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New-onset arrhythmias low in COVID-19 and flu
Among 3,970 patients treated during the early months of the pandemic, new onset AF/AFL was seen in 4%, matching the 4% incidence found in a historic cohort of patients hospitalized with influenza.
On the other hand, mortality was similarly high in both groups of patients studied with AF/AFL, showing a 77% increased risk of death in COVID-19 and a 78% increased risk in influenza, a team from Icahn School of Medicine at Mount Sinai in New York reported.
“We saw new onset Afib and flutter in a minority of patients and it was associated with much higher mortality, but the point is that this increase is basically the same as what you see in influenza, which we feel is an indication that this is more of a generalized response to the inflammatory milieu of such a severe viral illness, as opposed to something specific to COVID,” Vivek Y. Reddy, MD, said in the report, published online Feb. 25 in JACC: Clinical Electrophysiology.
“Here we see, with a similar respiratory virus used as controls, that the results are exactly what I would have expected to see, which is that where there is a lot of inflammation, we see Afib,” said John Mandrola, MD, of Baptist Medical Associates, Louisville, Ky., who was not involved with the study.
“We need more studies like this one because we know SARS-CoV-2 is a bad virus that may have important effects on the heart, but all the of research done so far has been problematic because it didn’t include controls.”
Atrial arrhythmias in COVID and flu
Dr. Reddy and coinvestigators performed a retrospective analysis of a large cohort of patients admitted with laboratory-confirmed COVID-19 during Feb. 4-April 22, 2020, to one of five hospitals within the Mount Sinai Health System.
Their comparator arm included 1,420 patients with confirmed influenza A or B hospitalized between Jan. 1, 2017, and Jan. 1, 2020. For both cohorts, automated electronic record abstraction was used and all patient data were de-identified prior to analysis. In the COVID-19 cohort, a manual review of 1,110 charts was also performed.
Compared with those who did not develop AF/AFL, COVID-19 patients with newly detected AF/AFL and COVID-19 were older (74 vs. 66 years; P < .01) and had higher levels of inflammatory markers, including C-reactive protein and interleukin-6, and higher troponin and D-dimer levels (all P < .01).
Overall, including those with a history of atrial arrhythmias, 10% of patients with hospitalized COVID-19 (13% in the manual review) and 12% of those with influenza had AF/AFL detected during their hospitalization.
Mortality at 30 days was higher in COVID-19 patients with AF/AFL compared to those without (46% vs. 26%; P < .01), as were the rates of intubation (27% vs. 15%; relative risk, 1.8; P < .01), and stroke (1.6% vs. 0.6%, RR, 2.7; P = .05).
Despite having more comorbidities, in-hospital mortality was significantly lower in the influenza cohort overall, compared to the COVID-19 cohort (9% vs. 29%; P < .01), reflecting the higher case fatality rate in COVID-19, Dr. Reddy, director of cardiac arrhythmia services at Mount Sinai Hospital, said in an interview.
But as with COVID-19, those influenza patients who had in-hospital AF/AFL were more likely to require intubation (14% vs. 7%; P = .004) or die (16% vs. 10%; P = .003).
“The data are not perfect and there are always limitations when doing an observational study using historic controls, but my guess would be that if we looked at other databases and other populations hospitalized for severe illness, we’d likely see something similar because when the body is inflamed, you’re more likely to see Afib,” said Dr. Mandrola.
Dr. Reddy concurred, noting that they considered comparing other populations to COVID-19 patients, including those with “just generalized severe illness,” but in the end felt there were many similarities between influenza and COVID-19, even though mortality in the latter is higher.
“It would be interesting for people to look at other illnesses and see if they find the same thing,” he said.
Dr. Reddy reported having no disclosures relevant to COVID-19. Dr. Mandrola is chief cardiology correspondent for Medscape.com. He reported having no relevant disclosures. MDedge is a member of the Medscape Professional Network.
Among 3,970 patients treated during the early months of the pandemic, new onset AF/AFL was seen in 4%, matching the 4% incidence found in a historic cohort of patients hospitalized with influenza.
On the other hand, mortality was similarly high in both groups of patients studied with AF/AFL, showing a 77% increased risk of death in COVID-19 and a 78% increased risk in influenza, a team from Icahn School of Medicine at Mount Sinai in New York reported.
“We saw new onset Afib and flutter in a minority of patients and it was associated with much higher mortality, but the point is that this increase is basically the same as what you see in influenza, which we feel is an indication that this is more of a generalized response to the inflammatory milieu of such a severe viral illness, as opposed to something specific to COVID,” Vivek Y. Reddy, MD, said in the report, published online Feb. 25 in JACC: Clinical Electrophysiology.
“Here we see, with a similar respiratory virus used as controls, that the results are exactly what I would have expected to see, which is that where there is a lot of inflammation, we see Afib,” said John Mandrola, MD, of Baptist Medical Associates, Louisville, Ky., who was not involved with the study.
“We need more studies like this one because we know SARS-CoV-2 is a bad virus that may have important effects on the heart, but all the of research done so far has been problematic because it didn’t include controls.”
Atrial arrhythmias in COVID and flu
Dr. Reddy and coinvestigators performed a retrospective analysis of a large cohort of patients admitted with laboratory-confirmed COVID-19 during Feb. 4-April 22, 2020, to one of five hospitals within the Mount Sinai Health System.
Their comparator arm included 1,420 patients with confirmed influenza A or B hospitalized between Jan. 1, 2017, and Jan. 1, 2020. For both cohorts, automated electronic record abstraction was used and all patient data were de-identified prior to analysis. In the COVID-19 cohort, a manual review of 1,110 charts was also performed.
Compared with those who did not develop AF/AFL, COVID-19 patients with newly detected AF/AFL and COVID-19 were older (74 vs. 66 years; P < .01) and had higher levels of inflammatory markers, including C-reactive protein and interleukin-6, and higher troponin and D-dimer levels (all P < .01).
Overall, including those with a history of atrial arrhythmias, 10% of patients with hospitalized COVID-19 (13% in the manual review) and 12% of those with influenza had AF/AFL detected during their hospitalization.
Mortality at 30 days was higher in COVID-19 patients with AF/AFL compared to those without (46% vs. 26%; P < .01), as were the rates of intubation (27% vs. 15%; relative risk, 1.8; P < .01), and stroke (1.6% vs. 0.6%, RR, 2.7; P = .05).
Despite having more comorbidities, in-hospital mortality was significantly lower in the influenza cohort overall, compared to the COVID-19 cohort (9% vs. 29%; P < .01), reflecting the higher case fatality rate in COVID-19, Dr. Reddy, director of cardiac arrhythmia services at Mount Sinai Hospital, said in an interview.
But as with COVID-19, those influenza patients who had in-hospital AF/AFL were more likely to require intubation (14% vs. 7%; P = .004) or die (16% vs. 10%; P = .003).
“The data are not perfect and there are always limitations when doing an observational study using historic controls, but my guess would be that if we looked at other databases and other populations hospitalized for severe illness, we’d likely see something similar because when the body is inflamed, you’re more likely to see Afib,” said Dr. Mandrola.
Dr. Reddy concurred, noting that they considered comparing other populations to COVID-19 patients, including those with “just generalized severe illness,” but in the end felt there were many similarities between influenza and COVID-19, even though mortality in the latter is higher.
“It would be interesting for people to look at other illnesses and see if they find the same thing,” he said.
Dr. Reddy reported having no disclosures relevant to COVID-19. Dr. Mandrola is chief cardiology correspondent for Medscape.com. He reported having no relevant disclosures. MDedge is a member of the Medscape Professional Network.
Among 3,970 patients treated during the early months of the pandemic, new onset AF/AFL was seen in 4%, matching the 4% incidence found in a historic cohort of patients hospitalized with influenza.
On the other hand, mortality was similarly high in both groups of patients studied with AF/AFL, showing a 77% increased risk of death in COVID-19 and a 78% increased risk in influenza, a team from Icahn School of Medicine at Mount Sinai in New York reported.
“We saw new onset Afib and flutter in a minority of patients and it was associated with much higher mortality, but the point is that this increase is basically the same as what you see in influenza, which we feel is an indication that this is more of a generalized response to the inflammatory milieu of such a severe viral illness, as opposed to something specific to COVID,” Vivek Y. Reddy, MD, said in the report, published online Feb. 25 in JACC: Clinical Electrophysiology.
“Here we see, with a similar respiratory virus used as controls, that the results are exactly what I would have expected to see, which is that where there is a lot of inflammation, we see Afib,” said John Mandrola, MD, of Baptist Medical Associates, Louisville, Ky., who was not involved with the study.
“We need more studies like this one because we know SARS-CoV-2 is a bad virus that may have important effects on the heart, but all the of research done so far has been problematic because it didn’t include controls.”
Atrial arrhythmias in COVID and flu
Dr. Reddy and coinvestigators performed a retrospective analysis of a large cohort of patients admitted with laboratory-confirmed COVID-19 during Feb. 4-April 22, 2020, to one of five hospitals within the Mount Sinai Health System.
