid plaques common amongst those with AD,” they add.

On the other hand, CMS garnered earlier support from influential Democrats. On Jan. 13, House Energy and Commerce Chairman Frank Pallone Jr (D-N.J.) and House Oversight and Reform Chairwoman Carolyn B. Maloney (D-N.Y.) released a letter praising CMS for its plan for covering aducanumab.

In addition to the HHS-OIG review of the FDA’s approval of the drug, the two House committees are in the midst of their own investigation of the agency’s decision to clear the drug.

“Any broader coverage determination before there is clarity on Aduhelm’s approval process and findings from the myriad ongoing investigations may put the health of millions of Alzheimer’s patients on the line and the financial stability of the nation’s health insurance program for American seniors at risk,” Rep. Pallone and Rep. Maloney wrote.

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

On Feb. 15, Robert Califf, MD, narrowly won Senate confirmation to once again serve as the commissioner of the Food and Drug Administration, overcoming protest votes from lawmakers about abortion and opioid issues.

FDA photo by Michael J. Ermarth

The Senate voted 50-46 in favor of Dr. Califf’s nomination. A cardiologist long affiliated with Duke University and a noted expert on clinical trials, Dr. Califf also led the FDA from February 2016 through January 2017.

In 2016, the Senate confirmed him as FDA chief in an 89-4 vote. At that time, Sen. Joe Manchin, D-WV, and a few other senators said they were concerned that Dr. Califf’s links to the drug industry would hamper his ability to regulate drugmakers, particularly in terms of rules on prescription painkillers.

Sen. Manchin also objected to Dr. Califf’s second nomination as FDA commissioner, as did several fellow Democrats, including Sen. Edward Markey of Massachusetts. In a statement issued after the Feb. 15 vote, Sen. Markey said he has “consistently raised concerns about the FDA’s egregious mishandling of opioid approvals and its role in enabling the current opioid epidemic.”

“To date, the FDA still has not implemented many of the reforms necessary to ensure that it is fulfilling its role as our nation’s top pharmaceutical cop on the beat,” Sen. Markey said. “I have not received any real commitment from Dr. Califf to truly reform the FDA or to learn from the failures that fueled this public health crisis.”

This time, Dr. Califf lost support among Republican senators due to objections raised by groups seeking to end women’s access to abortion. Susan B. Anthony List and National Right to Life asked senators in a January letter to oppose Dr. Califf’s nomination, citing their objections to how the FDA handled reporting of adverse events from abortions by medication during Dr. Califf’s Tenure.

But some Republicans supported Califf in the Tuesday vote. Sens. Roy Blunt of Missouri, Richard Burr of North Carolina, Susan Collins of Maine, Lisa Murkowski of Alaska, Mitt Romney of Utah, and Pat Toomey of Pennsylvania all voted in his favor.

On Feb. 14, Sen. Patty Murray, D-WA, chairwoman of the Senate Health, Education, Labor, and Pensions Committee, urged her colleagues to vote for Dr. Califf to give the FDA strong leadership to tackle urgent health needs such as the opioid crisis, youth tobacco use, antimicrobial resistance, and inequities in health care.

“At this critical moment, we need a trusted hand to lead the FDA,” she said in a floor speech. Dr. Califf’s previous service at the FDA and his years spent as a research scientist “give him the experience to take on this challenge.”

Separately, three former FDA commissioners on Feb. 15 published an opinion article that appeared in The Hill. Republican presidents nominated two of these former FDA chiefs: Scott Gottlieb, MD, and Mark McClellan, MD. The third, Margaret Hamburg, MD, was nominated by President Barack Obama, as was Dr. Califf for his first time as FDA chief.

There’s an urgent need for a confirmed leader at the FDA as the United States seeks to move beyond the pandemic, the former FDA chiefs wrote. The work ahead includes continued efforts with vaccines as well as efforts to bolster medical supply chains, they said.

Dr. Califf “knows how to advance the safe development and use of medical products and to bring a sound, science-based foundation to the FDA’s regulatory actions. Because of this, he has earned the confidence of FDA’s professional career staff, as well as a broad base of patient groups, academic experts, medical professionals, and public health organizations,” Dr. Gottlieb, Dr. Hamburg, and Dr. McClellan wrote.

The article also was signed by former Centers for Medicare and Medicaid Services Administrator Andy Slavitt, who served in the Obama administration.
 

Support of medical community

The American Heart Association issued a statement on Feb.15, congratulating Dr. Califf on his second confirmation after the Senate vote.

“With a distinguished career in public service and a long-time volunteer leader at the American Heart Association, Dr. Califf has honed his ability to communicate and build trust with diverse constituencies,” CEO Nancy Brown said in the statement. “He will use his experience as a cardiologist to safeguard the health and well-being of people throughout the country, and his background in research to prioritize science and evidence-based policymaking.”

Dr. Califf was also backed by the Association of American Medical Colleges, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American College of Physicians when he was nominated for the role last year by President Joe Biden.

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

On Feb. 15, Robert Califf, MD, narrowly won Senate confirmation to once again serve as the commissioner of the Food and Drug Administration, overcoming protest votes from lawmakers about abortion and opioid issues.

FDA photo by Michael J. Ermarth

The Senate voted 50-46 in favor of Dr. Califf’s nomination. A cardiologist long affiliated with Duke University and a noted expert on clinical trials, Dr. Califf also led the FDA from February 2016 through January 2017.

In 2016, the Senate confirmed him as FDA chief in an 89-4 vote. At that time, Sen. Joe Manchin, D-WV, and a few other senators said they were concerned that Dr. Califf’s links to the drug industry would hamper his ability to regulate drugmakers, particularly in terms of rules on prescription painkillers.

Sen. Manchin also objected to Dr. Califf’s second nomination as FDA commissioner, as did several fellow Democrats, including Sen. Edward Markey of Massachusetts. In a statement issued after the Feb. 15 vote, Sen. Markey said he has “consistently raised concerns about the FDA’s egregious mishandling of opioid approvals and its role in enabling the current opioid epidemic.”

“To date, the FDA still has not implemented many of the reforms necessary to ensure that it is fulfilling its role as our nation’s top pharmaceutical cop on the beat,” Sen. Markey said. “I have not received any real commitment from Dr. Califf to truly reform the FDA or to learn from the failures that fueled this public health crisis.”

This time, Dr. Califf lost support among Republican senators due to objections raised by groups seeking to end women’s access to abortion. Susan B. Anthony List and National Right to Life asked senators in a January letter to oppose Dr. Califf’s nomination, citing their objections to how the FDA handled reporting of adverse events from abortions by medication during Dr. Califf’s Tenure.

But some Republicans supported Califf in the Tuesday vote. Sens. Roy Blunt of Missouri, Richard Burr of North Carolina, Susan Collins of Maine, Lisa Murkowski of Alaska, Mitt Romney of Utah, and Pat Toomey of Pennsylvania all voted in his favor.

On Feb. 14, Sen. Patty Murray, D-WA, chairwoman of the Senate Health, Education, Labor, and Pensions Committee, urged her colleagues to vote for Dr. Califf to give the FDA strong leadership to tackle urgent health needs such as the opioid crisis, youth tobacco use, antimicrobial resistance, and inequities in health care.

“At this critical moment, we need a trusted hand to lead the FDA,” she said in a floor speech. Dr. Califf’s previous service at the FDA and his years spent as a research scientist “give him the experience to take on this challenge.”

Separately, three former FDA commissioners on Feb. 15 published an opinion article that appeared in The Hill. Republican presidents nominated two of these former FDA chiefs: Scott Gottlieb, MD, and Mark McClellan, MD. The third, Margaret Hamburg, MD, was nominated by President Barack Obama, as was Dr. Califf for his first time as FDA chief.

There’s an urgent need for a confirmed leader at the FDA as the United States seeks to move beyond the pandemic, the former FDA chiefs wrote. The work ahead includes continued efforts with vaccines as well as efforts to bolster medical supply chains, they said.

Dr. Califf “knows how to advance the safe development and use of medical products and to bring a sound, science-based foundation to the FDA’s regulatory actions. Because of this, he has earned the confidence of FDA’s professional career staff, as well as a broad base of patient groups, academic experts, medical professionals, and public health organizations,” Dr. Gottlieb, Dr. Hamburg, and Dr. McClellan wrote.

The article also was signed by former Centers for Medicare and Medicaid Services Administrator Andy Slavitt, who served in the Obama administration.
 

Support of medical community

The American Heart Association issued a statement on Feb.15, congratulating Dr. Califf on his second confirmation after the Senate vote.

“With a distinguished career in public service and a long-time volunteer leader at the American Heart Association, Dr. Califf has honed his ability to communicate and build trust with diverse constituencies,” CEO Nancy Brown said in the statement. “He will use his experience as a cardiologist to safeguard the health and well-being of people throughout the country, and his background in research to prioritize science and evidence-based policymaking.”

Dr. Califf was also backed by the Association of American Medical Colleges, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American College of Physicians when he was nominated for the role last year by President Joe Biden.

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

On Feb. 15, Robert Califf, MD, narrowly won Senate confirmation to once again serve as the commissioner of the Food and Drug Administration, overcoming protest votes from lawmakers about abortion and opioid issues.

FDA photo by Michael J. Ermarth

The Senate voted 50-46 in favor of Dr. Califf’s nomination. A cardiologist long affiliated with Duke University and a noted expert on clinical trials, Dr. Califf also led the FDA from February 2016 through January 2017.

In 2016, the Senate confirmed him as FDA chief in an 89-4 vote. At that time, Sen. Joe Manchin, D-WV, and a few other senators said they were concerned that Dr. Califf’s links to the drug industry would hamper his ability to regulate drugmakers, particularly in terms of rules on prescription painkillers.

Sen. Manchin also objected to Dr. Califf’s second nomination as FDA commissioner, as did several fellow Democrats, including Sen. Edward Markey of Massachusetts. In a statement issued after the Feb. 15 vote, Sen. Markey said he has “consistently raised concerns about the FDA’s egregious mishandling of opioid approvals and its role in enabling the current opioid epidemic.”

“To date, the FDA still has not implemented many of the reforms necessary to ensure that it is fulfilling its role as our nation’s top pharmaceutical cop on the beat,” Sen. Markey said. “I have not received any real commitment from Dr. Califf to truly reform the FDA or to learn from the failures that fueled this public health crisis.”

This time, Dr. Califf lost support among Republican senators due to objections raised by groups seeking to end women’s access to abortion. Susan B. Anthony List and National Right to Life asked senators in a January letter to oppose Dr. Califf’s nomination, citing their objections to how the FDA handled reporting of adverse events from abortions by medication during Dr. Califf’s Tenure.

But some Republicans supported Califf in the Tuesday vote. Sens. Roy Blunt of Missouri, Richard Burr of North Carolina, Susan Collins of Maine, Lisa Murkowski of Alaska, Mitt Romney of Utah, and Pat Toomey of Pennsylvania all voted in his favor.

On Feb. 14, Sen. Patty Murray, D-WA, chairwoman of the Senate Health, Education, Labor, and Pensions Committee, urged her colleagues to vote for Dr. Califf to give the FDA strong leadership to tackle urgent health needs such as the opioid crisis, youth tobacco use, antimicrobial resistance, and inequities in health care.

“At this critical moment, we need a trusted hand to lead the FDA,” she said in a floor speech. Dr. Califf’s previous service at the FDA and his years spent as a research scientist “give him the experience to take on this challenge.”

Separately, three former FDA commissioners on Feb. 15 published an opinion article that appeared in The Hill. Republican presidents nominated two of these former FDA chiefs: Scott Gottlieb, MD, and Mark McClellan, MD. The third, Margaret Hamburg, MD, was nominated by President Barack Obama, as was Dr. Califf for his first time as FDA chief.

