Researchers studying a large set of small cell lung cancer (SCLC) tumor samples have identified four SCLC subtypes, and they propose that matching baseline tumor subtypes to SCLC therapy may enhance the depth and duration of response.

Carl M. Gay, MD, PhD, of University of Texas MD Anderson Cancer Center in Houston, and colleagues conducted this research and described their findings in Cancer Cell.

The authors noted that survival rates in SCLC remain dismal despite recent modest gains in progression-free survival and overall survival achieved through adding immunotherapy to platinum-based frontline chemotherapy.

Based on transcription factors indicating which genes are activated, prior research had already identified three possible SCLC subtypes. Many SCLC tumors, however, do not fit into one of these three groups, the authors said.
 

Inflamed gene signature

The four groups were identified using tumor expression data and nonnegative matrix factorization from published sources on 81 SCLC patients, and then validated via the largest SCLC data set available (276 SCLC patients enrolled in the phase 3 IMpower133 trial).

The SCLC subtypes were defined largely by differential expression of transcription factors – subtype SCLC-A by ASCL1, subtype SCLC-N by NEUROD1, and subtype SCLC-P by POU2F3. The fourth subtype, SCLC-I, is characterized by low expression of all three transcription factor signatures and an inflamed gene signature with a high expression of multiple immune genes, including significantly greater levels of genes indicating the presence of CD8-positive cytotoxic T cells.

Because each subtype demonstrates unique vulnerability to investigational therapies, this subtype classification has significant clinical implications.

“We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients,” the authors stated.

“Our paper shows that the inflamed group has a distinct biology and environment and tends to be more responsive to immunotherapy,” study author Lauren Averett Byers, MD, also of the University of Texas MD Anderson Cancer Center, stated in a press release. “Identifying the inflamed group is very important because, so far, there have not been any validated biomarkers for small cell lung cancer that predict which patients get the most benefit from immunotherapy.”

In samples from the other three subtypes, SCLC-A was most responsive to BCL2 inhibitors, SCLC-N to Aurora kinase inhibitors, and SCLC-P to PARP inhibitors.

Treatment resistance

The tendency of SCLC to develop treatment resistance, even after an initial response, is a known challenge. Using single-cell RNA sequencing to evaluate tumor evolution, the authors observed a tendency of SCLC-A to switch to SCLC-I after chemotherapy treatment, a possible contributor to treatment resistance.

It will be necessary to verify the study findings through further investigations, particularly regarding the therapeutic vulnerabilities for each group.

“Now we can develop more effective strategies for each group in clinical trials, taking into account that they each have different biology and optimal drug targets,” Dr. Byers said. “As a field, small cell lung cancer is about 15 years behind non–small cell lung cancer’s renaissance of biomarkers and personalized therapies. This represents a huge step in understanding which drugs work best for which patients and gives us a path forward for personalized approaches for small cell lung cancer.”

“Dr. Gay’s work is the latest in a growing series of exciting studies demonstrating the utility of defining subtypes of small cell lung cancer based on expression of master transcriptional regulators,” commented Charles Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, in an interview.

He added, “While tumors can evolve between some of these categories, the dominant subtype assignment influences therapeutic vulnerabilities. It is an exciting time for those of us engaged in small cell research. Subtyping should help guide more focused and successful clinical trials for patients with small cell lung cancer.”

The authors disclosed multiple relationships with companies. The study was supported by the National Institutes of Health/National Cancer Institute, the University of Texas Southwestern and MD Anderson Cancer Center, and a variety of other governmental and nonprofit groups. Dr. Rudin is principal investigator of the NCI small cell lung cancer research consortium.

Researchers studying a large set of small cell lung cancer (SCLC) tumor samples have identified four SCLC subtypes, and they propose that matching baseline tumor subtypes to SCLC therapy may enhance the depth and duration of response.

Carl M. Gay, MD, PhD, of University of Texas MD Anderson Cancer Center in Houston, and colleagues conducted this research and described their findings in Cancer Cell.

The authors noted that survival rates in SCLC remain dismal despite recent modest gains in progression-free survival and overall survival achieved through adding immunotherapy to platinum-based frontline chemotherapy.

Based on transcription factors indicating which genes are activated, prior research had already identified three possible SCLC subtypes. Many SCLC tumors, however, do not fit into one of these three groups, the authors said.
 

Inflamed gene signature

The four groups were identified using tumor expression data and nonnegative matrix factorization from published sources on 81 SCLC patients, and then validated via the largest SCLC data set available (276 SCLC patients enrolled in the phase 3 IMpower133 trial).

The SCLC subtypes were defined largely by differential expression of transcription factors – subtype SCLC-A by ASCL1, subtype SCLC-N by NEUROD1, and subtype SCLC-P by POU2F3. The fourth subtype, SCLC-I, is characterized by low expression of all three transcription factor signatures and an inflamed gene signature with a high expression of multiple immune genes, including significantly greater levels of genes indicating the presence of CD8-positive cytotoxic T cells.

Because each subtype demonstrates unique vulnerability to investigational therapies, this subtype classification has significant clinical implications.

“We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients,” the authors stated.