Their comparator arm included 1,420 patients with confirmed influenza A or B hospitalized between Jan. 1, 2017, and Jan. 1, 2020. For both cohorts, automated electronic record abstraction was used and all patient data were de-identified prior to analysis. In the COVID-19 cohort, a manual review of 1,110 charts was also performed.
Compared with those who did not develop AF/AFL, COVID-19 patients with newly detected AF/AFL and COVID-19 were older (74 vs. 66 years; P < .01) and had higher levels of inflammatory markers, including C-reactive protein and interleukin-6, and higher troponin and D-dimer levels (all P < .01).
Overall, including those with a history of atrial arrhythmias, 10% of patients with hospitalized COVID-19 (13% in the manual review) and 12% of those with influenza had AF/AFL detected during their hospitalization.
Mortality at 30 days was higher in COVID-19 patients with AF/AFL compared to those without (46% vs. 26%; P < .01), as were the rates of intubation (27% vs. 15%; relative risk, 1.8; P < .01), and stroke (1.6% vs. 0.6%, RR, 2.7; P = .05).
Despite having more comorbidities, in-hospital mortality was significantly lower in the influenza cohort overall, compared to the COVID-19 cohort (9% vs. 29%; P < .01), reflecting the higher case fatality rate in COVID-19, Dr. Reddy, director of cardiac arrhythmia services at Mount Sinai Hospital, said in an interview.
But as with COVID-19, those influenza patients who had in-hospital AF/AFL were more likely to require intubation (14% vs. 7%; P = .004) or die (16% vs. 10%; P = .003).
“The data are not perfect and there are always limitations when doing an observational study using historic controls, but my guess would be that if we looked at other databases and other populations hospitalized for severe illness, we’d likely see something similar because when the body is inflamed, you’re more likely to see Afib,” said Dr. Mandrola.
Dr. Reddy concurred, noting that they considered comparing other populations to COVID-19 patients, including those with “just generalized severe illness,” but in the end felt there were many similarities between influenza and COVID-19, even though mortality in the latter is higher.
“It would be interesting for people to look at other illnesses and see if they find the same thing,” he said.
Dr. Reddy reported having no disclosures relevant to COVID-19. Dr. Mandrola is chief cardiology correspondent for Medscape.com. He reported having no relevant disclosures. MDedge is a member of the Medscape Professional Network.
FROM JACC: CLINICAL ELECTROPHYSIOLOGY
How to convince patients muscle pain isn’t a statin Achilles heel: StatinWISE
Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that .
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 .
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 .
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.
Myocardial injury seen on MRI in 54% of recovered COVID-19 patients
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.
No patients with “myocarditis-pattern” LGE had regional wall motion abnormalities, and neither admission nor peak troponin values were predictive of the diagnosis of myocarditis.
The results were published online Feb. 18 in the 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.
No patients with “myocarditis-pattern” LGE had regional wall motion abnormalities, and neither admission nor peak troponin values were predictive of the diagnosis of myocarditis.
The results were published online Feb. 18 in the 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.
No patients with “myocarditis-pattern” LGE had regional wall motion abnormalities, and neither admission nor peak troponin values were predictive of the diagnosis of myocarditis.
The results were published online Feb. 18 in the 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.
Study: Central sleep apnea is common in ticagrelor users post ACS
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.
“Whether this particular drug-induced central sleep apnea is consequential” is an open question, noted Dr. Jacobowitz. “There is no evidence that shows that this is definitely harmful.”
“The different types of central sleep apnea are caused by different mechanisms and this one, we don’t know,” Dr. Jacobwitz added.
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.
jremaly@mdedge.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.
“Whether this particular drug-induced central sleep apnea is consequential” is an open question, noted Dr. Jacobowitz. “There is no evidence that shows that this is definitely harmful.”
“The different types of central sleep apnea are caused by different mechanisms and this one, we don’t know,” Dr. Jacobwitz added.
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.
jremaly@mdedge.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.
“Whether this particular drug-induced central sleep apnea is consequential” is an open question, noted Dr. Jacobowitz. “There is no evidence that shows that this is definitely harmful.”
“The different types of central sleep apnea are caused by different mechanisms and this one, we don’t know,” Dr. Jacobwitz added.
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.
jremaly@mdedge.com
FROM SLEEP MEDICINE
Home devices screen for atrial fibrillation
In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.
KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.
The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
How effective is KardiaMobile at detecting AFib?
Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.1 In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.2
How does the Apple Watch find AFib?
Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.
The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.
In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.3 Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.4,5
What should we do with the results?
It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.
While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.
Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
References
1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.
2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.
3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.
4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.
5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.
In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.
KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.
The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
How effective is KardiaMobile at detecting AFib?
Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.1 In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.2
How does the Apple Watch find AFib?
Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.
The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.
In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.3 Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.4,5
What should we do with the results?
It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.
While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.
Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
References
1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.
2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.
3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.
4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.
5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.
In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.
KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.
The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
How effective is KardiaMobile at detecting AFib?
Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.1 In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.2
How does the Apple Watch find AFib?
Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.
The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.
In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.3 Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.4,5
What should we do with the results?
It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.
While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.
Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.
References
1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.
2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.
3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.
4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.
5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.
New light cast on type 2 MI aims to sharpen diagnosis, therapy
The hospital and postdischarge course of patients diagnosed with type 2 myocardial infarction, triggered when myocardial oxygen demand outstrips supply, differs in telling ways from those with the more common atherothrombotic type 1 MI, suggests a new registry analysis that aims to lift a cloud of confusion surrounding their management.
The observational study of more than 250,000 patients with either form of MI, said to be the largest of its kind, points to widespread unfamiliarity with distinctions between the two, and the diagnostic and therapeutic implications of misclassification. It suggests, in particular, that type 2 MI may be grossly underdiagnosed and undertreated.
The minority of patients with type 2 MI were more likely female and to have heart failure (HF), renal disease, valve disease, or atrial fibrillation, and less likely to have a lipid disorder, compared with those with type 1 MI. They were one-fifth as likely to be referred for coronary angiography and 20 times less likely to undergo revascularization.
Indeed, only about 2% of the type 2 cohort ultimately underwent percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG). Yet the analysis suggests that cardiovascular risk climbs regardless of MI type and that in patients with type 2 MI, coronary revascularization might well cut the risk of death in half over the short term.
There were also disparities in clinical outcomes in the analysis, based on data from the final 3 months of 2017 in the Nationwide Readmissions Database, which reportedly documents almost 60% of hospitalizations in the United States.
For example, those with type 1 or type 2 MI – as characterized in the then-current third Universal Definition of Myocardial Infarction and today’s UDMI-4 – were comparably at risk for both 30-day all-cause readmission and HF readmission. But type 2 patients were less likely to die in the hospital or be readmitted within 30 days for recurrent MI.
Revascularization uncertainty
Importantly, the study’s 3-month observation period immediately followed the debut of a code specifically for type 2 MI in the ICD-10-CM system.
Type 2 accounted for about 15% of MIs during that period, the percentage climbing sharply from the first to the third month. That suggests clinicians were still getting used to the code during the early weeks, “undercoding” for type-2 MI at first but less so after some experience, Cian P. McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston, said in an interview.
“I can imagine that as people become more aware of the coding, using it more often, the proportion of type 2 MI relative to the total MI cases will probably be much higher,” said McCarthy, lead author on the study published online Feb. 15, 2021, in the Journal of the American College of Cardiology.
What had been understood about type 2 MI came largely from single-center studies, he said. This “first national study of type-2 MI in the United States” sought to determine whether such findings are hospital specific or “representative of what people are doing nationally.”
The new analysis largely confirms that patients with type 2 MI are typically burdened with multiple comorbidities, Dr. McCarthy said, but also suggests that type 2 often was, and likely still is, incorrectly classified as type 1. So, it was “surprising” that they were rarely referred for angiography. “Only 1 in 50 received revascularization.”
Those diagnosed with type-2 MI were far less likely to receive coronary angiography (10.9% vs. 57.3%), PCI (1.7% vs. 38.5%), or CABG (0.4% vs. 7.8%) (P < .001 for all three differences), the report noted.
That, Dr. McCarthy said, “clearly shows that clinicians are uncertain about whether revascularization is beneficial” in type 2 MI.
Coding not in sync with UDMI
If there is confusion in practice about differentiating type 2 from type 1 MI, it likely has multiple sources, and one may be inconsistencies in how the UDMI and relevant ICD codes are applied in practice.
For example, the coding mandate is always to classify ST-segment elevation MI and non-STEMI as type 1, yet UDMI-4 itself states that a type 2 MI may be either STEMI or non-STEMI, noted Dr. McCarthy, as well as an editorial accompanying the report.
“It also can be difficult at times to distinguish type 2 MI from the diagnosis of myocardial injury,” both of which are partly defined by elevated cardiac troponin (cTn), adds the editorial, from Kristian Thygesen, MD, DSc, Aarhus (Denmark) University Hospital, Aarhus, Denmark, and Allan S. Jaffe, MD, Mayo Clinic, Rochester, Minn.
Crucially, but potentially sometimes overlooked, a diagnosis of infarction requires evidence of ischemia along with the biomarker elevation, whereas myocardial injury is defined by raised cTn without evidence of ischemia. Yet there is no ICD-10-CM code for “nonischemic myocardial injury,” Dr. Thygesen and Dr. Jaffe observed.
