User login
Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
FOURIER: Evolocumab follow-up shows no cognitive adverse effects
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients’ minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.
“We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels,” wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). “These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients.”
The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).
Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that’s easy to find on the Internet. “I estimate that about 20% of patients prescribed a statin won’t take it because of something they’ve heard” including that statins make you stupid. “It’s hard to undo that,” said Robert P. Giugliano, MD, a cardiologist at Brigham and Women’s Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.
“The information added by this study is very important,” commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). “The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today,” he said in an interview. “My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins.” Concerns about PCSK9 inhibitors have especially focused on “the possible risks from very low cholesterol levels on the brain.” The evidence from both studies and clinical experience “allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation,” said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).
FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study’s primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.
The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.
Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.
One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). “We asked patients what they have experienced, and in the end that is what’s important, so this adds to the neurocognitive testing,” run in EBBINGHAUS, Dr. Giugliano said in an interview.
“The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive” especially for a “nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins,” Dr. Mannarino said.
Should the new FOURIER data “be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.
In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn’t scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.
FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.
SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Correction: Dr. Giugliano's name was misspelled in an earlier version of this article.
FROM JACC
Key clinical point: A cognition survey of a large number of trial participants showed no signal of adverse effects from evolocumab treatment.
Major finding: Survey results showed cognitive compromise in 3.7% of patients on evolocumab and in 3.6% control patients on placebo.
Study details:
Disclosures: FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Guigliano has received personal fees and research support from Amgen and from several other companies.
Source: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.
Hydroxychloroquine-triggered QTc-interval prolongations mount in COVID-19 patients
The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.
A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.
The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.
These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.
The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.
In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.
None of the authors of the two reports and editorial had relevant commercial disclosures.
The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.
A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.
The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.
These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.
The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.
In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.
None of the authors of the two reports and editorial had relevant commercial disclosures.
The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.
A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.
The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.
These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.
The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.
In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.
None of the authors of the two reports and editorial had relevant commercial disclosures.
FROM JAMA CARDIOLOGY
REPLENISH: Oral estradiol/progesterone slowed bone turnover as it cut VMS
Menopausal women with an intact uterus treated for a year with a daily, oral, single-pill formulation of estradiol and progesterone for the primary goal of reducing moderate to severe vasomotor symptoms showed evidence of reduced bone turnover in a post hoc, subgroup analysis of 157 women enrolled in the REPLENISH trial.
These findings “provide support for a potential skeletal benefit” when menopausal women with an intact uterus regularly used the tested estradiol plus progesterone formulation to treat moderate to severe vasomotor symptoms (VMS), Risa Kagan, MD, and associates wrote in an abstract released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. ACOG canceled the meeting, and released abstracts for press coverage.
The reductions reported for three different markers of bone turnover compared with placebo control after 6 and 12 months on treatment with a U.S.-marketed estradiol plus progesterone formulation were ”reassuring and in line with expectations” said Lubna Pal, MBBS, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., who was not involved with the study. But the findings fell short of addressing the more clinically relevant issue of whether the tested regimen reduces the rate of bone fractures.
“Only longer-term data can tell us whether this magnitude of effect is sustainable,” which would need to happen to cut fracture incidence, said Dr. Pal, who directs the menopause program at her center. “The reduction in bone-turnover markers is adequate, but magnitude alone doesn’t entirely explain a reduction in fractures.”
The bone-marker findings came from a post hoc analysis of data collected in REPLENISH (Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms in Postmenopausal Women With an Intact Uterus), a phase 3 randomized trial run at 119 U.S. sites that during 2013-2015 enrolled 1,845 menopausal women aged 65 years with an intact uterus and with moderate to severe VMS. The researchers randomized women to alternative daily treatment regimens with a single, oral pill that combined a bioidentical form of 17 beta-estradiol at dosages of 1.0 mg/day, 0.50 mg/day, or 0.25 mg/day, and dosages of bioidentical progesterone at dosages of 100 mg/day or 50 mg/day, or to a placebo control arm; not every possible dosage combination underwent testing.
The original study’s primary safety endpoint was the incidence of endometrial hyperplasia after 12 months on treatment, and the results showed no such events in any dosage arm. The primary efficacy endpoints assessed the frequency and severity of VMS after 4 and 12 weeks on treatment, and the results showed that all four tested formulations of estradiol plus progesterone had similar, statistically significant effects on decreasing VMS frequency, and the four formulations reduced severity in a dose-dependent way (Obstet Gynecol. 2018 Jul;132[1]:161-70). Based in part on results from this pivotal trial, the 1-mg estradiol/100 mg progesterone formulation (Bijuva) received Food and Drug Administration marketing approval in late 2018.
The new analysis of bone-turnover markers focused on a subgroup of women selected from two of the drug-treated arms and control patients who had at least 50 moderate to severe VMS events per week at baseline, were at least 5 years out from their last menstrual period, and had data recorded for three markers of bone turnover at baseline, and after 6 and 12 months on treatment, according to the abstract published in Obstetrics and Gynecology.
The analysis included 56 women treated with 1.0 mg estradiol and 100 mg progesterone daily, 56 who received 0.5 mg estradiol and 100 mg progesterone daily, and 45 women in the placebo arm. It assessed changes from baseline in the on-treatment compared with placebo groups using immunoassays for bone-specific alkaline phosphatase (BSAP), C-terminal telopeptide of type 1 collagen (CTX-1), and N-terminal propeptide of type 1 procollagen (PINP). For this analysis, the researchers combined the two active-treatment arms, and found that all three markers showed statistically significant drops from baseline with treatment, compared with placebo at both 6- and 12-month follow-up. For all three markers, the declines on active treatment grew larger with time, and after 12 months the mean drops from baseline compared with placebo were an 18% relative reduction in BSAP, a 41% relative reduction in CTX-1, and a 29% relative reduction in PINP, reported Dr. Kagan, a gynecologist based in Berkeley, Calif., who is affiliated with the University of California San Francisco.
In addition to not yet providing more clinically meaningful results on bone fracture rates, Dr. Pal cited additional issues that limit interpretation of both these findings and the broader REPLENISH results. First, the new analysis of bone-turnover markers as reported in the abstract does not allow assessment of a possible dose-dependent effect on bone turnover. More importantly, while the full REPLENISH trial provided reassuring data on endometrial protection, it has not yet reported data on the other major safety concern of hormone replacement: the effects of treatment on breast cancer rates. “They need to show no harm” in breast tissue, Dr. Pal said in an interview. In addition, the positive effect reported on markers of bone turnover is not unique to this formulation. Other formulations with estrogen at similar dosages would have similar effects, she said.
Other considerations when using an oral formulation include the reduced risk for prothrombotic effects from estradiol when delivered transdermally instead of orally, although some women have trouble getting insurance coverage for transdermal formulations, Dr. Pal said. Oral estrogen is appropriate only for women without an elevated clotting risk. Daily progesterone treatment also is more problematic than a cyclical dosage regimen, but noncontinuous progesterone results in monthly bleeding, something that some women prefer to avoid. “I’m not convinced that continuous progesterone is a physiologic approach,” said Dr. Pal, a member of the Ob.Gyn. News editorial advisory board. In addition, some women may find the formulation attractive because both the estradiol and progesterone are bioidentical and not synthetic molecules.
In short, the oral estradiol plus progesterone formulation tested in REPLENISH “is another tool” that’s an option for selected menopausal women with a uterus. “The bone findings are in line with expectations and are reassuring. Long-term data are keenly awaited to understand whether the bone marker changes lead to fewer fractures. The impact of the treatment on breast safety will be especially important.” For women who want a bioidentical, oral option and to not have bleeding, the tested formulation can be an effective option providing both symptom benefit and endometrial protection, Dr. Pal said.
REPLENISH was funded by TherapeuticsMD, the company that markets the tested estradiol plus progesterone formulation (Bijuva). Dr. Kagan has been a consultant and adviser to and speaker on behalf of Therapeutics MD, and she has also been a consultant or adviser to or has spoken on behalf of AMAG, Amgen, Astellas, Lupin, Radius, and Warner Chilcott/Allergan, and she has received research funding from Endoceutics. Dr. Pal has been a consultant to Flow Health.
SOURCE: Kagan R et al. Obstet Gynecol. 2020 May;135:62S. doi: 10.1097/01.AOG.0000665076.20231.a8.
Menopausal women with an intact uterus treated for a year with a daily, oral, single-pill formulation of estradiol and progesterone for the primary goal of reducing moderate to severe vasomotor symptoms showed evidence of reduced bone turnover in a post hoc, subgroup analysis of 157 women enrolled in the REPLENISH trial.
These findings “provide support for a potential skeletal benefit” when menopausal women with an intact uterus regularly used the tested estradiol plus progesterone formulation to treat moderate to severe vasomotor symptoms (VMS), Risa Kagan, MD, and associates wrote in an abstract released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. ACOG canceled the meeting, and released abstracts for press coverage.
The reductions reported for three different markers of bone turnover compared with placebo control after 6 and 12 months on treatment with a U.S.-marketed estradiol plus progesterone formulation were ”reassuring and in line with expectations” said Lubna Pal, MBBS, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., who was not involved with the study. But the findings fell short of addressing the more clinically relevant issue of whether the tested regimen reduces the rate of bone fractures.
“Only longer-term data can tell us whether this magnitude of effect is sustainable,” which would need to happen to cut fracture incidence, said Dr. Pal, who directs the menopause program at her center. “The reduction in bone-turnover markers is adequate, but magnitude alone doesn’t entirely explain a reduction in fractures.”
The bone-marker findings came from a post hoc analysis of data collected in REPLENISH (Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms in Postmenopausal Women With an Intact Uterus), a phase 3 randomized trial run at 119 U.S. sites that during 2013-2015 enrolled 1,845 menopausal women aged 65 years with an intact uterus and with moderate to severe VMS. The researchers randomized women to alternative daily treatment regimens with a single, oral pill that combined a bioidentical form of 17 beta-estradiol at dosages of 1.0 mg/day, 0.50 mg/day, or 0.25 mg/day, and dosages of bioidentical progesterone at dosages of 100 mg/day or 50 mg/day, or to a placebo control arm; not every possible dosage combination underwent testing.
The original study’s primary safety endpoint was the incidence of endometrial hyperplasia after 12 months on treatment, and the results showed no such events in any dosage arm. The primary efficacy endpoints assessed the frequency and severity of VMS after 4 and 12 weeks on treatment, and the results showed that all four tested formulations of estradiol plus progesterone had similar, statistically significant effects on decreasing VMS frequency, and the four formulations reduced severity in a dose-dependent way (Obstet Gynecol. 2018 Jul;132[1]:161-70). Based in part on results from this pivotal trial, the 1-mg estradiol/100 mg progesterone formulation (Bijuva) received Food and Drug Administration marketing approval in late 2018.