There’s an urgent need for a confirmed leader at the FDA as the United States seeks to move beyond the pandemic, the former FDA chiefs wrote. The work ahead includes continued efforts with vaccines as well as efforts to bolster medical supply chains, they said.

Dr. Califf “knows how to advance the safe development and use of medical products and to bring a sound, science-based foundation to the FDA’s regulatory actions. Because of this, he has earned the confidence of FDA’s professional career staff, as well as a broad base of patient groups, academic experts, medical professionals, and public health organizations,” Dr. Gottlieb, Dr. Hamburg, and Dr. McClellan wrote.

The article also was signed by former Centers for Medicare and Medicaid Services Administrator Andy Slavitt, who served in the Obama administration.
 

Support of medical community

The American Heart Association issued a statement on Feb.15, congratulating Dr. Califf on his second confirmation after the Senate vote.

“With a distinguished career in public service and a long-time volunteer leader at the American Heart Association, Dr. Califf has honed his ability to communicate and build trust with diverse constituencies,” CEO Nancy Brown said in the statement. “He will use his experience as a cardiologist to safeguard the health and well-being of people throughout the country, and his background in research to prioritize science and evidence-based policymaking.”

Dr. Califf was also backed by the Association of American Medical Colleges, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American College of Physicians when he was nominated for the role last year by President Joe Biden.

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

Statin intolerance is far less common than previously reported, according to a new meta-analysis, with data on more than 4 million adults from around the world, looking at reported statin adverse effects.

The study puts the prevalence of statin intolerance at 6% to 10%, meaning that statin intolerance is “overestimated and overdiagnosed” in most cases, Maciej Banach, MD, PhD, from the Medical University of Lodz and the University of Zielona Góra, Poland, said in a news release.

It also means that “around 93% of patients on statin therapy can be treated effectively, with very good tolerability and without any safety issues,” Dr. Banach added.

The study, conducted on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration and the International Lipid Expert Panel, was published online Feb. 16 in the European Heart Journal.
 

Reassuring data

In a statement from the British nonprofit Science Media Center, Sir Nilesh J. Samani, MBChB, MD, medical director of the British Heart Foundation, said: “Decades of evidence have proven that statins save lives. This latest analysis, showing that the risk of side effects from statins are less than previously thought, should provide reassurance to those who are recommended this medicine to reduce their risk of a heart attack or stroke.”

The reported prevalence of statin intolerance varies widely, from 2% to 3% to as high as 50%, chiefly because “there is still a lack of a clear and easy way to apply the definition of statin intolerance,” Dr. Banach told this news organization.

“The ones we use in lipid clinics – by National Lipid Association (NLA), European Atherosclerosis Society (EAS), and International Lipid Expert Panel (ILEP) – are not used or are rarely used in everyday clinical practice by GPs and other specialists,” Dr. Banach explained.

He also blames “physician inertia: When they listen to a patient complain of muscle pain, or see elevated alanine aminotransferase (ALT), in most of the cases, they will immediately discontinue statins, without any further investigations. One should remember that there are many secondary causes of statin intolerance,” Dr. Banach said.

To get a better handle on the true prevalence of statin intolerance, the study team did a meta-analysis of 4,143,517 patients worldwide from 176 studies: 112 randomized controlled trials and 64 cohort studies.

The overall prevalence of statin intolerance was 9.1% (95% confidence interval, 8.0%-10.0%).

The prevalence of statin intolerance was even lower when assessed with diagnostic criteria from the NLA (7.0%; 95% CI, 6.0%-8.0%), the ILEP (6.7%; 95% CI, 5.0%-8.0%), and the EAS (5.9%; 95% CI, 4.0%-7.0%).

The main factors associated with an increased risk for statin intolerance are female gender, hypothyroidism, high statin dose, advanced age, concomitant use of anti-arrhythmic drugs, and obesity. Other factors include race (being Asian or African American), type 2 diabetes, alcohol use, and chronic liver and renal diseases.

“Our findings mean that we should evaluate patients’ symptoms very carefully, firstly to see whether symptoms are indeed caused by statins, and secondly to evaluate whether it might be patients’ perceptions that statins are harmful – so called nocebo or drucebo effect – which could be responsible for more than 50% of all symptoms, rather than the drug itself,” Dr. Banach said.

He encourages use of the Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) to assess the likelihood that a patient’s muscle symptoms are caused or worsened by statin use.

Substantial analysis, valid results

“This is a substantial analysis [and], based on what we know about statin side effects to date, the results are likely to be broadly valid and indicate that we should not overestimate statin side effects or be too quick to stop statins without due consideration,” Riyaz Patel, MBBS, professor of cardiology, University College London, told the Science Media Center.

“Some patients do experience real side effects, and we do our best to help them with alternative therapies, as with any other medicine. However, for the vast majority of people experiencing statin side effects, we can usually work with the patient to understand the symptoms, use proven strategies to manage these, and ensure they do not miss out on the well-established benefits of statins,” Mr. Patel said.

“This is especially important for people who have already had a heart attack or stroke, where statin therapy is really important in preventing further events,” Mr. Patel added.

Also weighing in on the results, Peter Sever, MB BChir, professor of clinical pharmacology and therapeutics, Imperial College London, said: “The importance for clinicians and patients is to realize that commonly reported symptoms, such as muscle aches and pains and lethargy, are not due to the chemistry of the drug.”

“These ‘nocebo’ symptoms may be psychological in origin, but they are no less real than pharmacological symptoms in how they affect quality of life,” Mr. Sever told the Science Media Center.

“However, it’s important to note that as they are not directly caused by the drug, they should not override the decision to prescribe and take statins on account of their proven benefit in reducing death and disability from heart attacks, strokes, and other cardiovascular conditions,” he added.

This meta-analysis was conducted independently; no company or institution supported it financially. Dr. Banach is on the speakers bureau for Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo Nordisk, Sanofi-Aventis, Teva, and Zentiva; is a consultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion, FreiaPharmaceuticals, Novartis, Polfarmex, and Sanofi-Aventis; has received grants from Amgen, Mylan/Viatris, Sanofi, and Valeant; and serves as CMO for Nomi Biotech Corporation. Dr. Samani has no relevant disclosures. Mr. Patel has received past honoraria and consulting fees from drug companies manufacturing new cholesterol-lowering drugs and currently works with NICE as a topic advisor for CVD prevention. Mr. Sever has received research grants and consultancy from Pfizer and Amgen.

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

Statin intolerance is far less common than previously reported, according to a new meta-analysis, with data on more than 4 million adults from around the world, looking at reported statin adverse effects.

The study puts the prevalence of statin intolerance at 6% to 10%, meaning that statin intolerance is “overestimated and overdiagnosed” in most cases, Maciej Banach, MD, PhD, from the Medical University of Lodz and the University of Zielona Góra, Poland, said in a news release.

It also means that “around 93% of patients on statin therapy can be treated effectively, with very good tolerability and without any safety issues,” Dr. Banach added.

The study, conducted on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration and the International Lipid Expert Panel, was published online Feb. 16 in the European Heart Journal.
 

Reassuring data

In a statement from the British nonprofit Science Media Center, Sir Nilesh J. Samani, MBChB, MD, medical director of the British Heart Foundation, said: “Decades of evidence have proven that statins save lives. This latest analysis, showing that the risk of side effects from statins are less than previously thought, should provide reassurance to those who are recommended this medicine to reduce their risk of a heart attack or stroke.”

The reported prevalence of statin intolerance varies widely, from 2% to 3% to as high as 50%, chiefly because “there is still a lack of a clear and easy way to apply the definition of statin intolerance,” Dr. Banach told this news organization.

“The ones we use in lipid clinics – by National Lipid Association (NLA), European Atherosclerosis Society (EAS), and International Lipid Expert Panel (ILEP) – are not used or are rarely used in everyday clinical practice by GPs and other specialists,” Dr. Banach explained.

He also blames “physician inertia: When they listen to a patient complain of muscle pain, or see elevated alanine aminotransferase (ALT), in most of the cases, they will immediately discontinue statins, without any further investigations. One should remember that there are many secondary causes of statin intolerance,” Dr. Banach said.

To get a better handle on the true prevalence of statin intolerance, the study team did a meta-analysis of 4,143,517 patients worldwide from 176 studies: 112 randomized controlled trials and 64 cohort studies.

The overall prevalence of statin intolerance was 9.1% (95% confidence interval, 8.0%-10.0%).

The prevalence of statin intolerance was even lower when assessed with diagnostic criteria from the NLA (7.0%; 95% CI, 6.0%-8.0%), the ILEP (6.7%; 95% CI, 5.0%-8.0%), and the EAS (5.9%; 95% CI, 4.0%-7.0%).

The main factors associated with an increased risk for statin intolerance are female gender, hypothyroidism, high statin dose, advanced age, concomitant use of anti-arrhythmic drugs, and obesity. Other factors include race (being Asian or African American), type 2 diabetes, alcohol use, and chronic liver and renal diseases.

“Our findings mean that we should evaluate patients’ symptoms very carefully, firstly to see whether symptoms are indeed caused by statins, and secondly to evaluate whether it might be patients’ perceptions that statins are harmful – so called nocebo or drucebo effect – which could be responsible for more than 50% of all symptoms, rather than the drug itself,” Dr. Banach said.

He encourages use of the Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) to assess the likelihood that a patient’s muscle symptoms are caused or worsened by statin use.

Substantial analysis, valid results

“This is a substantial analysis [and], based on what we know about statin side effects to date, the results are likely to be broadly valid and indicate that we should not overestimate statin side effects or be too quick to stop statins without due consideration,” Riyaz Patel, MBBS, professor of cardiology, University College London, told the Science Media Center.

“Some patients do experience real side effects, and we do our best to help them with alternative therapies, as with any other medicine. However, for the vast majority of people experiencing statin side effects, we can usually work with the patient to understand the symptoms, use proven strategies to manage these, and ensure they do not miss out on the well-established benefits of statins,” Mr. Patel said.

“This is especially important for people who have already had a heart attack or stroke, where statin therapy is really important in preventing further events,” Mr. Patel added.

Also weighing in on the results, Peter Sever, MB BChir, professor of clinical pharmacology and therapeutics, Imperial College London, said: “The importance for clinicians and patients is to realize that commonly reported symptoms, such as muscle aches and pains and lethargy, are not due to the chemistry of the drug.”

“These ‘nocebo’ symptoms may be psychological in origin, but they are no less real than pharmacological symptoms in how they affect quality of life,” Mr. Sever told the Science Media Center.

“However, it’s important to note that as they are not directly caused by the drug, they should not override the decision to prescribe and take statins on account of their proven benefit in reducing death and disability from heart attacks, strokes, and other cardiovascular conditions,” he added.

This meta-analysis was conducted independently; no company or institution supported it financially. Dr. Banach is on the speakers bureau for Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo Nordisk, Sanofi-Aventis, Teva, and Zentiva; is a consultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion, FreiaPharmaceuticals, Novartis, Polfarmex, and Sanofi-Aventis; has received grants from Amgen, Mylan/Viatris, Sanofi, and Valeant; and serves as CMO for Nomi Biotech Corporation. Dr. Samani has no relevant disclosures. Mr. Patel has received past honoraria and consulting fees from drug companies manufacturing new cholesterol-lowering drugs and currently works with NICE as a topic advisor for CVD prevention. Mr. Sever has received research grants and consultancy from Pfizer and Amgen.

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

Statin intolerance is far less common than previously reported, according to a new meta-analysis, with data on more than 4 million adults from around the world, looking at reported statin adverse effects.