“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” they wrote. “Unfortunately, although some have advocated using this code for myocardial injury, it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading” and thus worsen the potential for miscoding and “misattribution of MI diagnoses.”
In the current study, 84.6% of the cohort were classified with type 1 MI, 14.8% with type 2, and 0.6% with both types. Of those with type 1 MI, 22.1% had STEMI, 76.4% had non-STEMI with the remainder “unspecified.”
“I think the introduction of ICD codes for type-2 MI is helpful in that we can study type 2 MI more broadly, across institutions, and try and get a better sense of its outcomes and how these patients are treated,” Dr. McCarthy said. But the coding system’s deficiencies may often lead to misclassification of patients. Especially, patients with type 2 STEMI may be miscoded as having type-1 STEMI, and those with only myocardial injury may be miscoded as having type 2 MI.
Most type 2 MI is a complication
A profile of patients with type 2 MI may be helpful for making distinctions. The analysis showed that, compared with patients with type 1 MI, they were slightly but significantly older and more likely to have clinical depression, alcohol or other substance abuse disorder, and to be female. They also had more heart failure (27.9% vs. 10.9%), kidney disease (35.7% vs. 25.7%), atrial fibrillation (31% vs. 21%), and anemia (26% vs. 18.9%) (P < .001 for all differences).
Type 2 patients were less likely to have CV risk factors usually associated with plaque instability and atherothrombosis, including a history of smoking, dyslipidemia, MI, PCI, or CABG (P < .001 for all differences), the group noted.
Of the 37,765 patients with type 2 MI, 91% received the diagnosis as secondary to another condition, including sepsis in 24.5%, hypertension in 16.9%, arrhythmias in 6.1%, respiratory failure in 4.3%, and pneumonia in 2.8% of cases.
In multivariate analyses, patients with type 2 MI, compared with type 1, showed lower risks of in-hospital death and readmission for MI within 30 days. Their 30-day risks of readmission from any cause and from MI were similar.
In-hospital mortality was lower for patients with type 2 MI who underwent revascularization, compared with those who did not, “but they were a very select, small proportion of the patient group. I would say there are probably unmeasured confounders,” Dr. McCarthy said.
“There’s a real kind of equipoise, so I think we desperately need a trial to guide us on whether revascularization is beneficial.”
Dr. McCarthy has disclosed no relevant financial relationships. Dr. Thygesen disclosed no relevant financial relationships. Dr. Jaffe disclosed serving as a consultant for Abbott, Roche, Siemens, Beckman-Coulter, Radiometer, ET Healthcare, Sphingotec, Brava, Quidel, Amgen, Novartis, and Medscape for educational activities.
A version of this article first appeared on Medscape.com.
The hospital and postdischarge course of patients diagnosed with type 2 myocardial infarction, triggered when myocardial oxygen demand outstrips supply, differs in telling ways from those with the more common atherothrombotic type 1 MI, suggests a new registry analysis that aims to lift a cloud of confusion surrounding their management.
The observational study of more than 250,000 patients with either form of MI, said to be the largest of its kind, points to widespread unfamiliarity with distinctions between the two, and the diagnostic and therapeutic implications of misclassification. It suggests, in particular, that type 2 MI may be grossly underdiagnosed and undertreated.
The minority of patients with type 2 MI were more likely female and to have heart failure (HF), renal disease, valve disease, or atrial fibrillation, and less likely to have a lipid disorder, compared with those with type 1 MI. They were one-fifth as likely to be referred for coronary angiography and 20 times less likely to undergo revascularization.
Indeed, only about 2% of the type 2 cohort ultimately underwent percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG). Yet the analysis suggests that cardiovascular risk climbs regardless of MI type and that in patients with type 2 MI, coronary revascularization might well cut the risk of death in half over the short term.
There were also disparities in clinical outcomes in the analysis, based on data from the final 3 months of 2017 in the Nationwide Readmissions Database, which reportedly documents almost 60% of hospitalizations in the United States.
For example, those with type 1 or type 2 MI – as characterized in the then-current third Universal Definition of Myocardial Infarction and today’s UDMI-4 – were comparably at risk for both 30-day all-cause readmission and HF readmission. But type 2 patients were less likely to die in the hospital or be readmitted within 30 days for recurrent MI.
Revascularization uncertainty
Importantly, the study’s 3-month observation period immediately followed the debut of a code specifically for type 2 MI in the ICD-10-CM system.
Type 2 accounted for about 15% of MIs during that period, the percentage climbing sharply from the first to the third month. That suggests clinicians were still getting used to the code during the early weeks, “undercoding” for type-2 MI at first but less so after some experience, Cian P. McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston, said in an interview.
“I can imagine that as people become more aware of the coding, using it more often, the proportion of type 2 MI relative to the total MI cases will probably be much higher,” said McCarthy, lead author on the study published online Feb. 15, 2021, in the Journal of the American College of Cardiology.
What had been understood about type 2 MI came largely from single-center studies, he said. This “first national study of type-2 MI in the United States” sought to determine whether such findings are hospital specific or “representative of what people are doing nationally.”
The new analysis largely confirms that patients with type 2 MI are typically burdened with multiple comorbidities, Dr. McCarthy said, but also suggests that type 2 often was, and likely still is, incorrectly classified as type 1. So, it was “surprising” that they were rarely referred for angiography. “Only 1 in 50 received revascularization.”
Those diagnosed with type-2 MI were far less likely to receive coronary angiography (10.9% vs. 57.3%), PCI (1.7% vs. 38.5%), or CABG (0.4% vs. 7.8%) (P < .001 for all three differences), the report noted.
That, Dr. McCarthy said, “clearly shows that clinicians are uncertain about whether revascularization is beneficial” in type 2 MI.
Coding not in sync with UDMI
If there is confusion in practice about differentiating type 2 from type 1 MI, it likely has multiple sources, and one may be inconsistencies in how the UDMI and relevant ICD codes are applied in practice.
For example, the coding mandate is always to classify ST-segment elevation MI and non-STEMI as type 1, yet UDMI-4 itself states that a type 2 MI may be either STEMI or non-STEMI, noted Dr. McCarthy, as well as an editorial accompanying the report.
“It also can be difficult at times to distinguish type 2 MI from the diagnosis of myocardial injury,” both of which are partly defined by elevated cardiac troponin (cTn), adds the editorial, from Kristian Thygesen, MD, DSc, Aarhus (Denmark) University Hospital, Aarhus, Denmark, and Allan S. Jaffe, MD, Mayo Clinic, Rochester, Minn.
Crucially, but potentially sometimes overlooked, a diagnosis of infarction requires evidence of ischemia along with the biomarker elevation, whereas myocardial injury is defined by raised cTn without evidence of ischemia. Yet there is no ICD-10-CM code for “nonischemic myocardial injury,” Dr. Thygesen and Dr. Jaffe observed.
“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” they wrote. “Unfortunately, although some have advocated using this code for myocardial injury, it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading” and thus worsen the potential for miscoding and “misattribution of MI diagnoses.”
In the current study, 84.6% of the cohort were classified with type 1 MI, 14.8% with type 2, and 0.6% with both types. Of those with type 1 MI, 22.1% had STEMI, 76.4% had non-STEMI with the remainder “unspecified.”
“I think the introduction of ICD codes for type-2 MI is helpful in that we can study type 2 MI more broadly, across institutions, and try and get a better sense of its outcomes and how these patients are treated,” Dr. McCarthy said. But the coding system’s deficiencies may often lead to misclassification of patients. Especially, patients with type 2 STEMI may be miscoded as having type-1 STEMI, and those with only myocardial injury may be miscoded as having type 2 MI.
Most type 2 MI is a complication
A profile of patients with type 2 MI may be helpful for making distinctions. The analysis showed that, compared with patients with type 1 MI, they were slightly but significantly older and more likely to have clinical depression, alcohol or other substance abuse disorder, and to be female. They also had more heart failure (27.9% vs. 10.9%), kidney disease (35.7% vs. 25.7%), atrial fibrillation (31% vs. 21%), and anemia (26% vs. 18.9%) (P < .001 for all differences).
Type 2 patients were less likely to have CV risk factors usually associated with plaque instability and atherothrombosis, including a history of smoking, dyslipidemia, MI, PCI, or CABG (P < .001 for all differences), the group noted.
Of the 37,765 patients with type 2 MI, 91% received the diagnosis as secondary to another condition, including sepsis in 24.5%, hypertension in 16.9%, arrhythmias in 6.1%, respiratory failure in 4.3%, and pneumonia in 2.8% of cases.
In multivariate analyses, patients with type 2 MI, compared with type 1, showed lower risks of in-hospital death and readmission for MI within 30 days. Their 30-day risks of readmission from any cause and from MI were similar.
In-hospital mortality was lower for patients with type 2 MI who underwent revascularization, compared with those who did not, “but they were a very select, small proportion of the patient group. I would say there are probably unmeasured confounders,” Dr. McCarthy said.
“There’s a real kind of equipoise, so I think we desperately need a trial to guide us on whether revascularization is beneficial.”