“Our paper shows that the inflamed group has a distinct biology and environment and tends to be more responsive to immunotherapy,” study author Lauren Averett Byers, MD, also of the University of Texas MD Anderson Cancer Center, stated in a press release. “Identifying the inflamed group is very important because, so far, there have not been any validated biomarkers for small cell lung cancer that predict which patients get the most benefit from immunotherapy.”

In samples from the other three subtypes, SCLC-A was most responsive to BCL2 inhibitors, SCLC-N to Aurora kinase inhibitors, and SCLC-P to PARP inhibitors.

Treatment resistance

The tendency of SCLC to develop treatment resistance, even after an initial response, is a known challenge. Using single-cell RNA sequencing to evaluate tumor evolution, the authors observed a tendency of SCLC-A to switch to SCLC-I after chemotherapy treatment, a possible contributor to treatment resistance.

It will be necessary to verify the study findings through further investigations, particularly regarding the therapeutic vulnerabilities for each group.

“Now we can develop more effective strategies for each group in clinical trials, taking into account that they each have different biology and optimal drug targets,” Dr. Byers said. “As a field, small cell lung cancer is about 15 years behind non–small cell lung cancer’s renaissance of biomarkers and personalized therapies. This represents a huge step in understanding which drugs work best for which patients and gives us a path forward for personalized approaches for small cell lung cancer.”

“Dr. Gay’s work is the latest in a growing series of exciting studies demonstrating the utility of defining subtypes of small cell lung cancer based on expression of master transcriptional regulators,” commented Charles Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, in an interview.

He added, “While tumors can evolve between some of these categories, the dominant subtype assignment influences therapeutic vulnerabilities. It is an exciting time for those of us engaged in small cell research. Subtyping should help guide more focused and successful clinical trials for patients with small cell lung cancer.”

The authors disclosed multiple relationships with companies. The study was supported by the National Institutes of Health/National Cancer Institute, the University of Texas Southwestern and MD Anderson Cancer Center, and a variety of other governmental and nonprofit groups. Dr. Rudin is principal investigator of the NCI small cell lung cancer research consortium.

Researchers studying a large set of small cell lung cancer (SCLC) tumor samples have identified four SCLC subtypes, and they propose that matching baseline tumor subtypes to SCLC therapy may enhance the depth and duration of response.

Carl M. Gay, MD, PhD, of University of Texas MD Anderson Cancer Center in Houston, and colleagues conducted this research and described their findings in Cancer Cell.

The authors noted that survival rates in SCLC remain dismal despite recent modest gains in progression-free survival and overall survival achieved through adding immunotherapy to platinum-based frontline chemotherapy.

Based on transcription factors indicating which genes are activated, prior research had already identified three possible SCLC subtypes. Many SCLC tumors, however, do not fit into one of these three groups, the authors said.
 

Inflamed gene signature

The four groups were identified using tumor expression data and nonnegative matrix factorization from published sources on 81 SCLC patients, and then validated via the largest SCLC data set available (276 SCLC patients enrolled in the phase 3 IMpower133 trial).

The SCLC subtypes were defined largely by differential expression of transcription factors – subtype SCLC-A by ASCL1, subtype SCLC-N by NEUROD1, and subtype SCLC-P by POU2F3. The fourth subtype, SCLC-I, is characterized by low expression of all three transcription factor signatures and an inflamed gene signature with a high expression of multiple immune genes, including significantly greater levels of genes indicating the presence of CD8-positive cytotoxic T cells.

Because each subtype demonstrates unique vulnerability to investigational therapies, this subtype classification has significant clinical implications.

“We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients,” the authors stated.

“Our paper shows that the inflamed group has a distinct biology and environment and tends to be more responsive to immunotherapy,” study author Lauren Averett Byers, MD, also of the University of Texas MD Anderson Cancer Center, stated in a press release. “Identifying the inflamed group is very important because, so far, there have not been any validated biomarkers for small cell lung cancer that predict which patients get the most benefit from immunotherapy.”

In samples from the other three subtypes, SCLC-A was most responsive to BCL2 inhibitors, SCLC-N to Aurora kinase inhibitors, and SCLC-P to PARP inhibitors.

Treatment resistance

The tendency of SCLC to develop treatment resistance, even after an initial response, is a known challenge. Using single-cell RNA sequencing to evaluate tumor evolution, the authors observed a tendency of SCLC-A to switch to SCLC-I after chemotherapy treatment, a possible contributor to treatment resistance.

It will be necessary to verify the study findings through further investigations, particularly regarding the therapeutic vulnerabilities for each group.

“Now we can develop more effective strategies for each group in clinical trials, taking into account that they each have different biology and optimal drug targets,” Dr. Byers said. “As a field, small cell lung cancer is about 15 years behind non–small cell lung cancer’s renaissance of biomarkers and personalized therapies. This represents a huge step in understanding which drugs work best for which patients and gives us a path forward for personalized approaches for small cell lung cancer.”

“Dr. Gay’s work is the latest in a growing series of exciting studies demonstrating the utility of defining subtypes of small cell lung cancer based on expression of master transcriptional regulators,” commented Charles Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, in an interview.

He added, “While tumors can evolve between some of these categories, the dominant subtype assignment influences therapeutic vulnerabilities. It is an exciting time for those of us engaged in small cell research. Subtyping should help guide more focused and successful clinical trials for patients with small cell lung cancer.”