The new analysis of bone-turnover markers focused on a subgroup of women selected from two of the drug-treated arms and control patients who had at least 50 moderate to severe VMS events per week at baseline, were at least 5 years out from their last menstrual period, and had data recorded for three markers of bone turnover at baseline, and after 6 and 12 months on treatment, according to the abstract published in Obstetrics and Gynecology.
The analysis included 56 women treated with 1.0 mg estradiol and 100 mg progesterone daily, 56 who received 0.5 mg estradiol and 100 mg progesterone daily, and 45 women in the placebo arm. It assessed changes from baseline in the on-treatment compared with placebo groups using immunoassays for bone-specific alkaline phosphatase (BSAP), C-terminal telopeptide of type 1 collagen (CTX-1), and N-terminal propeptide of type 1 procollagen (PINP). For this analysis, the researchers combined the two active-treatment arms, and found that all three markers showed statistically significant drops from baseline with treatment, compared with placebo at both 6- and 12-month follow-up. For all three markers, the declines on active treatment grew larger with time, and after 12 months the mean drops from baseline compared with placebo were an 18% relative reduction in BSAP, a 41% relative reduction in CTX-1, and a 29% relative reduction in PINP, reported Dr. Kagan, a gynecologist based in Berkeley, Calif., who is affiliated with the University of California San Francisco.
In addition to not yet providing more clinically meaningful results on bone fracture rates, Dr. Pal cited additional issues that limit interpretation of both these findings and the broader REPLENISH results. First, the new analysis of bone-turnover markers as reported in the abstract does not allow assessment of a possible dose-dependent effect on bone turnover. More importantly, while the full REPLENISH trial provided reassuring data on endometrial protection, it has not yet reported data on the other major safety concern of hormone replacement: the effects of treatment on breast cancer rates. “They need to show no harm” in breast tissue, Dr. Pal said in an interview. In addition, the positive effect reported on markers of bone turnover is not unique to this formulation. Other formulations with estrogen at similar dosages would have similar effects, she said.
Other considerations when using an oral formulation include the reduced risk for prothrombotic effects from estradiol when delivered transdermally instead of orally, although some women have trouble getting insurance coverage for transdermal formulations, Dr. Pal said. Oral estrogen is appropriate only for women without an elevated clotting risk. Daily progesterone treatment also is more problematic than a cyclical dosage regimen, but noncontinuous progesterone results in monthly bleeding, something that some women prefer to avoid. “I’m not convinced that continuous progesterone is a physiologic approach,” said Dr. Pal, a member of the Ob.Gyn. News editorial advisory board. In addition, some women may find the formulation attractive because both the estradiol and progesterone are bioidentical and not synthetic molecules.
In short, the oral estradiol plus progesterone formulation tested in REPLENISH “is another tool” that’s an option for selected menopausal women with a uterus. “The bone findings are in line with expectations and are reassuring. Long-term data are keenly awaited to understand whether the bone marker changes lead to fewer fractures. The impact of the treatment on breast safety will be especially important.” For women who want a bioidentical, oral option and to not have bleeding, the tested formulation can be an effective option providing both symptom benefit and endometrial protection, Dr. Pal said.
REPLENISH was funded by TherapeuticsMD, the company that markets the tested estradiol plus progesterone formulation (Bijuva). Dr. Kagan has been a consultant and adviser to and speaker on behalf of Therapeutics MD, and she has also been a consultant or adviser to or has spoken on behalf of AMAG, Amgen, Astellas, Lupin, Radius, and Warner Chilcott/Allergan, and she has received research funding from Endoceutics. Dr. Pal has been a consultant to Flow Health.
SOURCE: Kagan R et al. Obstet Gynecol. 2020 May;135:62S. doi: 10.1097/01.AOG.0000665076.20231.a8.
Menopausal women with an intact uterus treated for a year with a daily, oral, single-pill formulation of estradiol and progesterone for the primary goal of reducing moderate to severe vasomotor symptoms showed evidence of reduced bone turnover in a post hoc, subgroup analysis of 157 women enrolled in the REPLENISH trial.
These findings “provide support for a potential skeletal benefit” when menopausal women with an intact uterus regularly used the tested estradiol plus progesterone formulation to treat moderate to severe vasomotor symptoms (VMS), Risa Kagan, MD, and associates wrote in an abstract released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. ACOG canceled the meeting, and released abstracts for press coverage.
The reductions reported for three different markers of bone turnover compared with placebo control after 6 and 12 months on treatment with a U.S.-marketed estradiol plus progesterone formulation were ”reassuring and in line with expectations” said Lubna Pal, MBBS, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., who was not involved with the study. But the findings fell short of addressing the more clinically relevant issue of whether the tested regimen reduces the rate of bone fractures.
“Only longer-term data can tell us whether this magnitude of effect is sustainable,” which would need to happen to cut fracture incidence, said Dr. Pal, who directs the menopause program at her center. “The reduction in bone-turnover markers is adequate, but magnitude alone doesn’t entirely explain a reduction in fractures.”
The bone-marker findings came from a post hoc analysis of data collected in REPLENISH (Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms in Postmenopausal Women With an Intact Uterus), a phase 3 randomized trial run at 119 U.S. sites that during 2013-2015 enrolled 1,845 menopausal women aged 65 years with an intact uterus and with moderate to severe VMS. The researchers randomized women to alternative daily treatment regimens with a single, oral pill that combined a bioidentical form of 17 beta-estradiol at dosages of 1.0 mg/day, 0.50 mg/day, or 0.25 mg/day, and dosages of bioidentical progesterone at dosages of 100 mg/day or 50 mg/day, or to a placebo control arm; not every possible dosage combination underwent testing.
The original study’s primary safety endpoint was the incidence of endometrial hyperplasia after 12 months on treatment, and the results showed no such events in any dosage arm. The primary efficacy endpoints assessed the frequency and severity of VMS after 4 and 12 weeks on treatment, and the results showed that all four tested formulations of estradiol plus progesterone had similar, statistically significant effects on decreasing VMS frequency, and the four formulations reduced severity in a dose-dependent way (Obstet Gynecol. 2018 Jul;132[1]:161-70). Based in part on results from this pivotal trial, the 1-mg estradiol/100 mg progesterone formulation (Bijuva) received Food and Drug Administration marketing approval in late 2018.
The new analysis of bone-turnover markers focused on a subgroup of women selected from two of the drug-treated arms and control patients who had at least 50 moderate to severe VMS events per week at baseline, were at least 5 years out from their last menstrual period, and had data recorded for three markers of bone turnover at baseline, and after 6 and 12 months on treatment, according to the abstract published in Obstetrics and Gynecology.
The analysis included 56 women treated with 1.0 mg estradiol and 100 mg progesterone daily, 56 who received 0.5 mg estradiol and 100 mg progesterone daily, and 45 women in the placebo arm. It assessed changes from baseline in the on-treatment compared with placebo groups using immunoassays for bone-specific alkaline phosphatase (BSAP), C-terminal telopeptide of type 1 collagen (CTX-1), and N-terminal propeptide of type 1 procollagen (PINP). For this analysis, the researchers combined the two active-treatment arms, and found that all three markers showed statistically significant drops from baseline with treatment, compared with placebo at both 6- and 12-month follow-up. For all three markers, the declines on active treatment grew larger with time, and after 12 months the mean drops from baseline compared with placebo were an 18% relative reduction in BSAP, a 41% relative reduction in CTX-1, and a 29% relative reduction in PINP, reported Dr. Kagan, a gynecologist based in Berkeley, Calif., who is affiliated with the University of California San Francisco.
In addition to not yet providing more clinically meaningful results on bone fracture rates, Dr. Pal cited additional issues that limit interpretation of both these findings and the broader REPLENISH results. First, the new analysis of bone-turnover markers as reported in the abstract does not allow assessment of a possible dose-dependent effect on bone turnover. More importantly, while the full REPLENISH trial provided reassuring data on endometrial protection, it has not yet reported data on the other major safety concern of hormone replacement: the effects of treatment on breast cancer rates. “They need to show no harm” in breast tissue, Dr. Pal said in an interview. In addition, the positive effect reported on markers of bone turnover is not unique to this formulation. Other formulations with estrogen at similar dosages would have similar effects, she said.
Other considerations when using an oral formulation include the reduced risk for prothrombotic effects from estradiol when delivered transdermally instead of orally, although some women have trouble getting insurance coverage for transdermal formulations, Dr. Pal said. Oral estrogen is appropriate only for women without an elevated clotting risk. Daily progesterone treatment also is more problematic than a cyclical dosage regimen, but noncontinuous progesterone results in monthly bleeding, something that some women prefer to avoid. “I’m not convinced that continuous progesterone is a physiologic approach,” said Dr. Pal, a member of the Ob.Gyn. News editorial advisory board. In addition, some women may find the formulation attractive because both the estradiol and progesterone are bioidentical and not synthetic molecules.
In short, the oral estradiol plus progesterone formulation tested in REPLENISH “is another tool” that’s an option for selected menopausal women with a uterus. “The bone findings are in line with expectations and are reassuring. Long-term data are keenly awaited to understand whether the bone marker changes lead to fewer fractures. The impact of the treatment on breast safety will be especially important.” For women who want a bioidentical, oral option and to not have bleeding, the tested formulation can be an effective option providing both symptom benefit and endometrial protection, Dr. Pal said.
REPLENISH was funded by TherapeuticsMD, the company that markets the tested estradiol plus progesterone formulation (Bijuva). Dr. Kagan has been a consultant and adviser to and speaker on behalf of Therapeutics MD, and she has also been a consultant or adviser to or has spoken on behalf of AMAG, Amgen, Astellas, Lupin, Radius, and Warner Chilcott/Allergan, and she has received research funding from Endoceutics. Dr. Pal has been a consultant to Flow Health.
SOURCE: Kagan R et al. Obstet Gynecol. 2020 May;135:62S. doi: 10.1097/01.AOG.0000665076.20231.a8.
FROM ACOG 2020
SGLT2 inhibitor ertugliflozin shows no CV death or renal benefit
The sodium-glucose transporter 2 (SGLT-2) inhibitor ertugliflozin broke ranks with the other drugs in its class and failed to produce statistically significant drops in the both the combined incidence of cardiovascular (CV) death or heart failure hospitalization, and the rate of adverse renal outcomes, in the mandated CV outcomes trial run for ertugliflozin with more than 8,200 patients with type 2 diabetes and established CV disease.
Merck, one of the companies that markets the drug, announced the topline results in a quarterly financial report released on April 28, 2020.