The study puts the prevalence of statin intolerance at 6% to 10%, meaning that statin intolerance is “overestimated and overdiagnosed” in most cases, Maciej Banach, MD, PhD, from the Medical University of Lodz and the University of Zielona Góra, Poland, said in a news release.

It also means that “around 93% of patients on statin therapy can be treated effectively, with very good tolerability and without any safety issues,” Dr. Banach added.

The study, conducted on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration and the International Lipid Expert Panel, was published online Feb. 16 in the European Heart Journal.
 

Reassuring data

In a statement from the British nonprofit Science Media Center, Sir Nilesh J. Samani, MBChB, MD, medical director of the British Heart Foundation, said: “Decades of evidence have proven that statins save lives. This latest analysis, showing that the risk of side effects from statins are less than previously thought, should provide reassurance to those who are recommended this medicine to reduce their risk of a heart attack or stroke.”

The reported prevalence of statin intolerance varies widely, from 2% to 3% to as high as 50%, chiefly because “there is still a lack of a clear and easy way to apply the definition of statin intolerance,” Dr. Banach told this news organization.

“The ones we use in lipid clinics – by National Lipid Association (NLA), European Atherosclerosis Society (EAS), and International Lipid Expert Panel (ILEP) – are not used or are rarely used in everyday clinical practice by GPs and other specialists,” Dr. Banach explained.

He also blames “physician inertia: When they listen to a patient complain of muscle pain, or see elevated alanine aminotransferase (ALT), in most of the cases, they will immediately discontinue statins, without any further investigations. One should remember that there are many secondary causes of statin intolerance,” Dr. Banach said.

To get a better handle on the true prevalence of statin intolerance, the study team did a meta-analysis of 4,143,517 patients worldwide from 176 studies: 112 randomized controlled trials and 64 cohort studies.

The overall prevalence of statin intolerance was 9.1% (95% confidence interval, 8.0%-10.0%).

The prevalence of statin intolerance was even lower when assessed with diagnostic criteria from the NLA (7.0%; 95% CI, 6.0%-8.0%), the ILEP (6.7%; 95% CI, 5.0%-8.0%), and the EAS (5.9%; 95% CI, 4.0%-7.0%).

The main factors associated with an increased risk for statin intolerance are female gender, hypothyroidism, high statin dose, advanced age, concomitant use of anti-arrhythmic drugs, and obesity. Other factors include race (being Asian or African American), type 2 diabetes, alcohol use, and chronic liver and renal diseases.

“Our findings mean that we should evaluate patients’ symptoms very carefully, firstly to see whether symptoms are indeed caused by statins, and secondly to evaluate whether it might be patients’ perceptions that statins are harmful – so called nocebo or drucebo effect – which could be responsible for more than 50% of all symptoms, rather than the drug itself,” Dr. Banach said.

He encourages use of the Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) to assess the likelihood that a patient’s muscle symptoms are caused or worsened by statin use.

Substantial analysis, valid results

“This is a substantial analysis [and], based on what we know about statin side effects to date, the results are likely to be broadly valid and indicate that we should not overestimate statin side effects or be too quick to stop statins without due consideration,” Riyaz Patel, MBBS, professor of cardiology, University College London, told the Science Media Center.

“Some patients do experience real side effects, and we do our best to help them with alternative therapies, as with any other medicine. However, for the vast majority of people experiencing statin side effects, we can usually work with the patient to understand the symptoms, use proven strategies to manage these, and ensure they do not miss out on the well-established benefits of statins,” Mr. Patel said.

“This is especially important for people who have already had a heart attack or stroke, where statin therapy is really important in preventing further events,” Mr. Patel added.

Also weighing in on the results, Peter Sever, MB BChir, professor of clinical pharmacology and therapeutics, Imperial College London, said: “The importance for clinicians and patients is to realize that commonly reported symptoms, such as muscle aches and pains and lethargy, are not due to the chemistry of the drug.”

“These ‘nocebo’ symptoms may be psychological in origin, but they are no less real than pharmacological symptoms in how they affect quality of life,” Mr. Sever told the Science Media Center.

“However, it’s important to note that as they are not directly caused by the drug, they should not override the decision to prescribe and take statins on account of their proven benefit in reducing death and disability from heart attacks, strokes, and other cardiovascular conditions,” he added.

This meta-analysis was conducted independently; no company or institution supported it financially. Dr. Banach is on the speakers bureau for Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo Nordisk, Sanofi-Aventis, Teva, and Zentiva; is a consultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion, FreiaPharmaceuticals, Novartis, Polfarmex, and Sanofi-Aventis; has received grants from Amgen, Mylan/Viatris, Sanofi, and Valeant; and serves as CMO for Nomi Biotech Corporation. Dr. Samani has no relevant disclosures. Mr. Patel has received past honoraria and consulting fees from drug companies manufacturing new cholesterol-lowering drugs and currently works with NICE as a topic advisor for CVD prevention. Mr. Sever has received research grants and consultancy from Pfizer and Amgen.

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

The vitamin D story exudes teaching points: It offers a master class in critical appraisal, connecting the concepts of biologic plausibility, flawed surrogate markers, confounded observational studies, and slews of randomized controlled trials (RCTs) showing no benefits on health outcomes.

Yet despite the utter lack of benefit seen in trials, the hype continues. And the pandemic has only enhanced this hype as an onslaught of papers have reported the association of low vitamin D levels and COVID-19 disease.

My questions are simple: Why doesn’t the evidence persuade people? How many nonsignificant trials do we need before researchers stop studying vitamin D, doctors stop (routinely) measuring levels, and patients stop wasting money on the unhelpful supplement? What are the implications for this lack of persuasion?

Before exploring these questions, I want to set out that symptomatic vitamin deficiencies of any sort ought to be corrected. 
 

Biologic plausibility and the pull of observational studies

It has long been known that vitamin D is crucial for bone health and that it can be produced in the skin with sun exposure. In the last decade, however, experts note that nearly every tissue and cell in our body has a vitamin D receptor. It then follows that if this many cells in the body can activate vitamin D, it must be vital for cardiovascular health, immune function, cancer prevention: basically, everything health related.

Oodles of observational studies have found that low serum levels of vitamin D correlate with higher mortality from all causes, cancer, cardiovascular disease, and now even COVID-19. Yet no matter the amount of statistical adjustment in these studies, we cannot know whether these associations are due to true causality.

The major issue is confounding: That is, people with low vitamin D levels have other conditions or diseases that lead to higher rates of ill health. Consider a patient with obesity, arthritis, and cognitive decline; this person is unlikely to do much exercise in the sun and may have low vitamin D levels. The low vitamin D level is simply a marker of overall poor health.
 

The randomized controlled trials tell a clear story

There are hundreds of vitamin D RCTs. The results simplify into one sentence: Vitamin D supplements do not improve health outcomes.

Here is a short summary of some recent studies.

VITAL, a massive (N > 25,000) RCT with 5 years of follow-up, compared vitamin D supplements to placebo and found no differences in the primary endpoints of cancer or cardiac events. Rates of death from any cause were nearly identical. Crucially, in subgroup analyses, the effects did not vary according to vitamin D levels at baseline.

The D-Health investigators randomly assigned more than 21,000 adults to vitamin D or placebo and after 5.7 years of follow-up reported no differences in the primary endpoint of overall mortality. There also were no differences in cardiovascular disease mortality.

Then you have the Mendelian randomized studies, which some have called nature’s RCT. These studies take advantage of the fact that some people are born with gene variations that predispose to low vitamin D levels. More than 60 Mendelian randomization studies have evaluated the consequences of lifelong genetically lowered vitamin D levels on various outcomes; most of these have found null effects.

Then there are the meta-analyses and systematic reviews. I loved the conclusion of this review of systematic reviews from the BMJ (emphasis mine):

“Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.”

 

The failure to persuade

My original plan was to emphasize the power of the RCT. Despite strong associations of low vitamin D levels with poor outcomes, the trials show no benefit to treatment. This strongly suggests (or nearly proves) that low vitamin D levels are akin to premature ventricular complexes after myocardial infarction: a marker for risk but not a target for therapy.

But I now see the more important issue as why scientists, funders, clinicians, and patients are not persuaded by clear evidence. Every day in clinic I see patients on vitamin D supplements; the journals keep publishing vitamin D studies. The proponents of vitamin D remain positive. And lately there is outsized attention and hope that vitamin D will mitigate SARS-CoV2 infection – based only on observational data.

You might argue against this point by saying vitamin D is natural and relatively innocuous, so who cares?

I offer three rebuttals to that point: Opportunity costs, distraction, and the insidious danger of poor critical appraisal skills. If you are burning money on vitamin D research, there is less available to study other important issues. If a patient is distracted by low vitamin D levels, she may pay less attention to her high body mass index or hypertension. And on the matter of critical appraisal, trust in medicine requires clinicians to be competent in critical appraisal. And these days, what could be more important than trust in medical professionals?

One major reason for the failure of persuasion of evidence is spin – or language that distracts from the primary endpoint. Here are two (of many) examples:

A meta-analysis of 50 vitamin D trials set out to study mortality. The authors found no significant difference in that primary endpoint. But the second sentence in their conclusion was that vitamin D supplements reduced the risk for cancer deaths by 15%. That’s a secondary endpoint in a study with nonsignificance in the primary endpoint. That is spin. This meta-analysis was completed before the Australian D-Health trial found that cancer deaths were 15% higher in the vitamin D arm, a difference that did not reach statistical significance.

The following example is worse: The authors of the VITAL trial, which found that vitamin D supplements had no effect on the primary endpoint of invasive cancer or cardiovascular disease, published a secondary analysis of the trial looking at a different endpoint: A composite incidence of metastatic and fatal invasive total cancer. They reported a 0.4% lower rate for the vitamin D group, a difference that barely made statistical significance at a P value of .04. 

But everyone knows the dangers of reanalyzing data with a new endpoint after you have seen the data. What’s more, even if this were a reasonable post hoc analysis, the results are neither clinically meaningful nor statistically robust.  Yet the fatally flawed paper has been viewed 60,000 times and picked up by 48 news outlets.

Another way to distract from nonsignificant primary outcomes is to nitpick the trials. The vitamin D dose wasn’t high enough, for instance. This might persuade me if there were one or two vitamin D trials, but there are hundreds of trials and meta-analyses, and their results are consistently null.
 

Conclusion: No, it is not hopeless

A nihilist would argue that fighting spin is futile. They would say you can’t fight incentives and business models. The incentive structure to publish is strong, and the journals and media know vitamin D studies garner attention – which is their currency.

I am not a nihilist and believe strongly that we must continue to teach critical appraisal and numerical literacy.

In fact, I would speculate that decades of poor critical appraisal by the medical profession have fostered outsized hope and created erroneous norms.

Imagine a counter-factual world in which clinicians have taught society that the human body is unlike an engine that can be repaired by fixing one part (i.e., the vitamin D level), that magic bullets (insulin) are rare, that most treatments fail, or that you can’t rely on association studies to prove efficacy.

In this world, people would be immune from spin and hype.

The norm would be that pills, supplements, and procedures are not what delivers good health. What delivers health is an amalgam of good luck, healthy habits, and lots of time spent outside playing in the sun.
 

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

The vitamin D story exudes teaching points: It offers a master class in critical appraisal, connecting the concepts of biologic plausibility, flawed surrogate markers, confounded observational studies, and slews of randomized controlled trials (RCTs) showing no benefits on health outcomes.

Yet despite the utter lack of benefit seen in trials, the hype continues. And the pandemic has only enhanced this hype as an onslaught of papers have reported the association of low vitamin D levels and COVID-19 disease.

My questions are simple: Why doesn’t the evidence persuade people? How many nonsignificant trials do we need before researchers stop studying vitamin D, doctors stop (routinely) measuring levels, and patients stop wasting money on the unhelpful supplement? What are the implications for this lack of persuasion?