The authors disclosed multiple relationships with companies. The study was supported by the National Institutes of Health/National Cancer Institute, the University of Texas Southwestern and MD Anderson Cancer Center, and a variety of other governmental and nonprofit groups. Dr. Rudin is principal investigator of the NCI small cell lung cancer research consortium.

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

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

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

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

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

Two new approaches to surveillance imaging after treatment of stage I testicular seminoma sharply reduce or eliminate radiation exposure relative to the standard approach, without substantially compromising relapse detection, the phase 3 TRISST study suggests.

Results were reported at the 2021 Genitourinary Cancers Symposium (Abstract 374).

“Stage I seminoma has a survival that approaches 100%. Over recent years, CT surveillance has become an international standard of care and has largely replaced the use of adjuvant treatment,” said investigator Robert A. Huddart, MRCP, FRCR, PhD, of The Royal Marsden NHS Foundation Trust, London.

“A typical surveillance protocol, however, consists of multiple CT scans taken over a period of a few years and results in quite a high diagnostic radiation dose, which has raised questions about the long-term risk of second malignancies related to this program,” he noted. “At the moment, there is no evidence base to inform how frequently imaging should be undertaken and the type of imaging that should be used.”

Results of TRISST showed that, with a median 6-year follow-up during which men were monitored with various surveillance protocols, 1.5% experienced a relapse that was advanced (stage IIC or higher) at detection.

The incidence of relapse was 0.3% with the standard schedule of seven abdominal surveillance scans and a statistically noninferior 2.8% with three more widely spaced scans. Also, compared with the standard CT scans, which yielded an incidence of 2.6%, MRI scans were noninferior, yielding an incidence of 0.6%.

“The three-scan schedule was noninferior to seven scans in our protocol, and in fact, with the three-scan schedule, we would use over 1,000 fewer scans at a cost of perhaps having four relapses that could have been avoided,” Dr. Huddart pointed out. “We can conclude that MRI is noninferior to CT and should be recommended to avoid irradiation. This study will provide an evidence base for making the transition to MRI, which is important. The MRI scan is more complex – it takes longer and is more resource heavy. So we do need to supply the evidence that it is the right thing to do for patients.”

Need for expertise in interpreting MRI scans is a valid concern, he acknowledged. “There is a degree of specialization in the UK for testis cancer management, and clearly, you had to be specialist to take part in the study. So I can’t say it is your everyday radiologist, but the data would suggest we actually saw less errors in terms of pickup with the MRI scan than with the CT scan,” he said. “You do need to have a level of expertise, but it doesn’t require super-specialist expertise. I suppose that will be a learning lesson for all of us, to learn better MRI interpretation if we are using MRI.”
 

Trial details

The 669 men randomized in TRISST (NCT00589537), a multicenter trial with a factorial and noninferiority design, had undergone orchiectomy for stage I seminoma and did not have any adjuvant therapy planned.

They were randomized once on number of surveillance scans: seven scans (at 6, 12, 18, 24, 36, 48, and 60 months) vs. three scans (at 6, 18, and 36 months). And they were randomized again on scan modality: CT versus MRI. All groups had similar follow-up otherwise, consisting of periodic chest radiographs, tumor marker tests, and clinical assessments.

The primary outcome, 6-year incidence of advanced relapse defined as stage IIC or higher (i.e., measuring 5 cm or greater) by Royal Marsden Hospital criteria, was chosen because, when the study began, this was the dividing point between using local therapy and using systemic multiagent chemotherapy to treat a relapse, Dr. Huddart explained.

Among men remaining on surveillance, compliance was good, with 94% of all scans attended and 79% performed on time, he reported.

Overall, 12% of the randomized population experienced a relapse of any stage during follow-up, with nearly all relapses occurring within the first 3 years.

The 6-year incidence of advanced relapse was just 1.5% in the entire trial population, lower than the 5.7% expected in trial planning, according to Dr. Huddart.

In intention-to-treat analyses, the incidence was 2.8% with the three-scan schedule and 0.3% with the seven-scan schedule, with the difference of 2.6% and the bounds of the 90% confidence interval falling within the predefined noninferiority margin of 5.7%.

Using three scans instead of seven scans increased the proportion of patients with relapse who had advanced stage from 3% to 20%. Four of the nine advanced relapses occurring with the three-scan schedule could possibly have been detected earlier with the seven-scan schedule.

The 6-year incidence of advanced relapse was 0.6% with MRI scans and 2.6% with CT scans. The difference of –1.9% and the bounds of the 90% confidence interval fell within the noninferiority margin. Use of MRI instead of CT reduced the proportion of patients with relapse who had advanced stage from 20% to 5%.

For both the scan frequency comparison and the scan modality comparison, findings were essentially the same in per protocol analyses and in analyses that instead looked at relapses measuring 3 cm or greater, according to Dr. Huddart.

Fully 89% of patients with advanced relapses were treated with chemotherapy only, and 56% of all patients with advanced relapse had a response to their treatment.

Most patients experiencing a relapse of any stage, 93%, were alive and free of disease at their most recent follow-up, Dr. Huddart reported. Overall survival for the trial population was 99% and similar across surveillance groups, with no deaths due to testicular cancer.
 

Risk-tailored surveillance

“Noninferiority trials are much more challenging than equivalence or superiority trials,” observed invited discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University, Turkey.