According to the report, the results from the ertugliflozin cardiovascular outcomes trial “achieved its primary endpoint of noninferiority for major adverse CV events (MACE), compared to placebo in patients with type 2 diabetes mellitus and established atherosclerotic CV disease,” but “the key secondary endpoints of superiority” of ertugliflozin, compared with placebo, “for time to the composite of CV death or hospitalization for heart failure, CV death alone, and the composite of renal death, dialysis/transplant or doubling of serum creatinine from baseline were not met.”
However, the report added that, “while not a prespecified hypothesis for statistical testing, a reduction in hospitalization for heart failure was observed” with ertugliflozin treatment, and the report further said that the drug’s safety profile in the trial “was consistent with that reported in previous studies.” The statement closed by saying that detailed results from the trial are scheduled to be presented on June 16, 2020, at the virtual American Diabetes Association’s 80th Scientific Sessions.
These results came from the VERTIS CV (Evaluation of Ertugliflozin EffIcacy and Safety Cardiovascular Outcomes) trial, which researchers said in 2018 had administered at least one investigational dose to 8,238 randomized patients at centers in any of 34 countries during two enrollment periods in 2013-2015 and 2016-2017 (Am Heart J. 2018 Dec;206:11-23). The tested agent, ertugliflozin (Steglatro) received Food and Drug Administration marketing approval late in 2017 for the indication of improving glycemic control in patients with type 2 diabetes.
The FDA mandated cardiovascular outcomes trials for new glycemic control drugs in guidance the agency issued in 2008 (the FDA released in March 2020 a draft of updated guidance on this topic).
Other FDA-approved agents from the SGLT2 inhibitor class include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), and all three showed evidence for a statistically significant effect on reducing the incidence of CV disease death and heart failure hospitalizations, as well as renal complications (Can J Diabetes. 2020 Feb;44[1]:61-7). The evidence showing that several SGLT2 drugs have important and consistent effects on endpoints like CV death, heart failure hospitalizations, and renal complications has helped propel this class of agents to the forefront of glycemic control treatments. More recently, one agent from this group, dapagliflozin, also significantly cut the rate of heart failure worsening or CV disease death in patients with heart failure with reduced ejection fraction but without diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). Based on this evidence, the FDA is currently considering adding a new indication for dapagliflozin that would also label it for use in patients with heart failure with reduced ejection fraction but without diabetes.
The sodium-glucose transporter 2 (SGLT-2) inhibitor ertugliflozin broke ranks with the other drugs in its class and failed to produce statistically significant drops in the both the combined incidence of cardiovascular (CV) death or heart failure hospitalization, and the rate of adverse renal outcomes, in the mandated CV outcomes trial run for ertugliflozin with more than 8,200 patients with type 2 diabetes and established CV disease.
Merck, one of the companies that markets the drug, announced the topline results in a quarterly financial report released on April 28, 2020.
According to the report, the results from the ertugliflozin cardiovascular outcomes trial “achieved its primary endpoint of noninferiority for major adverse CV events (MACE), compared to placebo in patients with type 2 diabetes mellitus and established atherosclerotic CV disease,” but “the key secondary endpoints of superiority” of ertugliflozin, compared with placebo, “for time to the composite of CV death or hospitalization for heart failure, CV death alone, and the composite of renal death, dialysis/transplant or doubling of serum creatinine from baseline were not met.”
However, the report added that, “while not a prespecified hypothesis for statistical testing, a reduction in hospitalization for heart failure was observed” with ertugliflozin treatment, and the report further said that the drug’s safety profile in the trial “was consistent with that reported in previous studies.” The statement closed by saying that detailed results from the trial are scheduled to be presented on June 16, 2020, at the virtual American Diabetes Association’s 80th Scientific Sessions.
These results came from the VERTIS CV (Evaluation of Ertugliflozin EffIcacy and Safety Cardiovascular Outcomes) trial, which researchers said in 2018 had administered at least one investigational dose to 8,238 randomized patients at centers in any of 34 countries during two enrollment periods in 2013-2015 and 2016-2017 (Am Heart J. 2018 Dec;206:11-23). The tested agent, ertugliflozin (Steglatro) received Food and Drug Administration marketing approval late in 2017 for the indication of improving glycemic control in patients with type 2 diabetes.
The FDA mandated cardiovascular outcomes trials for new glycemic control drugs in guidance the agency issued in 2008 (the FDA released in March 2020 a draft of updated guidance on this topic).
Other FDA-approved agents from the SGLT2 inhibitor class include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), and all three showed evidence for a statistically significant effect on reducing the incidence of CV disease death and heart failure hospitalizations, as well as renal complications (Can J Diabetes. 2020 Feb;44[1]:61-7). The evidence showing that several SGLT2 drugs have important and consistent effects on endpoints like CV death, heart failure hospitalizations, and renal complications has helped propel this class of agents to the forefront of glycemic control treatments. More recently, one agent from this group, dapagliflozin, also significantly cut the rate of heart failure worsening or CV disease death in patients with heart failure with reduced ejection fraction but without diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). Based on this evidence, the FDA is currently considering adding a new indication for dapagliflozin that would also label it for use in patients with heart failure with reduced ejection fraction but without diabetes.
The sodium-glucose transporter 2 (SGLT-2) inhibitor ertugliflozin broke ranks with the other drugs in its class and failed to produce statistically significant drops in the both the combined incidence of cardiovascular (CV) death or heart failure hospitalization, and the rate of adverse renal outcomes, in the mandated CV outcomes trial run for ertugliflozin with more than 8,200 patients with type 2 diabetes and established CV disease.
Merck, one of the companies that markets the drug, announced the topline results in a quarterly financial report released on April 28, 2020.
According to the report, the results from the ertugliflozin cardiovascular outcomes trial “achieved its primary endpoint of noninferiority for major adverse CV events (MACE), compared to placebo in patients with type 2 diabetes mellitus and established atherosclerotic CV disease,” but “the key secondary endpoints of superiority” of ertugliflozin, compared with placebo, “for time to the composite of CV death or hospitalization for heart failure, CV death alone, and the composite of renal death, dialysis/transplant or doubling of serum creatinine from baseline were not met.”
However, the report added that, “while not a prespecified hypothesis for statistical testing, a reduction in hospitalization for heart failure was observed” with ertugliflozin treatment, and the report further said that the drug’s safety profile in the trial “was consistent with that reported in previous studies.” The statement closed by saying that detailed results from the trial are scheduled to be presented on June 16, 2020, at the virtual American Diabetes Association’s 80th Scientific Sessions.
These results came from the VERTIS CV (Evaluation of Ertugliflozin EffIcacy and Safety Cardiovascular Outcomes) trial, which researchers said in 2018 had administered at least one investigational dose to 8,238 randomized patients at centers in any of 34 countries during two enrollment periods in 2013-2015 and 2016-2017 (Am Heart J. 2018 Dec;206:11-23). The tested agent, ertugliflozin (Steglatro) received Food and Drug Administration marketing approval late in 2017 for the indication of improving glycemic control in patients with type 2 diabetes.
The FDA mandated cardiovascular outcomes trials for new glycemic control drugs in guidance the agency issued in 2008 (the FDA released in March 2020 a draft of updated guidance on this topic).
Other FDA-approved agents from the SGLT2 inhibitor class include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), and all three showed evidence for a statistically significant effect on reducing the incidence of CV disease death and heart failure hospitalizations, as well as renal complications (Can J Diabetes. 2020 Feb;44[1]:61-7). The evidence showing that several SGLT2 drugs have important and consistent effects on endpoints like CV death, heart failure hospitalizations, and renal complications has helped propel this class of agents to the forefront of glycemic control treatments. More recently, one agent from this group, dapagliflozin, also significantly cut the rate of heart failure worsening or CV disease death in patients with heart failure with reduced ejection fraction but without diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). Based on this evidence, the FDA is currently considering adding a new indication for dapagliflozin that would also label it for use in patients with heart failure with reduced ejection fraction but without diabetes.
FDA reiterates hydroxychloroquine limitations for COVID-19
The U.S. Food and Drug Administration reinforced its March guidance on when it’s permissible to use hydroxychloroquine and chloroquine to treat COVID-19 patients and on the multiple risks these drugs pose in a Safety Communication on April 24.
The new communication reiterated the agency’s position from the Emergency Use Authorization (EUA) it granted on March 28 to allow hydroxychloroquine and chloroquine treatment of COVID-19 patients only when they are hospitalized and participation in a clinical trial is “not available,” or “not feasible.” The April 24 update to the EUA noted that “the FDA is aware of reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT-prolonging medicines. We are also aware of increased use of these medicines through outpatient prescriptions.”
In addition to reiterating the prior limitations on permissible patients for these treatment the agency also said in the new communication that “close supervision is strongly recommended, “ specifying that “we recommend initial evaluation and monitoring when using hydroxychloroquine or chloroquine under the EUA or in clinical trials that investigate these medicines for the treatment or prevention of COVID-19. Monitoring may include baseline ECG, electrolytes, renal function, and hepatic tests.” The communication also highlighted several potential serious adverse effects from hydroxychloroquine or chloroquine that include QT prolongation with increased risk in patients with renal insufficiency or failure, increased insulin levels and insulin action causing increased risk of severe hypoglycemia, hemolysis in selected patients, and interaction with other medicines that cause QT prolongation.
“If a healthcare professional is considering use of hydroxychloroquine or chloroquine to treat or prevent COVID-19, FDA recommends checking www.clinicaltrials.gov for a suitable clinical trial and consider enrolling the patient,” the statement added.
The FDA’s Safety Communication came a day after the European Medicines Agency issued a similar reminder about the risk for serious adverse effects from treatment with hydroxychloroquine and chloroquine, the need for adverse effect monitoring, and the unproven status of purported benefits from these agents.
The statement came after ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite a lack of evidence.
The FDA’s communication cited recent case reports sent to the FDA, as well as published findings, and reports to the National Poison Data System that have described serious, heart-related adverse events and death in COVID-19 patients who received hydroxychloroquine and chloroquine, alone or in combination with azithromycin or another QT-prolonging drug. One recent, notable but not peer-reviewed report on 368 patients treated at any of several U.S. VA medical centers showed no apparent benefit to hospitalized COVID-19 patients treated with hydroxychloroquine and a signal for increased mortality among certain patients on this drug (medRxiv. 2020 Apr 23; doi: 10.1101/2020.04.16.20065920). Several cardiology societies have also highlighted the cardiac considerations for using these drugs in patients with COVID-19, including a summary coauthored by the presidents of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society (Circulation. 2020 Apr 8. doi: 10.1161/CIRCULATIONAHA.120.047521), and in guidance from the European Society of Cardiology.