Before exploring these questions, I want to set out that symptomatic vitamin deficiencies of any sort ought to be corrected. 
 

Biologic plausibility and the pull of observational studies

It has long been known that vitamin D is crucial for bone health and that it can be produced in the skin with sun exposure. In the last decade, however, experts note that nearly every tissue and cell in our body has a vitamin D receptor. It then follows that if this many cells in the body can activate vitamin D, it must be vital for cardiovascular health, immune function, cancer prevention: basically, everything health related.

Oodles of observational studies have found that low serum levels of vitamin D correlate with higher mortality from all causes, cancer, cardiovascular disease, and now even COVID-19. Yet no matter the amount of statistical adjustment in these studies, we cannot know whether these associations are due to true causality.

The major issue is confounding: That is, people with low vitamin D levels have other conditions or diseases that lead to higher rates of ill health. Consider a patient with obesity, arthritis, and cognitive decline; this person is unlikely to do much exercise in the sun and may have low vitamin D levels. The low vitamin D level is simply a marker of overall poor health.
 

The randomized controlled trials tell a clear story

There are hundreds of vitamin D RCTs. The results simplify into one sentence: Vitamin D supplements do not improve health outcomes.

Here is a short summary of some recent studies.

VITAL, a massive (N > 25,000) RCT with 5 years of follow-up, compared vitamin D supplements to placebo and found no differences in the primary endpoints of cancer or cardiac events. Rates of death from any cause were nearly identical. Crucially, in subgroup analyses, the effects did not vary according to vitamin D levels at baseline.

The D-Health investigators randomly assigned more than 21,000 adults to vitamin D or placebo and after 5.7 years of follow-up reported no differences in the primary endpoint of overall mortality. There also were no differences in cardiovascular disease mortality.

Then you have the Mendelian randomized studies, which some have called nature’s RCT. These studies take advantage of the fact that some people are born with gene variations that predispose to low vitamin D levels. More than 60 Mendelian randomization studies have evaluated the consequences of lifelong genetically lowered vitamin D levels on various outcomes; most of these have found null effects.

Then there are the meta-analyses and systematic reviews. I loved the conclusion of this review of systematic reviews from the BMJ (emphasis mine):

“Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.”

 

The failure to persuade

My original plan was to emphasize the power of the RCT. Despite strong associations of low vitamin D levels with poor outcomes, the trials show no benefit to treatment. This strongly suggests (or nearly proves) that low vitamin D levels are akin to premature ventricular complexes after myocardial infarction: a marker for risk but not a target for therapy.

But I now see the more important issue as why scientists, funders, clinicians, and patients are not persuaded by clear evidence. Every day in clinic I see patients on vitamin D supplements; the journals keep publishing vitamin D studies. The proponents of vitamin D remain positive. And lately there is outsized attention and hope that vitamin D will mitigate SARS-CoV2 infection – based only on observational data.

You might argue against this point by saying vitamin D is natural and relatively innocuous, so who cares?

I offer three rebuttals to that point: Opportunity costs, distraction, and the insidious danger of poor critical appraisal skills. If you are burning money on vitamin D research, there is less available to study other important issues. If a patient is distracted by low vitamin D levels, she may pay less attention to her high body mass index or hypertension. And on the matter of critical appraisal, trust in medicine requires clinicians to be competent in critical appraisal. And these days, what could be more important than trust in medical professionals?

One major reason for the failure of persuasion of evidence is spin – or language that distracts from the primary endpoint. Here are two (of many) examples:

A meta-analysis of 50 vitamin D trials set out to study mortality. The authors found no significant difference in that primary endpoint. But the second sentence in their conclusion was that vitamin D supplements reduced the risk for cancer deaths by 15%. That’s a secondary endpoint in a study with nonsignificance in the primary endpoint. That is spin. This meta-analysis was completed before the Australian D-Health trial found that cancer deaths were 15% higher in the vitamin D arm, a difference that did not reach statistical significance.

The following example is worse: The authors of the VITAL trial, which found that vitamin D supplements had no effect on the primary endpoint of invasive cancer or cardiovascular disease, published a secondary analysis of the trial looking at a different endpoint: A composite incidence of metastatic and fatal invasive total cancer. They reported a 0.4% lower rate for the vitamin D group, a difference that barely made statistical significance at a P value of .04. 

But everyone knows the dangers of reanalyzing data with a new endpoint after you have seen the data. What’s more, even if this were a reasonable post hoc analysis, the results are neither clinically meaningful nor statistically robust.  Yet the fatally flawed paper has been viewed 60,000 times and picked up by 48 news outlets.

Another way to distract from nonsignificant primary outcomes is to nitpick the trials. The vitamin D dose wasn’t high enough, for instance. This might persuade me if there were one or two vitamin D trials, but there are hundreds of trials and meta-analyses, and their results are consistently null.
 

Conclusion: No, it is not hopeless

A nihilist would argue that fighting spin is futile. They would say you can’t fight incentives and business models. The incentive structure to publish is strong, and the journals and media know vitamin D studies garner attention – which is their currency.

I am not a nihilist and believe strongly that we must continue to teach critical appraisal and numerical literacy.

In fact, I would speculate that decades of poor critical appraisal by the medical profession have fostered outsized hope and created erroneous norms.

Imagine a counter-factual world in which clinicians have taught society that the human body is unlike an engine that can be repaired by fixing one part (i.e., the vitamin D level), that magic bullets (insulin) are rare, that most treatments fail, or that you can’t rely on association studies to prove efficacy.

In this world, people would be immune from spin and hype.

The norm would be that pills, supplements, and procedures are not what delivers good health. What delivers health is an amalgam of good luck, healthy habits, and lots of time spent outside playing in the sun.
 

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

The vitamin D story exudes teaching points: It offers a master class in critical appraisal, connecting the concepts of biologic plausibility, flawed surrogate markers, confounded observational studies, and slews of randomized controlled trials (RCTs) showing no benefits on health outcomes.

Yet despite the utter lack of benefit seen in trials, the hype continues. And the pandemic has only enhanced this hype as an onslaught of papers have reported the association of low vitamin D levels and COVID-19 disease.

My questions are simple: Why doesn’t the evidence persuade people? How many nonsignificant trials do we need before researchers stop studying vitamin D, doctors stop (routinely) measuring levels, and patients stop wasting money on the unhelpful supplement? What are the implications for this lack of persuasion?

Before exploring these questions, I want to set out that symptomatic vitamin deficiencies of any sort ought to be corrected. 
 

Biologic plausibility and the pull of observational studies

It has long been known that vitamin D is crucial for bone health and that it can be produced in the skin with sun exposure. In the last decade, however, experts note that nearly every tissue and cell in our body has a vitamin D receptor. It then follows that if this many cells in the body can activate vitamin D, it must be vital for cardiovascular health, immune function, cancer prevention: basically, everything health related.

Oodles of observational studies have found that low serum levels of vitamin D correlate with higher mortality from all causes, cancer, cardiovascular disease, and now even COVID-19. Yet no matter the amount of statistical adjustment in these studies, we cannot know whether these associations are due to true causality.

The major issue is confounding: That is, people with low vitamin D levels have other conditions or diseases that lead to higher rates of ill health. Consider a patient with obesity, arthritis, and cognitive decline; this person is unlikely to do much exercise in the sun and may have low vitamin D levels. The low vitamin D level is simply a marker of overall poor health.
 

The randomized controlled trials tell a clear story

There are hundreds of vitamin D RCTs. The results simplify into one sentence: Vitamin D supplements do not improve health outcomes.

Here is a short summary of some recent studies.

VITAL, a massive (N > 25,000) RCT with 5 years of follow-up, compared vitamin D supplements to placebo and found no differences in the primary endpoints of cancer or cardiac events. Rates of death from any cause were nearly identical. Crucially, in subgroup analyses, the effects did not vary according to vitamin D levels at baseline.

The D-Health investigators randomly assigned more than 21,000 adults to vitamin D or placebo and after 5.7 years of follow-up reported no differences in the primary endpoint of overall mortality. There also were no differences in cardiovascular disease mortality.

Then you have the Mendelian randomized studies, which some have called nature’s RCT. These studies take advantage of the fact that some people are born with gene variations that predispose to low vitamin D levels. More than 60 Mendelian randomization studies have evaluated the consequences of lifelong genetically lowered vitamin D levels on various outcomes; most of these have found null effects.

Then there are the meta-analyses and systematic reviews. I loved the conclusion of this review of systematic reviews from the BMJ (emphasis mine):

“Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.”

 

The failure to persuade

My original plan was to emphasize the power of the RCT. Despite strong associations of low vitamin D levels with poor outcomes, the trials show no benefit to treatment. This strongly suggests (or nearly proves) that low vitamin D levels are akin to premature ventricular complexes after myocardial infarction: a marker for risk but not a target for therapy.

But I now see the more important issue as why scientists, funders, clinicians, and patients are not persuaded by clear evidence. Every day in clinic I see patients on vitamin D supplements; the journals keep publishing vitamin D studies. The proponents of vitamin D remain positive. And lately there is outsized attention and hope that vitamin D will mitigate SARS-CoV2 infection – based only on observational data.

You might argue against this point by saying vitamin D is natural and relatively innocuous, so who cares?

I offer three rebuttals to that point: Opportunity costs, distraction, and the insidious danger of poor critical appraisal skills. If you are burning money on vitamin D research, there is less available to study other important issues. If a patient is distracted by low vitamin D levels, she may pay less attention to her high body mass index or hypertension. And on the matter of critical appraisal, trust in medicine requires clinicians to be competent in critical appraisal. And these days, what could be more important than trust in medical professionals?

One major reason for the failure of persuasion of evidence is spin – or language that distracts from the primary endpoint. Here are two (of many) examples:

A meta-analysis of 50 vitamin D trials set out to study mortality. The authors found no significant difference in that primary endpoint. But the second sentence in their conclusion was that vitamin D supplements reduced the risk for cancer deaths by 15%. That’s a secondary endpoint in a study with nonsignificance in the primary endpoint. That is spin. This meta-analysis was completed before the Australian D-Health trial found that cancer deaths were 15% higher in the vitamin D arm, a difference that did not reach statistical significance.

The following example is worse: The authors of the VITAL trial, which found that vitamin D supplements had no effect on the primary endpoint of invasive cancer or cardiovascular disease, published a secondary analysis of the trial looking at a different endpoint: A composite incidence of metastatic and fatal invasive total cancer. They reported a 0.4% lower rate for the vitamin D group, a difference that barely made statistical significance at a P value of .04. 

But everyone knows the dangers of reanalyzing data with a new endpoint after you have seen the data. What’s more, even if this were a reasonable post hoc analysis, the results are neither clinically meaningful nor statistically robust.  Yet the fatally flawed paper has been viewed 60,000 times and picked up by 48 news outlets.

Another way to distract from nonsignificant primary outcomes is to nitpick the trials. The vitamin D dose wasn’t high enough, for instance. This might persuade me if there were one or two vitamin D trials, but there are hundreds of trials and meta-analyses, and their results are consistently null.
 

Conclusion: No, it is not hopeless

A nihilist would argue that fighting spin is futile. They would say you can’t fight incentives and business models. The incentive structure to publish is strong, and the journals and media know vitamin D studies garner attention – which is their currency.

I am not a nihilist and believe strongly that we must continue to teach critical appraisal and numerical literacy.

In fact, I would speculate that decades of poor critical appraisal by the medical profession have fostered outsized hope and created erroneous norms.

Imagine a counter-factual world in which clinicians have taught society that the human body is unlike an engine that can be repaired by fixing one part (i.e., the vitamin D level), that magic bullets (insulin) are rare, that most treatments fail, or that you can’t rely on association studies to prove efficacy.