She expressed some reservations about TRISST results, including the much lower than expected incidence of advanced relapse, which may have affected comparisons, and problematic compliance, as about one-quarter of patients stopped surveillance before relapse or withdrew from the trial before 6 years of follow-up.

Recurrence after treatment of stage I seminoma is largely driven by the risk factors of tumor size exceeding 4 cm and presence of rete testis invasion, and 54% of TRISST patients did not have either of these factors, Dr. Laguna noted.

“While a more relaxed schedule may well suit those patients at low risk, more intense schedules will be appropriate for patients with risk factors,” she maintained. “I am pretty sure that the TRISST trial will impact future guideline recommendations, although still I think that one approach may not fit all.”

TRISST was funded by Cancer Research UK and the MRC Clinical Trials Unit. Dr. Huddart disclosed relationships with Janssen Oncology, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, and Roche. Dr. Laguna disclosed that she is chair of the EAU Testicular Cancer Guidelines Panel.

This past year, the referrals to my private practice have taken a noticeable shift and caused me to pause.

HRAUN/Getty Images

More calls have come from nurses, many who work directly with COVID-19 patients, understandably seeking mental health treatment, or support. Especially in this time, nurses are facing trauma and stress that is unimaginable to many, myself included. Despite the collective efforts we have made as a society to recognize their work, I do not think we have given enough consideration to the enormous sacrifice nurses are currently undertaking to save our collective psyche.

As physicians and mental health providers, we have a glimpse into the complexities and stressors of medical treatment. In our line of work, we support patients with trauma on a regular basis. We feel deeply connected to patients, some of whom we have treated until the end of their lives. Despite that, I am not sure that I, or anyone, can truly comprehend what nurses face in today’s climate of care.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com.

References

1. Rogers CR. J Consult Psychol. 1957;21(2):95-103.

2. Mallo CJ, Mintz DL. Psychodyn Psychiatry. 2013 Mar;41(1):13-37.

3. Resick PA et al. Cognitive Processing Therapy for PTSD: A Comprehensive Manual. Guilford Publications, 2016.

This past year, the referrals to my private practice have taken a noticeable shift and caused me to pause.

HRAUN/Getty Images

More calls have come from nurses, many who work directly with COVID-19 patients, understandably seeking mental health treatment, or support. Especially in this time, nurses are facing trauma and stress that is unimaginable to many, myself included. Despite the collective efforts we have made as a society to recognize their work, I do not think we have given enough consideration to the enormous sacrifice nurses are currently undertaking to save our collective psyche.

As physicians and mental health providers, we have a glimpse into the complexities and stressors of medical treatment. In our line of work, we support patients with trauma on a regular basis. We feel deeply connected to patients, some of whom we have treated until the end of their lives. Despite that, I am not sure that I, or anyone, can truly comprehend what nurses face in today’s climate of care.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com.

References

1. Rogers CR. J Consult Psychol. 1957;21(2):95-103.

2. Mallo CJ, Mintz DL. Psychodyn Psychiatry. 2013 Mar;41(1):13-37.

3. Resick PA et al. Cognitive Processing Therapy for PTSD: A Comprehensive Manual. Guilford Publications, 2016.

This past year, the referrals to my private practice have taken a noticeable shift and caused me to pause.

HRAUN/Getty Images

More calls have come from nurses, many who work directly with COVID-19 patients, understandably seeking mental health treatment, or support. Especially in this time, nurses are facing trauma and stress that is unimaginable to many, myself included. Despite the collective efforts we have made as a society to recognize their work, I do not think we have given enough consideration to the enormous sacrifice nurses are currently undertaking to save our collective psyche.

As physicians and mental health providers, we have a glimpse into the complexities and stressors of medical treatment. In our line of work, we support patients with trauma on a regular basis. We feel deeply connected to patients, some of whom we have treated until the end of their lives. Despite that, I am not sure that I, or anyone, can truly comprehend what nurses face in today’s climate of care.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com.

References

1. Rogers CR. J Consult Psychol. 1957;21(2):95-103.

2. Mallo CJ, Mintz DL. Psychodyn Psychiatry. 2013 Mar;41(1):13-37.

3. Resick PA et al. Cognitive Processing Therapy for PTSD: A Comprehensive Manual. Guilford Publications, 2016.

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

[email protected]

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

[email protected]

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

[email protected]

About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.

“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.

The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.

Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.

European Heart Journal

Glass half full

Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.

“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.

“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.

In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”

She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”

The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.

“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”

Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.

“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.

His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.

“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”

He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.

“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
 

Largest study to date

The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.

Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.

Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.

Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m².

CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.

On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”

The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”

What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.

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

About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.

“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.

The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.

Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.

European Heart Journal

Glass half full

Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.

“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.

“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.

In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”

She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”

The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.

“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”

Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.

“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.

His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.

“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”

He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.

“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
 

Largest study to date

The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.

Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.

Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.

Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m².

CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.

On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”

The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”

What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.

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

About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.

“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.

The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.

Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.

European Heart Journal

Glass half full

Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.

“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.

“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.

In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”

She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”

The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.

“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”

Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.

“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.

His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.

“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”

He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.

“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
 

Largest study to date

The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.

Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.

Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.

Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m².

CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.

On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”

The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”

What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.