Dr. McCarthy has disclosed no relevant financial relationships. Dr. Thygesen disclosed no relevant financial relationships. Dr. Jaffe disclosed serving as a consultant for Abbott, Roche, Siemens, Beckman-Coulter, Radiometer, ET Healthcare, Sphingotec, Brava, Quidel, Amgen, Novartis, and Medscape for educational activities.
A version of this article first appeared on Medscape.com.
The hospital and postdischarge course of patients diagnosed with type 2 myocardial infarction, triggered when myocardial oxygen demand outstrips supply, differs in telling ways from those with the more common atherothrombotic type 1 MI, suggests a new registry analysis that aims to lift a cloud of confusion surrounding their management.
The observational study of more than 250,000 patients with either form of MI, said to be the largest of its kind, points to widespread unfamiliarity with distinctions between the two, and the diagnostic and therapeutic implications of misclassification. It suggests, in particular, that type 2 MI may be grossly underdiagnosed and undertreated.
The minority of patients with type 2 MI were more likely female and to have heart failure (HF), renal disease, valve disease, or atrial fibrillation, and less likely to have a lipid disorder, compared with those with type 1 MI. They were one-fifth as likely to be referred for coronary angiography and 20 times less likely to undergo revascularization.
Indeed, only about 2% of the type 2 cohort ultimately underwent percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG). Yet the analysis suggests that cardiovascular risk climbs regardless of MI type and that in patients with type 2 MI, coronary revascularization might well cut the risk of death in half over the short term.
There were also disparities in clinical outcomes in the analysis, based on data from the final 3 months of 2017 in the Nationwide Readmissions Database, which reportedly documents almost 60% of hospitalizations in the United States.
For example, those with type 1 or type 2 MI – as characterized in the then-current third Universal Definition of Myocardial Infarction and today’s UDMI-4 – were comparably at risk for both 30-day all-cause readmission and HF readmission. But type 2 patients were less likely to die in the hospital or be readmitted within 30 days for recurrent MI.
Revascularization uncertainty
Importantly, the study’s 3-month observation period immediately followed the debut of a code specifically for type 2 MI in the ICD-10-CM system.
Type 2 accounted for about 15% of MIs during that period, the percentage climbing sharply from the first to the third month. That suggests clinicians were still getting used to the code during the early weeks, “undercoding” for type-2 MI at first but less so after some experience, Cian P. McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston, said in an interview.
“I can imagine that as people become more aware of the coding, using it more often, the proportion of type 2 MI relative to the total MI cases will probably be much higher,” said McCarthy, lead author on the study published online Feb. 15, 2021, in the Journal of the American College of Cardiology.
What had been understood about type 2 MI came largely from single-center studies, he said. This “first national study of type-2 MI in the United States” sought to determine whether such findings are hospital specific or “representative of what people are doing nationally.”
The new analysis largely confirms that patients with type 2 MI are typically burdened with multiple comorbidities, Dr. McCarthy said, but also suggests that type 2 often was, and likely still is, incorrectly classified as type 1. So, it was “surprising” that they were rarely referred for angiography. “Only 1 in 50 received revascularization.”
Those diagnosed with type-2 MI were far less likely to receive coronary angiography (10.9% vs. 57.3%), PCI (1.7% vs. 38.5%), or CABG (0.4% vs. 7.8%) (P < .001 for all three differences), the report noted.
That, Dr. McCarthy said, “clearly shows that clinicians are uncertain about whether revascularization is beneficial” in type 2 MI.
Coding not in sync with UDMI
If there is confusion in practice about differentiating type 2 from type 1 MI, it likely has multiple sources, and one may be inconsistencies in how the UDMI and relevant ICD codes are applied in practice.
For example, the coding mandate is always to classify ST-segment elevation MI and non-STEMI as type 1, yet UDMI-4 itself states that a type 2 MI may be either STEMI or non-STEMI, noted Dr. McCarthy, as well as an editorial accompanying the report.
“It also can be difficult at times to distinguish type 2 MI from the diagnosis of myocardial injury,” both of which are partly defined by elevated cardiac troponin (cTn), adds the editorial, from Kristian Thygesen, MD, DSc, Aarhus (Denmark) University Hospital, Aarhus, Denmark, and Allan S. Jaffe, MD, Mayo Clinic, Rochester, Minn.
Crucially, but potentially sometimes overlooked, a diagnosis of infarction requires evidence of ischemia along with the biomarker elevation, whereas myocardial injury is defined by raised cTn without evidence of ischemia. Yet there is no ICD-10-CM code for “nonischemic myocardial injury,” Dr. Thygesen and Dr. Jaffe observed.
“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” they wrote. “Unfortunately, although some have advocated using this code for myocardial injury, it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading” and thus worsen the potential for miscoding and “misattribution of MI diagnoses.”
In the current study, 84.6% of the cohort were classified with type 1 MI, 14.8% with type 2, and 0.6% with both types. Of those with type 1 MI, 22.1% had STEMI, 76.4% had non-STEMI with the remainder “unspecified.”
“I think the introduction of ICD codes for type-2 MI is helpful in that we can study type 2 MI more broadly, across institutions, and try and get a better sense of its outcomes and how these patients are treated,” Dr. McCarthy said. But the coding system’s deficiencies may often lead to misclassification of patients. Especially, patients with type 2 STEMI may be miscoded as having type-1 STEMI, and those with only myocardial injury may be miscoded as having type 2 MI.
Most type 2 MI is a complication
A profile of patients with type 2 MI may be helpful for making distinctions. The analysis showed that, compared with patients with type 1 MI, they were slightly but significantly older and more likely to have clinical depression, alcohol or other substance abuse disorder, and to be female. They also had more heart failure (27.9% vs. 10.9%), kidney disease (35.7% vs. 25.7%), atrial fibrillation (31% vs. 21%), and anemia (26% vs. 18.9%) (P < .001 for all differences).
Type 2 patients were less likely to have CV risk factors usually associated with plaque instability and atherothrombosis, including a history of smoking, dyslipidemia, MI, PCI, or CABG (P < .001 for all differences), the group noted.
Of the 37,765 patients with type 2 MI, 91% received the diagnosis as secondary to another condition, including sepsis in 24.5%, hypertension in 16.9%, arrhythmias in 6.1%, respiratory failure in 4.3%, and pneumonia in 2.8% of cases.
In multivariate analyses, patients with type 2 MI, compared with type 1, showed lower risks of in-hospital death and readmission for MI within 30 days. Their 30-day risks of readmission from any cause and from MI were similar.
In-hospital mortality was lower for patients with type 2 MI who underwent revascularization, compared with those who did not, “but they were a very select, small proportion of the patient group. I would say there are probably unmeasured confounders,” Dr. McCarthy said.
“There’s a real kind of equipoise, so I think we desperately need a trial to guide us on whether revascularization is beneficial.”
Dr. McCarthy has disclosed no relevant financial relationships. Dr. Thygesen disclosed no relevant financial relationships. Dr. Jaffe disclosed serving as a consultant for Abbott, Roche, Siemens, Beckman-Coulter, Radiometer, ET Healthcare, Sphingotec, Brava, Quidel, Amgen, Novartis, and Medscape for educational activities.
A version of this article first appeared on Medscape.com.
Long-term CPAP use linked with more physical activity
in new research.
“The aim of this study was to determine whether long-term CPAP treatment affects self-reported physical activity among participants with moderate-severe OSA and comorbid CV disease,” wrote David Stevens, PhD, of Flinders University, Adelaide, Australia, and his colleagues. The findings were recently published in the Journal of Clinical Sleep Medicine.
Researchers conducted a secondary analysis of the Sleep apnea cardiovascular endpoints (SAVE) trial that enrolled 2,687 adults aged 45-75 years old with OSA and confirmed CVD. In the study, participants were randomized to receive either CPAP plus usual care or usual care alone.
Physical activity levels were self-reported using the Leisure-Time Exercise Questionnaire (LTEQ) at baseline and at 6-, 24-, and 48-month follow-up intervals. The physical functioning subscale of the 36-item short form questionnaire (SF-36) was used to determine if activity levels were consistent with expert recommendations and to evaluate the effects on any self-perceived limitation of physical activity.
Moderate physical activity was higher among CPAP users
After a mean follow-up duration of 3.7 years, participants in the CPAP arm had approximately 20% higher levels of moderate physical activity, compared with the control arm (adjusted mean scores]: 8.7 points vs. 7.3 points; 95% confidence interval, 7.5-9.9 vs. 6.1-8.5; P = .003).
However, no significant difference was observed between treatment arms for mild physical activity (adjusted mean scores, 14.4 points vs. 14.2 points; 95% CI, 13.5-15.3 vs. 13.3-15.1; P = 0.599) or vigorous physical activity (adjusted mean scores, 3.4 points vs. 2.9 points; 95% CI 2.6-4.2 vs. 2.1-3.7; P = .125).
In addition, participants in the CPAP group reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score = 1.66; 95% CI, 0.87-2.45; P < .001) and were more likely to report activity levels consistent with guideline recommendations.