The U.S. Food and Drug Administration reinforced its March guidance on when it’s permissible to use hydroxychloroquine and chloroquine to treat COVID-19 patients and on the multiple risks these drugs pose in a Safety Communication on April 24.
The new communication reiterated the agency’s position from the Emergency Use Authorization (EUA) it granted on March 28 to allow hydroxychloroquine and chloroquine treatment of COVID-19 patients only when they are hospitalized and participation in a clinical trial is “not available,” or “not feasible.” The April 24 update to the EUA noted that “the FDA is aware of reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT-prolonging medicines. We are also aware of increased use of these medicines through outpatient prescriptions.”
In addition to reiterating the prior limitations on permissible patients for these treatment the agency also said in the new communication that “close supervision is strongly recommended, “ specifying that “we recommend initial evaluation and monitoring when using hydroxychloroquine or chloroquine under the EUA or in clinical trials that investigate these medicines for the treatment or prevention of COVID-19. Monitoring may include baseline ECG, electrolytes, renal function, and hepatic tests.” The communication also highlighted several potential serious adverse effects from hydroxychloroquine or chloroquine that include QT prolongation with increased risk in patients with renal insufficiency or failure, increased insulin levels and insulin action causing increased risk of severe hypoglycemia, hemolysis in selected patients, and interaction with other medicines that cause QT prolongation.
“If a healthcare professional is considering use of hydroxychloroquine or chloroquine to treat or prevent COVID-19, FDA recommends checking www.clinicaltrials.gov for a suitable clinical trial and consider enrolling the patient,” the statement added.
The FDA’s Safety Communication came a day after the European Medicines Agency issued a similar reminder about the risk for serious adverse effects from treatment with hydroxychloroquine and chloroquine, the need for adverse effect monitoring, and the unproven status of purported benefits from these agents.
The statement came after ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite a lack of evidence.
The FDA’s communication cited recent case reports sent to the FDA, as well as published findings, and reports to the National Poison Data System that have described serious, heart-related adverse events and death in COVID-19 patients who received hydroxychloroquine and chloroquine, alone or in combination with azithromycin or another QT-prolonging drug. One recent, notable but not peer-reviewed report on 368 patients treated at any of several U.S. VA medical centers showed no apparent benefit to hospitalized COVID-19 patients treated with hydroxychloroquine and a signal for increased mortality among certain patients on this drug (medRxiv. 2020 Apr 23; doi: 10.1101/2020.04.16.20065920). Several cardiology societies have also highlighted the cardiac considerations for using these drugs in patients with COVID-19, including a summary coauthored by the presidents of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society (Circulation. 2020 Apr 8. doi: 10.1161/CIRCULATIONAHA.120.047521), and in guidance from the European Society of Cardiology.
The U.S. Food and Drug Administration reinforced its March guidance on when it’s permissible to use hydroxychloroquine and chloroquine to treat COVID-19 patients and on the multiple risks these drugs pose in a Safety Communication on April 24.
The new communication reiterated the agency’s position from the Emergency Use Authorization (EUA) it granted on March 28 to allow hydroxychloroquine and chloroquine treatment of COVID-19 patients only when they are hospitalized and participation in a clinical trial is “not available,” or “not feasible.” The April 24 update to the EUA noted that “the FDA is aware of reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT-prolonging medicines. We are also aware of increased use of these medicines through outpatient prescriptions.”
In addition to reiterating the prior limitations on permissible patients for these treatment the agency also said in the new communication that “close supervision is strongly recommended, “ specifying that “we recommend initial evaluation and monitoring when using hydroxychloroquine or chloroquine under the EUA or in clinical trials that investigate these medicines for the treatment or prevention of COVID-19. Monitoring may include baseline ECG, electrolytes, renal function, and hepatic tests.” The communication also highlighted several potential serious adverse effects from hydroxychloroquine or chloroquine that include QT prolongation with increased risk in patients with renal insufficiency or failure, increased insulin levels and insulin action causing increased risk of severe hypoglycemia, hemolysis in selected patients, and interaction with other medicines that cause QT prolongation.
“If a healthcare professional is considering use of hydroxychloroquine or chloroquine to treat or prevent COVID-19, FDA recommends checking www.clinicaltrials.gov for a suitable clinical trial and consider enrolling the patient,” the statement added.
The FDA’s Safety Communication came a day after the European Medicines Agency issued a similar reminder about the risk for serious adverse effects from treatment with hydroxychloroquine and chloroquine, the need for adverse effect monitoring, and the unproven status of purported benefits from these agents.
The statement came after ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite a lack of evidence.
The FDA’s communication cited recent case reports sent to the FDA, as well as published findings, and reports to the National Poison Data System that have described serious, heart-related adverse events and death in COVID-19 patients who received hydroxychloroquine and chloroquine, alone or in combination with azithromycin or another QT-prolonging drug. One recent, notable but not peer-reviewed report on 368 patients treated at any of several U.S. VA medical centers showed no apparent benefit to hospitalized COVID-19 patients treated with hydroxychloroquine and a signal for increased mortality among certain patients on this drug (medRxiv. 2020 Apr 23; doi: 10.1101/2020.04.16.20065920). Several cardiology societies have also highlighted the cardiac considerations for using these drugs in patients with COVID-19, including a summary coauthored by the presidents of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society (Circulation. 2020 Apr 8. doi: 10.1161/CIRCULATIONAHA.120.047521), and in guidance from the European Society of Cardiology.
FROM THE FDA
AUGUSTUS: After ACS or PCI, aspirin gives AFib patients scant benefit
When patients with atrial fibrillation have an acute coronary syndrome event or undergo percutaneous coronary intervention, their window of opportunity for benefiting from a triple antithrombotic regimen was, at best, about 30 days, according to a post hoc analysis of AUGUSTUS, a multicenter, randomized trial with more than 4,600 patients.
Beyond 30 days out to 180 days, the incremental benefit from reduced ischemic events fell to essentially zero, giving it a clear back seat to the ongoing, increased bleeding risk from adding a third antithrombotic drug.
Patients randomized to receive aspirin in addition to an anticoagulant, either apixaban or a vitamin K antagonist such as warfarin, and a P2Y12 inhibitor such as clopidogrel “for up to approximately 30 days” had a roughly similar decrease in severe ischemic events and increase in severe bleeding events, suggesting that even acutely the overall impact of adding aspirin on top of the other two antithrombotics was a wash, John H. Alexander, MD, said in a presentation of research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
Using aspirin as a third antithrombotic in patients with atrial fibrillation (AFib) who have also recently had either an acute coronary syndrome event (ACS) or underwent percutaneous coronary intervention (PCI), “may be reasonable,” for selected patients, but is a decision that requires careful individualization, cautioned Dr. Alexander, professor of medicine and director of Cardiovascular Research at the Duke Clinical Research Institute of Duke University, Durham, N.C.
“This is a superb secondary analysis looking at the time course of potential benefit and harm with aspirin, and they found that aspirin was beneficial only in the first 30 days. After 30 days, it’s startling and remarkable that the ischemic event curves were completely on top of each other,” commented Julia H. Indik, MD, a cardiac electrophysiologist at Banner–University Medical Center Tuscon and designated discussant for the report. “This substudy will be essential for updating the guidelines,” she predicted. “When a treatment’s benefit equals its risks,” which happened when aspirin was part of the regimen during the first 30 days, “then it’s not even a class IIb recommendation; it’s class III,” the classification used by the ACC and collaborating groups to identify treatments where net benefit and net risk are similar and hence the treatment is considered not recommended.
A key element in the analysis Dr. Alexander presented was to define a spectrum of clinical events as representing broad, intermediate, or severe ischemic or bleeding events. The severe category for bleeding events included fatal, intracranial, and any bleed rated as major by the International Society on Thrombosis and Haemostasis (ISTH) criteria, while the broad bleeding definition included all of these plus bleeds that directly resulted in hospitalization and clinically relevant nonmajor bleeds. For ischemic events, the severe group consisted of cardiovascular death, MI, stent thrombosis, and ischemic stroke, while the broad category also tallied urgent revascularizations and cardiovascular hospitalizations.
“I believe the severe bleeds and severe ischemic events we identified are roughly equal in severity,” Dr. Alexander noted. “Where I think we need more analysis is which patients have more bleeding risk and which have more ischemia risk. We need a more tailored approach to identify patient subgroups, perhaps based on angiographic characteristics, or something else,” that modifies the trade-off that, on a population level, seems very evenly balanced.
Applying this approach to scoring the severity of adverse outcomes, Dr. Alexander reported that, during the first 30 days on treatment, patients on aspirin had a net absolute gain of 1.0% in severe bleeding events, compared with placebo, and a 3.4% gain in broad bleeds, while showing a 0.9% drop in severe ischemic events but no between-group difference in the rate of broadly defined ischemic events. During days 31-180, the addition of aspirin resulted in virtually no reductions in ischemic events regardless of whether they were severe, intermediate, or broad, but adding aspirin continued to produce an excess of bleeding episodes in all three categories. The results also appeared in an article published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046534).
“We did not see a time window when the ischemia risk was greater than the bleeding risk,” Dr. Alexander noted, and he also highlighted that the one option the analysis could not explore is never giving these patients any aspirin. “Patients received aspirin for some number of days before randomization,” a median of 6 days from the time of their ACS or PCI event until randomization, “so we don’t have great insight into whether no aspirin” is an reasonable option.
The AUGUSTUS trial randomized 4,614 patients with AFib and a recent ACS or PCI event at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the rate of major or clinically relevant nonmajor bleeding by the ISTH criteria during 6 months on treatment, while composites of death or hospitalization, and death plus ischemic events served as secondary outcomes. All patients received an antiplatelet P2Y12 inhibitor, with 93% of patients receiving clopidogrel, and were randomized in a 2 x 2 factorial design to one of four regimens: either apixaban or a vitamin K antagonist (such as warfarin), and to aspirin or placebo. The study’s primary findings showed that using apixaban instead of a vitamin K antagonist significantly reduced bleeding events as well as the rate of death or hospitalization, but the rate of death and ischemic events was similar in the two arms. The primary AUGUSTUS finding for the aspirin versus placebo randomization was that overall throughout the study ischemic events were balanced in the these two treatment arms while aspirin boosted bleeding (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
AUGUSTUS was sponsored by Bristol-Myers Squibb and Pfizer, the companies that market apixaban. Dr. Alexander has been a consultant to and received research funding from Bristol-Myers Squibb and Pfizer; has been a consultant to AbbVie, Bayer, CryoLife, CSL Behring, Novo Nordisk, Portola, Quantum Genomics, XaTek, and Zafgen; and has received research funding from Boehringer Ingelheim, CryoLife, CSL Behring, GlaxoSmithKline, and XaTek. Dr. Indik had no disclosures.