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

The prevalence of asymptomatic central sleep apnea after acute coronary syndrome is high and may be associated with the use of ticagrelor, a new study finds.
Prior studies have suggested that ticagrelor is associated with an increased likelihood of central sleep apnea. The drug’s label notes that two respiratory conditions – central sleep apnea and Cheyne-Stokes respiration – are adverse reactions that were identified after the drug’s approval in the United States in 2011. “Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the label says. 
Among 80 patients receiving ticagrelor, 24 had central sleep apnea hypopnea syndrome (CSAHS), whereas of 41 patients not taking ticagrelor, 3 had this condition (30% vs. 7.3%, P = .004), in the new study published online Jan. 20, 2021, in Sleep Medicine. A multivariable analysis included in the paper found that age and ticagrelor administration were the only two factors associated with the occurrence of CSAHS.

Findings are ‘striking’

The different rates of central sleep apnea in the study are striking, but it is not clear that asymptomatic central sleep apnea in patients taking ticagrelor is a concern, Ofer Jacobowitz, MD, PhD, associate professor of otolaryngology at Hofstra University, Hempstead, N.Y, said in an interview.

Study author continues to prescribe ticagrelor

One of the study authors, Philippe Meurin, MD, said that he continues to prescribe ticagrelor every day and that the side effect is not necessarily important. 
It is possible that central sleep apnea may resolve, although further studies would need to examine central sleep apnea over time to establish the duration of the condition, he added. Nevertheless, awareness of the association could have implications for clinical practice, Dr. Meurin said.
Central sleep apnea is rare, and if doctors detect it during a sleep study, they may perform extensive tests to assess for possible neurologic diseases, for example, when the cause may be attributed to the medication, he said. In addition, if a patient who is taking ticagrelor has dyspnea, the presence of central sleep apnea may suggest that dyspnea could be related to the drug, although this possibility needs further study, he noted.

Study included patients with ACS history, but no heart failure

Dr. Meurin, of Centre de Réadaptation Cardiaque de La Brie, Les Grands Prés, Villeneuve-Saint-Denis, France, and colleagues included in their study patients between 1 week and 1 year after acute coronary syndrome who did not have heart failure or a history of sleep apnea.
After an overnight sleep study, they classified patients as normal, as having CSAHS (i.e., an apnea-hypopnea index of 15 or greater, mostly with central sleep apneas), or as having obstructive sleep apnea hypopnea syndrome (OSAHS; i.e., an apnea-hypopnea index of 15 or greater, mostly with obstructive sleep apneas).
The prospective study included 121 consecutive patients between January 2018 and March 2020. Patients had a mean age of 56.8, and 88% were men.

Switching to another P2Y12 inhibitor ‘does not seem appropriate’

“CSAHS could be promoted by the use of ticagrelor, a relatively new drug that modifies the apneic threshold,” the study authors wrote. “Regarding underlying mechanisms, the most probable explanation seems to be increased chemosensitivity to hypercapnia by a direct P2Y12 inhibitory effect on the central nervous system.”
Doctors should not overestimate the severity of the adverse reaction or consider it the same way they do OSASH, they added. 
Among patients with acute coronary syndrome in the PLATO study, ticagrelor, compared with clopidogrel, “significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke,” Dr. Meurin and colleagues said. “Because in this study more than 9,000 patients received ticagrelor for 12 months, CSAHS (even if it seems frequent in our study) did not seem to impair the good efficacy/tolerance balance of the drug. Therefore, in asymptomatic CSAHS patients, switching from ticagrelor to another P2Y12 inhibitor does not seem appropriate.”
A recent analysis of data from randomized, controlled trials with ticagrelor did not find excess cases of sleep apnea with the drug. But an asymptomatic adverse event such as central sleep apnea “cannot emerge from a post hoc analysis,” Dr. Meurin and colleagues said.
The analysis of randomized trial data was conducted by Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital, and coauthors. It was published in JACC: Cardiovascular Interventions in April 2020.
They “used the gold standard for medical evidence (randomized, placebo-controlled trials) and found 158 cases of sleep apnea reported, with absolutely no difference between ticagrelor and placebo,” Dr. Sabatine said in an interview. Their analysis examined clinically overt apnea, he noted.
“It is quite clear that when looking at large numbers in placebo-controlled trials, there is no excess,” Dr. Sabatine said. “Meurin et al. are examining a different outcome: the results of a lab test in what may be entirely asymptomatic patients.”
A randomized trial could confirm the association, he said.
“The association may be real, but also may be play of chance or confounded,” said Dr. Sabatine. “To convince the medical community, the next step would be for the investigators to do a randomized trial and test whether ticagrelor increases the risk of central sleep apnea.”
Dr. Meurin and the study coauthors had no disclosures. The analysis of randomized, controlled trial data by Dr. Sabatine and colleagues was funded by AstraZeneca, which distributes ticagrelor under the trade name Brilinta. Dr. Sabatine has been a consultant for AstraZeneca and received research grants through Brigham and Women’s Hospital from AstraZeneca. He has consulted for and received grants through the hospital from other companies as well. Dr. Jacobowitz had no relevant disclosures.
[email protected] 

The prevalence of asymptomatic central sleep apnea after acute coronary syndrome is high and may be associated with the use of ticagrelor, a new study finds.
Prior studies have suggested that ticagrelor is associated with an increased likelihood of central sleep apnea. The drug’s label notes that two respiratory conditions – central sleep apnea and Cheyne-Stokes respiration – are adverse reactions that were identified after the drug’s approval in the United States in 2011. “Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the label says. 
Among 80 patients receiving ticagrelor, 24 had central sleep apnea hypopnea syndrome (CSAHS), whereas of 41 patients not taking ticagrelor, 3 had this condition (30% vs. 7.3%, P = .004), in the new study published online Jan. 20, 2021, in Sleep Medicine. A multivariable analysis included in the paper found that age and ticagrelor administration were the only two factors associated with the occurrence of CSAHS.