“We were pleasantly surprised to find that people assigned to CPAP reported more physical activity than their counterparts who received usual care, despite being given no specific exercise instructions,” Kelly A. Loffler, PhD, a coauthor of the study, said in an interview.
“While I don’t think this will result in any immediate changes to guidelines, it is a helpful reminder to clinicians who are treating such patients, that the symptomatic benefits people experience with CPAP present a window of opportunity to improve health more holistically,” Dr. Loffler explained.
The researchers acknowledged that a key limitation of the study was the use of self-reported outcome measures. In future studies, they recommended that recent technological innovations, such as the availability of activity tracking devices, should be used to measure physical activity.
They also noted that patients with excessive sleepiness and severe hypoxemia were excluded from the SAVE trial; thus, the findings may not be generalizable to all patients.
Study reinforces CPAP’s health benefits
Emerson M. Wickwire, PhD, associate professor of psychiatry and medicine at the University of Maryland, Baltimore, explained that CPAP treatment is associated with well-documented health benefits among patients with CVD, as well as enhanced quality of life.
“These results provide further evidence that treating OSA can provide direct and indirect health benefits, suggesting that increased physical activity can be a vital pathway to improved cardiovascular health and enjoyment of life,” Dr. Wickwire, who is also director of the Insomnia Program at the University of Maryland Midtown Medical Center, Baltimore, said in an interview.
Steven M. Scharf, MD, a pulmonologist who is director of the Sleep Disorders Center (Adults) at the University of Maryland, also said the study findings were consistent with previous research involving patients treated for OSA.
“It is no surprise that treatment of OSA improves patient’s daily physical functioning,” explained Dr. Scharf, who is also a clinical professor, in an interview. “These results are expected, but very welcome, and I was glad to see them.”
The study was funded by the National Health and Medical Research Council of Australia, the Respironics Sleep and Respiratory Research Foundation, and Philips Respironics. Some authors reported financial affiliations with medical device and pharmaceutical companies. Dr. Loffler, Dr. Wickwire, and Dr. Scharf reported no conflicts of interest related to this work.
in new research.
“The aim of this study was to determine whether long-term CPAP treatment affects self-reported physical activity among participants with moderate-severe OSA and comorbid CV disease,” wrote David Stevens, PhD, of Flinders University, Adelaide, Australia, and his colleagues. The findings were recently published in the Journal of Clinical Sleep Medicine.
Researchers conducted a secondary analysis of the Sleep apnea cardiovascular endpoints (SAVE) trial that enrolled 2,687 adults aged 45-75 years old with OSA and confirmed CVD. In the study, participants were randomized to receive either CPAP plus usual care or usual care alone.
Physical activity levels were self-reported using the Leisure-Time Exercise Questionnaire (LTEQ) at baseline and at 6-, 24-, and 48-month follow-up intervals. The physical functioning subscale of the 36-item short form questionnaire (SF-36) was used to determine if activity levels were consistent with expert recommendations and to evaluate the effects on any self-perceived limitation of physical activity.
Moderate physical activity was higher among CPAP users
After a mean follow-up duration of 3.7 years, participants in the CPAP arm had approximately 20% higher levels of moderate physical activity, compared with the control arm (adjusted mean scores]: 8.7 points vs. 7.3 points; 95% confidence interval, 7.5-9.9 vs. 6.1-8.5; P = .003).
However, no significant difference was observed between treatment arms for mild physical activity (adjusted mean scores, 14.4 points vs. 14.2 points; 95% CI, 13.5-15.3 vs. 13.3-15.1; P = 0.599) or vigorous physical activity (adjusted mean scores, 3.4 points vs. 2.9 points; 95% CI 2.6-4.2 vs. 2.1-3.7; P = .125).
In addition, participants in the CPAP group reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score = 1.66; 95% CI, 0.87-2.45; P < .001) and were more likely to report activity levels consistent with guideline recommendations.
“We were pleasantly surprised to find that people assigned to CPAP reported more physical activity than their counterparts who received usual care, despite being given no specific exercise instructions,” Kelly A. Loffler, PhD, a coauthor of the study, said in an interview.
“While I don’t think this will result in any immediate changes to guidelines, it is a helpful reminder to clinicians who are treating such patients, that the symptomatic benefits people experience with CPAP present a window of opportunity to improve health more holistically,” Dr. Loffler explained.
The researchers acknowledged that a key limitation of the study was the use of self-reported outcome measures. In future studies, they recommended that recent technological innovations, such as the availability of activity tracking devices, should be used to measure physical activity.
They also noted that patients with excessive sleepiness and severe hypoxemia were excluded from the SAVE trial; thus, the findings may not be generalizable to all patients.
Study reinforces CPAP’s health benefits
Emerson M. Wickwire, PhD, associate professor of psychiatry and medicine at the University of Maryland, Baltimore, explained that CPAP treatment is associated with well-documented health benefits among patients with CVD, as well as enhanced quality of life.
“These results provide further evidence that treating OSA can provide direct and indirect health benefits, suggesting that increased physical activity can be a vital pathway to improved cardiovascular health and enjoyment of life,” Dr. Wickwire, who is also director of the Insomnia Program at the University of Maryland Midtown Medical Center, Baltimore, said in an interview.
Steven M. Scharf, MD, a pulmonologist who is director of the Sleep Disorders Center (Adults) at the University of Maryland, also said the study findings were consistent with previous research involving patients treated for OSA.
“It is no surprise that treatment of OSA improves patient’s daily physical functioning,” explained Dr. Scharf, who is also a clinical professor, in an interview. “These results are expected, but very welcome, and I was glad to see them.”
The study was funded by the National Health and Medical Research Council of Australia, the Respironics Sleep and Respiratory Research Foundation, and Philips Respironics. Some authors reported financial affiliations with medical device and pharmaceutical companies. Dr. Loffler, Dr. Wickwire, and Dr. Scharf reported no conflicts of interest related to this work.
in new research.
“The aim of this study was to determine whether long-term CPAP treatment affects self-reported physical activity among participants with moderate-severe OSA and comorbid CV disease,” wrote David Stevens, PhD, of Flinders University, Adelaide, Australia, and his colleagues. The findings were recently published in the Journal of Clinical Sleep Medicine.
Researchers conducted a secondary analysis of the Sleep apnea cardiovascular endpoints (SAVE) trial that enrolled 2,687 adults aged 45-75 years old with OSA and confirmed CVD. In the study, participants were randomized to receive either CPAP plus usual care or usual care alone.
Physical activity levels were self-reported using the Leisure-Time Exercise Questionnaire (LTEQ) at baseline and at 6-, 24-, and 48-month follow-up intervals. The physical functioning subscale of the 36-item short form questionnaire (SF-36) was used to determine if activity levels were consistent with expert recommendations and to evaluate the effects on any self-perceived limitation of physical activity.
Moderate physical activity was higher among CPAP users
After a mean follow-up duration of 3.7 years, participants in the CPAP arm had approximately 20% higher levels of moderate physical activity, compared with the control arm (adjusted mean scores]: 8.7 points vs. 7.3 points; 95% confidence interval, 7.5-9.9 vs. 6.1-8.5; P = .003).
However, no significant difference was observed between treatment arms for mild physical activity (adjusted mean scores, 14.4 points vs. 14.2 points; 95% CI, 13.5-15.3 vs. 13.3-15.1; P = 0.599) or vigorous physical activity (adjusted mean scores, 3.4 points vs. 2.9 points; 95% CI 2.6-4.2 vs. 2.1-3.7; P = .125).
In addition, participants in the CPAP group reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score = 1.66; 95% CI, 0.87-2.45; P < .001) and were more likely to report activity levels consistent with guideline recommendations.
“We were pleasantly surprised to find that people assigned to CPAP reported more physical activity than their counterparts who received usual care, despite being given no specific exercise instructions,” Kelly A. Loffler, PhD, a coauthor of the study, said in an interview.
“While I don’t think this will result in any immediate changes to guidelines, it is a helpful reminder to clinicians who are treating such patients, that the symptomatic benefits people experience with CPAP present a window of opportunity to improve health more holistically,” Dr. Loffler explained.
The researchers acknowledged that a key limitation of the study was the use of self-reported outcome measures. In future studies, they recommended that recent technological innovations, such as the availability of activity tracking devices, should be used to measure physical activity.
They also noted that patients with excessive sleepiness and severe hypoxemia were excluded from the SAVE trial; thus, the findings may not be generalizable to all patients.
Study reinforces CPAP’s health benefits
Emerson M. Wickwire, PhD, associate professor of psychiatry and medicine at the University of Maryland, Baltimore, explained that CPAP treatment is associated with well-documented health benefits among patients with CVD, as well as enhanced quality of life.
“These results provide further evidence that treating OSA can provide direct and indirect health benefits, suggesting that increased physical activity can be a vital pathway to improved cardiovascular health and enjoyment of life,” Dr. Wickwire, who is also director of the Insomnia Program at the University of Maryland Midtown Medical Center, Baltimore, said in an interview.
Steven M. Scharf, MD, a pulmonologist who is director of the Sleep Disorders Center (Adults) at the University of Maryland, also said the study findings were consistent with previous research involving patients treated for OSA.