SOURCE: Alexander JH et al. ACC 2020, Abstract 409-08.
When patients with atrial fibrillation have an acute coronary syndrome event or undergo percutaneous coronary intervention, their window of opportunity for benefiting from a triple antithrombotic regimen was, at best, about 30 days, according to a post hoc analysis of AUGUSTUS, a multicenter, randomized trial with more than 4,600 patients.
Beyond 30 days out to 180 days, the incremental benefit from reduced ischemic events fell to essentially zero, giving it a clear back seat to the ongoing, increased bleeding risk from adding a third antithrombotic drug.
Patients randomized to receive aspirin in addition to an anticoagulant, either apixaban or a vitamin K antagonist such as warfarin, and a P2Y12 inhibitor such as clopidogrel “for up to approximately 30 days” had a roughly similar decrease in severe ischemic events and increase in severe bleeding events, suggesting that even acutely the overall impact of adding aspirin on top of the other two antithrombotics was a wash, John H. Alexander, MD, said in a presentation of research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
Using aspirin as a third antithrombotic in patients with atrial fibrillation (AFib) who have also recently had either an acute coronary syndrome event (ACS) or underwent percutaneous coronary intervention (PCI), “may be reasonable,” for selected patients, but is a decision that requires careful individualization, cautioned Dr. Alexander, professor of medicine and director of Cardiovascular Research at the Duke Clinical Research Institute of Duke University, Durham, N.C.
“This is a superb secondary analysis looking at the time course of potential benefit and harm with aspirin, and they found that aspirin was beneficial only in the first 30 days. After 30 days, it’s startling and remarkable that the ischemic event curves were completely on top of each other,” commented Julia H. Indik, MD, a cardiac electrophysiologist at Banner–University Medical Center Tuscon and designated discussant for the report. “This substudy will be essential for updating the guidelines,” she predicted. “When a treatment’s benefit equals its risks,” which happened when aspirin was part of the regimen during the first 30 days, “then it’s not even a class IIb recommendation; it’s class III,” the classification used by the ACC and collaborating groups to identify treatments where net benefit and net risk are similar and hence the treatment is considered not recommended.
A key element in the analysis Dr. Alexander presented was to define a spectrum of clinical events as representing broad, intermediate, or severe ischemic or bleeding events. The severe category for bleeding events included fatal, intracranial, and any bleed rated as major by the International Society on Thrombosis and Haemostasis (ISTH) criteria, while the broad bleeding definition included all of these plus bleeds that directly resulted in hospitalization and clinically relevant nonmajor bleeds. For ischemic events, the severe group consisted of cardiovascular death, MI, stent thrombosis, and ischemic stroke, while the broad category also tallied urgent revascularizations and cardiovascular hospitalizations.
“I believe the severe bleeds and severe ischemic events we identified are roughly equal in severity,” Dr. Alexander noted. “Where I think we need more analysis is which patients have more bleeding risk and which have more ischemia risk. We need a more tailored approach to identify patient subgroups, perhaps based on angiographic characteristics, or something else,” that modifies the trade-off that, on a population level, seems very evenly balanced.
Applying this approach to scoring the severity of adverse outcomes, Dr. Alexander reported that, during the first 30 days on treatment, patients on aspirin had a net absolute gain of 1.0% in severe bleeding events, compared with placebo, and a 3.4% gain in broad bleeds, while showing a 0.9% drop in severe ischemic events but no between-group difference in the rate of broadly defined ischemic events. During days 31-180, the addition of aspirin resulted in virtually no reductions in ischemic events regardless of whether they were severe, intermediate, or broad, but adding aspirin continued to produce an excess of bleeding episodes in all three categories. The results also appeared in an article published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046534).
“We did not see a time window when the ischemia risk was greater than the bleeding risk,” Dr. Alexander noted, and he also highlighted that the one option the analysis could not explore is never giving these patients any aspirin. “Patients received aspirin for some number of days before randomization,” a median of 6 days from the time of their ACS or PCI event until randomization, “so we don’t have great insight into whether no aspirin” is an reasonable option.
The AUGUSTUS trial randomized 4,614 patients with AFib and a recent ACS or PCI event at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the rate of major or clinically relevant nonmajor bleeding by the ISTH criteria during 6 months on treatment, while composites of death or hospitalization, and death plus ischemic events served as secondary outcomes. All patients received an antiplatelet P2Y12 inhibitor, with 93% of patients receiving clopidogrel, and were randomized in a 2 x 2 factorial design to one of four regimens: either apixaban or a vitamin K antagonist (such as warfarin), and to aspirin or placebo. The study’s primary findings showed that using apixaban instead of a vitamin K antagonist significantly reduced bleeding events as well as the rate of death or hospitalization, but the rate of death and ischemic events was similar in the two arms. The primary AUGUSTUS finding for the aspirin versus placebo randomization was that overall throughout the study ischemic events were balanced in the these two treatment arms while aspirin boosted bleeding (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
AUGUSTUS was sponsored by Bristol-Myers Squibb and Pfizer, the companies that market apixaban. Dr. Alexander has been a consultant to and received research funding from Bristol-Myers Squibb and Pfizer; has been a consultant to AbbVie, Bayer, CryoLife, CSL Behring, Novo Nordisk, Portola, Quantum Genomics, XaTek, and Zafgen; and has received research funding from Boehringer Ingelheim, CryoLife, CSL Behring, GlaxoSmithKline, and XaTek. Dr. Indik had no disclosures.
SOURCE: Alexander JH et al. ACC 2020, Abstract 409-08.
When patients with atrial fibrillation have an acute coronary syndrome event or undergo percutaneous coronary intervention, their window of opportunity for benefiting from a triple antithrombotic regimen was, at best, about 30 days, according to a post hoc analysis of AUGUSTUS, a multicenter, randomized trial with more than 4,600 patients.
Beyond 30 days out to 180 days, the incremental benefit from reduced ischemic events fell to essentially zero, giving it a clear back seat to the ongoing, increased bleeding risk from adding a third antithrombotic drug.
Patients randomized to receive aspirin in addition to an anticoagulant, either apixaban or a vitamin K antagonist such as warfarin, and a P2Y12 inhibitor such as clopidogrel “for up to approximately 30 days” had a roughly similar decrease in severe ischemic events and increase in severe bleeding events, suggesting that even acutely the overall impact of adding aspirin on top of the other two antithrombotics was a wash, John H. Alexander, MD, said in a presentation of research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
Using aspirin as a third antithrombotic in patients with atrial fibrillation (AFib) who have also recently had either an acute coronary syndrome event (ACS) or underwent percutaneous coronary intervention (PCI), “may be reasonable,” for selected patients, but is a decision that requires careful individualization, cautioned Dr. Alexander, professor of medicine and director of Cardiovascular Research at the Duke Clinical Research Institute of Duke University, Durham, N.C.
“This is a superb secondary analysis looking at the time course of potential benefit and harm with aspirin, and they found that aspirin was beneficial only in the first 30 days. After 30 days, it’s startling and remarkable that the ischemic event curves were completely on top of each other,” commented Julia H. Indik, MD, a cardiac electrophysiologist at Banner–University Medical Center Tuscon and designated discussant for the report. “This substudy will be essential for updating the guidelines,” she predicted. “When a treatment’s benefit equals its risks,” which happened when aspirin was part of the regimen during the first 30 days, “then it’s not even a class IIb recommendation; it’s class III,” the classification used by the ACC and collaborating groups to identify treatments where net benefit and net risk are similar and hence the treatment is considered not recommended.
A key element in the analysis Dr. Alexander presented was to define a spectrum of clinical events as representing broad, intermediate, or severe ischemic or bleeding events. The severe category for bleeding events included fatal, intracranial, and any bleed rated as major by the International Society on Thrombosis and Haemostasis (ISTH) criteria, while the broad bleeding definition included all of these plus bleeds that directly resulted in hospitalization and clinically relevant nonmajor bleeds. For ischemic events, the severe group consisted of cardiovascular death, MI, stent thrombosis, and ischemic stroke, while the broad category also tallied urgent revascularizations and cardiovascular hospitalizations.
“I believe the severe bleeds and severe ischemic events we identified are roughly equal in severity,” Dr. Alexander noted. “Where I think we need more analysis is which patients have more bleeding risk and which have more ischemia risk. We need a more tailored approach to identify patient subgroups, perhaps based on angiographic characteristics, or something else,” that modifies the trade-off that, on a population level, seems very evenly balanced.
Applying this approach to scoring the severity of adverse outcomes, Dr. Alexander reported that, during the first 30 days on treatment, patients on aspirin had a net absolute gain of 1.0% in severe bleeding events, compared with placebo, and a 3.4% gain in broad bleeds, while showing a 0.9% drop in severe ischemic events but no between-group difference in the rate of broadly defined ischemic events. During days 31-180, the addition of aspirin resulted in virtually no reductions in ischemic events regardless of whether they were severe, intermediate, or broad, but adding aspirin continued to produce an excess of bleeding episodes in all three categories. The results also appeared in an article published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046534).
“We did not see a time window when the ischemia risk was greater than the bleeding risk,” Dr. Alexander noted, and he also highlighted that the one option the analysis could not explore is never giving these patients any aspirin. “Patients received aspirin for some number of days before randomization,” a median of 6 days from the time of their ACS or PCI event until randomization, “so we don’t have great insight into whether no aspirin” is an reasonable option.
The AUGUSTUS trial randomized 4,614 patients with AFib and a recent ACS or PCI event at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the rate of major or clinically relevant nonmajor bleeding by the ISTH criteria during 6 months on treatment, while composites of death or hospitalization, and death plus ischemic events served as secondary outcomes. All patients received an antiplatelet P2Y12 inhibitor, with 93% of patients receiving clopidogrel, and were randomized in a 2 x 2 factorial design to one of four regimens: either apixaban or a vitamin K antagonist (such as warfarin), and to aspirin or placebo. The study’s primary findings showed that using apixaban instead of a vitamin K antagonist significantly reduced bleeding events as well as the rate of death or hospitalization, but the rate of death and ischemic events was similar in the two arms. The primary AUGUSTUS finding for the aspirin versus placebo randomization was that overall throughout the study ischemic events were balanced in the these two treatment arms while aspirin boosted bleeding (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
AUGUSTUS was sponsored by Bristol-Myers Squibb and Pfizer, the companies that market apixaban. Dr. Alexander has been a consultant to and received research funding from Bristol-Myers Squibb and Pfizer; has been a consultant to AbbVie, Bayer, CryoLife, CSL Behring, Novo Nordisk, Portola, Quantum Genomics, XaTek, and Zafgen; and has received research funding from Boehringer Ingelheim, CryoLife, CSL Behring, GlaxoSmithKline, and XaTek. Dr. Indik had no disclosures.