Findings are ‘striking’

The different rates of central sleep apnea in the study are striking, but it is not clear that asymptomatic central sleep apnea in patients taking ticagrelor is a concern, Ofer Jacobowitz, MD, PhD, associate professor of otolaryngology at Hofstra University, Hempstead, N.Y, said in an interview.

Study author continues to prescribe ticagrelor

One of the study authors, Philippe Meurin, MD, said that he continues to prescribe ticagrelor every day and that the side effect is not necessarily important. 
It is possible that central sleep apnea may resolve, although further studies would need to examine central sleep apnea over time to establish the duration of the condition, he added. Nevertheless, awareness of the association could have implications for clinical practice, Dr. Meurin said.
Central sleep apnea is rare, and if doctors detect it during a sleep study, they may perform extensive tests to assess for possible neurologic diseases, for example, when the cause may be attributed to the medication, he said. In addition, if a patient who is taking ticagrelor has dyspnea, the presence of central sleep apnea may suggest that dyspnea could be related to the drug, although this possibility needs further study, he noted.

Study included patients with ACS history, but no heart failure

Dr. Meurin, of Centre de Réadaptation Cardiaque de La Brie, Les Grands Prés, Villeneuve-Saint-Denis, France, and colleagues included in their study patients between 1 week and 1 year after acute coronary syndrome who did not have heart failure or a history of sleep apnea.
After an overnight sleep study, they classified patients as normal, as having CSAHS (i.e., an apnea-hypopnea index of 15 or greater, mostly with central sleep apneas), or as having obstructive sleep apnea hypopnea syndrome (OSAHS; i.e., an apnea-hypopnea index of 15 or greater, mostly with obstructive sleep apneas).
The prospective study included 121 consecutive patients between January 2018 and March 2020. Patients had a mean age of 56.8, and 88% were men.

Switching to another P2Y12 inhibitor ‘does not seem appropriate’

“CSAHS could be promoted by the use of ticagrelor, a relatively new drug that modifies the apneic threshold,” the study authors wrote. “Regarding underlying mechanisms, the most probable explanation seems to be increased chemosensitivity to hypercapnia by a direct P2Y12 inhibitory effect on the central nervous system.”
Doctors should not overestimate the severity of the adverse reaction or consider it the same way they do OSASH, they added. 
Among patients with acute coronary syndrome in the PLATO study, ticagrelor, compared with clopidogrel, “significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke,” Dr. Meurin and colleagues said. “Because in this study more than 9,000 patients received ticagrelor for 12 months, CSAHS (even if it seems frequent in our study) did not seem to impair the good efficacy/tolerance balance of the drug. Therefore, in asymptomatic CSAHS patients, switching from ticagrelor to another P2Y12 inhibitor does not seem appropriate.”
A recent analysis of data from randomized, controlled trials with ticagrelor did not find excess cases of sleep apnea with the drug. But an asymptomatic adverse event such as central sleep apnea “cannot emerge from a post hoc analysis,” Dr. Meurin and colleagues said.
The analysis of randomized trial data was conducted by Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital, and coauthors. It was published in JACC: Cardiovascular Interventions in April 2020.
They “used the gold standard for medical evidence (randomized, placebo-controlled trials) and found 158 cases of sleep apnea reported, with absolutely no difference between ticagrelor and placebo,” Dr. Sabatine said in an interview. Their analysis examined clinically overt apnea, he noted.
“It is quite clear that when looking at large numbers in placebo-controlled trials, there is no excess,” Dr. Sabatine said. “Meurin et al. are examining a different outcome: the results of a lab test in what may be entirely asymptomatic patients.”
A randomized trial could confirm the association, he said.
“The association may be real, but also may be play of chance or confounded,” said Dr. Sabatine. “To convince the medical community, the next step would be for the investigators to do a randomized trial and test whether ticagrelor increases the risk of central sleep apnea.”
Dr. Meurin and the study coauthors had no disclosures. The analysis of randomized, controlled trial data by Dr. Sabatine and colleagues was funded by AstraZeneca, which distributes ticagrelor under the trade name Brilinta. Dr. Sabatine has been a consultant for AstraZeneca and received research grants through Brigham and Women’s Hospital from AstraZeneca. He has consulted for and received grants through the hospital from other companies as well. Dr. Jacobowitz had no relevant disclosures.
[email protected] 

The prevalence of asymptomatic central sleep apnea after acute coronary syndrome is high and may be associated with the use of ticagrelor, a new study finds.
Prior studies have suggested that ticagrelor is associated with an increased likelihood of central sleep apnea. The drug’s label notes that two respiratory conditions – central sleep apnea and Cheyne-Stokes respiration – are adverse reactions that were identified after the drug’s approval in the United States in 2011. “Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the label says. 
Among 80 patients receiving ticagrelor, 24 had central sleep apnea hypopnea syndrome (CSAHS), whereas of 41 patients not taking ticagrelor, 3 had this condition (30% vs. 7.3%, P = .004), in the new study published online Jan. 20, 2021, in Sleep Medicine. A multivariable analysis included in the paper found that age and ticagrelor administration were the only two factors associated with the occurrence of CSAHS.