“It is no surprise that treatment of OSA improves patient’s daily physical functioning,” explained Dr. Scharf, who is also a clinical professor, in an interview. “These results are expected, but very welcome, and I was glad to see them.”
The study was funded by the National Health and Medical Research Council of Australia, the Respironics Sleep and Respiratory Research Foundation, and Philips Respironics. Some authors reported financial affiliations with medical device and pharmaceutical companies. Dr. Loffler, Dr. Wickwire, and Dr. Scharf reported no conflicts of interest related to this work.
FROM JOURNAL OF CLINICAL SLEEP MEDICINE
More from DAPA-HF: Dapagliflozin quickly reduces heart failure events
Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.
Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.
Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.
These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.
The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.
But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes
“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”
In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.
“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”
DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.
Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.
Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.
Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.
These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.
The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.
But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes
“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”
In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.
“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”
DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.
Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.
Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.
Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.
These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.
The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.
But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes
“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”
In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.
“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”
DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.
FROM JAMA CARDIOLOGY
Ivabradine knocks down heart rate, symptoms in POTS
The heart failure drug ivabradine (Corlanor) can provide relief from the elevated heart rate and often debilitating symptoms associated with postural orthostatic tachycardia syndrome (POTS), a new study suggests.
Ivabradine significantly lowered standing heart rate, compared with placebo (77.9 vs. 94.2 beats/min; P < .001). The typical surge in heart rate that occurs upon standing in these patients was also blunted, compared with baseline (13.0 vs. 21.4 beats/min; P = .001).
“There are really not a lot of great options for patients with POTS and, mechanistically, ivabradine just make sense because it’s a drug that lowers heart rate very selectively and doesn’t lower blood pressure,” lead study author Pam R. Taub, MD, told this news organization.
Surprisingly, the reduction in heart rate translated into improved physical (P = .008) and social (P = .021) functioning after just 1 month of ivabradine, without any other background POTS medications or a change in nonpharmacologic therapies, she said. “What’s really nice to see is when you tackle a really significant part of the disease, which is the elevated heart rate, just how much better they feel.”
POTS patients are mostly healthy, active young women, who after some inciting event – such as viral infection, trauma, or surgery – experience an increase in heart rate of at least 30 beats/min upon standing accompanied by a range of symptoms, including dizziness, palpitations, brain fog, and fatigue.
A COVID connection?
The study enrolled patients with hyperadrenergic POTS as the predominant subtype, but another group to keep in mind that might benefit is the post-COVID POTS patient, said Dr. Taub, from the University of California, San Diego.
“We’re seeing an incredible number of patients post COVID that meet the criteria for POTS, and a lot of these patients also have COVID fatigue,” she said. “So clinically, myself and many other cardiologists who understand ivabradine have been using it off-label for the COVID patients, as long as they meet the criteria. You don’t want to use it in every COVID patient, but if someone’s predominant complaint is that their heart rate is going up when they’re standing and they’re debilitated by it, this is a drug to consider.”
Anecdotal findings in patients with long-hauler COVID need to be translated into rigorous research protocols, but mechanistically, whether it’s POTS from COVID or from another type of infection – like Lyme disease or some other viral syndrome – it should work the same, Dr. Taub said. “POTS is POTS.”
There are no first-line drugs for POTS, and current class IIb recommendations include midodrine, which increases blood pressure and can make people feel awful, and fludrocortisone, which can cause a lot of weight gain and fluid retention, she observed. Other agents that lower heart rate, like beta-blockers, also lower blood pressure and can aggravate depression and fatigue.
Ivabradine regulates heart rate by specifically blocking the Ifunny channel of the sinoatrial node. It was approved in 2015 in the United States to reduce hospitalizations in patients with systolic heart failure, and it also has a second class IIb recommendation for inappropriate sinus tachycardia.
The present study, reported in the Feb. 23 issue of the Journal of the American College of Cardiology, is the first randomized clinical trial using ivabradine to treat POTS.
A total of 26 patients with POTS were started on ivabradine 5 mg or placebo twice daily for 1 month, then were crossed over to the other treatment for 1 month after a 1-week washout period. Six patients were started on a 2.5-mg twice-daily dose. Doses were adjusted during the study based on the patient’s heart rate response and tolerance. Patients had seven clinic visits in which norepinephrine (NE) levels were measured and head-up tilt testing conducted.
Four patients in the ivabradine arm withdrew because of adverse effects, and one withdrew during crossover.
Among the 22 patients who completed the study, exploratory analyses showed a strong trend for greater reduction in plasma NE upon standing with ivabradine (P = .056). The effect was also more profound in patients with very high baseline standing NE levels (at least 1,000 pg/mL) than in those with lower NE levels (600 to 1,000 pg/mL).
“It makes sense because that means their sympathetic nervous system is more overactive; they have a higher heart rate,” Dr. Taub said. “So it’s a potential clinical tool that people can use in their practice to determine, ‘okay, is this a patient I should be considering ivabradine on?’ ”
Although the present study had only 22 patients, “it should definitely be looked at as a step forward, both in terms of ivabradine specifically and in terms of setting the standard for the types of studies we want to see in our patients,” Satish R. Raj, MD, MSCI, University of Calgary (Alta.), said in an interview.
In a related editorial, however, Dr. Raj and coauthor Robert S. Sheldon, MD, PhD, also from the University of Calgary, point out that the standing heart rate in the placebo phase was only 94 beats/min, “suggesting that these patients may be affected only mildly by their POTS.”
Asked about the point, Dr. Taub said: “I don’t know if I agree with that.” She noted that the diagnosis of POTS was confirmed by tilt-table testing and NE levels and that patients’ symptoms vary from day to day. “The standard deviation was plus or minus 16.8, so there’s variability.”
Both Dr. Raj and Dr. Taub said they expect the results will be included in the next scientific statement for POTS, but in the meantime, it may be a struggle to get the drug covered by insurance.
“The challenge is that this is a very off-label use for this medication, and the medication’s not cheap,” Dr. Raj observed. The price for 60 tablets, which is about a 1-month supply, is $485 on GoodRx.
Another question going forward, he said, is whether ivabradine is superior to beta-blockers, which will be studied in a 20-patient crossover trial sponsored by the University of Calgary that is about to launch. The primary completion date is set for 2024.
The study was supported by a grant from Amgen. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA. Dr. Raj has received a research grant from the Canadian Institutes of Health Research and research grants from Dysautonomia International to address the pathophysiology of POTS. Dr. Sheldon has received a research grant from Dysautonomia International for a clinical trial assessing ivabradine and propranolol for the treatment of POTS.
A version of this article first appeared on Medscape.com.
The heart failure drug ivabradine (Corlanor) can provide relief from the elevated heart rate and often debilitating symptoms associated with postural orthostatic tachycardia syndrome (POTS), a new study suggests.
Ivabradine significantly lowered standing heart rate, compared with placebo (77.9 vs. 94.2 beats/min; P < .001). The typical surge in heart rate that occurs upon standing in these patients was also blunted, compared with baseline (13.0 vs. 21.4 beats/min; P = .001).
“There are really not a lot of great options for patients with POTS and, mechanistically, ivabradine just make sense because it’s a drug that lowers heart rate very selectively and doesn’t lower blood pressure,” lead study author Pam R. Taub, MD, told this news organization.
Surprisingly, the reduction in heart rate translated into improved physical (P = .008) and social (P = .021) functioning after just 1 month of ivabradine, without any other background POTS medications or a change in nonpharmacologic therapies, she said. “What’s really nice to see is when you tackle a really significant part of the disease, which is the elevated heart rate, just how much better they feel.”
POTS patients are mostly healthy, active young women, who after some inciting event – such as viral infection, trauma, or surgery – experience an increase in heart rate of at least 30 beats/min upon standing accompanied by a range of symptoms, including dizziness, palpitations, brain fog, and fatigue.
A COVID connection?
The study enrolled patients with hyperadrenergic POTS as the predominant subtype, but another group to keep in mind that might benefit is the post-COVID POTS patient, said Dr. Taub, from the University of California, San Diego.
“We’re seeing an incredible number of patients post COVID that meet the criteria for POTS, and a lot of these patients also have COVID fatigue,” she said. “So clinically, myself and many other cardiologists who understand ivabradine have been using it off-label for the COVID patients, as long as they meet the criteria. You don’t want to use it in every COVID patient, but if someone’s predominant complaint is that their heart rate is going up when they’re standing and they’re debilitated by it, this is a drug to consider.”
Anecdotal findings in patients with long-hauler COVID need to be translated into rigorous research protocols, but mechanistically, whether it’s POTS from COVID or from another type of infection – like Lyme disease or some other viral syndrome – it should work the same, Dr. Taub said. “POTS is POTS.”
There are no first-line drugs for POTS, and current class IIb recommendations include midodrine, which increases blood pressure and can make people feel awful, and fludrocortisone, which can cause a lot of weight gain and fluid retention, she observed. Other agents that lower heart rate, like beta-blockers, also lower blood pressure and can aggravate depression and fatigue.
Ivabradine regulates heart rate by specifically blocking the Ifunny channel of the sinoatrial node. It was approved in 2015 in the United States to reduce hospitalizations in patients with systolic heart failure, and it also has a second class IIb recommendation for inappropriate sinus tachycardia.