SOURCE: Alexander JH et al. ACC 2020, Abstract 409-08.
FROM ACC 2020
ACEI/ARBs linked with survival in hypertensive, Chinese COVID-19 patients
Hospitalized COVID-19 patients with hypertension and on treatment with an renin-angiotensin system inhibiting drug had significantly better survival, compared with similar hypertensive patients not on these drugs, in observational, propensity score–matched analyses that drew from a pool of more than 3,430 patients hospitalized at any of nine Chinese hospitals during December 2019–February 2020.
“Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI [ACE inhibitor]/ARB [angiotensin receptor blocker] was associated with lower risk of all-cause mortality, compared with ACEI/ARB nonusers, during 28 days of follow-up. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of mortality,” wrote Peng Zhang, MD, a cardiology researcher at Renmin Hospital of Wuhan University, China, and coauthors in Circulations Research, buttressing recent recommendations from several medical societies to maintain COVID-19 patients on these drugs.
“Our findings in this paper provide evidence supporting continuous use of ACEI/ARB for patients with hypertension infected with SARS-COV-2,” wrote the authors, backing up recent recommendations from cardiology societies that called for not stopping ACEI/ARB prescriptions in patients at risk for contracting or already have COVID-19 infection, including a statement from the American College of Cardiology, American Heart Association, and Heart Failure Society of America, and also guidance from the European Society of Cardiology.
The study included 1,128 patients with a history of hypertension, including 188 (17%) who received an ACEI/ARB drug during hospitalization. During 28-day follow-up, 99 died (9%), including 7 deaths among the 188 patients (4%) on an ACEI/ARB drug and 92 deaths among the 940 other hypertensive patients (10%).
The authors ran several analyses to try to adjust for the influence of possible confounders. A mixed-effect Cox model with four adjusted variables showed that treatment with an ACEI/ARB drug was tied to a statistically significant 58% lower death rate, compared with patients not receiving these drugs.
The researchers also ran several propensity score–adjusted analyses. One matched 174 of the patients who received an ACEI/ARB drug with 522 who did not, and comparing these two matched arms showed that ACEI/ARB use was linked with a statistically significant 63% cut in mortality, compared with patients not getting these drugs. A second propensity score–matched analysis first excluded the 383 patients who were hypertensive but received no antihypertensive medication during hospitalization. From the remaining 745 patients who received at least one antihypertensive medication, the authors identified 181 patients who received an ACEI/ARB and propensity-score matched them with 181 hypertensive patients on a different medication class, finding that ACEI/ARB use linked with a statistically significant 71% lower rate of all-cause mortality.
Additional analyses also showed that patients with hypertension had a statistically significant, 41% increased rate of all-cause death, compared with patients without hypertension, and another propensity score–matched analysis showed that among hypertensives treatment with an ACEI/ARB drug was linked with a statistically significant 68% reduced rate of septic shock.
Although this report was received with caution and some skepticism, it was also acknowledged as a step forward in the creation of an evidence base addressing ACEI/ARB treatment during COVID-19 infection.
“These drugs are lifesaving and should not be discontinued” for patients with hypertension, heart failure, and other cardiovascular disease, commented Gian Paolo Rossi, MD, professor and chair of medicine and director of the high blood pressure unit at the University of Padua (Italy). The analysis by Zhang and associates included the largest number of hospitalized COVID-19 patients with hypertension yet reported to assess the impact of treatment with ACEI/ARB drugs, and adds important evidence in favor of continuing these drugs in patients who develop COVID-19 infection, Dr. Rossi said in an interview. He recently coauthored a review that argued against ACEI/ARB discontinuation in COVID-19 patients based on previously reported evidence (Elife. 2020 Apr 6. doi: 10.7554/eLife.57278).
But other researchers take a wary view of the potential impact of ACEI/ARB agents. “If ACEI/ARB therapy increases ACE2 and the virus down-regulates it, and because ACE2 is the viral entry port into cells, why would ACE2-mediated down-regulation of the renin-angiotensin-aldosterone system lead to amelioration of [COVID-19] disease?” asked Laurence W. Busse, MD, a critical care physician at Emory University, Atlanta. “A number of issues could potentially confound the results, including the definition of COVID-19 and imbalance of antiviral therapy,” added Dr. Busse, who recently coauthored an editorial that posited using angiotensin II (Giapreza), an approved vasopressor drug, as an alternative renin-angiotensin system intervention for COVID-19 patients including both those in shock as well as potentially those not in shock (Crit Care. 2020 Apr 7. doi: 10.1186/s13054-020-02862-1). Despite these caveats, the new Chinese findings reported by Dr. Zhang and associates “are hypothesis generating and worth further exploration.”
The authors of an editorial that accompanied the Zhang study in Circulation Research made similar points. “While the investigators used standard techniques to attempt to reduce bias in this observational study via propensity matching, it is not a randomized study and the residual confounding inherent to this approach renders the conclusions hypothesis generating at best,” wrote Ravi V. Shah, MD, and two coauthors in the editorial (Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317174). They also agreed with the several society statements that have supported continued use of ACEI/ARB drugs in COVID-19 patients. “Withdrawal of these medications in the context of those conditions in which they have proven benefit (e.g., heart failure with reduced left ventricular ejection fraction) may actually inflict more harm than good,” they warned. “In the end we must rely on randomized clinical science,” and while this level of evidence is currently lacking, “the study by Zhang and colleagues is a direct step toward that goal.”
Dr. Zhang and coauthors had no commercial disclosures. Dr. Rossi and Dr. Busse had no disclosures. The authors of the Circulation Research editorial reported several disclosures.
SOURCE: Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.
Hospitalized COVID-19 patients with hypertension and on treatment with an renin-angiotensin system inhibiting drug had significantly better survival, compared with similar hypertensive patients not on these drugs, in observational, propensity score–matched analyses that drew from a pool of more than 3,430 patients hospitalized at any of nine Chinese hospitals during December 2019–February 2020.
“Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI [ACE inhibitor]/ARB [angiotensin receptor blocker] was associated with lower risk of all-cause mortality, compared with ACEI/ARB nonusers, during 28 days of follow-up. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of mortality,” wrote Peng Zhang, MD, a cardiology researcher at Renmin Hospital of Wuhan University, China, and coauthors in Circulations Research, buttressing recent recommendations from several medical societies to maintain COVID-19 patients on these drugs.
“Our findings in this paper provide evidence supporting continuous use of ACEI/ARB for patients with hypertension infected with SARS-COV-2,” wrote the authors, backing up recent recommendations from cardiology societies that called for not stopping ACEI/ARB prescriptions in patients at risk for contracting or already have COVID-19 infection, including a statement from the American College of Cardiology, American Heart Association, and Heart Failure Society of America, and also guidance from the European Society of Cardiology.
The study included 1,128 patients with a history of hypertension, including 188 (17%) who received an ACEI/ARB drug during hospitalization. During 28-day follow-up, 99 died (9%), including 7 deaths among the 188 patients (4%) on an ACEI/ARB drug and 92 deaths among the 940 other hypertensive patients (10%).
The authors ran several analyses to try to adjust for the influence of possible confounders. A mixed-effect Cox model with four adjusted variables showed that treatment with an ACEI/ARB drug was tied to a statistically significant 58% lower death rate, compared with patients not receiving these drugs.
The researchers also ran several propensity score–adjusted analyses. One matched 174 of the patients who received an ACEI/ARB drug with 522 who did not, and comparing these two matched arms showed that ACEI/ARB use was linked with a statistically significant 63% cut in mortality, compared with patients not getting these drugs. A second propensity score–matched analysis first excluded the 383 patients who were hypertensive but received no antihypertensive medication during hospitalization. From the remaining 745 patients who received at least one antihypertensive medication, the authors identified 181 patients who received an ACEI/ARB and propensity-score matched them with 181 hypertensive patients on a different medication class, finding that ACEI/ARB use linked with a statistically significant 71% lower rate of all-cause mortality.
Additional analyses also showed that patients with hypertension had a statistically significant, 41% increased rate of all-cause death, compared with patients without hypertension, and another propensity score–matched analysis showed that among hypertensives treatment with an ACEI/ARB drug was linked with a statistically significant 68% reduced rate of septic shock.
Although this report was received with caution and some skepticism, it was also acknowledged as a step forward in the creation of an evidence base addressing ACEI/ARB treatment during COVID-19 infection.
“These drugs are lifesaving and should not be discontinued” for patients with hypertension, heart failure, and other cardiovascular disease, commented Gian Paolo Rossi, MD, professor and chair of medicine and director of the high blood pressure unit at the University of Padua (Italy). The analysis by Zhang and associates included the largest number of hospitalized COVID-19 patients with hypertension yet reported to assess the impact of treatment with ACEI/ARB drugs, and adds important evidence in favor of continuing these drugs in patients who develop COVID-19 infection, Dr. Rossi said in an interview. He recently coauthored a review that argued against ACEI/ARB discontinuation in COVID-19 patients based on previously reported evidence (Elife. 2020 Apr 6. doi: 10.7554/eLife.57278).
But other researchers take a wary view of the potential impact of ACEI/ARB agents. “If ACEI/ARB therapy increases ACE2 and the virus down-regulates it, and because ACE2 is the viral entry port into cells, why would ACE2-mediated down-regulation of the renin-angiotensin-aldosterone system lead to amelioration of [COVID-19] disease?” asked Laurence W. Busse, MD, a critical care physician at Emory University, Atlanta. “A number of issues could potentially confound the results, including the definition of COVID-19 and imbalance of antiviral therapy,” added Dr. Busse, who recently coauthored an editorial that posited using angiotensin II (Giapreza), an approved vasopressor drug, as an alternative renin-angiotensin system intervention for COVID-19 patients including both those in shock as well as potentially those not in shock (Crit Care. 2020 Apr 7. doi: 10.1186/s13054-020-02862-1). Despite these caveats, the new Chinese findings reported by Dr. Zhang and associates “are hypothesis generating and worth further exploration.”
The authors of an editorial that accompanied the Zhang study in Circulation Research made similar points. “While the investigators used standard techniques to attempt to reduce bias in this observational study via propensity matching, it is not a randomized study and the residual confounding inherent to this approach renders the conclusions hypothesis generating at best,” wrote Ravi V. Shah, MD, and two coauthors in the editorial (Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317174). They also agreed with the several society statements that have supported continued use of ACEI/ARB drugs in COVID-19 patients. “Withdrawal of these medications in the context of those conditions in which they have proven benefit (e.g., heart failure with reduced left ventricular ejection fraction) may actually inflict more harm than good,” they warned. “In the end we must rely on randomized clinical science,” and while this level of evidence is currently lacking, “the study by Zhang and colleagues is a direct step toward that goal.”