Findings are ‘striking’

The different rates of central sleep apnea in the study are striking, but it is not clear that asymptomatic central sleep apnea in patients taking ticagrelor is a concern, Ofer Jacobowitz, MD, PhD, associate professor of otolaryngology at Hofstra University, Hempstead, N.Y, said in an interview.

Study author continues to prescribe ticagrelor

One of the study authors, Philippe Meurin, MD, said that he continues to prescribe ticagrelor every day and that the side effect is not necessarily important. 
It is possible that central sleep apnea may resolve, although further studies would need to examine central sleep apnea over time to establish the duration of the condition, he added. Nevertheless, awareness of the association could have implications for clinical practice, Dr. Meurin said.
Central sleep apnea is rare, and if doctors detect it during a sleep study, they may perform extensive tests to assess for possible neurologic diseases, for example, when the cause may be attributed to the medication, he said. In addition, if a patient who is taking ticagrelor has dyspnea, the presence of central sleep apnea may suggest that dyspnea could be related to the drug, although this possibility needs further study, he noted.

Study included patients with ACS history, but no heart failure

Dr. Meurin, of Centre de Réadaptation Cardiaque de La Brie, Les Grands Prés, Villeneuve-Saint-Denis, France, and colleagues included in their study patients between 1 week and 1 year after acute coronary syndrome who did not have heart failure or a history of sleep apnea.
After an overnight sleep study, they classified patients as normal, as having CSAHS (i.e., an apnea-hypopnea index of 15 or greater, mostly with central sleep apneas), or as having obstructive sleep apnea hypopnea syndrome (OSAHS; i.e., an apnea-hypopnea index of 15 or greater, mostly with obstructive sleep apneas).
The prospective study included 121 consecutive patients between January 2018 and March 2020. Patients had a mean age of 56.8, and 88% were men.

Switching to another P2Y12 inhibitor ‘does not seem appropriate’

“CSAHS could be promoted by the use of ticagrelor, a relatively new drug that modifies the apneic threshold,” the study authors wrote. “Regarding underlying mechanisms, the most probable explanation seems to be increased chemosensitivity to hypercapnia by a direct P2Y12 inhibitory effect on the central nervous system.”
Doctors should not overestimate the severity of the adverse reaction or consider it the same way they do OSASH, they added. 
Among patients with acute coronary syndrome in the PLATO study, ticagrelor, compared with clopidogrel, “significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke,” Dr. Meurin and colleagues said. “Because in this study more than 9,000 patients received ticagrelor for 12 months, CSAHS (even if it seems frequent in our study) did not seem to impair the good efficacy/tolerance balance of the drug. Therefore, in asymptomatic CSAHS patients, switching from ticagrelor to another P2Y12 inhibitor does not seem appropriate.”
A recent analysis of data from randomized, controlled trials with ticagrelor did not find excess cases of sleep apnea with the drug. But an asymptomatic adverse event such as central sleep apnea “cannot emerge from a post hoc analysis,” Dr. Meurin and colleagues said.
The analysis of randomized trial data was conducted by Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital, and coauthors. It was published in JACC: Cardiovascular Interventions in April 2020.
They “used the gold standard for medical evidence (randomized, placebo-controlled trials) and found 158 cases of sleep apnea reported, with absolutely no difference between ticagrelor and placebo,” Dr. Sabatine said in an interview. Their analysis examined clinically overt apnea, he noted.
“It is quite clear that when looking at large numbers in placebo-controlled trials, there is no excess,” Dr. Sabatine said. “Meurin et al. are examining a different outcome: the results of a lab test in what may be entirely asymptomatic patients.”
A randomized trial could confirm the association, he said.
“The association may be real, but also may be play of chance or confounded,” said Dr. Sabatine. “To convince the medical community, the next step would be for the investigators to do a randomized trial and test whether ticagrelor increases the risk of central sleep apnea.”
Dr. Meurin and the study coauthors had no disclosures. The analysis of randomized, controlled trial data by Dr. Sabatine and colleagues was funded by AstraZeneca, which distributes ticagrelor under the trade name Brilinta. Dr. Sabatine has been a consultant for AstraZeneca and received research grants through Brigham and Women’s Hospital from AstraZeneca. He has consulted for and received grants through the hospital from other companies as well. Dr. Jacobowitz had no relevant disclosures.
[email protected] 

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Successful innovation requires experimentation, according to a recent editorial in BMJ Quality & Safety – that’s why health systems should engage in more experimenting, more systematically, to improve health care.

“Most health systems implement interventions without testing them against other designs,” said co-author Mitesh S. Patel, MD, MBA, MS, of the University of Pennsylvania, Philadelphia. “This means that good ideas are often not spread (because we don’t know how impactful they are) and bad ones persist (because we don’t realize they don’t work).”