In this world, people would be immune from spin and hype.

The norm would be that pills, supplements, and procedures are not what delivers good health. What delivers health is an amalgam of good luck, healthy habits, and lots of time spent outside playing in the sun.
 

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

The CDC will soon update its COVID-19 guidance – including masking recommendations – as cases continue to drop, CDC Director Rochelle P. Walensky, MD, said on Feb. 16.

“As we consider future metrics, which will be updated soon, we recognize the importance of not just cases … but critically, medically severe disease that leads to hospitalizations,” Dr. Walensky said at a White House news briefing. “We must consider hospital capacity as an additional important barometer.”

She later added, “We are looking at an overview of much of our guidance, and masking in all settings will be a part of that.”

Coronavirus cases continue to drop nationwide. This week’s 7-day daily average of cases is 147,000, a decrease of 40%. Hospitalizations have dropped 28% to 9,500, and daily deaths are 2,200, a decrease of 9%.

“Omicron cases are declining, and we are all cautiously optimistic about the trajectory we’re on,” Dr. Walensky said. “Things are moving in the right direction, but we want to remain vigilant to do all we can so this trajectory continues.”

Dr. Walensky said public masking remains especially important if someone is symptomatic or not feeling well, or if there has been a COVID-19 exposure. Those who are within 10 days of being diagnosed with the virus should also remain masked in public.

“We all share the same goal: to get to a point where COVID-19 is no longer disrupting our daily lives. A time when it won’t be a constant crisis,” Dr. Walensky said. “Moving from this pandemic will be a process led by science and epidemiological trends, and one that relies on the powerful tools we already have.”
 

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

The CDC will soon update its COVID-19 guidance – including masking recommendations – as cases continue to drop, CDC Director Rochelle P. Walensky, MD, said on Feb. 16.

“As we consider future metrics, which will be updated soon, we recognize the importance of not just cases … but critically, medically severe disease that leads to hospitalizations,” Dr. Walensky said at a White House news briefing. “We must consider hospital capacity as an additional important barometer.”

She later added, “We are looking at an overview of much of our guidance, and masking in all settings will be a part of that.”

Coronavirus cases continue to drop nationwide. This week’s 7-day daily average of cases is 147,000, a decrease of 40%. Hospitalizations have dropped 28% to 9,500, and daily deaths are 2,200, a decrease of 9%.

“Omicron cases are declining, and we are all cautiously optimistic about the trajectory we’re on,” Dr. Walensky said. “Things are moving in the right direction, but we want to remain vigilant to do all we can so this trajectory continues.”

Dr. Walensky said public masking remains especially important if someone is symptomatic or not feeling well, or if there has been a COVID-19 exposure. Those who are within 10 days of being diagnosed with the virus should also remain masked in public.

“We all share the same goal: to get to a point where COVID-19 is no longer disrupting our daily lives. A time when it won’t be a constant crisis,” Dr. Walensky said. “Moving from this pandemic will be a process led by science and epidemiological trends, and one that relies on the powerful tools we already have.”
 

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

The CDC will soon update its COVID-19 guidance – including masking recommendations – as cases continue to drop, CDC Director Rochelle P. Walensky, MD, said on Feb. 16.

“As we consider future metrics, which will be updated soon, we recognize the importance of not just cases … but critically, medically severe disease that leads to hospitalizations,” Dr. Walensky said at a White House news briefing. “We must consider hospital capacity as an additional important barometer.”

She later added, “We are looking at an overview of much of our guidance, and masking in all settings will be a part of that.”

Coronavirus cases continue to drop nationwide. This week’s 7-day daily average of cases is 147,000, a decrease of 40%. Hospitalizations have dropped 28% to 9,500, and daily deaths are 2,200, a decrease of 9%.

“Omicron cases are declining, and we are all cautiously optimistic about the trajectory we’re on,” Dr. Walensky said. “Things are moving in the right direction, but we want to remain vigilant to do all we can so this trajectory continues.”

Dr. Walensky said public masking remains especially important if someone is symptomatic or not feeling well, or if there has been a COVID-19 exposure. Those who are within 10 days of being diagnosed with the virus should also remain masked in public.

“We all share the same goal: to get to a point where COVID-19 is no longer disrupting our daily lives. A time when it won’t be a constant crisis,” Dr. Walensky said. “Moving from this pandemic will be a process led by science and epidemiological trends, and one that relies on the powerful tools we already have.”
 

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

Women are at higher risk of severe adverse events (AEs) from cancer therapy than men, and this is seen with chemotherapy, targeted agents, and especially with immunotherapy.

The finding comes from a review of more than 23,000 participants across 202 trials of various cancers (excluding sex-related cancers) that has been conducted over the past 40 years.

The investigators found a 34% increased risk of severe AEs among women, compared with men, climbing to a 49% higher risk with immunotherapy.

Women had a substantially greater risk of severe symptomatic AEs, including with immune checkpoint inhibitors and targeted tyrosine kinase inhibitors, and were more likely to experience severe hematologic AEs with chemotherapy and immunotherapy.

The particularly large sex differences with immunotherapy suggest “that studying AEs from these agents is a priority,” the investigators comment.

The article was published online on Feb. 4 in the Journal of Clinical Oncology.

“It has been understood that women have more toxicity from chemotherapy than men, but almost no research has aimed to understand whether that pattern held for novel treatments like immunotherapy or targeted therapies. We found similar large differences, especially for immune treatments,” said lead investigator Joseph Unger, PhD, a biostatistician and health services researcher at the Fred Hutchinson Cancer Research Center, Seattle, in an institutional press release.

A “better understanding of the nature of the underlying mechanisms could potentially lead to interventions or delivery modifications to reduce toxicity in women,” the investigators comment in their article.

Among a sea of possible explanations for the finding, there could be differences in how men and women metabolize cancer therapies or differences in how they perceive symptoms. Women may also receive relatively higher doses because of their body size or have higher adherence to treatment.

Whatever the case, as cancer treatment becomes increasingly individualized, “sex may be an important consideration,” Dr. Unger said.
 

Study details

The study involved 8,838 women and 14,458 men across the trials, which were phase 2 or 3 investigations conducted by the SWOG Cancer Research Network from 1980 to 2019. Trials including sex-related cancers were excluded. In the trials included in the review, the most common cancers were gastrointestinal and lung, followed by leukemia.

Seventy-five percent of the subjects received chemotherapy, and the rest received either targeted therapy or immunotherapy.

Two-thirds of the subjects had at least one grade 3 or higher AE; women had a 25% higher risk than men of having AEs of grade 5 or higher.

After adjusting for age, race, disease prognosis, and other factors, women were at increased risk of severe symptomatic AEs, such as nausea and pain, across all treatment lines and especially with immunotherapy, for which reports of symptomatic AEs were 66% higher.

Women also had a higher risk of symptomatic gastrointestinal AEs with all three treatments and a higher risk of sleep-related AEs with chemotherapy and immunotherapy, which “could be a function of hormonal effects interacting with cancer treatment,” the investigators said.

As for readily measurable AEs, women were at higher risk than men for objective hematologic AEs with chemotherapy, immunotherapy, and targeted therapy. There were no statistically significant sex differences in the risk of nonhematologic objective AEs.

The team notes that increased toxicity among women has been associated with improved survival, which may give AEs more time to develop. Higher rates of AEs might also signal increased delivery or efficacy of cancer treatments.

However, a previous study found that men may have a better response to immunotherapy than women. Immune checkpoint inhibitors were twice as effective as standard cancer therapies in the treatment of men with advanced solid tumors compared to their female counterparts, concluded a team that carried out a meta-analysis of 20 randomized controlled trials involving more than 11,351 patients.

The study was funded by the National Cancer Institute and others. Dr. Unger has disclosed no relevant financial relationships. Several coauthors have reported ties to a handful of companies, including Johnson & Johnson and Seattle Genetics. One is an employee of AIM Specialty Health.

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

Women are at higher risk of severe adverse events (AEs) from cancer therapy than men, and this is seen with chemotherapy, targeted agents, and especially with immunotherapy.

The finding comes from a review of more than 23,000 participants across 202 trials of various cancers (excluding sex-related cancers) that has been conducted over the past 40 years.

The investigators found a 34% increased risk of severe AEs among women, compared with men, climbing to a 49% higher risk with immunotherapy.

Women had a substantially greater risk of severe symptomatic AEs, including with immune checkpoint inhibitors and targeted tyrosine kinase inhibitors, and were more likely to experience severe hematologic AEs with chemotherapy and immunotherapy.

The particularly large sex differences with immunotherapy suggest “that studying AEs from these agents is a priority,” the investigators comment.

The article was published online on Feb. 4 in the Journal of Clinical Oncology.

“It has been understood that women have more toxicity from chemotherapy than men, but almost no research has aimed to understand whether that pattern held for novel treatments like immunotherapy or targeted therapies. We found similar large differences, especially for immune treatments,” said lead investigator Joseph Unger, PhD, a biostatistician and health services researcher at the Fred Hutchinson Cancer Research Center, Seattle, in an institutional press release.

A “better understanding of the nature of the underlying mechanisms could potentially lead to interventions or delivery modifications to reduce toxicity in women,” the investigators comment in their article.

Among a sea of possible explanations for the finding, there could be differences in how men and women metabolize cancer therapies or differences in how they perceive symptoms. Women may also receive relatively higher doses because of their body size or have higher adherence to treatment.

Whatever the case, as cancer treatment becomes increasingly individualized, “sex may be an important consideration,” Dr. Unger said.
 

Study details

The study involved 8,838 women and 14,458 men across the trials, which were phase 2 or 3 investigations conducted by the SWOG Cancer Research Network from 1980 to 2019. Trials including sex-related cancers were excluded. In the trials included in the review, the most common cancers were gastrointestinal and lung, followed by leukemia.

Seventy-five percent of the subjects received chemotherapy, and the rest received either targeted therapy or immunotherapy.

Two-thirds of the subjects had at least one grade 3 or higher AE; women had a 25% higher risk than men of having AEs of grade 5 or higher.

After adjusting for age, race, disease prognosis, and other factors, women were at increased risk of severe symptomatic AEs, such as nausea and pain, across all treatment lines and especially with immunotherapy, for which reports of symptomatic AEs were 66% higher.

Women also had a higher risk of symptomatic gastrointestinal AEs with all three treatments and a higher risk of sleep-related AEs with chemotherapy and immunotherapy, which “could be a function of hormonal effects interacting with cancer treatment,” the investigators said.

As for readily measurable AEs, women were at higher risk than men for objective hematologic AEs with chemotherapy, immunotherapy, and targeted therapy. There were no statistically significant sex differences in the risk of nonhematologic objective AEs.

The team notes that increased toxicity among women has been associated with improved survival, which may give AEs more time to develop. Higher rates of AEs might also signal increased delivery or efficacy of cancer treatments.

However, a previous study found that men may have a better response to immunotherapy than women. Immune checkpoint inhibitors were twice as effective as standard cancer therapies in the treatment of men with advanced solid tumors compared to their female counterparts, concluded a team that carried out a meta-analysis of 20 randomized controlled trials involving more than 11,351 patients.

The study was funded by the National Cancer Institute and others. Dr. Unger has disclosed no relevant financial relationships. Several coauthors have reported ties to a handful of companies, including Johnson & Johnson and Seattle Genetics. One is an employee of AIM Specialty Health.

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

Women are at higher risk of severe adverse events (AEs) from cancer therapy than men, and this is seen with chemotherapy, targeted agents, and especially with immunotherapy.

The finding comes from a review of more than 23,000 participants across 202 trials of various cancers (excluding sex-related cancers) that has been conducted over the past 40 years.