Dr. Zhang and coauthors had no commercial disclosures. Dr. Rossi and Dr. Busse had no disclosures. The authors of the Circulation Research editorial reported several disclosures.
SOURCE: Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.
Hospitalized COVID-19 patients with hypertension and on treatment with an renin-angiotensin system inhibiting drug had significantly better survival, compared with similar hypertensive patients not on these drugs, in observational, propensity score–matched analyses that drew from a pool of more than 3,430 patients hospitalized at any of nine Chinese hospitals during December 2019–February 2020.
“Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI [ACE inhibitor]/ARB [angiotensin receptor blocker] was associated with lower risk of all-cause mortality, compared with ACEI/ARB nonusers, during 28 days of follow-up. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of mortality,” wrote Peng Zhang, MD, a cardiology researcher at Renmin Hospital of Wuhan University, China, and coauthors in Circulations Research, buttressing recent recommendations from several medical societies to maintain COVID-19 patients on these drugs.
“Our findings in this paper provide evidence supporting continuous use of ACEI/ARB for patients with hypertension infected with SARS-COV-2,” wrote the authors, backing up recent recommendations from cardiology societies that called for not stopping ACEI/ARB prescriptions in patients at risk for contracting or already have COVID-19 infection, including a statement from the American College of Cardiology, American Heart Association, and Heart Failure Society of America, and also guidance from the European Society of Cardiology.
The study included 1,128 patients with a history of hypertension, including 188 (17%) who received an ACEI/ARB drug during hospitalization. During 28-day follow-up, 99 died (9%), including 7 deaths among the 188 patients (4%) on an ACEI/ARB drug and 92 deaths among the 940 other hypertensive patients (10%).
The authors ran several analyses to try to adjust for the influence of possible confounders. A mixed-effect Cox model with four adjusted variables showed that treatment with an ACEI/ARB drug was tied to a statistically significant 58% lower death rate, compared with patients not receiving these drugs.
The researchers also ran several propensity score–adjusted analyses. One matched 174 of the patients who received an ACEI/ARB drug with 522 who did not, and comparing these two matched arms showed that ACEI/ARB use was linked with a statistically significant 63% cut in mortality, compared with patients not getting these drugs. A second propensity score–matched analysis first excluded the 383 patients who were hypertensive but received no antihypertensive medication during hospitalization. From the remaining 745 patients who received at least one antihypertensive medication, the authors identified 181 patients who received an ACEI/ARB and propensity-score matched them with 181 hypertensive patients on a different medication class, finding that ACEI/ARB use linked with a statistically significant 71% lower rate of all-cause mortality.
Additional analyses also showed that patients with hypertension had a statistically significant, 41% increased rate of all-cause death, compared with patients without hypertension, and another propensity score–matched analysis showed that among hypertensives treatment with an ACEI/ARB drug was linked with a statistically significant 68% reduced rate of septic shock.
Although this report was received with caution and some skepticism, it was also acknowledged as a step forward in the creation of an evidence base addressing ACEI/ARB treatment during COVID-19 infection.
“These drugs are lifesaving and should not be discontinued” for patients with hypertension, heart failure, and other cardiovascular disease, commented Gian Paolo Rossi, MD, professor and chair of medicine and director of the high blood pressure unit at the University of Padua (Italy). The analysis by Zhang and associates included the largest number of hospitalized COVID-19 patients with hypertension yet reported to assess the impact of treatment with ACEI/ARB drugs, and adds important evidence in favor of continuing these drugs in patients who develop COVID-19 infection, Dr. Rossi said in an interview. He recently coauthored a review that argued against ACEI/ARB discontinuation in COVID-19 patients based on previously reported evidence (Elife. 2020 Apr 6. doi: 10.7554/eLife.57278).
But other researchers take a wary view of the potential impact of ACEI/ARB agents. “If ACEI/ARB therapy increases ACE2 and the virus down-regulates it, and because ACE2 is the viral entry port into cells, why would ACE2-mediated down-regulation of the renin-angiotensin-aldosterone system lead to amelioration of [COVID-19] disease?” asked Laurence W. Busse, MD, a critical care physician at Emory University, Atlanta. “A number of issues could potentially confound the results, including the definition of COVID-19 and imbalance of antiviral therapy,” added Dr. Busse, who recently coauthored an editorial that posited using angiotensin II (Giapreza), an approved vasopressor drug, as an alternative renin-angiotensin system intervention for COVID-19 patients including both those in shock as well as potentially those not in shock (Crit Care. 2020 Apr 7. doi: 10.1186/s13054-020-02862-1). Despite these caveats, the new Chinese findings reported by Dr. Zhang and associates “are hypothesis generating and worth further exploration.”
The authors of an editorial that accompanied the Zhang study in Circulation Research made similar points. “While the investigators used standard techniques to attempt to reduce bias in this observational study via propensity matching, it is not a randomized study and the residual confounding inherent to this approach renders the conclusions hypothesis generating at best,” wrote Ravi V. Shah, MD, and two coauthors in the editorial (Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317174). They also agreed with the several society statements that have supported continued use of ACEI/ARB drugs in COVID-19 patients. “Withdrawal of these medications in the context of those conditions in which they have proven benefit (e.g., heart failure with reduced left ventricular ejection fraction) may actually inflict more harm than good,” they warned. “In the end we must rely on randomized clinical science,” and while this level of evidence is currently lacking, “the study by Zhang and colleagues is a direct step toward that goal.”
Dr. Zhang and coauthors had no commercial disclosures. Dr. Rossi and Dr. Busse had no disclosures. The authors of the Circulation Research editorial reported several disclosures.
SOURCE: Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.
FROM CIRCULATION RESEARCH
PCSK9 inhibitors unexpectedly link with lower VTE, aortic stenosis
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.
The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.
One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.
The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).
The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.
In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).
The aortic stenosis connection
A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.
During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.
Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.
The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
What it could mean
These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.
“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.
“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”
“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.
“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.
“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
How it might work
A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).
Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”
Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.
The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”
Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
The future of Lp(a) lowering
This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).
“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”
“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.
Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”
FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.
REPORTING FROM ACC 20
Imaging recommendations issued for COVID-19 patients
A consensus statement on the role of imaging during the acute work-up of COVID-19 patients called for liberal use in patients with moderate to severe clinical features indicative of infection, regardless of their COVID-19 test results, but limited use in patients who present with mild symptoms or are asymptomatic.
The consensus statement on The Role of Imaging in Patient Management during the COVID-19 Pandemic released by the Fleischner Society on April 7 was designed to highlight the “key decision points around imaging” in COVID-19 patients.
“We developed the statement to be applicable across settings” so that each clinic or hospital managing COVID-19 patients could decide the situations where chest radiography (CXR) or CT would work best, said Geoffrey D. Rubin, MD, professor of cardiovascular research, radiology, and bioengineering at Duke University in Durham, N.C., and lead author of the statement.
Written by 15 thoracic radiologists and 10 pulmonologists/intensivists including an anesthesiologist, a pathologist, and additional experts in emergency medicine, infection control, and laboratory medicine, and with members from any of 10 countries on three continents, the panel arrived at agreement by more than 70% for each of the 14 questions.
“I was impressed and a little surprised that consensus was achieved for every question” posed to the panel by the Fleischner Society for Thoracic Imaging and Diagnosis, Dr. Rubin said in an interview. The panel also placed their 14 decisions about imaging within the context of three distinct clinical scenarios chosen to mirror common real-world situations: mild COVID-19 features, moderate to severe features with no critical-resource constraints, and moderate to severe features with constrained resources. The statement also summarized its conclusions as five main recommendations and three additional recommendations.
Main recommendations
- Imaging is not routinely indicated for COVID-19 screening in asymptomatic people.
- Imaging is not indicated for patients with mild features of COVID-19 unless they are at risk for disease progression.
- Imaging is indicated for patients with features of moderate to severe COVID-19 regardless of COVID-19 test results.
- Imaging is indicated for patients with COVID-19 and evidence of worsening respiratory status.
- When access to CT is limited, chest radiography may be preferred for COVID-19 patients unless features of respiratory worsening warrant using CT.
Additional recommendations
- Daily chest radiographs are not indicated in stable, intubated patients with COVID-19.
- CT is indicated in patients with functional impairment, hypoxemia, or both, after COVID-19 recovery.
- COVID-19 testing is warranted in patients incidentally found to have findings suggestive of COVID-19 on a CT scan.
The statement particularly called out one of its recommendations – that a COVID-19 diagnosis “may be presumed when imaging findings are strongly suggestive of COVID-19 despite negative COVID-19 testing” in a patient who has moderate to severe clinical features of COVID-19 and whose pretest probability is high. The panel voted unanimously in favor of this concept, that imaging is “indicated” in hospitalized patients with moderate to severe symptoms consistent with COVID-19 despite a negative COVID-19 test result. “This guidance represents variance from other published recommendations which advise against the use of imaging for the initial diagnosis of COVID-19,” the statement acknowledged and specifically cited the recommendations issued in March 2020 by the American College of Radiology. Despite that, the ACR and Fleischner recommendations “are not at odds with one another,” maintained Dr. Rubin. The panel based its take on this question on the “direct experience” of its members caring for COVID-19 patients, according to the statement.
“I wholeheartedly agree with the suggested uses of imaging outlined by the panel,” commented Sachin Gupta, MD, FCCP, a pulmonologist and critical care physician in San Francisco. “The consensus statement brings a practical way to consider obtaining imaging. It leaves the door open to local standards and best judgment for using CXR or CT. Many physicians are unclear whether to image low-risk and mildly symptomatic patients. This statement gives support to a watchful waiting approach.” Another recommendation advises against daily CXR in stable, intubated COVID-19 patients. This “now gives backing from an important society and thought leaders while giving an explanation” for why daily imaging is problematic, he noted in an interview. The daily CXR in these patients adds no value, and skipping unneeded imaging minimizes SARS-CoV-2 exposure to radiology personnel, and conserves personal protection equipment, said the statement.
“The Fleischner Society is known worldwide for its recommendations. Having the society lend its weight on triage with imaging for COVID-19 patients is important. I suspect it will help standardize practice.”
Dr. Gupta also highlighted that lung imaging with a portable ultrasound unit has quickly become recognized as a very useful imaging tool with increasing use as the pandemic has unfolded, an option not covered by the Fleischner statement. Study results have “confirmed excellent sensitivity, specificity, and reproducibility” with lung ultrasound, and it’s also “easy to use,” Dr. Gupta said.