The present study, reported in the Feb. 23 issue of the Journal of the American College of Cardiology, is the first randomized clinical trial using ivabradine to treat POTS.
A total of 26 patients with POTS were started on ivabradine 5 mg or placebo twice daily for 1 month, then were crossed over to the other treatment for 1 month after a 1-week washout period. Six patients were started on a 2.5-mg twice-daily dose. Doses were adjusted during the study based on the patient’s heart rate response and tolerance. Patients had seven clinic visits in which norepinephrine (NE) levels were measured and head-up tilt testing conducted.
Four patients in the ivabradine arm withdrew because of adverse effects, and one withdrew during crossover.
Among the 22 patients who completed the study, exploratory analyses showed a strong trend for greater reduction in plasma NE upon standing with ivabradine (P = .056). The effect was also more profound in patients with very high baseline standing NE levels (at least 1,000 pg/mL) than in those with lower NE levels (600 to 1,000 pg/mL).
“It makes sense because that means their sympathetic nervous system is more overactive; they have a higher heart rate,” Dr. Taub said. “So it’s a potential clinical tool that people can use in their practice to determine, ‘okay, is this a patient I should be considering ivabradine on?’ ”
Although the present study had only 22 patients, “it should definitely be looked at as a step forward, both in terms of ivabradine specifically and in terms of setting the standard for the types of studies we want to see in our patients,” Satish R. Raj, MD, MSCI, University of Calgary (Alta.), said in an interview.
In a related editorial, however, Dr. Raj and coauthor Robert S. Sheldon, MD, PhD, also from the University of Calgary, point out that the standing heart rate in the placebo phase was only 94 beats/min, “suggesting that these patients may be affected only mildly by their POTS.”
Asked about the point, Dr. Taub said: “I don’t know if I agree with that.” She noted that the diagnosis of POTS was confirmed by tilt-table testing and NE levels and that patients’ symptoms vary from day to day. “The standard deviation was plus or minus 16.8, so there’s variability.”
Both Dr. Raj and Dr. Taub said they expect the results will be included in the next scientific statement for POTS, but in the meantime, it may be a struggle to get the drug covered by insurance.
“The challenge is that this is a very off-label use for this medication, and the medication’s not cheap,” Dr. Raj observed. The price for 60 tablets, which is about a 1-month supply, is $485 on GoodRx.
Another question going forward, he said, is whether ivabradine is superior to beta-blockers, which will be studied in a 20-patient crossover trial sponsored by the University of Calgary that is about to launch. The primary completion date is set for 2024.
The study was supported by a grant from Amgen. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA. Dr. Raj has received a research grant from the Canadian Institutes of Health Research and research grants from Dysautonomia International to address the pathophysiology of POTS. Dr. Sheldon has received a research grant from Dysautonomia International for a clinical trial assessing ivabradine and propranolol for the treatment of POTS.
A version of this article first appeared on Medscape.com.
The heart failure drug ivabradine (Corlanor) can provide relief from the elevated heart rate and often debilitating symptoms associated with postural orthostatic tachycardia syndrome (POTS), a new study suggests.
Ivabradine significantly lowered standing heart rate, compared with placebo (77.9 vs. 94.2 beats/min; P < .001). The typical surge in heart rate that occurs upon standing in these patients was also blunted, compared with baseline (13.0 vs. 21.4 beats/min; P = .001).
“There are really not a lot of great options for patients with POTS and, mechanistically, ivabradine just make sense because it’s a drug that lowers heart rate very selectively and doesn’t lower blood pressure,” lead study author Pam R. Taub, MD, told this news organization.
Surprisingly, the reduction in heart rate translated into improved physical (P = .008) and social (P = .021) functioning after just 1 month of ivabradine, without any other background POTS medications or a change in nonpharmacologic therapies, she said. “What’s really nice to see is when you tackle a really significant part of the disease, which is the elevated heart rate, just how much better they feel.”
POTS patients are mostly healthy, active young women, who after some inciting event – such as viral infection, trauma, or surgery – experience an increase in heart rate of at least 30 beats/min upon standing accompanied by a range of symptoms, including dizziness, palpitations, brain fog, and fatigue.
A COVID connection?
The study enrolled patients with hyperadrenergic POTS as the predominant subtype, but another group to keep in mind that might benefit is the post-COVID POTS patient, said Dr. Taub, from the University of California, San Diego.
“We’re seeing an incredible number of patients post COVID that meet the criteria for POTS, and a lot of these patients also have COVID fatigue,” she said. “So clinically, myself and many other cardiologists who understand ivabradine have been using it off-label for the COVID patients, as long as they meet the criteria. You don’t want to use it in every COVID patient, but if someone’s predominant complaint is that their heart rate is going up when they’re standing and they’re debilitated by it, this is a drug to consider.”
Anecdotal findings in patients with long-hauler COVID need to be translated into rigorous research protocols, but mechanistically, whether it’s POTS from COVID or from another type of infection – like Lyme disease or some other viral syndrome – it should work the same, Dr. Taub said. “POTS is POTS.”
There are no first-line drugs for POTS, and current class IIb recommendations include midodrine, which increases blood pressure and can make people feel awful, and fludrocortisone, which can cause a lot of weight gain and fluid retention, she observed. Other agents that lower heart rate, like beta-blockers, also lower blood pressure and can aggravate depression and fatigue.
Ivabradine regulates heart rate by specifically blocking the Ifunny channel of the sinoatrial node. It was approved in 2015 in the United States to reduce hospitalizations in patients with systolic heart failure, and it also has a second class IIb recommendation for inappropriate sinus tachycardia.
The present study, reported in the Feb. 23 issue of the Journal of the American College of Cardiology, is the first randomized clinical trial using ivabradine to treat POTS.
A total of 26 patients with POTS were started on ivabradine 5 mg or placebo twice daily for 1 month, then were crossed over to the other treatment for 1 month after a 1-week washout period. Six patients were started on a 2.5-mg twice-daily dose. Doses were adjusted during the study based on the patient’s heart rate response and tolerance. Patients had seven clinic visits in which norepinephrine (NE) levels were measured and head-up tilt testing conducted.
Four patients in the ivabradine arm withdrew because of adverse effects, and one withdrew during crossover.
Among the 22 patients who completed the study, exploratory analyses showed a strong trend for greater reduction in plasma NE upon standing with ivabradine (P = .056). The effect was also more profound in patients with very high baseline standing NE levels (at least 1,000 pg/mL) than in those with lower NE levels (600 to 1,000 pg/mL).
“It makes sense because that means their sympathetic nervous system is more overactive; they have a higher heart rate,” Dr. Taub said. “So it’s a potential clinical tool that people can use in their practice to determine, ‘okay, is this a patient I should be considering ivabradine on?’ ”
Although the present study had only 22 patients, “it should definitely be looked at as a step forward, both in terms of ivabradine specifically and in terms of setting the standard for the types of studies we want to see in our patients,” Satish R. Raj, MD, MSCI, University of Calgary (Alta.), said in an interview.
In a related editorial, however, Dr. Raj and coauthor Robert S. Sheldon, MD, PhD, also from the University of Calgary, point out that the standing heart rate in the placebo phase was only 94 beats/min, “suggesting that these patients may be affected only mildly by their POTS.”
Asked about the point, Dr. Taub said: “I don’t know if I agree with that.” She noted that the diagnosis of POTS was confirmed by tilt-table testing and NE levels and that patients’ symptoms vary from day to day. “The standard deviation was plus or minus 16.8, so there’s variability.”
Both Dr. Raj and Dr. Taub said they expect the results will be included in the next scientific statement for POTS, but in the meantime, it may be a struggle to get the drug covered by insurance.
“The challenge is that this is a very off-label use for this medication, and the medication’s not cheap,” Dr. Raj observed. The price for 60 tablets, which is about a 1-month supply, is $485 on GoodRx.
Another question going forward, he said, is whether ivabradine is superior to beta-blockers, which will be studied in a 20-patient crossover trial sponsored by the University of Calgary that is about to launch. The primary completion date is set for 2024.
The study was supported by a grant from Amgen. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA. Dr. Raj has received a research grant from the Canadian Institutes of Health Research and research grants from Dysautonomia International to address the pathophysiology of POTS. Dr. Sheldon has received a research grant from Dysautonomia International for a clinical trial assessing ivabradine and propranolol for the treatment of POTS.
A version of this article first appeared on Medscape.com.
Cardiovascular trials lose more women than men
A new analysis of 11 phase 3/4 cardiovascular clinical trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) group shows that women are more likely than men to discontinue study medications, and to withdraw from trials. The differences could not be explained by different frequencies of reporting adverse events, or by baseline differences.
The findings are significant, since cardiovascular drugs are routinely prescribed to women based on clinical trials that are populated largely by men, according to lead study author Emily Lau, MD, who is an advanced cardiology fellow at Massachusetts General Hospital, Boston. “It highlights an important disparity in clinical research in cardiology, because if women are already not represented well in clinical trials, and if once in clinical trials they don’t complete the study, it’s very hard to extrapolate the clinical trial findings to our female population in an accurate way,” Dr. Lau said in an interview. She also noted that sex-specific and reproductive factors are increasingly recognized as being important in the development and progression of cardiovascular disease.