The investigators found a 34% increased risk of severe AEs among women, compared with men, climbing to a 49% higher risk with immunotherapy.

Women had a substantially greater risk of severe symptomatic AEs, including with immune checkpoint inhibitors and targeted tyrosine kinase inhibitors, and were more likely to experience severe hematologic AEs with chemotherapy and immunotherapy.

The particularly large sex differences with immunotherapy suggest “that studying AEs from these agents is a priority,” the investigators comment.

The article was published online on Feb. 4 in the Journal of Clinical Oncology.

“It has been understood that women have more toxicity from chemotherapy than men, but almost no research has aimed to understand whether that pattern held for novel treatments like immunotherapy or targeted therapies. We found similar large differences, especially for immune treatments,” said lead investigator Joseph Unger, PhD, a biostatistician and health services researcher at the Fred Hutchinson Cancer Research Center, Seattle, in an institutional press release.

A “better understanding of the nature of the underlying mechanisms could potentially lead to interventions or delivery modifications to reduce toxicity in women,” the investigators comment in their article.

Among a sea of possible explanations for the finding, there could be differences in how men and women metabolize cancer therapies or differences in how they perceive symptoms. Women may also receive relatively higher doses because of their body size or have higher adherence to treatment.

Whatever the case, as cancer treatment becomes increasingly individualized, “sex may be an important consideration,” Dr. Unger said.
 

Study details

The study involved 8,838 women and 14,458 men across the trials, which were phase 2 or 3 investigations conducted by the SWOG Cancer Research Network from 1980 to 2019. Trials including sex-related cancers were excluded. In the trials included in the review, the most common cancers were gastrointestinal and lung, followed by leukemia.

Seventy-five percent of the subjects received chemotherapy, and the rest received either targeted therapy or immunotherapy.

Two-thirds of the subjects had at least one grade 3 or higher AE; women had a 25% higher risk than men of having AEs of grade 5 or higher.

After adjusting for age, race, disease prognosis, and other factors, women were at increased risk of severe symptomatic AEs, such as nausea and pain, across all treatment lines and especially with immunotherapy, for which reports of symptomatic AEs were 66% higher.

Women also had a higher risk of symptomatic gastrointestinal AEs with all three treatments and a higher risk of sleep-related AEs with chemotherapy and immunotherapy, which “could be a function of hormonal effects interacting with cancer treatment,” the investigators said.

As for readily measurable AEs, women were at higher risk than men for objective hematologic AEs with chemotherapy, immunotherapy, and targeted therapy. There were no statistically significant sex differences in the risk of nonhematologic objective AEs.

The team notes that increased toxicity among women has been associated with improved survival, which may give AEs more time to develop. Higher rates of AEs might also signal increased delivery or efficacy of cancer treatments.

However, a previous study found that men may have a better response to immunotherapy than women. Immune checkpoint inhibitors were twice as effective as standard cancer therapies in the treatment of men with advanced solid tumors compared to their female counterparts, concluded a team that carried out a meta-analysis of 20 randomized controlled trials involving more than 11,351 patients.

The study was funded by the National Cancer Institute and others. Dr. Unger has disclosed no relevant financial relationships. Several coauthors have reported ties to a handful of companies, including Johnson & Johnson and Seattle Genetics. One is an employee of AIM Specialty Health.

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

The Centers for Medicare & Medicaid Services (CMS) will expand eligibility guidelines for lung cancer screening with low-dose computed tomography for Medicare recipients.

According to the final decision, announced February 10, CMS will lower the age for screening from 55 to 50 years up to 77 years and reduce criteria for tobacco smoking history from at least 30 pack-years to 20 pack-years. The expanded Medicare recommendation will address racial disparities associated with lung cancer, given evidence that one third of Black patients are diagnosed with lung cancer before age 55.

The updated CMS guidelines align closely with recommendations made by the U.S. Preventive Services Task Force (USPSTF) in March 2021. The USPSTF expanded its guidelines for screening to include individuals ages 50 to 80 years, as well as those who have a 20–pack-year smoking history and who currently smoke or have quit within the past 15 years.

Overall, the expanded guidelines will nearly double the number of individuals who are eligible for screening and have the potential to save significantly more lives by identifying cancers at an earlier, more treatable stage.

“Expanding coverage broadens access for lung cancer screening to at-risk populations,” said Lee Felisher, MD, CMS chief medical officer and director of the Center for Clinical Standards and Quality, in a statement. “Today’s decision not only expands access to quality care but is also critical to improving health outcomes for people by helping to detect lung cancer earlier.”

CMS’s decision also simplifies requirements for counseling and shared decision-making visits and removes an initial requirement for the reading radiologist to document participation in continuing medical education, which will reduce administrative burden. CMS also added a requirement back to the National Coverage Determination criteria that requires radiology imaging facilities to use a standardized lung nodule identification, classification, and reporting system.

The American Lung Association applauds the decision to update eligibility.

“[The] announcement from CMS will give more people enrolled in Medicare access to lifesaving lung cancer screening. Screening for individuals at high risk is the only tool to catch this disease early when it is more curable,” Harold Wimmer, president and CEO of the American Lung Association, said in a statement. “Unfortunately, only 5.7% of people who are eligible have been screened, so it’s important that we talk with our friends and family who are at high risk about getting screened.”

While access to screening will significantly increase, the American Lung Association recommends CMS go a step further and expand eligibility to individuals up to 80 years of age, as the USPSTF recommendations do, as well as remove the recommendation that individuals cease screening once they have stopped smoking for 15 years.

Given the new guidelines, most private insurance plans will need to update screening coverage policies to reflect the updated guidelines for plan years beginning after March 31.

To read the final decision, visit the CMS website.

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

The Centers for Medicare & Medicaid Services (CMS) will expand eligibility guidelines for lung cancer screening with low-dose computed tomography for Medicare recipients.

According to the final decision, announced February 10, CMS will lower the age for screening from 55 to 50 years up to 77 years and reduce criteria for tobacco smoking history from at least 30 pack-years to 20 pack-years. The expanded Medicare recommendation will address racial disparities associated with lung cancer, given evidence that one third of Black patients are diagnosed with lung cancer before age 55.

The updated CMS guidelines align closely with recommendations made by the U.S. Preventive Services Task Force (USPSTF) in March 2021. The USPSTF expanded its guidelines for screening to include individuals ages 50 to 80 years, as well as those who have a 20–pack-year smoking history and who currently smoke or have quit within the past 15 years.

Overall, the expanded guidelines will nearly double the number of individuals who are eligible for screening and have the potential to save significantly more lives by identifying cancers at an earlier, more treatable stage.

“Expanding coverage broadens access for lung cancer screening to at-risk populations,” said Lee Felisher, MD, CMS chief medical officer and director of the Center for Clinical Standards and Quality, in a statement. “Today’s decision not only expands access to quality care but is also critical to improving health outcomes for people by helping to detect lung cancer earlier.”

CMS’s decision also simplifies requirements for counseling and shared decision-making visits and removes an initial requirement for the reading radiologist to document participation in continuing medical education, which will reduce administrative burden. CMS also added a requirement back to the National Coverage Determination criteria that requires radiology imaging facilities to use a standardized lung nodule identification, classification, and reporting system.

The American Lung Association applauds the decision to update eligibility.

“[The] announcement from CMS will give more people enrolled in Medicare access to lifesaving lung cancer screening. Screening for individuals at high risk is the only tool to catch this disease early when it is more curable,” Harold Wimmer, president and CEO of the American Lung Association, said in a statement. “Unfortunately, only 5.7% of people who are eligible have been screened, so it’s important that we talk with our friends and family who are at high risk about getting screened.”

While access to screening will significantly increase, the American Lung Association recommends CMS go a step further and expand eligibility to individuals up to 80 years of age, as the USPSTF recommendations do, as well as remove the recommendation that individuals cease screening once they have stopped smoking for 15 years.

Given the new guidelines, most private insurance plans will need to update screening coverage policies to reflect the updated guidelines for plan years beginning after March 31.

To read the final decision, visit the CMS website.

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

The Centers for Medicare & Medicaid Services (CMS) will expand eligibility guidelines for lung cancer screening with low-dose computed tomography for Medicare recipients.

According to the final decision, announced February 10, CMS will lower the age for screening from 55 to 50 years up to 77 years and reduce criteria for tobacco smoking history from at least 30 pack-years to 20 pack-years. The expanded Medicare recommendation will address racial disparities associated with lung cancer, given evidence that one third of Black patients are diagnosed with lung cancer before age 55.

The updated CMS guidelines align closely with recommendations made by the U.S. Preventive Services Task Force (USPSTF) in March 2021. The USPSTF expanded its guidelines for screening to include individuals ages 50 to 80 years, as well as those who have a 20–pack-year smoking history and who currently smoke or have quit within the past 15 years.

Overall, the expanded guidelines will nearly double the number of individuals who are eligible for screening and have the potential to save significantly more lives by identifying cancers at an earlier, more treatable stage.

“Expanding coverage broadens access for lung cancer screening to at-risk populations,” said Lee Felisher, MD, CMS chief medical officer and director of the Center for Clinical Standards and Quality, in a statement. “Today’s decision not only expands access to quality care but is also critical to improving health outcomes for people by helping to detect lung cancer earlier.”

CMS’s decision also simplifies requirements for counseling and shared decision-making visits and removes an initial requirement for the reading radiologist to document participation in continuing medical education, which will reduce administrative burden. CMS also added a requirement back to the National Coverage Determination criteria that requires radiology imaging facilities to use a standardized lung nodule identification, classification, and reporting system.

The American Lung Association applauds the decision to update eligibility.

“[The] announcement from CMS will give more people enrolled in Medicare access to lifesaving lung cancer screening. Screening for individuals at high risk is the only tool to catch this disease early when it is more curable,” Harold Wimmer, president and CEO of the American Lung Association, said in a statement. “Unfortunately, only 5.7% of people who are eligible have been screened, so it’s important that we talk with our friends and family who are at high risk about getting screened.”

While access to screening will significantly increase, the American Lung Association recommends CMS go a step further and expand eligibility to individuals up to 80 years of age, as the USPSTF recommendations do, as well as remove the recommendation that individuals cease screening once they have stopped smoking for 15 years.

Given the new guidelines, most private insurance plans will need to update screening coverage policies to reflect the updated guidelines for plan years beginning after March 31.

To read the final decision, visit the CMS website.

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

Tonsillectomy with or without adenoidectomy (T&A) is the second most common pediatric surgical procedure in the United States.¹ It is most often performed during childhood between 5 and 8 years of age with a second peak observed between 17 and 21 years of age in the adolescent and young adult populations.² While recurrent tonsillitis has been traditionally associated with tonsillectomy, sleep disordered breathing with obstructive sleep apnea is now the primary indication for the procedure.¹

Up to 97% of T&As are performed as an outpatient same-day surgery not requiring inpatient admission.² Although largely a safe and routinely performed surgery, several complications have been described. Due to the outpatient nature of the procedure, the complications are often encountered in the emergency department (ED) and sometimes in primary care settings. Common complications (outside of the perioperative time frame) include nausea, vomiting, otalgia, odynophagia, infection of the throat (broadly), and hemorrhage; uncommon complications include subcutaneous emphysema, taste disorders, and Eagle syndrome. Some complications are rarer still and carry significant morbidity and even mortality, including mediastinitis, cervical osteomyelitis, and Grisel syndrome.³ The following case encourages the clinician to expand the differential for a patient presenting after T&A.