Dr. Patel, who is director of the Penn Medicine Nudge Unit at the Perelman Center for Advanced Medicine, encourages health systems and clinicians to implement new interventions in testable ways such as through a randomized trial, so that we can learn what works and why. A more systematic approach could help to expand programs that work and improve workflow and patient care.

“First, we must embed research teams within health systems in order to create the capacity for this kind of work. Expertise is required to identify a promising intervention, design the conceptual approach, conduct the technical implementation and rigorously evaluate the trial. These teams are also able to design interventions within the context of existing workflows in order to ensure that successful projects can be quickly scaled and that ineffective initiatives can be seamlessly terminated.” the authors wrote.

“Second, we must take advantage of existing data systems. The field of health care is ripe with detailed and reliable administrative data and electronic medical record data. These data offer the potential to do high-quality, low-cost, rapid trials. Third, we must measure a wide range of meaningful outcomes. We should examine the effect of interventions on health care costs, health care utilization and health outcomes.”

Next steps could be focused on thinking about the key priority areas and how can experiments be used to generate new knowledge on what works and what does not. “Luckily, the complex world of health care provides endless opportunities for rapid-cycle, randomized trials that target health care costs and outcomes,” Dr. Patel said.
 

Reference

1. Oakes AH, Patel MS. A nudge towards increased experimentation to more rapidly improve healthcare. BMJ Qual Saf. 2020;29:179-181. doi: 10.1136/bmjqs-2019-009948. Accessed Dec 3, 2019.

Successful innovation requires experimentation, according to a recent editorial in BMJ Quality & Safety – that’s why health systems should engage in more experimenting, more systematically, to improve health care.

“Most health systems implement interventions without testing them against other designs,” said co-author Mitesh S. Patel, MD, MBA, MS, of the University of Pennsylvania, Philadelphia. “This means that good ideas are often not spread (because we don’t know how impactful they are) and bad ones persist (because we don’t realize they don’t work).”

Dr. Patel, who is director of the Penn Medicine Nudge Unit at the Perelman Center for Advanced Medicine, encourages health systems and clinicians to implement new interventions in testable ways such as through a randomized trial, so that we can learn what works and why. A more systematic approach could help to expand programs that work and improve workflow and patient care.

“First, we must embed research teams within health systems in order to create the capacity for this kind of work. Expertise is required to identify a promising intervention, design the conceptual approach, conduct the technical implementation and rigorously evaluate the trial. These teams are also able to design interventions within the context of existing workflows in order to ensure that successful projects can be quickly scaled and that ineffective initiatives can be seamlessly terminated.” the authors wrote.

“Second, we must take advantage of existing data systems. The field of health care is ripe with detailed and reliable administrative data and electronic medical record data. These data offer the potential to do high-quality, low-cost, rapid trials. Third, we must measure a wide range of meaningful outcomes. We should examine the effect of interventions on health care costs, health care utilization and health outcomes.”

Next steps could be focused on thinking about the key priority areas and how can experiments be used to generate new knowledge on what works and what does not. “Luckily, the complex world of health care provides endless opportunities for rapid-cycle, randomized trials that target health care costs and outcomes,” Dr. Patel said.
 

Reference

1. Oakes AH, Patel MS. A nudge towards increased experimentation to more rapidly improve healthcare. BMJ Qual Saf. 2020;29:179-181. doi: 10.1136/bmjqs-2019-009948. Accessed Dec 3, 2019.

Successful innovation requires experimentation, according to a recent editorial in BMJ Quality & Safety – that’s why health systems should engage in more experimenting, more systematically, to improve health care.

“Most health systems implement interventions without testing them against other designs,” said co-author Mitesh S. Patel, MD, MBA, MS, of the University of Pennsylvania, Philadelphia. “This means that good ideas are often not spread (because we don’t know how impactful they are) and bad ones persist (because we don’t realize they don’t work).”

Dr. Patel, who is director of the Penn Medicine Nudge Unit at the Perelman Center for Advanced Medicine, encourages health systems and clinicians to implement new interventions in testable ways such as through a randomized trial, so that we can learn what works and why. A more systematic approach could help to expand programs that work and improve workflow and patient care.

“First, we must embed research teams within health systems in order to create the capacity for this kind of work. Expertise is required to identify a promising intervention, design the conceptual approach, conduct the technical implementation and rigorously evaluate the trial. These teams are also able to design interventions within the context of existing workflows in order to ensure that successful projects can be quickly scaled and that ineffective initiatives can be seamlessly terminated.” the authors wrote.

“Second, we must take advantage of existing data systems. The field of health care is ripe with detailed and reliable administrative data and electronic medical record data. These data offer the potential to do high-quality, low-cost, rapid trials. Third, we must measure a wide range of meaningful outcomes. We should examine the effect of interventions on health care costs, health care utilization and health outcomes.”

Next steps could be focused on thinking about the key priority areas and how can experiments be used to generate new knowledge on what works and what does not. “Luckily, the complex world of health care provides endless opportunities for rapid-cycle, randomized trials that target health care costs and outcomes,” Dr. Patel said.
 

Reference

1. Oakes AH, Patel MS. A nudge towards increased experimentation to more rapidly improve healthcare. BMJ Qual Saf. 2020;29:179-181. doi: 10.1136/bmjqs-2019-009948. Accessed Dec 3, 2019.