The study was published in the journal Circulation.
The study refutes previously advanced explanations for higher withdrawal among women, including sex difference and comorbidities, according to an accompanying editorial by Sofia Sederholm Lawesson, MD, PhD, Eva Swahn, MD, PhD, and Joakim Alfredsson, MD, PhD, of Linköping University, Sweden. They also pointed out that the study found a larger between-sex difference in failure to adhere to study drug in North America (odds ratio, 1.35; 95% confidence interval, 1.30-1.41), but a more moderate difference among participants in Europe/Middle East/Africa (OR, 1.13; 95% CI, 1.09-1.17) and Asia/Pacific (OR, 1.13; 95% CI, 1.03-1.23) regions. And there were no sex differences at all among South/Central American populations.
They noted that high rates of nonadherence increase the chances of a false negative finding and overestimation of drug safety. “We know the associations between nonadherence and clinical outcomes. The next step should be to better understand the underlying reasons for, as well as consistent reporting of, nonadherence, and discontinuation in RCTs,” the editorial authors wrote.
Dr. Lau suggested a simple method to better understand reasons for withdrawal: Addition of questions to the case report form that asks about reasons for drug discontinuation or study withdrawal. “Was it an adverse event? Was it because I’m a mother of three and I can’t get to the clinical trial site after work and also pick up my kids? Are there societal barriers for women, or was it the experience of the clinical trial that was maybe less favorable for women compared to men? Or maybe there are medical reasons we simply don’t know. Something as simple as asking those questions can help us better understand the barriers to female retention,” said Dr. Lau.
The analysis included data from 135,879 men (72%) and 51,812 women (28%) enrolled in the trials. After adjustment for baseline differences, women were more likely than were men to permanently discontinue study drug (adjusted odds ratio [aOR], 1.22: P < .001), which did not vary by study duration. The finding was consistent regardless of the type of drug studied, as well as across placebo and active study arms.
Women also were more likely to prematurely discontinue study drug (trial-adjusted OR, 1.18; P < .001). The rate of drug discontinuation due to adverse event was identical in both men and women, at 36%.
Women were more likely to withdraw consent than were men in a meta-analysis and when individual patient-level results were pooled (aOR, 1.26; P < .001 for both).
Dr. Lau received funding from the National Institutes of Health and has no relevant financial disclosures. The editorial authors had various disclosures, including lecture fees from Bayer, Pfizer, and Boehringer Ingelheim, and they served on advisory boards for AstraZeneca and MSD.
A new analysis of 11 phase 3/4 cardiovascular clinical trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) group shows that women are more likely than men to discontinue study medications, and to withdraw from trials. The differences could not be explained by different frequencies of reporting adverse events, or by baseline differences.
The findings are significant, since cardiovascular drugs are routinely prescribed to women based on clinical trials that are populated largely by men, according to lead study author Emily Lau, MD, who is an advanced cardiology fellow at Massachusetts General Hospital, Boston. “It highlights an important disparity in clinical research in cardiology, because if women are already not represented well in clinical trials, and if once in clinical trials they don’t complete the study, it’s very hard to extrapolate the clinical trial findings to our female population in an accurate way,” Dr. Lau said in an interview. She also noted that sex-specific and reproductive factors are increasingly recognized as being important in the development and progression of cardiovascular disease.
The study was published in the journal Circulation.
The study refutes previously advanced explanations for higher withdrawal among women, including sex difference and comorbidities, according to an accompanying editorial by Sofia Sederholm Lawesson, MD, PhD, Eva Swahn, MD, PhD, and Joakim Alfredsson, MD, PhD, of Linköping University, Sweden. They also pointed out that the study found a larger between-sex difference in failure to adhere to study drug in North America (odds ratio, 1.35; 95% confidence interval, 1.30-1.41), but a more moderate difference among participants in Europe/Middle East/Africa (OR, 1.13; 95% CI, 1.09-1.17) and Asia/Pacific (OR, 1.13; 95% CI, 1.03-1.23) regions. And there were no sex differences at all among South/Central American populations.
They noted that high rates of nonadherence increase the chances of a false negative finding and overestimation of drug safety. “We know the associations between nonadherence and clinical outcomes. The next step should be to better understand the underlying reasons for, as well as consistent reporting of, nonadherence, and discontinuation in RCTs,” the editorial authors wrote.
Dr. Lau suggested a simple method to better understand reasons for withdrawal: Addition of questions to the case report form that asks about reasons for drug discontinuation or study withdrawal. “Was it an adverse event? Was it because I’m a mother of three and I can’t get to the clinical trial site after work and also pick up my kids? Are there societal barriers for women, or was it the experience of the clinical trial that was maybe less favorable for women compared to men? Or maybe there are medical reasons we simply don’t know. Something as simple as asking those questions can help us better understand the barriers to female retention,” said Dr. Lau.
The analysis included data from 135,879 men (72%) and 51,812 women (28%) enrolled in the trials. After adjustment for baseline differences, women were more likely than were men to permanently discontinue study drug (adjusted odds ratio [aOR], 1.22: P < .001), which did not vary by study duration. The finding was consistent regardless of the type of drug studied, as well as across placebo and active study arms.
Women also were more likely to prematurely discontinue study drug (trial-adjusted OR, 1.18; P < .001). The rate of drug discontinuation due to adverse event was identical in both men and women, at 36%.
Women were more likely to withdraw consent than were men in a meta-analysis and when individual patient-level results were pooled (aOR, 1.26; P < .001 for both).
Dr. Lau received funding from the National Institutes of Health and has no relevant financial disclosures. The editorial authors had various disclosures, including lecture fees from Bayer, Pfizer, and Boehringer Ingelheim, and they served on advisory boards for AstraZeneca and MSD.
A new analysis of 11 phase 3/4 cardiovascular clinical trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) group shows that women are more likely than men to discontinue study medications, and to withdraw from trials. The differences could not be explained by different frequencies of reporting adverse events, or by baseline differences.
The findings are significant, since cardiovascular drugs are routinely prescribed to women based on clinical trials that are populated largely by men, according to lead study author Emily Lau, MD, who is an advanced cardiology fellow at Massachusetts General Hospital, Boston. “It highlights an important disparity in clinical research in cardiology, because if women are already not represented well in clinical trials, and if once in clinical trials they don’t complete the study, it’s very hard to extrapolate the clinical trial findings to our female population in an accurate way,” Dr. Lau said in an interview. She also noted that sex-specific and reproductive factors are increasingly recognized as being important in the development and progression of cardiovascular disease.
The study was published in the journal Circulation.
The study refutes previously advanced explanations for higher withdrawal among women, including sex difference and comorbidities, according to an accompanying editorial by Sofia Sederholm Lawesson, MD, PhD, Eva Swahn, MD, PhD, and Joakim Alfredsson, MD, PhD, of Linköping University, Sweden. They also pointed out that the study found a larger between-sex difference in failure to adhere to study drug in North America (odds ratio, 1.35; 95% confidence interval, 1.30-1.41), but a more moderate difference among participants in Europe/Middle East/Africa (OR, 1.13; 95% CI, 1.09-1.17) and Asia/Pacific (OR, 1.13; 95% CI, 1.03-1.23) regions. And there were no sex differences at all among South/Central American populations.
They noted that high rates of nonadherence increase the chances of a false negative finding and overestimation of drug safety. “We know the associations between nonadherence and clinical outcomes. The next step should be to better understand the underlying reasons for, as well as consistent reporting of, nonadherence, and discontinuation in RCTs,” the editorial authors wrote.
Dr. Lau suggested a simple method to better understand reasons for withdrawal: Addition of questions to the case report form that asks about reasons for drug discontinuation or study withdrawal. “Was it an adverse event? Was it because I’m a mother of three and I can’t get to the clinical trial site after work and also pick up my kids? Are there societal barriers for women, or was it the experience of the clinical trial that was maybe less favorable for women compared to men? Or maybe there are medical reasons we simply don’t know. Something as simple as asking those questions can help us better understand the barriers to female retention,” said Dr. Lau.
The analysis included data from 135,879 men (72%) and 51,812 women (28%) enrolled in the trials. After adjustment for baseline differences, women were more likely than were men to permanently discontinue study drug (adjusted odds ratio [aOR], 1.22: P < .001), which did not vary by study duration. The finding was consistent regardless of the type of drug studied, as well as across placebo and active study arms.
Women also were more likely to prematurely discontinue study drug (trial-adjusted OR, 1.18; P < .001). The rate of drug discontinuation due to adverse event was identical in both men and women, at 36%.
Women were more likely to withdraw consent than were men in a meta-analysis and when individual patient-level results were pooled (aOR, 1.26; P < .001 for both).
Dr. Lau received funding from the National Institutes of Health and has no relevant financial disclosures. The editorial authors had various disclosures, including lecture fees from Bayer, Pfizer, and Boehringer Ingelheim, and they served on advisory boards for AstraZeneca and MSD.
FROM CIRCULATION