Case Presentation

A child aged < 3 years was brought to the ED by their mother. She reported neck pain and stiffness 10 days after T&A with concurrent tympanostomy tube placement at an outside pediatric hospital. At triage, their heart rate was 94 bpm, temperature was 98.2 °F, respiratory rate, 22 breaths per minute, and oxygen saturation, 97% on room air. The mother of the patient (MOP) had been giving the prescribed oral liquid formulations of ibuprofen and acetaminophen with hydrocodone as directed. No drug allergies were reported, and immunizations were up to date for age. Other medical and surgical history included eczema and remote cutaneous hemangioma resection. The patient lived at home with 2 parents and was not exposed to smoke; their family history was noncontributory.

Since the surgery, the MOP had noticed constant and increasing neck stiffness, specifically with looking up and down but not side to side. She also had noticed swelling behind both ears. She reported no substantial decrease in intake by mouth or decrease in urine or bowel frequency. On review of systems, she reported no fever, vomiting, difficulty breathing, bleeding from the mouth or nose, eye or ear drainage, or rash.

On physical examination, the patient was alert and in no acute distress; active and playful on an electronic device but was notably not moving their head, which was held in a forward-looking position without any signs of trauma. When asked, the child would not flex or extend their neck but would rotate a few degrees from neutral to both sides. Even with moving the electronic device up and down in space, no active neck extension or flexion could be elicited. The examination of the head, eyes, ears, nose, and throat was otherwise only remarkable for palpable and mildly tender postauricular lymph nodes and diffuse erythema in the posterior pharynx. Cardiopulmonary, abdominal, skin, and extremity examinations were unremarkable.

With concern for an infectious process, the physician ordered blood chemistry and hematology tests along with neck radiography. While awaiting the results, the patient was given a weight-based bolus of normal saline, and the home pain regimen was administered. An attempt was made to passively flex and extend the neck as the child slept in their mother’s arms, but the patient immediately awoke and began to cry.

All values of the comprehensive metabolic panel were within normal limits except for a slight elevation in the blood urea nitrogen to 21 mg/dL and glucose to 159 mg/dL. The complete blood count was unrevealing. The computed tomography (CT) scan with contrast of the soft tissues of the neck was limited by motion artifact but showed a head held in axial rotation with soft tissue irregularity in the anterior aspect of the adenoids (Figure 1). There was what appeared to be normal lymphadenopathy in the hypopharynx, but the soft tissues were otherwise unremarkable.

Discussion

Grisel syndrome is the atraumatic rotary subluxation of the atlantoaxial joint, specifically, the atlas (C1 vertebra) rotates to a fixed, nonanatomic position while the axis (C2 vertebra) remains in normal alignment in relation to the remainder of the spinal column. The subluxation occurs in the absence of ligamentous injury but is associated with an increase in ligamentous laxity.⁴ The atlas is a ring-shaped vertebra with 2 lateral masses connected by anterior and posterior arches; it lacks a spinous process unlike other vertebrae. It articulates with the skull by means of the 2 articular facets on the superior aspect of the lateral masses. Articulation with the axis occurs at 3 sites: 2 articular facets on the inferior portion of the lateral masses of the atlas and a facet for the dens on the posterior portion of the anterior arch. The dens projects superiorly from the body of the axis and is bound posteriorly by the transverse ligament of the atlas.⁵

The degree of subluxation seen in Grisel syndrome correlates to the disease severity and is classified by the Fielding and Hawkins (FH) system (Table). This system accounts for the distance from the atlas to the dens (atlantodens interval) and the relative asymmetry of the atlantoaxial joint.⁶ In a normal adult, the upper limit of normal for the atlantodens interval is 3 mm, whereas this distance increases to 4.5 mm for the pediatric population.⁷ Type I (FH-I) involves rotary subluxation alone without any increase in the atlantodens interval; in FH-II, that interval has increased from normal but to no more than 5 mm. FH-I and FH-II are the most encountered and are not associated with neurologic impairment. In FH-III, neurologic deficits can be present, and the atlantodens interval is increased to > 5 mm. Different from FH-II and FH-III in which anterior dislocation of the atlas with reference to the dens is observed, FH-IV involves a rotary movement of the atlas with concurrent posterior displacement and often involves spinal cord compression.⁶

Subluxation and displacement without trauma are key components of Grisel syndrome. The 2-hit hypothesis is often used to explain how this can occur, ie, 2 anomalies must be present simultaneously for this condition to develop. First, the laxity of the transverse ligament, the posterior wall of the dens, and other atlantoaxial ligaments must be increased. Second, an asymmetric contraction of the deep erector muscles of the neck either abruptly or more insidiously rotate and dislocate the atlas.⁸ The pathophysiology is not exactly understood, but the most commonly held hypothesis describes contiguous spread of infection or inflammatory mediators from the pharynx to the ligaments and muscles described.⁶

Spread could occur via the venous system. The posterior superior pharyngeal region is drained by the periodontoidal venous plexus; the connections here with the pharyngovertebral veins allow for the embolization of infectious or other proinflammatory material to the prevertebral fascia. These emboli induce fasciitis and subsequent aberrant relaxation of the ligaments. In reaction to the inflammation or increased laxity, contiguous muscles of the deep neck contract and freeze the joint out of anatomic alignment.⁴

The abnormal alignment is apparent grossly as torticollis. Most broadly, torticollis describes an anomalous head posture due to involuntary muscle contractions of neck muscles and specifically describes chin deviation to the side. The antecollis and retrocollis subtypes of torticollis describe forward flexion and backward extension of the neck, respectively.⁷ Torticollis (broadly) is the most frequently reported condition of those found to have Grisel syndrome (90.7%); other common presenting conditions include neck pain (81.5%) and neck stiffness (31.5%). Fever is found in only 27.8% of cases. Pediatric patients (aged ≤ 12 years) are the most commonly affected, accounting for 87% of cases with an observed 4:1 male to female predominance.^7,8 Symptoms begin most often within the first week from the inciting event in 85% of the cases.⁸ Head and neck surgery precedes up to 67% of cases, and infectious etiologies largely account for the remaining cases.⁷ Of the postsurgical cases, 55.6% had undergone T&A.⁸

Although anomalous head posture or neck stiffness following T&A would be of great clinic concern for Grisel syndrome, radiographic studies play a confirmatory role. CT scan is used to evaluate the bony structures, with 3D reconstruction of the cervical spine being most useful to determine the presence and degree of subluxation.⁸ Magnetic resonance imaging also aids in diagnosis to evaluate ligamentous structures in the area of concern as well as in the evaluation of spinal cord compression.⁶ Laboratory tests are largely unhelpful in making or excluding the diagnosis.⁸

If Grisel syndrome is suspected, both the original surgeon (if preceded by surgery) and the neurosurgical team should be consulted. Although no widely adopted guidelines exist for the management of this rare disease, general practice patterns have emerged with the degree of intervention predictably correlating to disease severity. FH-I is usually treated with nonsteroidal anti-inflammatory drugs and muscle relaxants with or without a soft cervical collar. For FH-II, closed reduction and immobilization in a stiff cervical collar is recommended. If no neurologic defect is present, FH-III is treated with bed rest, a period of inline cervical traction, and subsequent immobilization. FH-III with neurologic sequelae and all FH-IV necessitate emergent neurosurgical consultation.⁴ Surgical intervention is a last resort but is required in up to 24.1% of cases.⁸

Antibiotic therapy is not routinely given unless clear infectious etiology is identified. No standard antibiotic regimen exists, but coverage for typical upper respiratory pathogens likely suffices. Empiric antibiotic therapy is not recommended for all causes of Grisel syndrome, ie, when the underlying cause is not yet elucidated.⁶ One case of Grisel syndrome occurring in the setting of cervical osteomyelitis has been described, though, and required prolonged IV antibiotics.³ Physical therapy is recommended as adjunct with no limitations for range of motion save for that of the patient’s individual pain threshold.⁴

Possibly attributable to waxing and waning ligamentous laxity and strength of the neck muscle contraction, the atlantodens interval and the degree of subluxation can change, making Grisel syndrome dynamic. As such, the FH classification can change, necessitating more or less aggressive therapy. A neurologic evaluation is recommended at least every 2 weeks after the diagnosis is made. If initial identification or recognition of known disease progression is delayed, serious complications can develop. Acutely, spinal cord compression can lead to quadriplegia and death; more insidious complications include reduced neck mobility, dysphonia, and dysphagia.⁴ As serious, life-threatening complications can arise from Grisel syndrome while good functional outcomes can be achieved with timely and appropriate treatment, the clinician should be inspired to have a high clinical suspicion for this syndrome given the right context.

Conclusions

The patient experienced a desirable outcome with minimal, conservative treatment. As such, the pathology in this case was likely attributed to the mildest form of Grisel syndrome (FH-I). The follow-up was reassuring as well, revealing no worsening or progression of symptoms. The initial evaluation in this case was limited by the inadequacy of the CT scan. Motion artifact in the pharynx prevented the definite exclusion of deep space infection, while the rotation of the head in combination with motion artifact in the cranial-most portions of the vertebral column made determining alignment difficult. One clear axial image, though, does show rotation of the atlas (Figure 2). The uncertainty at the end of our workup prompted surgical consultation, not, admittedly, concern for Grisel syndrome. Awareness of this disease entity is nevertheless important and clinically relevant. Early identification and treatment is associated with decreased morbidity and improvement in long-term functional outcomes.⁶ Despite its rarity, the clinician should consider Grisel syndrome in any pediatric patient presenting with neck stiffness following the commonly performed T&A.

Tonsillectomy with or without adenoidectomy (T&A) is the second most common pediatric surgical procedure in the United States.¹ It is most often performed during childhood between 5 and 8 years of age with a second peak observed between 17 and 21 years of age in the adolescent and young adult populations.² While recurrent tonsillitis has been traditionally associated with tonsillectomy, sleep disordered breathing with obstructive sleep apnea is now the primary indication for the procedure.¹

Up to 97% of T&As are performed as an outpatient same-day surgery not requiring inpatient admission.² Although largely a safe and routinely performed surgery, several complications have been described. Due to the outpatient nature of the procedure, the complications are often encountered in the emergency department (ED) and sometimes in primary care settings. Common complications (outside of the perioperative time frame) include nausea, vomiting, otalgia, odynophagia, infection of the throat (broadly), and hemorrhage; uncommon complications include subcutaneous emphysema, taste disorders, and Eagle syndrome. Some complications are rarer still and carry significant morbidity and even mortality, including mediastinitis, cervical osteomyelitis, and Grisel syndrome.³ The following case encourages the clinician to expand the differential for a patient presenting after T&A.

Case Presentation

A child aged < 3 years was brought to the ED by their mother. She reported neck pain and stiffness 10 days after T&A with concurrent tympanostomy tube placement at an outside pediatric hospital. At triage, their heart rate was 94 bpm, temperature was 98.2 °F, respiratory rate, 22 breaths per minute, and oxygen saturation, 97% on room air. The mother of the patient (MOP) had been giving the prescribed oral liquid formulations of ibuprofen and acetaminophen with hydrocodone as directed. No drug allergies were reported, and immunizations were up to date for age. Other medical and surgical history included eczema and remote cutaneous hemangioma resection. The patient lived at home with 2 parents and was not exposed to smoke; their family history was noncontributory.

Since the surgery, the MOP had noticed constant and increasing neck stiffness, specifically with looking up and down but not side to side. She also had noticed swelling behind both ears. She reported no substantial decrease in intake by mouth or decrease in urine or bowel frequency. On review of systems, she reported no fever, vomiting, difficulty breathing, bleeding from the mouth or nose, eye or ear drainage, or rash.