Ultrasound chest imaging of COVID-19 patients did not get included in the statement despite the reliance some U.S. sites have already placed on it largely because few on the panel had direct experience using it. “We didn’t feel we could contribute” to a discussion of ultrasound, Dr. Rubin said.
The statement’s recommendations appear to have already begun influencing practice. “The feedback I’ve gotten is that people are relying on them,” said Dr. Rubin, and some programs have sent him screen shots of the recommendations embedded in their local electronic health record.
The Radiological Society of North America is hosting a webinar on the statement on April 17.
A consensus statement on the role of imaging during the acute work-up of COVID-19 patients called for liberal use in patients with moderate to severe clinical features indicative of infection, regardless of their COVID-19 test results, but limited use in patients who present with mild symptoms or are asymptomatic.
The consensus statement on The Role of Imaging in Patient Management during the COVID-19 Pandemic released by the Fleischner Society on April 7 was designed to highlight the “key decision points around imaging” in COVID-19 patients.
“We developed the statement to be applicable across settings” so that each clinic or hospital managing COVID-19 patients could decide the situations where chest radiography (CXR) or CT would work best, said Geoffrey D. Rubin, MD, professor of cardiovascular research, radiology, and bioengineering at Duke University in Durham, N.C., and lead author of the statement.
Written by 15 thoracic radiologists and 10 pulmonologists/intensivists including an anesthesiologist, a pathologist, and additional experts in emergency medicine, infection control, and laboratory medicine, and with members from any of 10 countries on three continents, the panel arrived at agreement by more than 70% for each of the 14 questions.
“I was impressed and a little surprised that consensus was achieved for every question” posed to the panel by the Fleischner Society for Thoracic Imaging and Diagnosis, Dr. Rubin said in an interview. The panel also placed their 14 decisions about imaging within the context of three distinct clinical scenarios chosen to mirror common real-world situations: mild COVID-19 features, moderate to severe features with no critical-resource constraints, and moderate to severe features with constrained resources. The statement also summarized its conclusions as five main recommendations and three additional recommendations.
Main recommendations
- Imaging is not routinely indicated for COVID-19 screening in asymptomatic people.
- Imaging is not indicated for patients with mild features of COVID-19 unless they are at risk for disease progression.
- Imaging is indicated for patients with features of moderate to severe COVID-19 regardless of COVID-19 test results.
- Imaging is indicated for patients with COVID-19 and evidence of worsening respiratory status.
- When access to CT is limited, chest radiography may be preferred for COVID-19 patients unless features of respiratory worsening warrant using CT.
Additional recommendations
- Daily chest radiographs are not indicated in stable, intubated patients with COVID-19.
- CT is indicated in patients with functional impairment, hypoxemia, or both, after COVID-19 recovery.
- COVID-19 testing is warranted in patients incidentally found to have findings suggestive of COVID-19 on a CT scan.
The statement particularly called out one of its recommendations – that a COVID-19 diagnosis “may be presumed when imaging findings are strongly suggestive of COVID-19 despite negative COVID-19 testing” in a patient who has moderate to severe clinical features of COVID-19 and whose pretest probability is high. The panel voted unanimously in favor of this concept, that imaging is “indicated” in hospitalized patients with moderate to severe symptoms consistent with COVID-19 despite a negative COVID-19 test result. “This guidance represents variance from other published recommendations which advise against the use of imaging for the initial diagnosis of COVID-19,” the statement acknowledged and specifically cited the recommendations issued in March 2020 by the American College of Radiology. Despite that, the ACR and Fleischner recommendations “are not at odds with one another,” maintained Dr. Rubin. The panel based its take on this question on the “direct experience” of its members caring for COVID-19 patients, according to the statement.
“I wholeheartedly agree with the suggested uses of imaging outlined by the panel,” commented Sachin Gupta, MD, FCCP, a pulmonologist and critical care physician in San Francisco. “The consensus statement brings a practical way to consider obtaining imaging. It leaves the door open to local standards and best judgment for using CXR or CT. Many physicians are unclear whether to image low-risk and mildly symptomatic patients. This statement gives support to a watchful waiting approach.” Another recommendation advises against daily CXR in stable, intubated COVID-19 patients. This “now gives backing from an important society and thought leaders while giving an explanation” for why daily imaging is problematic, he noted in an interview. The daily CXR in these patients adds no value, and skipping unneeded imaging minimizes SARS-CoV-2 exposure to radiology personnel, and conserves personal protection equipment, said the statement.
“The Fleischner Society is known worldwide for its recommendations. Having the society lend its weight on triage with imaging for COVID-19 patients is important. I suspect it will help standardize practice.”
Dr. Gupta also highlighted that lung imaging with a portable ultrasound unit has quickly become recognized as a very useful imaging tool with increasing use as the pandemic has unfolded, an option not covered by the Fleischner statement. Study results have “confirmed excellent sensitivity, specificity, and reproducibility” with lung ultrasound, and it’s also “easy to use,” Dr. Gupta said.
Ultrasound chest imaging of COVID-19 patients did not get included in the statement despite the reliance some U.S. sites have already placed on it largely because few on the panel had direct experience using it. “We didn’t feel we could contribute” to a discussion of ultrasound, Dr. Rubin said.
The statement’s recommendations appear to have already begun influencing practice. “The feedback I’ve gotten is that people are relying on them,” said Dr. Rubin, and some programs have sent him screen shots of the recommendations embedded in their local electronic health record.
The Radiological Society of North America is hosting a webinar on the statement on April 17.
A consensus statement on the role of imaging during the acute work-up of COVID-19 patients called for liberal use in patients with moderate to severe clinical features indicative of infection, regardless of their COVID-19 test results, but limited use in patients who present with mild symptoms or are asymptomatic.
The consensus statement on The Role of Imaging in Patient Management during the COVID-19 Pandemic released by the Fleischner Society on April 7 was designed to highlight the “key decision points around imaging” in COVID-19 patients.
“We developed the statement to be applicable across settings” so that each clinic or hospital managing COVID-19 patients could decide the situations where chest radiography (CXR) or CT would work best, said Geoffrey D. Rubin, MD, professor of cardiovascular research, radiology, and bioengineering at Duke University in Durham, N.C., and lead author of the statement.
Written by 15 thoracic radiologists and 10 pulmonologists/intensivists including an anesthesiologist, a pathologist, and additional experts in emergency medicine, infection control, and laboratory medicine, and with members from any of 10 countries on three continents, the panel arrived at agreement by more than 70% for each of the 14 questions.
“I was impressed and a little surprised that consensus was achieved for every question” posed to the panel by the Fleischner Society for Thoracic Imaging and Diagnosis, Dr. Rubin said in an interview. The panel also placed their 14 decisions about imaging within the context of three distinct clinical scenarios chosen to mirror common real-world situations: mild COVID-19 features, moderate to severe features with no critical-resource constraints, and moderate to severe features with constrained resources. The statement also summarized its conclusions as five main recommendations and three additional recommendations.
Main recommendations
- Imaging is not routinely indicated for COVID-19 screening in asymptomatic people.
- Imaging is not indicated for patients with mild features of COVID-19 unless they are at risk for disease progression.
- Imaging is indicated for patients with features of moderate to severe COVID-19 regardless of COVID-19 test results.
- Imaging is indicated for patients with COVID-19 and evidence of worsening respiratory status.
- When access to CT is limited, chest radiography may be preferred for COVID-19 patients unless features of respiratory worsening warrant using CT.
Additional recommendations
- Daily chest radiographs are not indicated in stable, intubated patients with COVID-19.
- CT is indicated in patients with functional impairment, hypoxemia, or both, after COVID-19 recovery.
- COVID-19 testing is warranted in patients incidentally found to have findings suggestive of COVID-19 on a CT scan.
The statement particularly called out one of its recommendations – that a COVID-19 diagnosis “may be presumed when imaging findings are strongly suggestive of COVID-19 despite negative COVID-19 testing” in a patient who has moderate to severe clinical features of COVID-19 and whose pretest probability is high. The panel voted unanimously in favor of this concept, that imaging is “indicated” in hospitalized patients with moderate to severe symptoms consistent with COVID-19 despite a negative COVID-19 test result. “This guidance represents variance from other published recommendations which advise against the use of imaging for the initial diagnosis of COVID-19,” the statement acknowledged and specifically cited the recommendations issued in March 2020 by the American College of Radiology. Despite that, the ACR and Fleischner recommendations “are not at odds with one another,” maintained Dr. Rubin. The panel based its take on this question on the “direct experience” of its members caring for COVID-19 patients, according to the statement.
“I wholeheartedly agree with the suggested uses of imaging outlined by the panel,” commented Sachin Gupta, MD, FCCP, a pulmonologist and critical care physician in San Francisco. “The consensus statement brings a practical way to consider obtaining imaging. It leaves the door open to local standards and best judgment for using CXR or CT. Many physicians are unclear whether to image low-risk and mildly symptomatic patients. This statement gives support to a watchful waiting approach.” Another recommendation advises against daily CXR in stable, intubated COVID-19 patients. This “now gives backing from an important society and thought leaders while giving an explanation” for why daily imaging is problematic, he noted in an interview. The daily CXR in these patients adds no value, and skipping unneeded imaging minimizes SARS-CoV-2 exposure to radiology personnel, and conserves personal protection equipment, said the statement.
“The Fleischner Society is known worldwide for its recommendations. Having the society lend its weight on triage with imaging for COVID-19 patients is important. I suspect it will help standardize practice.”
Dr. Gupta also highlighted that lung imaging with a portable ultrasound unit has quickly become recognized as a very useful imaging tool with increasing use as the pandemic has unfolded, an option not covered by the Fleischner statement. Study results have “confirmed excellent sensitivity, specificity, and reproducibility” with lung ultrasound, and it’s also “easy to use,” Dr. Gupta said.
Ultrasound chest imaging of COVID-19 patients did not get included in the statement despite the reliance some U.S. sites have already placed on it largely because few on the panel had direct experience using it. “We didn’t feel we could contribute” to a discussion of ultrasound, Dr. Rubin said.
The statement’s recommendations appear to have already begun influencing practice. “The feedback I’ve gotten is that people are relying on them,” said Dr. Rubin, and some programs have sent him screen shots of the recommendations embedded in their local electronic health record.
The Radiological Society of North America is hosting a webinar on the statement on April 17.
FROM CHEST
Evidence suggests possible RAS-blocker benefit in COVID-19 patients
Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.
“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).
“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.
The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.
Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).
In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.
Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.
None of the authors had any disclosures.
Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.
“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).
“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.
The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.
Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).
In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.
Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.
None of the authors had any disclosures.
Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.
“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).
“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.
The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.
Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).
In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.
Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.
None of the authors had any disclosures.
REPORTING FROM JACC