On physical examination, the patient was alert and in no acute distress; active and playful on an electronic device but was notably not moving their head, which was held in a forward-looking position without any signs of trauma. When asked, the child would not flex or extend their neck but would rotate a few degrees from neutral to both sides. Even with moving the electronic device up and down in space, no active neck extension or flexion could be elicited. The examination of the head, eyes, ears, nose, and throat was otherwise only remarkable for palpable and mildly tender postauricular lymph nodes and diffuse erythema in the posterior pharynx. Cardiopulmonary, abdominal, skin, and extremity examinations were unremarkable.

With concern for an infectious process, the physician ordered blood chemistry and hematology tests along with neck radiography. While awaiting the results, the patient was given a weight-based bolus of normal saline, and the home pain regimen was administered. An attempt was made to passively flex and extend the neck as the child slept in their mother’s arms, but the patient immediately awoke and began to cry.

All values of the comprehensive metabolic panel were within normal limits except for a slight elevation in the blood urea nitrogen to 21 mg/dL and glucose to 159 mg/dL. The complete blood count was unrevealing. The computed tomography (CT) scan with contrast of the soft tissues of the neck was limited by motion artifact but showed a head held in axial rotation with soft tissue irregularity in the anterior aspect of the adenoids (Figure 1). There was what appeared to be normal lymphadenopathy in the hypopharynx, but the soft tissues were otherwise unremarkable.

Discussion

Grisel syndrome is the atraumatic rotary subluxation of the atlantoaxial joint, specifically, the atlas (C1 vertebra) rotates to a fixed, nonanatomic position while the axis (C2 vertebra) remains in normal alignment in relation to the remainder of the spinal column. The subluxation occurs in the absence of ligamentous injury but is associated with an increase in ligamentous laxity.⁴ The atlas is a ring-shaped vertebra with 2 lateral masses connected by anterior and posterior arches; it lacks a spinous process unlike other vertebrae. It articulates with the skull by means of the 2 articular facets on the superior aspect of the lateral masses. Articulation with the axis occurs at 3 sites: 2 articular facets on the inferior portion of the lateral masses of the atlas and a facet for the dens on the posterior portion of the anterior arch. The dens projects superiorly from the body of the axis and is bound posteriorly by the transverse ligament of the atlas.⁵

The degree of subluxation seen in Grisel syndrome correlates to the disease severity and is classified by the Fielding and Hawkins (FH) system (Table). This system accounts for the distance from the atlas to the dens (atlantodens interval) and the relative asymmetry of the atlantoaxial joint.⁶ In a normal adult, the upper limit of normal for the atlantodens interval is 3 mm, whereas this distance increases to 4.5 mm for the pediatric population.⁷ Type I (FH-I) involves rotary subluxation alone without any increase in the atlantodens interval; in FH-II, that interval has increased from normal but to no more than 5 mm. FH-I and FH-II are the most encountered and are not associated with neurologic impairment. In FH-III, neurologic deficits can be present, and the atlantodens interval is increased to > 5 mm. Different from FH-II and FH-III in which anterior dislocation of the atlas with reference to the dens is observed, FH-IV involves a rotary movement of the atlas with concurrent posterior displacement and often involves spinal cord compression.⁶

Subluxation and displacement without trauma are key components of Grisel syndrome. The 2-hit hypothesis is often used to explain how this can occur, ie, 2 anomalies must be present simultaneously for this condition to develop. First, the laxity of the transverse ligament, the posterior wall of the dens, and other atlantoaxial ligaments must be increased. Second, an asymmetric contraction of the deep erector muscles of the neck either abruptly or more insidiously rotate and dislocate the atlas.⁸ The pathophysiology is not exactly understood, but the most commonly held hypothesis describes contiguous spread of infection or inflammatory mediators from the pharynx to the ligaments and muscles described.⁶

Spread could occur via the venous system. The posterior superior pharyngeal region is drained by the periodontoidal venous plexus; the connections here with the pharyngovertebral veins allow for the embolization of infectious or other proinflammatory material to the prevertebral fascia. These emboli induce fasciitis and subsequent aberrant relaxation of the ligaments. In reaction to the inflammation or increased laxity, contiguous muscles of the deep neck contract and freeze the joint out of anatomic alignment.⁴

The abnormal alignment is apparent grossly as torticollis. Most broadly, torticollis describes an anomalous head posture due to involuntary muscle contractions of neck muscles and specifically describes chin deviation to the side. The antecollis and retrocollis subtypes of torticollis describe forward flexion and backward extension of the neck, respectively.⁷ Torticollis (broadly) is the most frequently reported condition of those found to have Grisel syndrome (90.7%); other common presenting conditions include neck pain (81.5%) and neck stiffness (31.5%). Fever is found in only 27.8% of cases. Pediatric patients (aged ≤ 12 years) are the most commonly affected, accounting for 87% of cases with an observed 4:1 male to female predominance.^7,8 Symptoms begin most often within the first week from the inciting event in 85% of the cases.⁸ Head and neck surgery precedes up to 67% of cases, and infectious etiologies largely account for the remaining cases.⁷ Of the postsurgical cases, 55.6% had undergone T&A.⁸

Although anomalous head posture or neck stiffness following T&A would be of great clinic concern for Grisel syndrome, radiographic studies play a confirmatory role. CT scan is used to evaluate the bony structures, with 3D reconstruction of the cervical spine being most useful to determine the presence and degree of subluxation.⁸ Magnetic resonance imaging also aids in diagnosis to evaluate ligamentous structures in the area of concern as well as in the evaluation of spinal cord compression.⁶ Laboratory tests are largely unhelpful in making or excluding the diagnosis.⁸

If Grisel syndrome is suspected, both the original surgeon (if preceded by surgery) and the neurosurgical team should be consulted. Although no widely adopted guidelines exist for the management of this rare disease, general practice patterns have emerged with the degree of intervention predictably correlating to disease severity. FH-I is usually treated with nonsteroidal anti-inflammatory drugs and muscle relaxants with or without a soft cervical collar. For FH-II, closed reduction and immobilization in a stiff cervical collar is recommended. If no neurologic defect is present, FH-III is treated with bed rest, a period of inline cervical traction, and subsequent immobilization. FH-III with neurologic sequelae and all FH-IV necessitate emergent neurosurgical consultation.⁴ Surgical intervention is a last resort but is required in up to 24.1% of cases.⁸

Antibiotic therapy is not routinely given unless clear infectious etiology is identified. No standard antibiotic regimen exists, but coverage for typical upper respiratory pathogens likely suffices. Empiric antibiotic therapy is not recommended for all causes of Grisel syndrome, ie, when the underlying cause is not yet elucidated.⁶ One case of Grisel syndrome occurring in the setting of cervical osteomyelitis has been described, though, and required prolonged IV antibiotics.³ Physical therapy is recommended as adjunct with no limitations for range of motion save for that of the patient’s individual pain threshold.⁴

Possibly attributable to waxing and waning ligamentous laxity and strength of the neck muscle contraction, the atlantodens interval and the degree of subluxation can change, making Grisel syndrome dynamic. As such, the FH classification can change, necessitating more or less aggressive therapy. A neurologic evaluation is recommended at least every 2 weeks after the diagnosis is made. If initial identification or recognition of known disease progression is delayed, serious complications can develop. Acutely, spinal cord compression can lead to quadriplegia and death; more insidious complications include reduced neck mobility, dysphonia, and dysphagia.⁴ As serious, life-threatening complications can arise from Grisel syndrome while good functional outcomes can be achieved with timely and appropriate treatment, the clinician should be inspired to have a high clinical suspicion for this syndrome given the right context.

Conclusions

The patient experienced a desirable outcome with minimal, conservative treatment. As such, the pathology in this case was likely attributed to the mildest form of Grisel syndrome (FH-I). The follow-up was reassuring as well, revealing no worsening or progression of symptoms. The initial evaluation in this case was limited by the inadequacy of the CT scan. Motion artifact in the pharynx prevented the definite exclusion of deep space infection, while the rotation of the head in combination with motion artifact in the cranial-most portions of the vertebral column made determining alignment difficult. One clear axial image, though, does show rotation of the atlas (Figure 2). The uncertainty at the end of our workup prompted surgical consultation, not, admittedly, concern for Grisel syndrome. Awareness of this disease entity is nevertheless important and clinically relevant. Early identification and treatment is associated with decreased morbidity and improvement in long-term functional outcomes.⁶ Despite its rarity, the clinician should consider Grisel syndrome in any pediatric patient presenting with neck stiffness following the commonly performed T&A.

Tonsillectomy with or without adenoidectomy (T&A) is the second most common pediatric surgical procedure in the United States.¹ It is most often performed during childhood between 5 and 8 years of age with a second peak observed between 17 and 21 years of age in the adolescent and young adult populations.² While recurrent tonsillitis has been traditionally associated with tonsillectomy, sleep disordered breathing with obstructive sleep apnea is now the primary indication for the procedure.¹

Up to 97% of T&As are performed as an outpatient same-day surgery not requiring inpatient admission.² Although largely a safe and routinely performed surgery, several complications have been described. Due to the outpatient nature of the procedure, the complications are often encountered in the emergency department (ED) and sometimes in primary care settings. Common complications (outside of the perioperative time frame) include nausea, vomiting, otalgia, odynophagia, infection of the throat (broadly), and hemorrhage; uncommon complications include subcutaneous emphysema, taste disorders, and Eagle syndrome. Some complications are rarer still and carry significant morbidity and even mortality, including mediastinitis, cervical osteomyelitis, and Grisel syndrome.³ The following case encourages the clinician to expand the differential for a patient presenting after T&A.

Case Presentation

A child aged < 3 years was brought to the ED by their mother. She reported neck pain and stiffness 10 days after T&A with concurrent tympanostomy tube placement at an outside pediatric hospital. At triage, their heart rate was 94 bpm, temperature was 98.2 °F, respiratory rate, 22 breaths per minute, and oxygen saturation, 97% on room air. The mother of the patient (MOP) had been giving the prescribed oral liquid formulations of ibuprofen and acetaminophen with hydrocodone as directed. No drug allergies were reported, and immunizations were up to date for age. Other medical and surgical history included eczema and remote cutaneous hemangioma resection. The patient lived at home with 2 parents and was not exposed to smoke; their family history was noncontributory.

Since the surgery, the MOP had noticed constant and increasing neck stiffness, specifically with looking up and down but not side to side. She also had noticed swelling behind both ears. She reported no substantial decrease in intake by mouth or decrease in urine or bowel frequency. On review of systems, she reported no fever, vomiting, difficulty breathing, bleeding from the mouth or nose, eye or ear drainage, or rash.

On physical examination, the patient was alert and in no acute distress; active and playful on an electronic device but was notably not moving their head, which was held in a forward-looking position without any signs of trauma. When asked, the child would not flex or extend their neck but would rotate a few degrees from neutral to both sides. Even with moving the electronic device up and down in space, no active neck extension or flexion could be elicited. The examination of the head, eyes, ears, nose, and throat was otherwise only remarkable for palpable and mildly tender postauricular lymph nodes and diffuse erythema in the posterior pharynx. Cardiopulmonary, abdominal, skin, and extremity examinations were unremarkable.

With concern for an infectious process, the physician ordered blood chemistry and hematology tests along with neck radiography. While awaiting the results, the patient was given a weight-based bolus of normal saline, and the home pain regimen was administered. An attempt was made to passively flex and extend the neck as the child slept in their mother’s arms, but the patient immediately awoke and began to cry.

All values of the comprehensive metabolic panel were within normal limits except for a slight elevation in the blood urea nitrogen to 21 mg/dL and glucose to 159 mg/dL. The complete blood count was unrevealing. The computed tomography (CT) scan with contrast of the soft tissues of the neck was limited by motion artifact but showed a head held in axial rotation with soft tissue irregularity in the anterior aspect of the adenoids (Figure 1). There was what appeared to be normal lymphadenopathy in the hypopharynx, but the soft tissues were otherwise unremarkable.